Comprehensive Guide to Herbs by James Meschino

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Meschino Health Comprehensive Guide to Herbs

Authored by: Dr. James Meschino

2 Meschino Health Comprehensive Guide to Herbs

Table of Contents INTRODUCTION ........................................................................................................................................................................ 1 TABLE OF CONTENTS ................................................................................................................................................................ 2 ABOUT MESCHINO HEALTH COMPREHENSIVE GUIDE TO VITAMINS ......................................................................................... 4 MESCHINO HEALTH NATURAL HEALTH ASSESSMENT ............................................................................................................... 5 ALOE VERA ............................................................................................................................................................................... 6 ANGELICA SPECIES .................................................................................................................................................................... 9 ASTRAGALUS .......................................................................................................................................................................... 11 BACOPA .................................................................................................................................................................................. 15 BETA SITOSTEROL ................................................................................................................................................................... 17 BILBERRY ................................................................................................................................................................................ 20 BLACK COHOSH ...................................................................................................................................................................... 24 BOSWELLIA ............................................................................................................................................................................. 28 BROMELAIN ............................................................................................................................................................................ 31 CAPSICUM .............................................................................................................................................................................. 36 CERNITIN POLLEN EXTRACT .................................................................................................................................................... 39 CHASTE TREE .......................................................................................................................................................................... 42 CHINESE SKULL CAP ................................................................................................................................................................ 45 COLEUS FORSKOHLII (FORSKOLIN) .......................................................................................................................................... 50 CRANBERRY ......................................................................................................................................................................... 544 DANDELION (TARAXACUM OFFICINALE) ................................................................................................................................. 57 DEVIL’S CLAW ......................................................................................................................................................................... 59 ECHINACEA (PURPLE CONEFLOWER)....................................................................................................................................... 62 EPHEDRA ................................................................................................................................................................................ 66 FEVERFEW .............................................................................................................................................................................. 70 FLAXSEED AND FLAXSEED POWDER ....................................................................................................................................... 73 GARLIC (ALLIUM SATIVUM) .................................................................................................................................................... 78 GINGER ................................................................................................................................................................................... 83 GINKGO BILOBA...................................................................................................................................................................... 87 GINSENG ................................................................................................................................................................................. 93 GOLDENSEAL (HYDRASTIS CANADENSIS) ................................................................................................................................ 99 GOTU KOLA (CENTELLA ASIATICA) ........................................................................................................................................ 102

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GUGULIPID (GUM GUGGUL) ................................................................................................................................................ 106 HAWTHORN (CRATAEGUS OXYACANTHA) ............................................................................................................................ 110 HORSECHESTNUT SEED (AESCULUS HIPPOCASTANUM) ........................................................................................................ 115 HUPERZINE A ........................................................................................................................................................................ 119 KAVA (PIPER METHYSTICUM) ............................................................................................................................................... 122 LICORICE (GLYCYRRHIZA GLABRA) ........................................................................................................................................ 127 MILK THISTLE (SILYBUM MARIANUM) ................................................................................................................................ 1333 MUIRA PUAMA (POTENCY WOOD) ................................................................................................................................... 13939 PICRORHIZA ...................................................................................................................................................................... 14141 PYGEUM (PYGEUM AFRICANUM) ..................................................................................................................................... 14545 RED CLOVER (TRIFOLIUM PRATENSE) ............................................................................................................................... 14848 REISHI MUSHROOM EXTRACT........................................................................................................................................... 15353 SAW PALMETTO (SERENOA REPENS) ................................................................................................................................ 15858 SHIITAKE MUSHROOM ....................................................................................................................................................... 1644 ST. JOHN’S WORT (HYPERICUM PERFORATUM) ................................................................................................................ 16767 STINGING NETTLE OR NETTLE (URTICA DIOICA) ................................................................................................................ 17373 TRIBULUS TERRESTRIS (PUNCTURE VINE) ......................................................................................................................... 17777 TURMERIC (CURCUMIN) ................................................................................................................................................... 17979 UVA URSI (BEARBERRY) .................................................................................................................................................... 18383 VALERIAN (VALERIANA OFFICINALIS) ................................................................................................................................ 18585 VINPOCETINE .................................................................................................................................................................... 18989 WHITE WILLOW BARK (SALIX SPP) .................................................................................................................................... 19292 WILD YAM (DIOSCOREA VILLOSA) ......................................................................................................................................... 196

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About the Meschino Health Comprehensive Guide to Herbs The Meschino Health Comprehensive Guide to Vitamins is one of four eBooks on nutrients written by Dr. James Meschino: 1. 2. 3. 4.

Meschino Health Comprehensive Guide to Vitamins Meschino Health Comprehensive Guide to Herbs Meschino Health Comprehensive Guide to Minerals Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils

All four books were written to both educate and provide an easy to use quick reference to answer important questions regarding nutrients. Users of the guide can quickly find which health conditions the nutrient can impact, proper dosage, possible effects of a deficiency or the effect any potential toxicity associated with the nutrient. Finally any drug-nutrient Interactions associated with the nutrient. More eBook and eQuick Guides Meschino Health is excited to be able to provide tools and resources to help you achieve your healthy living objectives. Sharing the Healthy Living message and helping anyone who is interested in living a healthy happy life is what Meschino Health is all about. Visit www.MeschinoHealth.com to learn the latest a science based research on diet and supplementation that can prevent and treat health conditions often associated with aging. New eBooks and eGuides are added every month and can be downloaded free of charge.

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5 Meschino Health Comprehensive Guide to Herbs

Meschino Health Natural Health Assessment Welcome to the Nutrition, Lifestyle and Anti-aging Assessment. The most powerful health assessment on the internet   

Easy to Complete Online Questionnaire Your Personal Health Assessment is generated Instantly and can be downloaded to your computer The Meschino Health Assessment is a 15 to 20 page comprehensive report complete with diet, lifestyle and supplement considerations that are specific to your profile.

The Meschino Health Assessment is a free service created by Dr. James Meschino. The feedback in your report is based on your answers to the questions in the Health Assessment, and highlights the dietary, lifestyle and supplementation practices that are best suited to your circumstances, according to currently available scientific studies The Meschino Health Assessment is a Free Service

Why take it? We all know that we should eat better, exercise more and change some of our less then desirable lifestyle habits. Did you know that 7 out of 10 North Americans are taking some form of nutritional supplements to augment their diet? While that might sound like good news, the downside is that many people are guessing at what supplements to take! So which one should you take? Better yet, what does eating better look like? You need a plan. But where would you even begin to find a health assessment that takes into account your personal health status, diet, lifestyle activities and family health history-before recommending a plan of action? Where? Right here.

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6 Meschino Health Comprehensive Guide to Herbs

Aloe Vera General Features Aloe Vera is a perennial plant with yellow flowers. The leaves contain active ingredients, including the polysaccharide acemannan and anthraquinones.1 Aloe Vera gel and juice has been used therapeutically for the treatment of peptic ulcers and other intestinal disturbances, including its use as a natural laxative. Aloe Vera gel can also be applied topically to aid in the healing of burns, wounds, and other skin conditions.4

Principle Active Constituents Acemannan and Other Polysaccharides – Acemannan, in particular, has shown impressive immune-stimulating and anti-viral effects. Anthraquinones – these agents have been shown to account for the natural laxative effect induced by Aloe Vera ingestion.1

Clinical Application and Mechanism of Action 1. Peptic Ulcer and Gastritis Aloe Vera gel inactivates pepsin release when the stomach is empty. The gel also inhibits the release of hydrochloric acid by interfering with the binding of histamine to parietal cells. Clinical studies on humans have shown that Aloe Vera gel can be effective in healing peptic ulcers in a percentage of patients. 2 (Author’s Note: More substantial evidence exists for the use of DGL-licorice chewable tablets in regards to the natural treatment of peptic ulcers, although both interventions can be used concurrently (see Licorice in this document). 2. Improved Protein Digestion Aloe Vera Juice (50% Aloe gel plus 50% other fluids) has been shown to improve protein absorption and reduces the degree to which intestinal bacteria are engaged in putrefactive processes. This may be of benefit in cases of poor protein digestion.1 (also consider the use of Digestive Enzymes and/or Betaine Hydrochloride supplementation). 3. Laxative Effect The latex form of Aloe Vera is reported to have a natural laxative effect.4 Oral Dosage Range 1. General Intestinal Tract Support (e.g., improved digestion, laxation) Up to 1 quart per day of Aloe Vera juice can be consumed. No formal dosages are established. 2. Peptic Ulcers For Aloe gel, a tablespoon of the gel in mineral oil was taken once daily for the treatment of peptic ulcers. 2

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Topical Application of Aloe Gel 1. Burns: Aloe Vera Gel has been used successfully to treat sunburn, radiation burn, and chemical burns. In 1935 a group of physicians first documented improvement in the treatment of facial burns due to X-rays, using topically applied fresh Aloe Vera juice.3,4,5 Scientists think Aloe enhances the body’s natural-healing systems while stimulating the activity of collagen and elastin synthesis, which are responsible for regenerating and maintaining connective tissue structure and integrity.6 As such, Aloe Vera is a common ingredient in many topical creams and lotions intended to heal the skin from sunburn, as well as other burns and wounds.4 2. Diabetic and Chronic Pressure Ulcers (leg ulcers and deeper wounds) - in more severe cases including, leg ulcers, diabetic and pressure ulcers, Aloe gel is applied to ulcers on gauze bandages.3,4 3. Genital Herpes – several double-blind, placebo-controlled trials have shown that Aloe cream applied topically reduced the time necessary for lesions to heal (4.9 days versus 12 days) compared to the placebo group.8 4. Psoriasis and Seborrhea – double-blind, placebo-controlled studies have also shown that topical Aloe Vera extract (0.5%) has been effective in minimizing the severity of psoriasis and seborrhea. The usual application is three time daily.9,10

Topical Dosage Aloe Vera Gel can be applied liberally for topical applications.3 The usual application for the skin lesions noted above is three times per day, using a 0.5% Aloe Vera cream.8,9,10

Adverse Side Effects, Toxicity, and Contraindications Although rare, allergic reactions by the skin have been reported with use of Aloe Vera creams and lotions. Aloe Vera gel may also delay wound healing in cases of surgical wounds such as those produced during laparotomy or cesarean delivery, thus it is contraindicated for deep, vertical (surgical) wounds.3

Drug-Nutrient Interactions Laxative Effect – as Aloe Vera is known to act as a laxative it may reduce the absorption of medications, if taken at the same time. Thus, other medications and supplements should not be taken at the same time as Aloe Vera ingestion. 7

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References: Pregnancy and Lactation 1. Encyclopedia of Nutritional Supplements. Murray M. Prima Publishing 1998. 2. Reavley NM. The New Encyclopedia of Vitamins, Minerals, Supplements, and Herbs. Evans and Company Inc. 1998. 3. The Healing Power of Herbs (2nd edition). Murray M. Prima Publishing 1995. 4. Boon H and Smith M. Health Care Professional Training Program in Complementary Medicine. Institute of Applied Complementary Medicine Inc. 1997.

1. 2. 3. 4. 5. 6. 7. 8.

Sheltom RW, Aloe Vera, Its Chemical and Therapeutic Properties, Int J Dermatol 1991;30:679-83. Blitz JJ, Smith JW, and Gerard JR, Aloe Vera Gel in Peptic Ulcer Therapy: Preliminary Report, J Am Osteopathol Soc 1963;62:731-5. Davis RH, Kabbani JM, and Maro NP, Aloe and Wound Healing, J Am Pod Med Assoc 1987;77:165-9. Dietary Supplement Information Bureau. www.content.intramedicine.com: Aloe Vera. Collins CE, et al. Roentgen dermatitis treated with fresh whole leaf Aloe vera. Am J Roentgenol.1935; 33: 396-97. Chithra P et al. Influence of Aloe Vera on collagen characteristics in healing wounds in rats. Mol Cell Biochem. 1998; 181 (I-2): 71-6. Ishii Y, et al. Studies of Aloe .III. Mechanism of cathartic effect. (2). Chem Pharm Bull.Tokyo.1990; 38 (1): 197-200. Syed TA, Cheeman KM, Ashfaq A, et al. Aloe Vera extract 0.5% in a hydrophilic cream versus Aloe Vera gel for the management of genital herpes in males. A placebo-controlled, double-blind, comparative study. J Eur Acad Detmatol Venereol. 1996;7: 294-95. 9. 9 Syed TA, Ahmed SA, Holt AH, et al. Management of psoriasis with Aloe Vera extract in a hydrophilic cream: a placebo-controlled, double blind study. Trop Med Int Health. 1996; 1: 505-509. 10. 10 Vardy DA, Cohen AD, Tchetov T, et al. A double-blind, placebo-controlled trial of Aloe Vera emulsion in the treatment of seborrheic dermatitis. J Dermatol Treat. 1999; 10: 7-11.

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Angelica Species (Angelica sinesis, e.g. Dong Quai) General Features The Angelica Species is native to China. The plant’s active ingredients are found in the roots and rhizomes. Dong Quai has traditionally been used to treat menstrual cramps or dysmenorrhea and PMS, as well as hot flashes and other menopausal symptoms. The scientific evidence to support these applications is not strong compared to the use of other herbal agents such as Black Cohosh, Gamma Oryzanol and Chasteberry, which have been shown to provide consistently reliable outcomes in the management of these cases. 1,3

Principle Active Constituents The primary active constituents for menopausal and menstrual symptoms are coumarin and phytoestrogens. Angelica phytoestrogens exhibit 1:400 the biological activity of animal-based estrogens (i.e., Premarin). 1,4,5

Clinical Application and Mechanism of Action Menopausal Symptoms and Menstrual Irregularities: Phytoestrogens are known to provide hormonal support in the regulation of reproductive tissues and organs, although more research is required to evaluate the effects of Dong Quai in this regard. At present there are no well-controlled studies illustrating that Dong Quai is highly effective in the management of PMS, menopausal symptoms and related female conditions. Its use is based primarily upon historical applications and some animal studies. 3 As a general statement, phytoestrogens (plant-based estrogens) compete with the body’s own estrogens for binding sites on estrogen receptors on reproductive and other tissues, helping to guard against estrogen over-stimulation, which can exacerbate or cause PMS and related symptoms. During menopause, when the body’s estrogen secretion drops off, phytoestrogens can provide estrogenic support to help reduce hot flashes and other menopausal symptoms.1,2,4,5 (see Black Cohosh, Soy Isoflavones and Red Clover in this document for a more detailed explanation of phytoestrogens) Angelica may reduce smooth muscle spasm, easing cramping and related menstrual symptoms .1,2

Dosage and Standardized Grade Management of PMS and Menopausal Symptoms: Powdered root or as a tea: 1-2 gms, 3 times per day Tincture (1:5): 4 ml (1 teaspoon), 3 times per day Fluid extract: 1 ml (1/4 teaspoon), 3 times per day Solid Extract (capsule) – 200 mg, two times daily, standardized to 0.8-1.1% ligustilide content.

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Adverse Side Effects, Toxicity and Contraindications Angelica contains coumarins that can react with sunlight to cause photo-sensitivity induced skin rash or severe sunburn upon exposure to sunlight. Therefore, women using this supplement should avoid prolonged exposure to direct sunlight.1 Animal studies reveal Dong Quai is very non toxic. Side effects in humans are rare and consist of mild gastrointestinal distress and occasional allergic reactions (such as rash). 3 However, the use of Dong quai has resulted in several cases of bleeding disorders (in the brain), most likely due to the anti-coagulant effect of Dong Quaiâ&#x20AC;&#x2122;s coumarin content.6

Drug-Nutrient Interactions Anticoagulants (warfarin, coumadin, aspirin etc) â&#x20AC;&#x201C; animal studies demonstrate that Angelica Species potentiates the anti-clotting effects of warfarin and thereby, may increase the chance of a serious bleeding disorder. Several reports of this consequence in humans have been reported, even in women not taking concurrent anticoagulant therapy. Therefore, women should not take Dong Quai concurrently with any anticoagulant drug.6,7,8,9 (note that Black Cohosh, Soy Isoflavones, Gamma Oryzanol and Chasteberry are not associated with this risk).

Duke JA, Handbook of Medicinal Herbs. Boca Raton, FL. CRC Press. 1985:43-4. Murray MT, The Healing Power of Herbs (2nd edition), Prima Publishing, 1995. Natural Health Products Encyclopedia. www.consumerlab.com: Dong Quai Hikino H: Recent research on Oriental medicinal plants. Econ Med Plant Res. 1985; 1: 53-85 Zhu DPQ: Dong Quai. Am J Chin Med. 1985;15: 117-125. Heck A, et al. Potential interactions between alternative therapies and warfarin. Am J Health-Syst Pharm.2000;57 (13): 1221-1227 Lo AC, et al. Danggui (Angelica sinensis). Affects the Pharmacodynamics But Not the Pharmacokinetics of Warfarin in Rabbits. Eur J Drug Metab and Pharmacokinet. 1995;20(1): 55-60 Ellis GR, Stephens MR. Untitled (brief case report). BMJ 1999;319:650 Page RL II, Lawrence JD. Potentiation of Warfarin by Dong Quai.Pharmacotherapy 1999;19(7):870-76

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Astragalus General Features Astragalus has been used for at least 2000 years in China and continues to be widely used as a herb that is known to enhance function of the immune system and facilitates an increase in energy production within the heart muscle, in cases where certain forms of heart disease exist.1,2,3,4,5 It is one of the most widely used herbs in Fu-zheng therapy â&#x2C6;&#x2019; the use of herbs to augment the host defense mechanisms. 1,2,3,6 Astragalus is a herbaceous perennial with the root of the plant used for medicinal purposes.7

Active Constituents These primarily include: 1. Triterpene glycosides (saponins): astragalosides, etc. 2. Polysaccharides: astragalans 3. Flavonoids7,8,9,10,11

Clinical Application and Mechanism of Action Immune Function (The common cold and minimizing the effects of chemotherapy and radiation treatment) Astragalus is used as an immune stimulant to treat and help prevent the common cold. 4,8 It has also been used to reduce the side effects of chemotherapy and radiation treatment in human studies. A large clinical study of 572 cancer patients demonstrated that Astragalus supplementation was able to protect adrenal cortical function during radiation and chemotherapy treatment. It also helped to greatly minimize bone marrow depression and gastrointestinal side effects, such as nausea, vomiting and intestinal tract ulcerations in these patients. 6 In patients with very low white blood cell counts, as a side effect of drugs, radiation or chemotherapy, Astragalus supplementation has been shown to help significantly increase the number of circulating white blood cells, helping to restore normal function of the immune system in these severely immune-compromised patients.12 The biological activity that can account for these outcomes is related the active constituents in Astragalus, primarily its triperpene glycosides and polysaccharide content, which have been shown to significantly increase the proliferation of lymphocytes,3,12 enhance interferon and interleukin-2 production and activity- two powerful signalling agents that enhance the effectiveness of immune cells,13,14,15,16 activate T cell blastogenesis,17 increase T cell cytotoxicity,2,17 enhance the secretion of the immune modifying chemical known as tumor necrosis factor (TNF),9 enhance phagocytosis by immune cells,18 increase natural killer cell cytotoxicity â&#x20AC;&#x201C; the ability of these white blood cells to destroy developing cancer cells, viruses and other pathogens, 17,19 increase the activity of peritoneal macrophages,18 and provide direct anti-viral effects.20,21,22,23 2. Congestive Heart Failure and Angina Pectoris The active constituents of Astragalus appear to provide an inotropic effect on the heart muscle, in a similar manner to hawthorn. An inotropic effect implies that these active ingredients in some way enhance the ability of the heart muscle to synthesize ATP energy, which is required for heart muscle contraction. In congestive heart failure the heart muscle becomes weak, partly due to insufficient ATP production, and preliminary evidence suggests that Astragalus may help to improve these cases. Thus far, two small clinical trials have shown that patients with

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congestive heart failure demonstrate improvement in chest distress, dyspnea (shortness of breath), exercise tolerance and other parameters of cardiac function, when given Astragalus intravenously. 10,24 Astragalus has also been used effectively in patients suffering from ischemic heart disease 25 and it has been shown to increase cardiac output in 20 patients with angina pectoris.26 3. Anti-Cancer Effects The immune- enhancing effects of Astragalus make this herb an interesting compound in terms of its potential in cancer treatment. A clinical study of 54 patients with small cell lung cancer were treated with regular medical interventions plus Traditional Chinese Medicine (including Astragalus). Increased survival was noted in comparison to the average survival statistics of conventional medicine alone.27 Animal studies demonstrate quite strongly that Astragalus has the potential to prevent some cancers and has curative potential in others (e.g., renal cell carcinome model in mice).28,29 Intensive research continues in an attempt to establish the true anti-tumor potential of Astragalus. 4. Male Fertility Astragalus has been shown to significantly increase the motility of human sperm in vitro. 30 This may be of value in the treatment of male infertility where poor sperm motility is a suspected factor. Note that L-carnitine and zinc supplementation have demonstrated similar capabilities (see details in this document under their individual headings.)

Dosage and Standardized Grade (2:1 powdered extract) 1. Common Cold – For general prevention consider 100-200 mg per day. During the preliminary stages of a cold consider up to 500 mg, three times daily if used as single agent. 31 2. Radiation Treatment, Chemotherapy – Consider up to 500 mg, three times per day if taken as a single agent. (Consider combining Astragalus with reishi mushroom extract to minimize side effects of these treatments.) (Requires attending physician’s approval) 3. Congestive Heart Failure, Angina Pectoris and Ischemic Heart Disease – No oral dose values have been established. 4. Decreased Sperm Motility Causing Infertilty – Dosage not established, however taking up to 500 mg, three times daily is considered to be safe.

Toxicity and Adverse Side Effects There are no reported side effects or toxicity associated with the use of Astragalus at recommended doses. 31

Drug-Nutrient Interactions Immunosuppressive Medications – As Astragalus has been shown to enhance immune function, it may counter the efficacy of immnosuppressive drugs.32,33

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Foster S, ChongxlY. Herbal Emissaries. Bringing Chinese Herbs to the West. Rochester, VT; Healing Arts Press, 1992:p356 Zhao KS, Manoinin C, Doria G. Enhancement of the immune response in mice by Astragalus membranaceous extracts. Immunopharmacology. 1990:20(3):225-233 Sun, Y, et al. Preliminary observations on the effects of the Chinese medicinal herbs Astragalus membranaceous and Ligustrum lucid on lymphocyte blastogenic responses. Journal of Biological Response Modifiers. 1983;2:227-237 Geng CS, et al. Advances in Immuno-pharmacological Studies on Astragalus membranaceous. Chung, Hsi i Chieh Ho Tsa Chih. 1986;6(1):62-64 Chen, LX, Liao, JX., Guo, WQ. Effects of Astragalus membranaceous on left Ventribular Function and Oxygen Free Radical in Acute Myocardial Infarction Patients and Mechanism of its Cardiotonic Action. Chung Kuo, Chung Hsi, I Chieh Ho Tsa Chih. Mar 1995;15 (3):1413 Sun Y, Change YH, Uy Gq, et al. Effect of Fu-zheng therapy in the management of malignant diseases. Chinese Med Journal, 1981;61:97101 Leung AY, Foster S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. 2nd ed. Toronto/New York: John Wiley and Sons Inc;1996:p649 Chevallier A. The Encyclopedia of Medicnal Plants. London: Readers Digest;1996:p336 Zhao, K W, Kong, HY. Effect of Astragalan on secretion of tumour necrosis factor in human peripheral blood monomuclear cells. Chung-Kuo Chung Hsi i Chieh, Ho Tsa Chih. 1993 Luo HM, Dai RH, Li Y. Nuclear cardiology study on effective ingredients of Astragalus membranaceous in treating heart failure. Chung-Kuo Chung His i Chieh, Ho Tsa Chih. 1995; 15(12):709-9 Hirotani M, Zhou Y, Rui H, Furuya T. Cycloartane triterpene glycosides from the hairy root cultures of Astragalus membranaceous. Phytochemistry. 1994;37(5):1403-7 Weng XS. Treatment of leucopenia with pure Astragalus preparation â&#x20AC;&#x201C; an analysis of 115 leucopenic cases 9Chinese). Chung-Kuo Chung Hsi i Chieh, Ho Tsa Chih. 1995;15(8):462-4 Chu, DT et al. Immunotherapy with Chinese medicinal herbs. II. Reversal of cyclophosphamide-induced immune suppression by administration of fractionated Astragalus membranaceus in vivo. Journal of Clinical Laboratory Immunology. 1988;25:125-129 Chen YC. Experimental studies on the effects of danggui buxue decoction on IL-2 production of blood-deficient mice (Chinese). Chung-Kuo Chung Hsi i Chieh. 1994; 19(12): p739-41,p763 Liang H, Zhang Y, Geng B. The effect of Astragalus polysaccharides (APS) on cell medicated immunity (GMI) in burned mice. Chung-Hua Cheng Hsing Shao Shang Wai Ko Tsa Chih.

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16. Hou YD, Ma GL, Wu SH, Li HT. Effect of radix Astrageli seu Hedysari on the interferon system. Chinese Medical Journal. 1981;94:35-40 17. Jin R, Wan LL, Mitsuishi T. Effects of shi-ka-ron and Chinese herbs in mice treated with anti-tumor agent mito mycin C (Chinese). ChungKuo Chung Hsi i Chieh, Ho Tsa Chih. 1995;15(2):101-3 18. Sugiura H, Nishida H, Indaba R, Iwata H. Effects of exercise in the growing stage in mice and of Astragalus membranaceous on immune functions (Japanese). Nippon Eiseigaku Zasshi – Japanese Journal of hygiene, 1993;47(6):1021-31 19. Yang YZ, Jin PY, Guo Q, et al. Effect of Astragalus membranaceous on natural killer cell activity and induction of a- and g- interferon in patients with coxsackie B viral myocarditis. Chinese Medical Journal 1990;103(4):304-307 20. Yang YZ, Guo Q, Jin PY, et al. Effect of Astragalus membranaceous injection on Coxsackie B-2 virus infected rat beating heart cell culture. Chinese Medical Journal. 1987;100-595 21. Hou YD. Study on the biological active ingredients of Astragalus membranaceous. Chung His i Chieh Ho Tsa Chih. 1984;4:p420 22. Zhang Xq, et al. Studies of Astragalus membranaceous on antiinfluenza virus activity, interferon induction and immunostimulation in mice. Chinese Journal of Microbiology and Immunology. 1984;4:p92 23. Research Group of Common Cold and Bronchitis. Investigation into Astragalus membranaceous. II. A research on some of its mechanism of reinforcing the Qi (vital energy.) Journal of Traditional Chinese Medicine. 1980;3:p67 24. Shi HM, Dai RH, Fan WH. Intervention of lidocaine and Astragalus membranaceous on ventricular late potentials (Chinese). Chung-Kuo Chung Hsi i Chieh, Ho Tsa Chih. 1994;14 (10):598-600 25. Li SQ, Yuan RX, Gao H. Clinical observation of the treatment of ischemic heart disease with Astragalus membranaceous (Chinese). ChungKuo Chung Hsi i Chieh, Ho Tsa Chih. 1995;15(2):77-80 26. Lei ZY, Qin H, Liao JZ. Action of Astragalus membranaceous on left ventricular function of antina pectoris (Chinese). Chung-Kuo Chung Hsi I Chieh, Ho Tsa Chih. 1994;14(4):199-202 27. Cha RJ, Zeng DW, Chang QS. Non-surgical treatment of small cell lung cancer with chemo-radio-immunotherapy and traditional Chinese medicine (Chinese). Chung-Hua Nei Ko Tsa Chih – Chinese Journal of Internal medicine. 1994;33(7):462-6 28. Lau BH, Ruckle HC, Botolazzo T, Lui, PD. Chinese medicinal herbs inhibit growth of murine renal cell carcinoma. Cancer Biotherapy. 1994;9(2):153-61 29. Chu DT, Lin JR, Wong W. The in vitro potentiation of LAK cell cytotoxidicty in cancer and AIDS patients induced by F3 – a fractionated extract of Astragalus membranaceous (Chinese). Chung-Hun Chung Liu Tsa Chih – Chinese Journal of Oncology. 1994;16(3):167-71 30. Hong C, Ku J, et al. Astragalus membranaceous stimulates human sperm motility in vitro. American journal of Chinese Medicine. 1992;20:289-94 31. Murray MT. The Healing Power of Herbs. Rocklin, CA: Prima Publishing;1992:p246 32. Zhao KS, et al. Enhancement of the Immune Response in Mice by Astragalus membranaceous Extracts. Immunopharmacology. 1990;20(3):225-33 33. Chu, DT, et al. Immune Resoration of Local Xenogeneic Graft-versus-host Reaction in Cancer Patients in In-vitro and Reversal of Cyclophosphamide-induced Immune suppression in the Rat in Vivo by Fractionated Astragalus membranaceous. Chung Hsi i Chieh Ho Tsa Chih. Jun 1989;9:351-54.

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Bacopa (Bacopa monnieri) General Features The leaf of Bacopa, or water hyssop, has been used in the Indian medical system of Ayurveda since the 6th century A.D. to help improve mental performance. Its active ingredients (bacosides A and B) have been shown to enhance nerve transmission and are potent antioxidants, which may help to protect brain cells and other lipid-rich tissues in the body from free radical damage (including LDL-cholesterol). Under experimental conditions 100 mcgs of Bacopa monnieri extract was equivalent to 247 micrograms of EDTA and 58 micrograms of Vitamin E in regards to its antioxidant potency. Bacopa is presently being used and studied as a natural substance to strengthen memory and general cognition and to help control epilepsy.1,.2 It has been used as a mild sedative in cases of insomnia.2

Active Constituents The primary active constituents include Bacosides A and B.1 The alcohol fraction of Bacopa extract has been shown to provide its strong antioxidant properties.2

Clinical Application and Mechanism of Action 1. Enhancement of Memory, Learning Ability and Intellectual Activity Studies demonstrate that Bacopa supplementation can increase learning ability in laboratory animals. Human studies have also provided evidence that Bacopa may improve intellectual activity in children as well as improve memory and mental performance in adults. As such, it may be of value in the preservation of cognitive function and memory as we age and in the treatment of dementia and other severe cognitive dysfunction states (e.g., Alzheimerâ&#x20AC;&#x2122;s disease).3,4 In the study by C Stough et al, healthy volunteers were given Bacopa monnieri supplementation (300 mg per day) or a placebo, with follow-up neuropsychological testing performed at weeks 5 and 12. Compared to the placebo group, the subjects given the Bacopa significantly improved speed of visual information processing, learning rate, memory consolidation and demonstrated a reduced state of anxiety. The researchers concluded that these findings suggest that Bacopa monnieri may improve higher order cognitive processes that are critically dependent on the input of information from our environment such as learning and memory.4 Ayurvedic practitioners have routinely recommended Bacopa supplementaion for impaired memory or cognitive dysfunction for many centuries with reported good results.1 2. Epilepsy Some preliminary evidence indicates that Bacopa may be useful in improving the symptoms and occurrence of epileptic seizures.5 A study published in 2000 by D Vohora et al, has strengthened this argument and provided evidence that Bacopa supplementation can also correct much of the cognitive impairment induced by anti-epileptic drugs such as Phenytoin, which is known to adversely affect cognitive function. Thus, the concurrent use of antiepileptic drugs and Bacopa supplementation may effectively reduce epileptic seizures and significantly reverse Phenytoin-induced cognitive impairment.6

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Dosage and Standardized Grade Bacopa monnieri extract should be standardized to 20% bacosides A and B content. 1. General Support of Mental Acuity - Consider 100 mg, one to two times per day (if used as a single agent). 2. Early to Moderate Memory Loss or Cognitive Impairment - Consider 50-150 mg, up to three times per day (if used as a single agent). 3. Epilepsy - Consider 100 mg, one or two times per day.1

Adverse Side Effects and Toxicity There are no well known side effects from the use of Bacopa monnieri at recommended doses. It has demonstrated a long and safe history of use in Ayurvedic medicine.1,2 Drug-Nutrient Interaction Calcium Channel Blocker Antihypertensive Drugs - Bacopa may increase the effects of these medications and thus, the dose of these drugs required for treatment may need to be reduced.7

Pregnancy and Lactation

References: Pregnancy and Lactation

1. 2. 3. 4.

1. Encyclopedia of Nutritional Supplements. Murray M. Prima Publishing 1998. 2. Reavley NM. The New Encyclopedia of Vitamins, Minerals, Supplements, and Herbs. Evans and Company Inc. 1998. 3. The Healing Power of Herbs (2nd edition). Murray M. Prima Publishing 1995. 4. Boon H and Smith M. Health Care Professional Training Program in Complementary Medicine. Institute of Applied Complementary Medicine Inc. 1997.

1. 2. 3.

Dietary Supplement Information Bureau. www.content.intramedicine.com: Bacopa monnieri Tripathi YB et al. Bacopa monniera linn. As an antioxidant: Mechanism of action. Indian J Exp Biol. Jun1996;34(6):523-6 Kidd PM. A review of nutrients and botanicals in the integrative management of cognitive dysfunction. Altern Med Rev. Jun1999;4(3):144-61 4. Stough C, Lloyd J, Clarke J, Downey LA, Hutchison CW, Rodgers T, et la. The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. Psychopharmacology (Berl), Aug2001;156(4):481-4 5. Mukherjee GD et al. Clinical trial on brahmi. I. J Exp Med Sci, 1966;10(1):5-11 6. Vohora D, Pal SN, Pillai KK. Protection from phenbytoin-induced cognitive deficit by Bacopa monniera, a reputed Indian nootropic plant. J Ethnopharmacol, Aug2000;71(3):383-90 7. Dar A, Channa S. Calcium antagonistic activity of Bacopa monniera on vascular intestinal smooth muscles of rabbit and ginea-pig. J Ethnopharmacol, 1999;66(2):167-74

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Beta Sitosterol General Features Phytosterols or plant sterols are structurally similar to cholesterol. The most common plant sterols are beta-sitosterol, campesterol and stigmasterol. Epidemiological and experimental studies suggest that dietary phytosterols may offer protection from the most common cancers in Western societies, such as colon, breast and prostate cancer. Phytosterols have been shown to behave as protective nutrients via a number of physiological effects, including their effect on cell membrane structure and function of tumor and host tissue, signal transduction pathways that regulate tumor growth and apoptosis (programmed cell death), immune function and cholesterol metabolism.

Primary Active Constituents Phytosterols are the counterpart of cholesterol in animal products. Found only in plant foods, phytosterol consumption averages 345-400 mg per day on a vegetarian or Japanese diet, whereas the Western diet provides only 80 mg per day of plant sterols, on average.1 Of the phytosterols, beta-sitosterol has been studied most extensively. Alone, or in combination with other plant sterols, beta-sitosterol supplementation has been shown to be effective in the treatment of benign prostatic hyperplasia, high cholesterol and as a means to enhance immune system function. 2,3,4,5,6 Studies with lab animals and human cancer cell lines indicate that beta-sitosterol reduces colon cancer incidence in animals exposed to known carcinogens and inhibits the growth of LNCaP, human prostate cancer cells, under experimental conditions. In conjunction with epidemiological evidence, these findings have prompted the further study of beta-sitosterol as a potential chemopreventive or therapeutic agent for colon, prostate, and breast cancers.1

Clinical Application and Mechanism of Action 1. Benign Prostatic Hyperplasia A number of randomized, placebo-controlled, double-blind clinical trials and other intervention studies have demonstrated that beta-sitosterol supplementation is an effective therapy in cases of benign prostatic hyperplasia. The usual dose is 20 mg, three times daily or 65 mg, twice daily. Plant sterols are known to inhibit hepatic and prostatic 5-alpha reductase enzyme, which is the enzyme responsible for the coversion of testosterone to dihydrotestosterone (DHT). DHT increases prostate cell growth and division and is strongly linked to prostate enlargement. Plant sterols are also known to inhibit prostatic aromatase enzyme, which synthesizes estrone hormone. This enzyme inhibition action of beta-sitosterol is thought to be one of its primary means by which it reverses benign prostatic hyperplasia.1,4,5,7,8 2. Cholesterol-Lowering Beta-sitosterol supplementation has been shown to lower blood cholesterol. However, the daily dosage to achieve this effect is several times greater than that for the treatment of benign prostatic hyperplasia. Daily dosages of 500 mg to 10,000 mg per day of beta-sitosterol are necessary to produce a cholesterol-lowering effect.1,2,3 An LDLcholesterol lowering effect of 7% to 33% has been reported in a review of 8 clinical phytosterol trials.1,5

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3. Autoimmune Diseases (including Rheumatoid Arthritis) Evidence points to the fact that certain phytosterols selectively stimulate activity of Th1-helper cells and suppress activity of Th2-helper cells. This modulation of the immune system is related to a reduction in inflammatory processes and improved immune system function.9 4. Immune System Support (including HIV-Infection) A clinical trial involving eighty patients with HIV-infection was conducted over 36 months. Supplementation with sterols/sterolins demonstrated that it may slow the progression of the disease due to its modulating effects on the immune system.10 Some evidence also exists to show that supplementation with beta-sitosterol and beta-sitosterol glucoside enhances immune system parameters in patients with pulmonary tuberculosis. Supplemented patients experienced improved weight gain, and higher lymphocyte and eosinophil counts compared to the placebo group. 11

Dosage Ranges 1. Benign Prostatic Hyperplasia - 20 mg beta-sitosterol, three times per day or 65 mg beta-sitosterol, twice per day.4,5,7,8 2. Cholesterol Lowering - 500 mg to 10,000 mg per day of beta-sitosterol.2,3 3. Autoimmune Diseases - 1 capsule sterinol, three times daily on an empty stomach.12 (i.e., Moducare) 4. HIV and Tuberculosis Infection - 2 capsules of sterinol, three times a day for one week, and 1 capsule, three times a day for maintenance13 (i.e., Moducare). Other infectious diseases may also be aided with sterinol supplementation.13

Adverse Side Effects and Toxicity Oral Beta-sitosterol is very non-toxic as demonstrated by various studies. Other than occasional mild constipation or diarrhea at very high doses, beta-sitosterol is not associated with any significant side effects. 9

Drug-Nutrient Interactions There are no well-known drug-nutrient interactions with beta-sitosterol.14

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Awad, AB, et.al., Phytosterols as Anticancer Dietary Components: Evidence and Mechanism of Action, J Nutr 2000;130:2127-30. Lees, AM, et.al., Plant Sterols as Cholesterol-lowering Agents: Clinical Trials in Patients with Hypercholesterolemia and Studies of Sterol Balance, Atheroscles 1997;28:325-38. Pelletier, X, et.al., A Diet Moderately Enriched in Phytosterols Lowers Plasma Cholesterol Concentrations in Normocholesterolemic Humans, Ann Nurt. Metab 1995;39:291-5. Berger, RR, et.al., Randomised, Placebo-controlled, Double-blind Clinical Trial of Beta-sitosterol in Patients with Benign Prostatic Hyperplasia, Lancet 1995;345:1429-532. Klippel, KF, et.al., A Multicentric, Placebo-controlled Double-blind Clinical Trial of Beta-sitosterol for the Treatment of Benign Prostatic Hyperplasia, Br J Urol, 1997;80:427-432. Bouic, PJ, et.al., Plant Sterols and Sterolins: A Review of Their Immune-modulating Properties, Altern Med Rev 1999;3:170-7. Berger, R, et.al., Treatment of Symptomatic Benign Prostatic Hyperplasia with Beta-sitosterol, an 18-month Follow-up, Br J Urol 2000;85(7):842-6. Wilt, TJ, et.al., Beta-sitosterol for the Treatment of Benign Prostatic Hyperplasia: A Systematic Review, BR J Urol Int. 1999;83(9):976-83. Pegel, KH, The Importance of Sitosterol and Sitosterolin in Human and Animal Nutrition, South African J Sci. 1997;93:263-8. Bouic, P, Immunomodulation in HIV/AIDS: The Typerberg:/Stellenbosch University Experience, Bouic, P AIDS Bulletin, 1997;6:18-20. Donald, PR, et.al., A Randomized, Placebo-controlled Trial of the Efficacy of Beta-sitosterol and its Glucoside as Adjuvants in the Treatment of Pulmonary Tuberculosis, Int J Tuberc Lung Dis. 1999;1(5):518-22. Vanderhaeghe, L and Bouic P, The Immune System Cure, Prentice-Hall Canada Inc, 1999:125-55. Vanderhaeghe, L and Bouic P, The Immune System Cure, Prentice-Hall Canada Inc, 1999:175-96. Healthnotes Online, Healthnotes 2000, Inc.

Ostland RE,(Jr), et al. Sitostanol administration in lecithin micelles potently reduces cholesterol absorption in humans. Am J Clin Nutr. 1999; 70: 826-831.

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Bilberry (Vaccinium Myrtilus) General Features Bilberry extract is well recognized for its ability to support collagen tissue (especially in blood vessel supporting connective tissues) and provides antioxidant protection to the macula of the eye. As such, it is recommended for certain eye conditions, such as macular degeneration, diabetic retinopathy, and in cases of capillary fragility. During World War II British fighter pilots taking Bilberry reported an improved ability to adjust to glare and an increase in their visual acuity and nighttime vision.21,22,23

Active Ingredients Research has focused primarily upon the anthocyanosides, which are flavonoid compounds, unique to Bilberry extract. They are formed by an anthocyanidin backbone bound to one of three sugars (arabinose, glucose or galactose). The concentration of anthocyanosides in the fresh fruit is only 0.1 to 0.25 percent, whereas concentrated extracts of Bilberry taken as supplements yield an anthocyanidin content of 25 percent.1,2,3,21,22

Mechanism of Action 1. Collagen Stabilizing action â&#x20AC;&#x201C; Bilberry preserves collagen and related ground substance by increasing the cross-linking of collagen fibers, acting as a free radical scavenger, inhibiting enzymatic cleavage of collagen by enzymes secreted by leukocytes during inflammation, reducing the release of histamine, serine proteases, prostaglandins and leukotrienes and by promoting the synthesis of glycosaminoglycans (see glucosamine in this document) and collagen by chondrocytes.4,5,6,7 2. Anti-aggregation of platelets Like many other flavonoids anthocyanosides heve been shown to decrease platelet aggregation in experimental studies.8,9,10 3. Antioxidant The anthocyanodins derived from Bilberry also demonstrate very potent antioxidant properties.4

Clinical Applications 1. Macular Degeneration of the Eye Macular degeneration is the most common cause of blindness in individuals over the age of 55 (see also Lutein and Zeazanthin in this document) in North America. Bilberry anthocyanidins appear to be able to help defend against and manage macular degeneration and other eye conditions via several biological actions. The first is that these unique flavonoids have been shown to improve the delivery of oxygen and blood to the eye. The second is that they provide antioxidant protection against ultra-violet light induced free radical damage (from sunlight) to the macula of the eye, which has been shown to contribute to the development and progression of macular degeneration. Third, anthocyanidins from Bilberry have been shown to stabilize the blood vessel wall of small blood vessels in the macular region of the eye, helping to prevent leaking of blood (micro-hemorrhaging) into the macular region as often occurs in diabetic retinopathy and the wet form of macular degeneration. Like the antioxidant carotenoids lutein and zeazanthin, Bilberry anthocyanosides are known to concentrate in the macula of the eye, where they have the opportunity to quench ultra-violet light induced free radicals.21,22

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In one study, 31 patients with various retinopathies (20 diabetic, 5 retinitis pigmentosa, 4 macular degeneration, hemorrhagic retinopathy) were treated with Bilberry extract. There was a tendency toward reduced permeability and hemorrhage observed in all patients, especially in those with diabetic retinopathy.18 2. Cataract In the study by Bravetti G. (1989), Bilberry extract, plus vitamin E stopped progression of cataract formation in 97 percent of 50 patients with senile cortical cataracts. This effect is thought to be due to its powerful antioxidant properties, protecting the lens of the eye from oxidation and regenerating its collagen fibers. 17 3. Night Vision Bilberry anthocyanosides have an affinity for the pigmented epithelium or visual purple of the retina, which is the portion of the retina responsible for night vision (rhodopson pigment formed from vitamin A on the rods). The Royal Air Force pilots reported improved night vision during World War II with the use of Bilberry extract (also, quicker adjustment to darkness and faster recovery from glare). Even individuals with retinitis pigmentosa and hemeralopia (day blindness) have realized impressive improvement with Bilberry extract 11,12,13,14,15,16,17,18 supplementation. 4. Varicose Veins and Capillary Fragility Via its effects on collagen and connective tissues, which include increased synthesis of glycosaminoglycans (cement substance between fibers), reduced permeability and impaired prostaglandin synthesis, Bilberry has been used in clinical trials with capillary fragility problems. In one study, 47 patients with varicose veins treated with Bilberry extract (480 mg per day) witnessed significant improvement with edema, heaviness feeling, parethesia, pain and skin dystrophy.19,20 ( see also Horse chestnut and Grape seed extract in this document).

Dosage and Standardized Grade For most eye conditions and capillary fragility conditions, the following recommendations can be considered: 80 to 160 mgs of Bilberry extract, (standardized to 25 percent anthocyanidin content), three times per day.

Adverse Side Effects, Toxicity and Contraindications Bilberry extract has been shown to be very non toxic and has not produced any significant side effects is studies to date. There are no well known health conditions that preclude the use of Bilberry extract.21,22

Drug-Nutrient Interactions Anticoagulant Medications (e.g. warfarin, coumadin, aspirin) â&#x20AC;&#x201C; as Bilberry extract has been shown in experimental studies to reduce the clotting action of blood platelets, it may potentiate the action of other anticoagulant drugs. In these cases, prothrombin time (INR) should be monitored closely to guard against a possible bleeding disorder, although no human reports of such an occurrence have yet been reported.24

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Kuhnau J, The flavonoids, A Class of Semi-essential Food Components: Their Role in Human Nutrition, World Rev Nutr Diet 1976;24:117-91. Gabor M, Pharmacologic Effects of Flavonoids on Blood Vessels, Angiologica 1972;9:355-74. Havsteen B, Flavonoids, A Class of Natural Products of High Pharmacological Potency, Biochem Pharmacol 1983;32:1141-8. Monboisse JC, et. al. Non-enzymatic Degradation of Acid Soluble Calf Skin Collagen by Superoxide Ion: Protective Effect of Flavonoids, Biochem Pharmacol 1983;32:53-8. Monboisse JC, Braquet P, Borel JP. Oxygen-free Radicals as Mediators of Collagen Breakage. Agents Actions 1984;15:49-50. Rao CN, Rai VH, And Steinman B, Influence of Bioflavonoids on the Collagen Metabolism in Rats with Adjuvant Induced Arthritis. Ital J Biochem 1981;30:54-62. Ronziere MC, et. al., Influence of Some Flavonoids on Reticulation of Collagen Fibrils in Vitro. Biochem Pharmacol 1981;30:771-6. Middleton E, The Flavonoids, Trends Pharm Sci 1984;5:335-8. Amella M, et. al., Inhibition of Mass Cell Histamine Release by Flavonoids and Bioflavonoids. Planta Medica 1985;51:16-20. Jonadet M, et. al., Anthocyanosides Extracted from Vitis Vinifera, Vaccinium Myrtillus and Pinus Maritimus, I. Elastese-inhibiting Activities in Vitro, II. Compared Angioprotective Activities in Vivo, J Pharm Belg 1983;38:41-6. Detre A, et. al., Studies on Vascular Permeability in Hypertension: Action of Anthocyanosides. Clin Physiol Biochem 1986;4:143-9. Jayle GE and Aubert L, Action des Glucosides D’Anthocyanes sur la Vision Scotopique et Mesopique du Sujet Normal Therapie 1964;19:171-85. Terrasse J and Moinade S, Premiers Resultats Obtenus Avec un Nouveau Facteur Vitaminique P “les Anthocyanosides” Extraits du Vaccinium Myrtillus, Presse Med 1964;72:397-400. Sala D, Rolando M, Rossi PL and Pissarello L, Effects of Anthocyanosides on Visual Performances at Low Illumination. Minerva Oftalmol 21, 283-285, 1979. Gloria E and Peria A, Effect of Anthocyanosides on the Absolute Visual Threshold, Ann Ottalmol Clin Ocul 1966;92:595-607. Junemann G, On the Effect of Anthocyanosides on Hemeralopia Following Quinine Poisoning. Klin Monatsbl Augenheilkd 1967;151:8916. Caselli L, Clinical and Electroretinographic Study on Activity of Anthocyanosides. Arch Med Int 1985;37:29-35. Wegman R, Maeda K, Troche P, and Bastide P. Effects of Anthocyanosides on Photoreceptors, Cytoenzymatic Aspects. Ann Histochim 1969;14:237-56. Bravetti G, Preventive Medical Treatment of Senile Cataract with Vitamin E and Anthocyanosides: Clinical Evaluation. Ann Ottalmol Clin Ocul 1989;115:109.

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18. Scharrer A and Ober M, Anthocyanosides in the Treatment of Retinopathies. Klin Monatbsl Augenheilkd 1981;178:386-9. 19. Mian E, et.al., Anthocyanosides and the Walls of Microvessels, Further Aspects of the Mechanism in the Action of their Protective Effect in Syndromes due to Abnormal Capillary Fragility. Minerva Med 1977;68:3565-81. 20. Ghiringhelli G, Gregoratti F, and Marastoni F, Capillarotropic Activity of the Anthocyanosides in High Doses in Phlebopathis Stasis. Min Cardioangiol 1978;26:255-76. 21. Murray MT, The Healing Power of Herbs (2nd edition), Prima Publishing, 1995. 22. Dietary Supplement Information Bureau. www.content.intramedicine.com: Bilberry 23. Jayle GE, et al. Study concerning the action of athocyanoside extracts of Vaccinium myrtillus on night vision. Ann Occul Paris. 1965; 198 (6): 556-62. 24. Moranzonni P, et al. Vaccinium myrtillus. Fitoterapia. 1996; vol LXVII (1): 3-29

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Black Cohosh (cimicifuga racemosa) Black Cohosh is an upright perennial plant, which contains active constituents shown to be of importance in the management of menopause and various female reproductive conditions, especially PMS. Black Cohosh commercial stocks come from the United States and Canada, although it is especially popular in Germany. Historically, it has been used for its medicinal properties by peoples of the First Nations.1

Principle Active Constituents Terpenoids (triterpene glycosides, which are saponins), Formononetin.1 Black Cohosh triterpenes have been shown to mimic the effects of estriol, the weakest endogenous estrogen formed in the body.2

Clinical Application and Mechanism of Action 1. Menopause A number of studies (double-blind, placebo-controlled and open trials) involving postmenopausal women have demonstrated that Black Cohosh supplementation can: reduce hot flashes and other menopausal symptoms (insomnia, profuse sweating, dizziness, headache, heart palpitation, tinnitus, nervousness/irritability, anxiety, depressive moods). Black Cohosh has also been shown to maintain integrity of the vaginal lining (mucosa) in postmenopausal women, preserving sexual function and preventing atrophy and dryness of these tissues that often accompanies menopause.3,4,5,6,7,8 Black Cohosh triterpenes appear to account for these therapeutic effects as these active constituents are known to exert a weak, but significant estrogenic effect, that has been shown to be sufficient to compensate for the 90% decline in estrogen production that occurs in the menopausal years of a women’s life. A very high percentage of women in these studies reported significant benefits from the use of Black Cohosh extract in controlling their menopausal symptoms and improvement was on par or better than the relief afforded by estrogen or hormone replacement therapy.3,4,5,6,7,8 N.B. These effects of Black Cohosh were evident in head to head trials against hormone replacement therapy, diazepam and in patients where hormone replacement therapy was contraindicated, or refused. 2. Premenstrual Syndrome Several published trials revealed that Black Cohosh is highly effective in reducing the symptoms of PMS. 9,10 Some reports suggest that PMS is caused or aggravated by a high estrogen to progesterone ratio in affected women. It has been proposed that Black Cohosh triterpenes act as phytoestrogens, competing with the body’s more powerful estrogens, for binding to estrogen receptors on reproductive tissues. In this capacity Black Cohosh triterpenes can reduce the stimulation of the body’s more powerful estrogens (estradiol, estrone), toning down (down-regulating) their influence upon the breast, uterus and other tissues. In turn, this reduces the estrogen over-stimulation that may be a factor in the promotion of PMS. Another aspect of PMS management involves the fact that Black Cohosh triterpenes have also been shown to be a precursor (building block) for the body’s synthesis of progesterone. It appears that some women display corpus luteum failure, in that the ovaries secrete insufficient amounts of progesterone during the second half of the menstrual cycle. This can aggravate the high estrogen to progesterone

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ratio described above. Thus, the use of Black Cohosh extract is proposed to provide relief of PMS in as much as its triterpene constituents can block the over-stimulation effect of the body’s more powerful estrogens and enable the body to increase its production of natural progesterone. Further, Black Cohosh triterpenes have also been shown to be anti-spasmodic, helping to reduce abdominal and uterine cramping associated with PMS. No other natural agent has been shown to provide all three of these biological actions, which appear to be of significance in the management of PMS.13,18 Other Female Conditions Preliminary trials suggest that Black Cohosh may provide benefit in other gynaecological complaints such as amenorrhea (both primary and secondary) dysmenorrhea, polymenorrhea, uterine fibroids, and fibrocystic breast disease.9,10,11

Breast Cancer and Other Safety Concerns The BGA, the German equivalent to the FDA in the United States and HPB in Canada, includes no contraindications or limitations of use for black cohosh. To date its effects on established breast tumor cell line has shown no stimulatory effects but rather inhibitory effects of cancer cell replication.12 From our current understanding, Black Cohosh offers an appropriate natural alternative to hormone replacement therapy for menopause (unless osteoporosis is well established), especially where hormone replacement therapy is contraindicated (i.e., women with a history of estrogen-dependent cancer, unexplained uterine bleeding, liver and gallbladder disease, pancreatitis, endometriosis, uterine fibroids or fibrocystic breast disease. 13 The phytoestrogens contained in black cohosh, exhibit a relative binding affinity for estrogen receptors that is only 1/100 as strong as 17-beta-estradiol (the body’s most potent estrogen).14 Black Cohosh phytoestrogens do not stimulate growth of endometrial cells therefore, concurrent progesterone replacement is not required to reduce risk of endometrial cancer (with estrogen replacement therapy, progesterone is used to block the stimulatory effects of estrogen on endometrial overgrowth and the known cancer risk associated with this effect). As such, Black Cohosh may be beneficial as a treatment for endometriosis.14 Commission E, a German regulatory agency, considers Black Cohosh useful in the management of premenstrual syndrome, dysmenorrhea and nervous conditions associated with menopause.15 In 1997, over ten million monthly units of a popular German Black Cohosh product (Remifemin) were sold in Germany, the United States, and Australia.13

Dosage and Standardized Grade Black Cohosh extract standardized to 2.5% triterpenes is the clinical extract used in most studies (often calculated as 27 – deoxyacteine). Menopause and PMS - the dosage for PMS and Menopause ranges from 40 mg, twice per day, to two 40 mg capsules or caplets (80 mg), twice per day, for a daily total intake ranging from 80 – 160 mg of Black Cohosh extract, standardized to 2.5% triterpenes.16

Adverse Side Effects, Toxicity and Contra-Indications Detailed toxicology studies reveal no birth defects, teratogenic effects, mutagenic or carcinogenic effects using 1,800 mg/kg body weight (approximately nine times the therapeutic dose) in rats (Remifemin). 17 Large doses in humans have produced abdominal discomfort, nausea, vomiting, dizziness, and headaches on rare occasions. 15,19,20 Based on currently available data, Black Cohosh extract is appropriate for long-term continued use.13

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Drug-Nutrient Interactions There are no well-known drug interactions for black cohosh.15

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Boon & Smith, Health Care Professional training program in complementary medicine, 39-43. Warnecke G. Beeinflussung klimakterisch beschwerden durch ein Phyto-terapeutikum, die medizinische welt 1985;36:871-4. Stolze H. An Alternative to treat menopausal complaints. Gyne 1982;3:1416. Wainecke G. Influencing menopausal symptoms with a phytotherapeutic agent. Med West 1985;36:871-4. Stoll W. Phytopharmacon influences atrophic vaginal epithelium, double-blind study, cimicifuga vs. estrogenic substances. Therapeuticum 1987;1:23-31. Daiber W. Menopause symptoms: success without hormones. Arztliche Praxis 1983;35:1946-7. Vorberg G. Treatment of menopause symptoms. ZFA 1984;60:626-9. Petho A. Menopause symptoms: is it possible to switch from hormone treatment to a botanical gynecologicum?. Arztliche Praxis 1987;47:1551-3. Schlidge E. Essay on the treatment of premenstrual and menopausal mood swings and depressive states. Rigelh Biol Umsch 1964;19(2):18-22. Brukes A. Essay on the phytotherapy of hormonal disorders in women. Med Welt 1960;44:2331-3. Gorlich W. Treatment of ovarian disorders in general practice. Arztl Praxis 1962;14:1742-3. Nesselhut T, et.al. Influence of cimicifuga vacemosa extracts with estrogen-like activity on the in vitro proliferation of mammary carcinoma cells. Institute of Tumor Immunology. Duderstadt, Germany, 1994. & Arch Gypecol Obstet 1993;254:817-8. Murray M and Pizzorno J, Encyclopedia of natural medicine. (revised 2nd edition). Prima Health 1998,639-41. Miksicek RJ. Commonly occurring plant flavonoids have estrogenic activity, moleculas. Pharmacology 1993;44:37-43. Blumenthal M, et.al. The complete commission E monographs. Austin, TX. American Botanical Council 1998:685. Bradley P. British herbal compendium. Gournemouth. BHMA 1992:239. Koin WD. Six-month oral toxicity study with remifemin: granulate in rats followed by an 8 week recovery peiod. Hannover, Germany. International Bioresearch 1991.

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18. Limon L. Use of alternative medicine in womenâ&#x20AC;&#x2122;s health. Am Pharmaceutical Assoc Annual Meeting. A Ph A, 2000. Pharmacists Conference Summaries 2000, Medscape Inc. 19. Healthnotes, Inc. 2001.www.healthnotes.com: Black Cohosh 20. Dietary Supplement Information Bureau. www.content.intramedicine.com: Black Cohosh

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Boswellia (Boswellia Serata) General Features Boswellia is a moderate to large branching tree found in India, whose trunk yields a gummy oleoresin when tapped. A purified extract of this resin is used in modern herbal preparations as an effective anti-inflammatory agent in the management of injuries, arthritis, inflammatory bowel diseases, and certain respiratory illnesses.1,6,7

Principle Active Constituents Pentacyclic triterpenes - The terpenoid portion gives rise to the boswellic acids that have been shown to be the active constituents.1

Clinical Application and Mechanism of Action 1. Arthritis Boswellic acids inhibit the synthesis of pro-inflammatory mediators such as leukotrienes, by inhibiting the 5lipoxygenase enzyme.2 Unlike non-steroidal anti-inflammatory drugs, long-term use of Boswellia does not lead to irritation or ulceration of the stomach.3 Boswellia extract has been shown to reduce inflammation and provide significant symptom relief in patients with rheumatoid arthritis and osteoarthritis, in several human studies. 3,6,7 2. Ulcerative Colitis Boswellia extract has been shown to be useful in the treatment of ulcerative colitis in controlled, double blind studies. In one trial, Boswellia produced a similar benefit as the drug sulfalazine (1gm, tid), which is used to treat ulcerative colits.4 Other studies demonstrate its ability to reduce signs and symptoms of Crohnâ&#x20AC;&#x2122;s disease and chronic colitis.8,9 In one study Boswellia supplementation performed equally as well as did the drug mesalazine in Crohns disease patients, and some researchers indicate that given the benefit to risk evaluation of sulfalazine and mesalazine compared to Boswellia, that Boswellia appears to be as effective and safer than these drugs for some patients with inflammatory bowel diseases.4,6,7,8,9 3. Chronic Respiratory Illnesses Some investigators suggest that Boswellia may be of benefit in the management of asthma, emphysema and/or chronic bronchitis. In a double-blind, placebo-controlled study, forty patients with bronchial asthma (18-75 years of age) were treated with Boswellia extract (300 mg, three time per day) for six consecutive weeks. 70% showed improvement of the disease as evidenced by disappearance of physical symptoms and signs of dyspnea (shortness of breath), rhonchi, number of attacks, decreased eosinophil and ESR blood count, and improved lung capacity and performance test results. In the placebo group 27% of patients showed overall improvement by comparison. It has been proposed that the ability of boswellic acids to improve certain chronic respiratory illnesses results from their biological action involving the inhibition of leukotriene formation in white blood cells (via inhibition of 5-lipoxygenase enzyme that converts arachidonic acid to inflammatory leukotienes, e.g. LTB4). 10,11

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Dosage and Standardized Grade 1. Arthritis and Joint Inflammatory Conditions - 150 mg, (standardized to 37.5 – 75% boswellic acids), three times per day – as a single agent for the treatment of rheumatoid and osteoarthritis, as well as other joint inflammatory states.3,7 2. Inflammatory Bowel Diseases – 150 mg, (standardized to 37.5 – 75% boswellic acids), three times per day.4,6,7,8,9 3. Chronic Respiratory Illnesses – 300 mg, three times per day of Boswellia extract, standardized to 37.5 – 75% boswellic acids.11

Adverse Side Effects, Toxicity and Contraindications Boswellia has been shown to be very safe at recommended doses. 3,4,5,6,7,8,9,11 Rare side effects include diarrhea, skin rash and nausea.6

Drug Interactions There are no well-known drug interactions reported to date in regards to the use of Boswellia.5,6,7

1. 2. 3. 4. 5. 6.

Safayhi H, Sailer ER, Amnon HPT. 5-lipoxygenase inhibition by acetyl-11-keto-b-boswellic acid. Phytomed 1996;3:71-2. Safayhi H, Mack T, Saieraj J, et.al. Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase. J Pharmacol Exp Ther 1992;261:1143-6. Etzel R. Special extract of Boswellia serrata (H15) in the treatment of rheumatoid arthritis. Phytomed 1996;3:91-4. Gupta I, Parihar A, Malhotra P, et.al. Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur J Med Res 1997;2:37-43. Singh GB, Atal CK. Pharmacology of an extract of salai guggal ex-Boswellia serrata, a new non-steroidal anti-inflammatory agent. Agents Actions 1986;18: 407-12. Healthnotes Online, Healthnotes Inc., 1999.

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30 Meschino Health Comprehensive Guide to Herbs

7. 8. 9.

10.

Dietary Supplement Information Bureau. www.content.intramedicine.com: Boswellia Gerhadt H, Seifert F, Buvari P, Vogelsang H, et al. Therapy of active Crohn disease with Boswellia serrata H 15. Gastroenterol. 2001; 39 (1): 11-7 Gupta I, Parihar A, Malhotra P, et al. Effects of gum resin of Boswellia serrata in patients with chronic colitis. Planta Med. 2001; 67 Safayhi H, et al. Inhibition by boswellic acids of human leukocyte elastase. J Pharmacol. Exp ther. 1997; 281 (1): 460-63

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31 Meschino Health Comprehensive Guide to Herbs

Bromelain General Features Bromelain refers to a group of sulfur-containing enzymes that digest protein (proteolytic enzymes or proteases). Bromelain is derived from the stem of the pineapple plant (Ananas comosus).1 Experimental and clinical studies reveal that Bromelain exhibits anti-inflammatory properties, which include: a. Inhibition of the biosynthesis of pro-inflammatory prostaglandins and induction of prostaglandin E1 (which tends to inhibit inflammation) b. Activation of proteolytic activity at sites of inflammation and fibrinolysis activity via the plasminogen-plasmin system (Bromelain stimulates the conversion of plasminogen to plasmin, which in turn activates fibrinolytic activity, dissolving fibrin-based clots and reducing swelling). 2,3,4,5,6,7 c. Bromelain has also been shown to reduce plasma kininogen levels, which inhibits the production of kinins. Kinins are known to cause inflammation, swelling and pain.8 Human and animal studies verify that Bromelain, administered orally, is absorbed intact, from the gastrointestinal tract to the bloodstream (up to 40 percent absorption rate). 9,10,11 The human adult intestinal epithelium has traditionally been described as non-permeable to proteins. Recently, Castell, J.V., et al, demonstrated in the American Journal of Physiology (1997) that, after oral administration of Bromelain in 19 healthy men (oral multi-dosing of 3 gms per day), plasma concentrations reached as much as 5,000 pg/mL by 48 hours. From the plasma concentration curve, it could be estimated that an average of 10.8 micrograms of Bromelain was present in plasma in the 3-to-51 hour period. The presence of undegraded Bromelain in plasma was shown unequivocally by immunoprecipitation of plasma samples with antiBromelain antibodies, followed by gel electrophoresis and immunodetection. Moreover, the enzyme retained its biological activity.12

Principle Active Constituents Bromelain enzymes, which are a group of sulfur-containing proteolytic (protein digesting) enzymes.1

Clinical Application and Mechanism of Action 1. Anti-Inflammatory Agent For Arthritis In clinical trials, Bromelain supplementation has been shown to reduce swelling and pain in patients with rheumatoid and osteoarthritis. In one study, twenty-five patients with severe rheumatoid arthritis, three patients with osteoarthritis and one patient with gout who had residual joint swelling and impaired mobility following longterm corticosteroid therapy, were given Bromelain (20 to 40 mgs, 3-4 times daily). Twenty-eight percent of patients reported excellent improvement in regards to swelling and pain, forty-five percent had good results, fourteen percent had fair results and fourteen percent had poor results, including the patient with gouty arthritis. Smaller amounts of steroids were required with concurrent administration of Bromelain (steroid dosing was tapered according to improvement with Bromelain). The follow-up period was 3 weeks to 13 months.13

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32 Meschino Health Comprehensive Guide to Herbs

In a recent double-blind clinical trial, 73 patients with gonarthritis were randomized to receive 3 weeks of treatment with an oral enzyme preparation, containing Bromelain, trypsin and rutin (n=36) or the NSAID diclofenac (n=37). Efficacy was primarily evaluated using the Lequesne index (measuring pain and function of the affected knee). Other investigations included assessment of pain symptoms using a visual analogue scale (VAS), global assessment of efficacy and tolerability (by both patients and one physician), and various laboratory parameters. Patients were evaluated at baseline, at weekly intervals throughout the 3-week treatment period, and at 7 weeks (i.e. 4 weeks after discontinuing therapy). The Lequesne index improved continuously in both groups: from 13.56 at baseline to 3.10 after 3 weeks (end of therapy) to 2.05 at 7 weeks (follow-up) in the enzyme group, and from 14.04 to 3.50 to 2.24 respectively, in the diclofenac group. The researchers conclude, “short-term evaluation indicates that oral enzymes may be considered an effective and safe alternative to NSAIDs, such as diclofenac in the treatment of painful gonarthritis”.14 Singer, et al, also reported anti-inflammatory activity of oral enzymes similar to that of diclofenac in patients with progressive gonarthritis.15 Klein, et al, demonstrated that proteolytic oral enzyme therapy was equally effective as was diclofenac in reducing pain in periarthritis of the shoulder in a clinical trial. Previously, these researchers had shown that proteolytic oral enzyme therapy was as effective as NSAIDs in reducing painful vertebral syndrome.16 2. Sports Injuries and Blunt Injuries to the Musculoskeletal System Dating back to the 1960’s Bromelain has been used (oral administration) in the treatment of sports-related injuries. In one clinical trial, fifty-eight of seventy-four boxers receiving Bromelain reported that all signs of bruising had completely healed within 4 days. Of the remaining sixteen; complete healing took 8 to 10 days. Of the seventy-two controls, only ten showed complete resolution of healing by the fourth day, the remainder taking 7 to 14 days for complete healing to occur.17 The effect of orally administered Bromelain or the reduction of swelling, bruising, healing time, and pain following various surgical procedures has been demonstrated in several clinical studies. 6,18,19,20 In the study by Tassman, et al,18after oral surgery, swelling decreased within 3.8 days with Bromelain, compared with 7 days for the placebo in a double-blind study. In the same study, pain duration was reduced within 5.1 days in the Bromelain group, compared with 8.1 days in the placebo group. Recently, in an open case observation study involving patients with blunt injuries to the musculoskeletal system, the efficacy and tolerability of high-dose Bromelain was investigated by an orthopedic surgeon. In addition to usual therapeutic measures, 59 patients were treated with Bromelain preparations for one to three weeks based upon healing response. Treatment with Bromelain resulted in clear reduction of swelling, pain at rest and during movement, and tenderness to palpation. The addition of Bromelain to the treatment regime accelerated the rate of healing compared to the usual rate of healing observed for blunt injuries to the musculoskeletal system. The tolerability of the Bromelain preparation was very good, and patient compliance was correspondingly high.21 Experimental Investigations Demonstrating The Anti-inflammatory Properties of Bromelain Recent reviews have confirmed the analgesic, anti-inflammatory and edema-reducing properties of Bromelain and other proteolytic enzyme combinations.1,16 As reported by Kleef, et al, Bromelain-treated lymphocytes from healthy human donors displayed a 60 percent to 90 percent reduction in cell surface adhesion compared to untreated lymphocytes in vitro. The selective modulation of cell adhesion molecules may help explain some of the clinical effects observed after Bromelain treatment in patients suffering from chronic inflammatory disease, HIV and cancer.22

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33 Meschino Health Comprehensive Guide to Herbs

Over the past few years, a number of studies have demonstrated the effects of oral enzymes, including Bromelain, on suppressing the synthesis of pro-inflammatory cytokines14,34 and adhesion molecules,22,35 the latter are expressed on the surface of cells, enabling cell-cell interactions, which are fundamental processes of the inflammatory reaction.36,37 In summary, oral enzyme therapy reduces various parameters of inflammation and pain by affecting the release of mediators of inflammation, modulation of adhesion molecules, reduction of immune complexes, activation of fibrinolysis and direct influences on nociceptors.14,16 3. Digestive Aid Bromelain in combination with other digestive enzymes and ox bile has been reported to help digest food 41, but is not generally used alone for this purpose.

Dosage Anti-inflammatory: 250-750 mg, three times daily on an empty stomach. Bromelain is often standardize to 2,000 milk clotting units (MCU) which is 1333.3 Gelatin Dissolving Units (GDU) 38,47 Adverse Side Effects and Toxicity Currently, NSAIDs are first-line therapy in osteoarthritis. However, endoscopic studies have shown that lesions of the gastric mucosa developed in 14 to 31 percent of patients receiving long-term treatment with NSAIDs.23,24,25,26 In particular, the elderly may be seven times more likely to have silent ulcers from NSAID use.24,25,27,28 Other potential adverse effects of NSAIDs include cardiac, renal, hepatic and central nervous system damage.14 From an economic standpoint, the treatment of gastrointestinal adverse effects from NSAIDs has been calculated to add 45 percent to the cost of arthritis care. 29,30 By comparison, therapy with oral enzymes is not associated with severe gastrointestinal irritation, erosion, ulcerations, and related risks 14,1 and is generally well tolerated.14, 21,31,32,33 Determination of pepsinogen A and C, which are indicators of the function and morphological condition of the gastric mucosa, confirmed good gastric tolerability with administration of oral enzymes, including Bromelain.14 Unpublished data from trials of up to 4 years duration in patients with various clinical conditions (i.e. rheumatoid arthritis, multiple sclerosis) suggest that oral enzyme therapy, including Bromelain, is very well tolerated over longer periods.14 In regards to toxicity, animal studies have shown no toxic effects with Bromelain doses up to 10 grams per kilogram as no LD50 (50 percent lethal dose) exists for Bromelain doses in this range.38

Drug-Nutrient Interactions 1. Anticoagulant Medications (warfarin, coumadin etc) - In regards to potential adverse drug-nutrient interactions, studies using Bromelain on isolated human platelets in vitro revealed that Bromelain prevented thrombin-induced platelet aggregation, whereas papain enzyme was less active in preventing platelet aggregation. There is strong biological plausibility that Bromelain may further potentiate the anti-clotting influence of warfarin and coumadin, potentially increasing risk of a bleeding disorder. As well, animal studies and reports with humans indicate that Bromelain treatment can reduce thrombus formation via its thrombolytic action. To date there are no published reports of bleeding disorders occurring in humans using Bromelain supplementation. However, until more information is available, it is advisable to use caution and proper patient monitoring (prothrombin time, INR), when recommending Bromelain to patients on warfarin or anticoagulant therapy.39,40

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34 Meschino Health Comprehensive Guide to Herbs

2. Antibiotics – Bromelain has been shown to increase the amount of antibiotics in the blood and urine with concurrent orally administration.42,43,44,45,46

Pregnancy and Lactation

During pregnancy and lactation, the only supplements that are considered safe include standard prenatal vitamin and mineral supplements. All other supplements or dose alterations may pose a threat to the developing fetus and there is generally insufficient evidence at this time to determine an absolute level of safety for most dietary supplements other than a prenatal supplement. Any supplementation practices beyond a prenatal supplement should involve the cooperation of the attending physician (e.g., magnesium and the treatment of preeclampsia.) References: Pregnancy and Lactation 1. Encyclopedia of Nutritional Supplements. Murray M. Prima Publishing 1998. 2. Reavley NM. The New Encyclopedia of Vitamins, Minerals, Supplements, and Herbs. Evans and Company Inc. 1998. 3. The Healing Power of Herbs (2nd edition). Murray M. Prima Publishing 1995. 4. Boon H and Smith M. Health Care Professional Training Program in Complementary Medicine. Institute of Applied Complementary Medicine Inc. 1997. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

5.. Tausssig SJ et al. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application. An update. J Ethnopharmacol. 1988;2:191-203 Ako H et al. Isolation of fibrinolysis enzyme activator from commercial Bromelain. Arch Int Pharmacodyn. 1981;254:157-67 Taussing S. The mechanism of the physiological action of Bromelain. Med Hypothesis 1980;6:99-104 Seligman B. Bromelain: an anti-inflammatory agent. Angiology. 1962;13:508-10 Pirotta F et al. Bromelain – a deeper pharmacological study. Note I. Anti-inflammatory and serum fibrinolytic activity after oral administration in the rat. Drugs Exp Clin Res. 1978;4:1-20 Tassman G et al. Evaluation of a plant proteolytic enzyme for the control of inflammation and pain. J Dent Med 1964;19:3-77 Felton G. Does kinin released by pineapple stem Bromelain stimulate production of prostaglandin E1-like compounds? Hawaii Med J 1977;36:39-47 Katori M et al. A possible role of prostaglandins and bradykinin as a trigger of exudation in carrageenan-induced rat pleurisy. Agents Action 1978;8:108-12 Miller J et al. The increased proteolytic activity of human blood serum after oral administration of Bromelain. Exp Med Surg 1964;22:27780 Izaka K et al. Gastrointestinal absorption and anti-inflammatory effect of Bromelain. Jpn J Pharmacol 1972;22:519-34 Seifert J et al. Absorption of a proteolytic enzyme of plant origin from the gastro-intestinal tract into the blood and lymph of adult rats. Z Gastroenterol 1979;17:1-18 Castell JV et al. Intestinal absorption of undegraded proteins in men: presence of Bromelain in plasma after oral intake. Am J Physiol 1997;273:139-46 Cohen A et al. Bromelain therapy in rheumatoid arthritis. Pennsyl Med J 1964;67:27-30 Klein G et al. Short-term treatment of painful osteoarthritis of the knee with oral enzymes : A randomized, double-blind study versus diclofenac. Clin Drug Invest 2000;19 (1):15-23 Singer F et a. Therpie der aktivierten Arthrose: Zur effektivitat eines enzymgemisches versus diclofenac. Wien Med Wochenschr 1996;3:55-8 Klein G et al. Reducing pain by oral enzyme therapy in rheumatic diseases. Wein Med Wochenschr 1999;149:577-80 Blonstein J. Control of swelling in boxing injuries. Practitioner 1960:203-6 Tassman G et al. A Double-blind crossover study of a plant proteolytic enzyme in oral surgery. J Dent Med 1965;20:51-4 Howat R et al. The effect of Bromelain therapy on episiotomy wounds – a double-blind controlled clinical trial. J Obstet Gynecol Br Common 1972;79:951-3 Ztuchni G et al. Bromelain therapy for the prevention of episiotomy pain. Obstet Gynecol 1967;29:275-8

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35 Meschino Health Comprehensive Guide to Herbs

21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.

Masson M. Bromelain in blunt injuries of the locomotor system. A study of observed application in general practice. Fortschr med 1995;113:303-6 Kleef R et al. Selective modulation of cell adhesion molecules of lymphocytes by Bromelain protease. Pathobiology 1996;64:339-46 Baskin WN et al. Aspirin-induced ultra structural changes in human gastric mucosa: correlation with potential difference. Ann Intern Med 1976;85:299-303 Miller DR. Treatment of nonsteroidal anti-inflammatory drug induced gastropathy. Clin Pharm 1992;11:690-704 Shallcross TM et al. Effect of nonsteroidal anti-inflammatory drugs on dyseptic symptoms. BMJ 1990;300:368-9 Soll AH et al. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med 1991;114:307-19 Clinch D et al. Absence of abdominal pain in elderly patients with peptic ulcers. Age Ageing 1984;13:120-3 Singh G et al. Gastrointestinal trct complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern Med 1996;156:1530-6 Bloom BS. Direct medical costs of disease and gastrointestinal side effects during treatment for arthritis. Am J Med 1988;84 Suppl(2A):20-4 Green JM et al. Cost-conscious prescribing of nonsteroidal anti-inflammatory drugs for adults with arthritis. Arch Intern Med 1992;152:1995-2002 Miehlke K. Rheumabehandlung mit enzymen ist mehr als nur antiphlogistische therapie. In: Medizinische Enzym-Forschungsgesellschaft e.V.systemishe Enzym-therapie,15th working symposium, Munich, German. Grafelfing: Forum Medizin Verlag 1991 Miehlke K. Enyme minimieren Risiken der Rheymatherapie. In: Medizinische Enzym-Forschungs-gesellschaft e.V.Systemische Enzymtherapie, 10th working symposium, Franfurt, germany. Grafelfing: Forum Medizin Verlag, 1990 Gutfreund A et al. Effect of oral Bromelain on blood pressure and heart rate of hypertensive patients. Hawaii Med J 1978;37:143-6 Lehmann VP. Immunomodulation of proteolytic enzymes. Nephrol Dial Transplant 1996;9:253-63 Munzig E et al. Bromelain protease F9 reduces the CD44 mediated adhesion of human peripheral blood lymphocytes t human umbilical vein endothelial cells. FEBS Lett 1994;351:215-18 Mojcik C et al.Adhesion molecules. Arthritis Rheum 1997;40 :991-1004 Veale DJ et al. Cell adhesion molecules in rheumatoid arthritis. Drugs Aging. 1996;9:87-92 Murray M. The Healing Power of Herbs (2nd ed.) Prima Publishing 1995;Bromelain:60-9 Metzig C et al. Bromelain proteases reduce human platelet aggregation in vitro, adhesion bovine endothelial cells and thrombus formation in rat vessel in vivo. In Vivo 1999;13(1):7-12 Heck A. Potential interactions between alternative therapies an warfarin. Am J Health-Syst Pharm. 2000;57(13):1221-7 Balakrishnan V et al. Double-blind cross-over trial of an enzyme preparation in pancreatic steatorrhea. J. Assoc. Phys. Ind. 1981;29:2079 Tinozzie S, Venegoni A. Efect of Bromelain on serum and tissue levels of Amoxycillin. Drugs Exptl Clin Res. 1978;4:39-44 Renzinni G, Varengo M. The absorption of tetracycline in combination with Bromelain by oral application. Arzneim-Forsch. 1972;22:41012 Luerti M, Vignali ML. Influence of broemlain on penetration of antiobiotics in uterus, salpinx and ovary. Drugs Exp Clin Res. 1978;4:45-8 Bradbook ID et al. The effect of Bromelain on the absorption of orally administered tetracycline. Dr J Clin Pharmacol. Dec1978;6(6) :5524 Lucchi R et al. Chronic infections of the lower respiratory tract. Antibiotic therapy. Results of a double-blind study: tetracycline-HCL as monosubstance versus tetracycline and bromeline. ZFA (Stuttgart). Apr1980;56(11):807-12 Dietary Supplement Information Bureau. www.content.intramedicine.com:Bromelain

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Capsicum (Capsicum Annuum) General Features Capsicum is one of the oldest and most widely used spices in the world. It is a member of the solanaceae family and its synonyms include chili peppers, red pepper, cayenne pepper and hot pepper.1

Principle Active Constituents Capsaicinoids, especially capsaicin.2

Clinical Application and Mechanism of Action Pain Relief (topical agent) As an ingredient in topical agents, capsaicin depletes substance P (SP), a substance that mediates pain transmission from the peripheral nerves to the spinal cord.3,4 This occurs in four stages: 1. SP is immediately released from both central and peripheral terminals. 2. SP fibers become functionally impaired. 3. The axoplasmic transport of SP is inhibited. 4. SP is depleted. (This begins after one day of use and may last for weeks).5 Diabetic Neuropathy The Capsaicin Study Group has resulted in a number of trials that have proven the efficacy of topical application of capsaicin for the relief of diabetic neuropathy. Most of the studies have used topical capsaicin 0.075% in a cream base. In several published trials, approximately 90% of patients reported significant improvement in pain relief.6,7,8,9,10,11 Post-herpetic Neuralgia A lower strength capsaicin topical cream, containing 0.025% capsaicin has been used successfully in many trials and provides significant relief of post-herpetic neuralgia pain. Approximately 40 â&#x20AC;&#x201C; 70% of patients report improvement from the available studies performed to date.12,13,14,15,16,17 Arthritis and Other Painful Conditions Capsaicin cream has been reported to reduce the pain of rheumatoid arthritis, 18 osteoarthritis18,19 cluster headaches20,21 reflex sympathetic dystrophy22, idiopathic trigeminal neuralgia,23 and post-mastectomy pain syndrome.24,25

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Dosage and Standardized Grade Topical Agent: 1.

Diabetic neuropathy â&#x20AC;&#x201C; 0.075% in a cream base.

Post-herpetic neuropathy â&#x20AC;&#x201C; 0.025% in a cream base.

Arthritis and other listed painful conditions - either of the above concentrations can be utilized.1

Adverse Side Effects, Toxicity and Contraindications The following adverse side effects have been reported for topical application of capsaicin creams: 1. Allergic contact dermatitis has been reported26,27 with topical cream. 2.

Erythema; burning and stinging sensations (no vesication) common at both 0.025% and 0.075% concentrations when applied topically. Intensity diminishes after 2 weeks.6,7,8,9 Inhalation reactions (coughing, sneezing) occur occasionally 6,8 with topical application. The primary contraindication for topical use is known allergy to Capsicum.1

Drug Interactions There are no well- known drug-nutrient interactions for topical application of capsaicin creams.1 N.B.: Note that capsaicin is found in a variety of commercially available external analgesic preparations. 1

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38 Meschino Health Comprehensive Guide to Herbs

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

Boon H, Smith M. Health care professional training program in complementary medicine. Institute of Applied Complementary Medicine Inc. 1997:53-60. Leung AY, Foster S. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. , 2 nd edition. Toronto/New York. John Wiley and Sons Inc. 1996:649. Tyler VE. Herbs of choice, the therapeutic use of Phytomedicinals. Binghamton, New York. Pharmaceutical Products Press 1994:2090. Locock RA. Capsicum. Canadian Pharmaceutical Journal 1985;118:517-9. Skofitsch G, Donnerer J, et.al. Comparison of nonivamide and capsaicin with regard to their pharmacokinetics and effects on sensory neurons. Arzneimittell Forsch 1984;341:154-6. Donofrio PD, Walker F, Hunt V, et.al. Treatment of painful diabetic neuropathy with topical capsaicin: a multicentre, double-blind, behicle-controlled study. Archives of Internal Medicine 1991;151:2225-9. Dailey GE. Effect of treatment with capsaicin on daily activities of patients with diabetic neuropathy. Diabetes Care 1992; 15(2):15965. Scheffler NM, et.al. Treatment of painful diabetic neuropathy with capsaicin 0.075%. Journal of the American Podiatric Medical Association 1991;81(6):288-93. Basha KM, Whitehouse FW. Capsaicin: a therapeutic option for painful diabetic neuropathy. Henry Ford Hospital Medical Journal 1991; 39(2):138-40. Pfeifer MA, et.al. A highly successful and novel model for treatment of chronic painful diabetic peripheral neuropathy. Diabetes Care 1993; 16(8):1103-15. Chad D, Ross D, Molitch M, et.al. Treatment of painful diabetic neuropathy with topical capsaicin â&#x20AC;&#x201C; a double-blind multicentre investigations. Pain 1990;42:387-8. Watson CP, et.al. Post-herpetic neuralgia and topical capsaicin. Pain 1988;35:289-97. Watson CP, Evans RJ, Wait VR, Birkett N. Post-herpetic neuralgia: 208 cases. Pain 1988;35:289-97. Bernstein JE, Korman NJ, Bickers DR, Dahl MV, Millikan LE. Topical capsaicin treatment of chronic postherpetic neuralgia. Journal of the American Academy of Dermatology 1989;21(2,Pt.1):265-70. Bernstein JE, Bickers DR, Dahl MV, Roshal JY. Treatment of chronic postherapetic neuralgia with topical capsaicin, a preliminary study. Journal of the American Academy of Dermatology 1987;17(1):93-6. Bernstein JE. Capsaicin in the treatment of dermatologic disease. Cutis 1987;39:352-3. Peikert A, Hentrich M, Ocas G. Topical 0.025% capsaicin in chronic post-herpetic neuralgia: efficacy, predictors of response and long-term course. Journal of Neurology 1991;238(8):452-6. Deal CL, Schnitzer TJ, Lipstein E, et.al. Treatment of arthritis with topical capsaicin: a double-blind trial. Clinical Therapeutics 1991;13(3):383-95. McCarthy G, McCarty D. Effect of topical capsaicin on asteoarthritis of the hands. Journal of Theumatology 1992;19:604-7. Sicuteri F, Fusco BM, Marabini S, et.al. Beneficial effect of capsaicin application to the nasal mucosa in cluster headache. Clinical Journal of Pain 1989;5:49-53. Marks DR, Rapoport A, Padla D, et.al. A double-blind, placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia 1993;13(20):114-6. Chesire WP, Snyder CR. Treatment of reflex sympathetic dystrophy with topical capsaicin. Pain 1990;43:307-11. Fuscu BM, Alessandri M. Analgesic effect of capsaicin in idiopathic trigeminal. Neuralgia, Anesthesia and Analgesia 1992;74(3):375-7. Watson CPN, Evans RJ, Watt VR. The post-mastectomy pain syndrome and the effect of topical capsaicin. Pain 1989;38:177-86. Watson CP, Evans RJ. The postmastectomy pain syndrome and topical capsaicin: a randomized trial. Pain 1992;51(3):375-9. Futrell JM, Tietschel RL. Spice allergy evaluated by results of patch tests. Cutis 1993;52:288-90. Niinimaki A, Hannuksela M, Makinen-Kiljunen S. Skin prick tests and in vitro immunoassays with native spices and spice extracts. Annals of Allergy, Asthma, & Immunology 1995;75:280-6.

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39 Meschino Health Comprehensive Guide to Herbs

Cernitin Pollen Extract (Cernilton ) General Features Cernilton is a flower (graminaceae) pollen extract (rye-grass pollen extract) that has been used in Europe to treat nonbacterial prostatitis and benign prostatic hyperplasia (BPF) for more than thirty-five years.1 It is a registered pharmaceutical product throughout Western Europe, Japan, Korea, and Argentina.2 Cernilton is documented to provide anti-inflammatory and anti-congestive effects, which have made it a useful treatment for the aforementioned prostate conditions.3 Cernilton also has been shown to decrease resistance of the prostatic urethra (relaxes the muscles that surround the urethra), improve detrusor activity, and suppresses prostate cell growth .4,5,6,7

Principle Active Constituents Proprietary rye-grass pollen extract (Cernilton), contains hydroxamic acid. Hydroxamic acid has been shown to inhibit the growth of a common human prostate cancer cell line, in vitro.10

Clinical Application and Mechanism of Action Benign Prostatic Hyperplasia (BPH) and Non Bacterial Prostatitis Results of clinical studies using Cernilton demonstrate a marked reduction in residual urine volume, prostate volume and substantial improvement in urinary flow rate in patients with BPH. Enlargement and congestion of the prostate gland are the principal factors responsible for the urinary obstruction symptoms in BPH. The anticongestive action of Cernilton is based on the inhibition of prostaglandin and leukotrienes biosynthesis. It specifically inhibits the 5-lipoxygenase and cyclo-oxygenase enzymes, inhibiting the arachidonic cascade from converting arachidonic acid to inflammatory prostaglandin and leukotriene hormones at a local tissue level. In turn, this helps to reverse or prevent intraprostatic tissue edema and fibrosis.8 The overall success rate of Cernilton in patients with BPH is reported to be approximately seventy percent.9 A systematic review of Cernilton for the treatment of benign prostatic hyperplasia concludes â&#x20AC;&#x153;the available evidence suggests that Cernilton is well-tolerated and modestly improves overall urological symptoms, including nocturia. Additional randomized placebo and active-controlled trials are needed to evaluate the long-term clinical effectiveness and safety of Cernilton .2 In general, well-documented evidence from double-blind, placebo-controlled, randomized studies demonstrate that cernitin pollen extract can be a useful phytotherapy treatment for these prostate conditions, especially in the reduction of tissue edema and swelling. 1,2,3,4,5,6,7,8,9

Dosage BPH and Non Bacterial Prostatitis - a typical dosage is 63 mg, twice daily of cernitin pollen extract.1

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40 Meschino Health Comprehensive Guide to Herbs

Adverse Side Effects and Toxicity Cernitin pollen extract is well-tolerated and very non-toxic at recommended intake levels. In a major systematic review regarding the clinical efficacy of Cernilton pollen extract, only one patient reported an adverse side effect from it use. 2

Drug-Nutrient Interactions No drug-nutrient interactions for cernitin pollen extract are known at this time.2 NB: In Germany, phytotherapy is the primary treatment for mild to moderate urinary obstructive symptoms and represents more than 90 percent of all pharmaceuticals prescribed for the treatment of Benign Prostatic Hyperplasia. 2 A partial list of widely used Phytonutrients for Benign Prostatic Hyperplasia includes: Saw Palmetto Pygeum Africanum Beta-sitosterol Urtica dioica (stinging nettle) Cernitin pollen extract

Yasumoto R, et.al., Clinical Evaluation of Long-term Treatment Using Cernitin Pollen Extract in Patients with Benign Prostatic Hyperplasia, Clinical Therapeutics, 17, 1995, 82-86. MacDonald R, et.al., A Systematic Review of Cernilton for the Treatment of Benign Prostatic Hyperplasia, Br J Urol International, 85, 1999, 836-841. Ito R, et.al., Anti-inflammatory Effects of Cernitin Pollen Extract (Cernilton ), Pharmacometrics, 28, 1984, 55-65. Nakaari K, et.al., Effect of the Prostatic Extract (Robaveron) on Bladder Function: An Experimental Study, Acta Urol Jpn, 18, 1972, 501-515. Kimura M, et.al., Micturition Activity of Pollen Extract: Contractile Effects on Bladder and Inhibitory Effects on Urethral Smooth Muscle of Mouse and Pig, Planta Med., 2, 1986, 148-151.

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41 Meschino Health Comprehensive Guide to Herbs

Habib FK, et.al., In Vitro Evaluation of the Pollen Extract, Cernitin T-60, in the Regulation of Prostate Cell Growth, Br J Urol, 66, 1990, 393-397. 7. Ito R, et.al., Anti-prostatic Hypertrophic Action of Cernitin Pollen Extract (Cernilton ), Pharmacometrics, 31, 1986, 1-11. 8. Dutkiewicz S, Usefulness of Cernilton in the Treatment of Benign Prostatic Hyperplasia, International Urol and Nephrol, 28, 1996, 49-53. 9. Buck AC, et.al., Treatment of Outflow Tract Obstruction Ode to Benign Prostatic Hyperplasia with the Pollen Extract, Cernilton : A Double-blind, Placebo-controlled Study, Br J Urol, 66, 4, 1990, 398-404. 10. Habib ZX, et al. Isolation and characteristics of a cyclic hydroxamic acid from a pollen extract, which inhibits cancerous cell growth in vitro. J Med Chem.1994; 38 (4): 735-8

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Chaste Tree (Vitex Agnus-Castus) General Features Chaste Tree is a deciduous shrub native to Mediterranean Europe and Central Asia. It has a long folk history of use in women’s health and remains a popular and effective natural treatment for premenstrual syndrome. 1

Primary Active Constituents Chaste Tree appears to contain a number of different active constituents of importance including, flavonoids, iridoids and, volatile oils. The iridoid agnuside is often used as a marker molecule to confirm authenticity and biological activity.2 Ketosteroids, with a structure similar to sex hormones, have also been isolated from the leaves and flowers.3

Clinical Application and Mechanism of Action Premenstrual Syndrome Agnolyt , a proprietary brand of Chaste Tree extract, has demonstrated good success in the management of PMS in regards to relief of physical and psychological symptoms. Several studies have reported improvement (usually within three months) in mood alterations, reduced feelings of anger, headache, breast fullness, and bloating. 4,5 Abnormal Uterine Bleeding Disorders A number of studies have shown that Chaste Tree extract has been used successfully to treat menorrhagia, hypomenorrhea, hypermenorrhea, metorrhagia and dysmenorrhea. In a multi-center trial in women (n=1571) presenting with menstrual disorders, 89.1% of women reported improvement, with a mean treatment time of 135 days.6,7 Mastodynia Mastodynon , a proprietary Chaste Tree product, demonstrated a 74.5% improvement in women (n=55) suffering from severe mastopathy with cyclic mastodynia, in a placebo-controlled trial.8 Other Female Applications Infertility – numerous reports exist to suggest that Chaste Tree extract may help to overcome some cases of female infertility.9,10,11,12 Increased Lactation – Chaste Tree extract acts as a galactagogue, increasing production of milk in nursing mothers. Two studies support this action in humans, but the onset of action requires several weeks to be effective. However, the increased milk production is marked.13,14,15,16 Mechanism of Action: The current understanding is that constituents of Chaste Tree extract inhibit the secretion of prolactin, likely by binding to central dopamine receptors. The net result is that Chaste Tree extract appears to indirectly help raise progesterone levels and balance out the estrogen to progesterone ratio. This is thought to help correct an underlying estrogen to progesterone imbalance that may contribute to numerous female conditions. Some women may secrete insufficient progesterone due to corpus luteum deficiency, which is one reported cause of a high estrogen to progesterone ratio linked to these problems. Thus, chasteberry tree extract may help correct this imbalance by indirectly raising progesterone secretion.17

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Dosage and Standardized Grade Many of the clinical trials have used Agnolyt  with a daily dose of 40 drops per day.18 As a tablet or capsule, the dosage is 175-225 mg per day (standardized extract of 0.5% agnuside content) if not using the Agnolyt product.19

Adverse Side Effects, Toxicity and Contraindications Reported infrequent side effects from the use of Chaste Tree extract include, dry mouth, disturbed sleep, tachycardia, nausea, allergic skin reactions, vomiting, epigastric pressure sensation, confusion, giddiness, acne, pruritis, alopecia, erythema, headache, and increased menstrual flow. Chaste Tree has been shown to be very non toxic when used at recommended doses. 5,6,16,21

Drug-Nutrient Interactions Hormone Replacement Therapy and Oral Contraceptives – Chaste Tree extract should be used with caution in patients taking these drugs. 18,20,22,23,24 5. L-Dopa, Levodopa, Haloperidol, Metoclopramide and other Dopamine Agonist Drugs – Studies reveal that Chaste Tree extract may act in the body like some of these medications, which may alter the dose requirement of these drugs. As such, appropriate patient monitoring is required in these cases.25 4.

1. 2. 3. 4. 5.

Du Mee C. Vitex Agnus Castus. Australian Journal of Medical Herbalism 1993;5(3):63-5. Boon H, Smith M. The botanical pharmacy. Quarry Health Books 1998:76-81. Houghton P. Agnus Castus. The Pharmaceutical Journal 1994;253:720-1. Coeugniet E, Elek E, Kuhnast R. Premenstrual Syndrome (PMS) and its treatment. Arztezitchr Naturheilverf, 1986;27(9):61922. Dittmar F, Bohnert K, Peeters M. Premenstrual Syndrome: treatment with a phytopharmaceutical. Therapiewoche Gynakol 1992;5(1):60-8.

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6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.

Loch E, Bohnert K, Peeters M. The treatment of menstrual disorders with Vitex Agnus Castus tincture. Der Frauenarzt 1991;32(8):867-70. Marie-Snow J. Vitex Agnus-Castus L. The Protocol Journal of Botanical Medicine 1996;1(4):20-3. Kubista E, Muller G, Spona J. Treatment of mastopathy with cyclic mastodynia, clinical results and hormone profiles. Gynakologische Rundschav 1986;26:65-79. Bleier W. Therapie von zyklus und blutungsstorungen und weiteren endokrin bedingten erkrankungen der frau mit pflanzlichen wirkstoffen. Zentralblatt Fur Gynakologie 1959;81(18):701-9. Propping D, Katzorke T, Belkein I. Diagnosis and therapy of corpus luteum defiociency in general practice. Therapiewoche 1988;38:2992-3001. Milewicz A, Gejdel E, Sworen H, et.al. Vitex Agnus-Castus extract in the treatment of luteal phase defects due to latent hyperprolactinemia: results of a randomised placebo-controlled double-blind study. Arzneimittelforschung 1993;43(7):752-6. Propping D, Katzorke T. Treatment of corpus luteum insufficiency. Zeitis Allgemeinmedizin 1987;63:932-3. Newall C, Anderson L, David Phillipson J. Herbal medicines: a guide for health-care professionals. London. The Pharmaceutical Press 1996:296. Bruckner C. In mitteleuropa genutze heilpflanzen mit milchsekretionsfordernder wirkung (galactagoga). Gleditschia 1989;17:189-210. Du Mee C. Vitex agnus castus. Australian Journal of Medical Herbalism 1993;5(3):63-5. Brown D. Vitex agnus castus clinical monograph. Quarterly Review of Natural Medicine 1994;2(2):111-21. Boon H, Smith M. Health care professional training program in complementary medicine. Institute of Applied Complementary Medicine Inc. 1997. Houghton P. Agnus castus. The Pharmaceutical Journal 1994;253:720-1. Murray M, Pizzarno J. Encyclopedia of natural medicine. Revised 2nd Edition. Prima Health 1998:750-1. Bohnert K. The use of vitex agnus castus for hyperprolactinemia. Quarterly Review of Natural Medicine. 1997;5(1):19-21. Merz P, Gorkow C, Schroder A, et al. The effects of a special agnus castus extract (BP1095el) of prolactin secretion in healthy male subjects. Endocrinology and Diabetes 1996; 104: 447-53. Milewicz A, et al. Vitex Agnus castus extract in the treatment of luteal phase defects due to latent hyperprolactinemia. Results of a randomized, placebo-controlled double-blind study. Arzneim Forsch/ Drug Res. 1993; 43 (7): 752-56. Amann W. Amenorrhea. Favorable effects of Agnus castus (Agnolyt) on amenorrhea. ZFA. (Stuttgart). 1082; 58 (4): 228-31. Sliutz G, etal. Agnus castus extracts inhibit prolactin secretion of rat pituitary cells. Hormone and Metabolic Research. 1993; 25: 253-55 Jarry H, et al. In vitro prolactin but not LH and FSH release is inhibited by compounds in extracts of Agnus castus: Direct evidence for a dopaminergic principle by the dopamine receptor assay. Exp Clin Endocrinol. 1994; 102 (6): 448-54

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Chinese Scullcap (Baicalein) General Features Scutellaria baicalensis or Chinese scullcap is a member of the mint family and grows in China and Russia.1,2 The plant root is a rich source of over 35 flavonoids, giving it a yellow color, and hence its traditional name of golden root or Huang qin, the Chinese term for yellow gold (known as Ogon in Japanese).3,4 One of the major flavonoids contained in the root of the plant is baicalin, a flavone glycoside (12-17% of all scullcap root flavonoids), which yields the aglycone flavone baicalein, once hydrolyzed by gut bacteria.3 Baicalein is readily absorbed into the bloodstream where it has been shown to exert a broad spectrum of important biological activities.5 Baicalein has been incorporated into a number of herbal combinations in Traditional Chinese Medicine that treat a wide array of health conditions, including the widely used Asian herbal remedy, â&#x20AC;&#x153;Sho-saiko-toâ&#x20AC;?.6,7 Currently, baicalein is being studied for its anticancer, anti-inflammatory, anti-viral, anti-bacterial and anti-allergy effects.8,9,10,11 As explained below, its ability to halt the replication of various human cancer cell lines, via the inhibition of the 12 lipoxygenase enzyme system, is attracting a great deal of attention from the scientific community as a premiere agent in cancer research.

Active Constituents Primarily Flavonoids â&#x20AC;&#x201C; The flavonoid Baicalein within Chinese scullcap is considered to be its most important active constituent.3,5

Clinical Application and Mechanism of Action 1.

Anti-Cancer Effects Many experimental studies indicate that baicalein (5,6,7-trihydroxyflavone) prevents and inhibits cancer growth via a number of direct and indirect physiological actions: Inhibits 12-lipoxygenase enzyme and induces apoptosis of cancer cells - Baicalein has been shown to inhibit the 12-lipoxygenase enzyme, which converts arachidonic acid into a specific leukotriene (eicosanoid) that is required for cancer cells to proliferate. Studies demonstrate that by inhibiting the 12-lipoxygenase enzyme baicalein has been shown to inhibit cancer cell proliferation and induce apoptosis (programmed cell death) of human gastric cancer cell lines.12 Further, activation of arachidonic acid by the 12-lipoxygenase enzyme has been shown to be critical for metastasis of human prostate cancer cells. Experimental evidence demonstrates that after intraprostatic injection of mice with human prostate cancer cells, the prostate cells pre-treated with baicalein failed to metastasize to the lung and failed to express activity of the 12-lipoxygenase enzyme. This evidence suggests that, in the presence of baicalein, various cancer cells can be prevented from multiplying and metastasizing to other tissues and that a primary mechanism through which this occurs is via the inhibition of the 12-lipoxygenase enzyme.13 The inhibition of cancer cell proliferation also lends itself to increased apoptosis and a better opportunity for immune cells to destroy tumor cells.12,13 Other studies testing baicalein as an anti-tumor agent have shown that it selectively induces apoptosis in human hepatoma cell lines (liver cancer cells) with minimal influence on non-cancer cells.14,15,28,29 Its ability to induce apoptosis is under intensive investigation as many studies provide evidence that baicalein exhibits an extraordinary ability to selectively encourage apoptosis of many different human cancer cells. This is likely one of the primary ways in which it has been a useful addition to herbal combinations that have been used in cancer treatment.16,17,18 www.meschinohealth.com

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Anti-proliferative - Baicalein has also demonstrated anti-proliferative effects on human bladder cancer cell lines and a murine bladder cancer cell line, in vitro. In an in vivo experiment, mice were injected with bladder cancer cells with concurrent oral administration of a high baicalein-yielding supplement in one group, or with no baicalein supplementation in the control group. All the control mice showed a progressive increase in tumor volume over the ensuing days of the study, whereas the mice treated with baicalein (scutellaria) showed a significant inhibition of tumor growth.19 In other experiments, baicalein has demonstrated anti-proliferative effects on human pancreatic cancer cell lines and T lymphoid leukemia cells. The mechanism of action was shown to be through the reduction of protein tyrosine kinase activity and protein kinase C activity. Both of these enzyme activities are required for normal cellular proliferation to occur. Thus, in addition to inhibiting the 12 lipoxygenase enzyme pathway and inducing apoptosis of cancer cells, baicalein is also known to reduce cancer cell proliferation by directly or indirectly inhibiting specific enzymes (protein tyrosine kinase and protein kinase C) required for cellular division and proliferation.28 Antioxidant - Baicalein is also a strong antioxidant, and has been shown to protect DNA from undergoing cancerous mutations in challenge studies using potent carcinogens such as benzo{a}pyrene, and toxins such as aflatoxin (AF) B.1,20,21 Stimulates DNA repair enzymes - In vitro evidence indicates baicalein stimulates recombination and repair of damaged DNA, supporting its traditional inclusion in cancer formulas, and suggesting possible use after sunburn and radiation damage.22 Inhibits the 5alpha-reductase enzyme - Baicalein has been shown to inhibit the 5alpha-reductase enzyme, which converts testosterone to dihydrotestosterone (DHT). DHT is strongly associated with the development of prostate enlargement (benign prostatic hyperplasia) and prostate cancer. As such, baicalein is reported to be potentially useful for the prevention and/or treatment of androgen-dependent (testosterone-driven) disorders, including prostate enlargement and prostate cancer.23 Human Studies Involving Prostate Cancer Patients Studies on humans have primarily involved patients with advanced prostate cancer, who were shown to be unresponsive to traditional medical drugs and other interventions. In a study performed by researchers from the University of California at San Francisco and Memorial Sloan-Kettering Cancer Center in New York, the oral administration of a herbal combination containing baicalein to patients with metastatic prostate cancer (previously unresponsive to standard treatments) demonstrated reversal and/or stabilization of their condition with significantly improved survival, quality of life scores and other positive outcomes in almost all patients receiving the supplement. After a median treatment period of 57 weeks, 100% of patients with androgen-dependent cancer had a decline of 80% or more in their prostate-specific antigen (PSA) levels, and these levels were undetectable in 81% of the patients. In 31 of 32 patients, the testosterone level declined to that seen in castrated men. Of nine men with elevated prostatic acid phosphatase levels (a marker for cancer progression), all had declines of more than 50%. Of two patients with positive bone scans, one had a complete disappearance of cancerous bone lesions, and the other showed improvement. One patient had a complete disappearance of a bladder mass, demonstrated by CT scan. Of 35 patients with androgen-independent prostate cancer 54% showed a drop in their PSA levels by 50% or more, and of 25 patients with metastasis to bone, 2 showed marked improvement, 7 remained stable, 11 progressed, and 5 had no further bone scan follow up due to an increasing trend in their PSA levels.24 Other

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studies involving men with known prostate cancer, taking this herbal combination, have demonstrated similar results. In one study PSA levels dropped from 100ng/mL to 24 and from 386ng/mL to 114 within 16 months of supplementation in a two case report of hormone-refractory prostate cancer.25 Studies following larger groups of men with prostate cancer for up to four years have also shown this herbal formula to significantly reduce PSA levels and improve survival and quality of life scores.26,27 Researchers attribute much of the anti-tumor effects of this herbal combination to the presence of baicalein. According to researchers, baicalein has demonstrated impressive anti-cancer effects against androgendependent and androgen-independent human prostate cancer cells lines, and many of its anti-cancer mechanisms have been uncovered in recent years, in vitro and in vivo experiments.16,17,18,24,25,26,27,28 It appears to be of particular benefit in prostate cancer treatment and in combination with other phytonutrients (plant-based nutrients) and micronutrients (vitamins and minerals) may help to prevent the development of clinically important prostate cancer, reducing prostate cancer incidence.26 Animal studies indicate that baicalein may be effective in the treatment of other cancers as well, with experimental evidence supporting its potential use in stomach, pancreatic, bladder, liver12, 14, 15,19, 28 and breast cancer. 29, 30, 31 Hepatoma and Leukemia Patients Based on its traditional use, and the documentation of its anti-tumor effects against various human cancer cell lines, Baicalein has been used recently by doctors in Asia as a complementary supplemental agent in the treatment of hepatomas and leukemia in human subjects.29 2.

Anti-viral/Anti-HIV Baicalein has been shown in experimental studies to inhibit the activity of HIV-1 integrase enzyme, which is an essential enzyme in the life cycle of the HIV-virus. This enzyme is responsible for catalyzing the insertion of the viral genome into the host cell chromosome. It is an attractive target for the design of a HIV antiviral drug because the integrase enzyme has no human counterpart.32 In a review of all herbal medicines frequently used as an alternative medical therapy by HIV positive patients and AIDS patients, JA Wu et al, emphasized that experimental data suggest that the flavonoid, Baicalein inhibits infectivity and replication of HIV, and shows great promise as an important component to be included in herbal remedies used for HIV treatment.33

Asthma and Allergies Baicalein inhibits type I and II hypersensitivity reactions, confirming its traditional use in asthma34,35 and allergic dermatitis.3

4. Anti-inflammatory Baicalein has shown impressive anti-inflammatory effects that appear to be mediated via repression of leukotriene B4 (inhibition of the 5-lipoxygenase enzyme), inhibition of interleukin-1B, and prostaglandin E2. Studies reveal it may be of benefit in the treatment of gingivitis (gum inflammation).29, 36, 37

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5. Alzheimer’s and Dementia In a rat model Baicalein has been shown to prevent the build up of amyloid beta peptide (Abeta), which is known to generate free radical damage to brain cells and participate to a significant degree in the development and progression of Alzheimer’s disease. Additionally, chronic inflammation occurs in Alzheimer’s pathogenesis and Baicalein was shown to inhibit the 12- lipoxygenase enzyme responsible for brain inflammation, to a large degree. When tested against other known 12-lipoxygenase inhibitor agents, only Baicalein was able to attenuate both nerve cell death (apoptosis) and over-expression of Abeta production. As such, Baicalein may help to prevent or forestall the development of Alzheimer’s disease by reducing the build up of the toxic brain protein, Abeta and inflammatory mediators, and preventing brain cell death, which has been shown to be triggered by the accumulation of Abeta in affected brain cells. 38 In studies using human neuroblastoma cells, the antioxidant properties of Baicalein were shown to inhibit free radical damage to these nerve cells induced by treatment with hydrogen peroxide (a powerful free radical generating agent). The researchers argue that oxidative (free radical) stress plays an important role in the development of neurodegenerative diseases (e.g. Alzheimer’s disease, Multiple Sclerosis, Parkinson’s disease) and that antioxidants such as Baicalein and Quercetin (also a flavonoid) may be useful bioactive agents in the prevention and/or management of these conditions, pending further studies. Both of these flavonoids have shown impressive protective effects under experimental conditions.39 6. Inhibition of Xanthine Oxidase (Gout Treatment) Baicalein is one of few bioactive agents that has been shown to inhibit the enzyme xanthine oxidase, which is responsible for the conversion of hypoxanthine to xanthine, and xanthine to uric acid, in the pathway for degradation of purines in the body. High levels of uric acid is a hallmark feature of gout and thus, Baicalein supplementation may be an effective complementary intervention in the long-term management of this condition.40 The drug Allopurinol is a Xanthine Oxidase inhibitor and is a primary medication prescribed for the treatment of gout.

Dosage Therapeutic Purposes: The usual doses for therapeutic purposes ranges from 150 to 200 mg per day of Baicalein.6 General wellness: Consider 50-100mg per day. Toxicity and Adverse Side Effects Baicalein supplementation at therapeutic doses appears to be safe with no reports of significant side effects or toxicity. Baicalein or Chinese scullcap are not known to be contraindicated for any health conditions.41,42

Drug-Nutrient Interaction There are no known drug-nutrient interactions for Baicalein or Chinese skullcap.42

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2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Encyclopedia of Nutritional Supplements. Murray M. Prima Publishing 1998. Reavley NM. The New Encyclopedia of Vitamins, Minerals, Supplements, and Herbs. Evans and Company Inc. 1998. The Healing Power of Herbs (2nd edition). Murray M. Prima Publishing 1995. Boon H and Smith M. Health Care Professional Training Program in Complementary Medicine. Institute of Applied Complementary Medicine Inc. 1997. Bone K. Clinical Applications of Ayurvedic and Chinese herbs: Monographs for the Western herbal practitioner. Warwick, Australia 1996;p.75-9 Newall CA, Anderson LA, Phillipson JD. Herbal Medicines: A Guide For Health-Care Professionals. London; Pharmaceutical Press 1996;p.239-40 Tang W, Eisenbrand G. Chinese Drugs of Plant origin: Chemistry, Pharmacology, and Use in Traditional and Modern Medicine. New York; Springer-Verlag 1992. Hsu HY. Oriental Materia Medica: a concise guide. Long Beach CA; Oriental Healing Arts Institute 1986. Nishioka Y, Kyotani S, Miyamura M, Kusunose M. Influence of time of administration of Shosaiko-To extract granule on blood concentration of its active constituents. Chem Pharm Bull 1992; 40:p.1335-7. Chen S, Ruan Q, Bedner E, Deptala A, Wang X, Hsieh TC et al. Effects of the flavonoid baicalin and its metabolite baicalein on androgen receptor expression, cell cycle progression and apoptosis of prostate cancer cell lines. Cell Prolif 2001 Oct; vol 34(5):p.293-304. Rossi M, Meyer R, Constantinou P, Caruso F, Castelbuono D, O’Brien M, et al. Molecular structure and activity toward DNA of baicalein, a flavone constituent of the Asian herbal medicine ‘Sho-saiko-to’. J Nat Prod 2001 Jan; vol 64(1):p.26-31. Kubo M, Kimura Y, Odani T, et al. Studies on Scutellariae radix. Part II: The antibacterial substance. Planta Medica 1981; 43:p.194201. Mahmood N, Pizza C, Aquino R, et al. Inhibition of HIV infection by flavonoids. Antivir Res 1993; 22:p.189-99. Ono K, Nakane H, Fukushima M, et al. Differential inhibitory effects of various flavonoids on the activities of reverse transcriptase and cellular DNA and RNA polymerases. Eur J Biochem 1990; 190:p.469-79. Razina TG, Udintsev SN, Tiutrin II, et al. The role of thrombocyte aggregation function in the mechanism of the antimetastatic action of an extract of Baikal scullcap. Vopr Onkologii 1989; 35:p.331-5. Wong, BC, Wang WP, Cho CH, Fan XM Lin MC, Kung HF, et al. 12-Lipoxygenase inhibition induced apoptosis in human gastric cancer cells. Carcinogenesis 2001 Sep; vol 22(9):p.1349-54.

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Coleus Forskohlii (Forskolin) General Features Coleus Forskohlii is a small perennial member of the mint family, which has been extensively used for many applications in Aryuredic medicine. Its unique active ingredient, the diterpene, forskolin, has been shown to activate the enzyme adenylate cyclase in various tissues, which in turn, increases cellular levels of cyclic AMP (Cyclic Adenosine Monophosphate). Cyclic AMP is nicknamed “the second messenger” as its synthesis triggers the action of various hormones, enzymes and other biological activities that have profound effects on local cells, as well as systemic effects, in some instances, on the entire body. It is primarily via the increased synthesis of cyclic AMP that Coleus Forskohlii may exert its medicinal influences on a significant number of common health conditions. 1,11

Principle Active Constituents The primary active constituent in coleus forkohlii is a diterpene compound (saponin) that is unique to this herb, known as Forskolin.1,11 Other diterpene compounds have also been isolated from coleus forskohlii, which may provide synergistic physiological effects. 12

Clinical Application and Mechanism of Action Cardiovascular Conditions 6. Congestive Heart Failure – as a therapeutic intervention in congestive heart failure forskolin has been shown to activate the enzyme adenylate cyclase, which increases production of cyclic adenosine monophosphate (cAMP) in heart muscle cells (cardiac muscle). Epinephrine has a similar effect on increasing cAMP. Increased levels of cAMP in turn, increases the ability of the heart muscle to produce ATP, which is the energy required for heart muscle contraction and optimal force of muscle contraction with each beat (increased stroke volume). Forskolin also relaxes the artery wall, decreasing blood pressure and thus, pre-load stress on the heart muscle. All of these effects appear to be mediated via increased cAMP synthesis, which acts as a secondary messenger on various cellular processes that manifest the stated outcomes. 7. Hypertension - as mentioned, forskolin relaxes blood vessel smooth muscles via increased cAMP synthesis, helping to reduce high blood pressure, by reducing resistance to blood flow. 8. Platelet Function - forskolin antagonizes the action of platelet-activating factor (PAF) by interfering with the binding of PAF to receptor sites on cells. In turn, this reduces platelet stickiness as well as smooth muscle contraction of blood vessels and bronchiole air passageways. Once again, these effects are mediated through increased synthesis of cAMP.1,2,3,4,5

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Asthma and Skin Conditions Asthma and Eczema â&#x20AC;&#x201C; both of these conditions are associated with a relative decrease in cAMP in bronchial smooth muscle and skin cells, respectively. In turn, this results in degranulation of mast cells and increased contraction of smooth muscle in the bronchiole passageways. Increased PAF also contributes to this problem. Pharmaceutical drugs for allergic conditions, asthma, and eczema are often aimed at increasing cAMP levels (corticosteroids, methylxanthines).6 Corticosteroid drugs stimulate adenylate cyclase enzyme, increasing the synthesis of cAMP whereas, methylxanthine-containing drugs inhibit phosphodiesterase enzyme, which breaks down cAMP. Forskolin may be utilized alone or in conjunction with these drugs in the complementary management of these conditions. 1,7,11 Psoriasis - low levels of cAMP appears to disrupt the balance of cAMP with cGMP (Cyclic Guanine Monophosphate). In turn, this has been shown to cause rapid cellular proliferation (a rate that is 1,000 times faster than normal cells), which is a main feature of the psoriatic condition. In experimental studies Coleus Forskohlii administration has been shown to slow the proliferation rate of skin cells by improving the relative balance of cAMP to cGMP. 7 Authorâ&#x20AC;&#x2122;s Note: In general, the above noted physiological effects associated with Coleus Forskohlii explain its historical use for the treatment of cardiovascular conditions, asthma, skin conditions, and as an antispasmodic in the management of irritable bowel syndrome and uterine cramps. Unfortunately, no well-designed, large, clinical studies have been performed to establish its true therapeutic efficacy for any of these conditions and as such, recommending this herb for these conditions is primarily based upon historical use and animal experimental evidence supporting its role as an adenylate cyclase enzyme activator.11,13

Lipolysis and Body Fat Reduction Recent evidence suggests that supplementation with Coleus Forskohliimay help to reduce body fat in overweight adults. As with other substances that increase cAMP (caffeine, adrenaline, ephedrine, epinephrine), forskolin enhances the breakdown and release of fat from fat cells. The synthesis of cAMP in fat cells initiates a chain events that results in hydrolysis of stored triglycerides by hormone sensitive lipase enzyme, with the subsequent release of free fatty acids and glycerol from fat cells.8,9,10 Unlike ephedrine and other central nervous system stimulants, forskolin does not stimulate the nervous system. Therefore, it does not produce the serious undesirable side effects associated with stimulant drugs and supplements (e.g. ephedrine) such as rapid heart rate, elevated blood pressure, seizures, sudden death heart attack, stroke, nervousness, anxiety, insomnia, atrial fibrillation of the heart etc. Forskolin appears to facilitate an increase in cAMP within fat cells in a manner that by-passes stimulation of beta-adrenergic receptors on the fat cell membrane. By comparison, stimulant drugs, hormones, and supplements, such as ephedrine stimulate beta-adrenergic receptors on fat cells, heart muscle and on the sympathetic nervous system, which results in increased cAMP levels and induces a direct stimulatory effect on the heart, cardiovascular and nervous system. Several small clinical trials have shown that Coleus Forskohlii supplementation may help reduce body fat in overweight adults. In one study, subjects showed an average of 10 lbs of weight loss within an eight-week period. Subjects also showed an increase in their lean mass in this study. Experimental evidence indicates that forskolin also mildly stimulates thyroid cells, which may explain its reported thermogenic properties. This may further account for its ability to facilitate reductions in body fat in overweight subjects.14,15,16,17,18

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Dosage and Standardized Grade For all of the above conditions â&#x20AC;&#x201C; the usual dose of Coleus Forskohliiis 250 mg, twice per day (standardized grade of 1% forskolin content) or 50 mg, twice per day (standardized grade of 18% forskolin, or 9 mg of forskolin per 50 mg tablet).11,19

Adverse Side Effects, Toxicity and Contraindications Coleus Forskohliihas been shown to be very non-toxic and is not associated with any significant side effects. It should be avoided in patients with peptic ulcers as it may increase stomach acidity, although no adverse events of this nature have been published.11,20

Drug-Nutrient Interactions Use with caution with patients on anti-asmathic and antihypertensive drugs, as forskolin may potentiate the effects of these drugs. As such, appropriate patient monitoring under these conditions is recommended .11,19

Pregnancy and Lactation During pregnancy and lactation, the only supplements that are considered safe include standard prenatal vitamin and mineral supplements. All other supplements or dose alterations may pose a threat to the developing fetus and there is generally insufficient evidence at this time to determine an absolute level of safety for most dietary supplements other than a prenatal supplement. Any supplementation practices beyond a prenatal supplement should involve the cooperation of the attending physician (e.g., magnesium and the treatment of preeclampsia.) References: Pregnancy and Lactation 1. Encyclopedia of Nutritional Supplements. Murray M. Prima Publishing 1998. 2. Reavley NM. The New Encyclopedia of Vitamins, Minerals, Supplements, and Herbs. Evans and Company Inc. 1998. 3. The Healing Power of Herbs (2nd edition). Murray M. Prima Publishing 1995. 4. Boon H and Smith M. Health Care Professional Training Program in Complementary Medicine. Institute of Applied Complementary Medicine Inc. 1997.

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Laurenza A, Sutkowski AM, Seamon KB. Forskolin: a specific stimulator of Adenylyl Cyclase or a Diterpene with multiple sites of action? Trends Pharmacol Sci 1989;10:442-7. Wong S, et.al. Forskolin inhibits platelet-activating factor binding to platelet receptors independently of Adenylyl Cyclase activation. Eur J Pharmacol 1993;245:55-61. Kramer W, et.al. Effects of Forskolin on left ventribular function in dilated Cardiomyopathy. Arzneimittel-Forsch 1987;37:364-7. Schlepper M, Thormann J, Mitrovic V. Cardiovascular effects of Forskolin and phosphodiesterase III inhibitors. Basic Res Cardiol 1989;84(Suppl 1):197-212. Wysman DG, Brotherton AF, Heistad DD. Effects of Forskolin on cerebral blood flow: implications for a role of adenylate cyclase. Stroke 1986;17:1299-1303. Lichey J, et.al. Effect of Forskolin on metacholine-induced bronchoconstruction in entrinsic asthmatics. Lancet 1984;ii:167. Allen DD and Quesenberry JT, Quantitative Differences in the Cyclic AMP-lipolysis Relationships for Isoproterenol and Forskolin, J Pharmacol Exp Ther 1988;244:862-858. Allen DO, Ahmed B, Naseer K. Relationship between cyclic AMP-levels and lipolysis in fat cells after isoprotenol and Forskolin stimulation. J Pharmacol Exp Ther 1986;238:659-64. Okuda H, Morimoto C, Tsujita T. Relationship between cyclic AMP production and lipolysis induced by Forskolin in rat fat cells. J Lipid Res 1992;33:225-31. Bianco AC, Kieffer JD, Silva JE. Adenosine 3â&#x20AC;&#x2122;, 5â&#x20AC;&#x2122;-monophosphate and thyroide hormone control of uncoupling protein messenger ribonucleic acid in freshly dispersed brown adipocytes. Endocrinology 1992;130:2625-33. Murray MT. The healing power of herbs. 2nd edition. Prima Publishing 1995. Gabetta B, et al. Minor diterpenoids of coleus forskohlii. Phytochemistry.1989;28(3):859-862. Natural Products Encyclopedia. www.consumerslab.com: Coleus Forskohlii. Palou A, et al.The uncoupling protein, thermogenin. Int J Biochem. Cell Biol. 1983;30(1):7-11. Murray MT. The unique pharmacology of coleus forskohlii. Health Counselor. 1995;7(2):33-35. Research Report, Sabinsa Corporation, 1999 Allen DO, et al. Relationships between cyclin AMP levels and lipolysis in fat cells after isoproterenol and forskolin stimulation. J Pharmacol and Exper Therap,1986;238(2):659-664 Haye B, et al. Chronic and acute effects of forskolin on isolated thyroid cell metabolism. Molecular and Cellular Endocrin. 1985;43:41-50. Dietary Supplement Information Bureau. www.content.intramedicine.com: Coleus Fosrkohlii

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Cranberry General Features Cranberry is an evergreen yielding shiny red berries and is native to the marshland of Northern Europe, Eastern Canada, and Eastern United States.1 It is a member of the same family as blueberry and bilberry. Its historical use as a treatment for bladder infections, originating with Native Americans, has recently been supported scientifically, and is the most well recognized application for Cranberry supplementation.1,4,6

Principle Active Constituents The active constituents in Cranberry include proanthocyanidins, flavonol glycosides, catechin and triterpenoids. 2,3 Of these, the unique proanthocyanidin flavonoids present in Cranberry have been shown to provide the most significant effects against recurring bladder infections.15

Clinical Application and Mechanism of Action Urinary Tract Infections Several small preliminary trials and one recent double-blind, placebo-controlled trial (n=153 elderly women) suggest that daily intake of high quality, unsweetened Cranberry juice or Cranberry extract capsules, reduce the incidence of urinary tract infections in women.4,5,6,7 Although these findings require confirmation, test tube experiments reveal that the proanthocyanidins in Cranberry extract (and concentrated juice products) prevent E.coli bacteria from adhering to the cells that line the wall of the bladder.8,9,10,11,15 E. coli is the most common bacterial cause of urinary tract infections.15 As well, Cranberry supplementation has been shown to reduce bacteria levels in the urinary bladders of older women significantly better than placebo, an action that may help to prevent urinary tract infections. 5 As presented at the June 2001 meeting of the American Urological Association, a one year study (doubleblind,placebo-controlled) of 150 sexually active women showed that Cranberry juice and/or Cranberry extract tablets significantly reduced the number of episodes of bladder infections compared to placebo.18 Initially (1920’s) it was revealed that Cranberry may acidify the urine, blocking bacterial growth through this action. However, it has been shown more recently that the more likely preventive and therapeutic action is that Cranberry proanthocyanidins inhibit the ability of bacteria from attaching to the lining of the urinary tract via their anti-adherence properties.12,13

Dosage and Standardized Grade For prevention of urinary tract infections - 300-400 mg of concentrated Cranberry juice capsules, twice daily, standardized to 11-12% quinic acid (e.g.Pharmacaps),14,16 or 150-600 ml (5-20 ounces) Cranberry juice daily (Ocean Spray Cranberry Juice Cocktail used in juice study).4,12 It may be advisable to use an unsweetened, non diluted Cranberry juice to achieve the highest possible intake of proanthocyanidins. 16 As a rule, 6 ounces of juice is the equivalent of 90 gms of fresh Cranberry fruit.16

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55 Meschino Health Comprehensive Guide to Herbs

Adverse Side Effects, Toxicity and Contraindications There are no reported side effects or toxicity associated with use of Cranberry extract or juice at the recommended levels of intake. Larger dose may cause diarrhea and stomach upset.1,16

Drug-Nutrient Interactions There are no reported drug-nutrient interactions for Cranberry , although weakly alkaline drugs may be affected, including antidepressants and prescription painkillers.1,17

Boon H, Smith M. Health care professional training program in complementary medicine. Institute of Applied Complementary Medicine Inc. 1997:77-81. 2. Marles RJ. Review of medicinal plant modules for CCNM. Brandon, Manitoba. University of Brandon 1997. 3. Leung AY, Foster S. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. 2 nd edition. Toronto/New York. John Wiley and Sons Inc. 1996:649. 4. Gibson L, Pike L, Kilbourn JP. Effectiveness of cranberry juice in preventing urinary tract infections in long-term care facility patients. The Journal of Naturopathic Medicine 1991;2(1):45-7. 5. Avorn J, Manone M, Gurwitz JH, Glynn RJ, Choodnovskiy I, Lipsitz LA. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. Journal of the American Medical Association 1994;271:751-4. 6. Kilbourne JP. Cranberry juice appears to prevent urinary tract infections. CCML Newsletter 1986Jan. 7. Haverkorn MJ, Mandigers J. Reduction of bacteriuria and pyuria using cranberry juice. Journal of the American Medical Association 1994;272(8):590. 8. Katz LM. Reduction of bacteriuria and pyuria using cranberry juice. Journal of the American Medical Association 1994;272(8):588. 9. Hamilton-Miller JMT. Reduction of bacteriuria and pyuria using cranberry juice. Journal of the American Medical Association 1994;272(8):588. 10. Goodfriend R. Reduction of bacteriuria and pyuria using cranberry juice. Journal of the American Medical Association 1994;272(8):588. 11. Hopkins WJ, Heisey DM, Jonier M, Uehling DT. Reduction of bacteriuria and pyuria using cranberry juice. Journal of the American Medical Association 1994;272(8):588-9.

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12. Sobota AE. Inhibition of bacterial adherence by cranberry juice: potential use for the treatment of urinary tract infection. Journal of Urology 1984;131:1013-6. 13. Zafriri D, Ofek I, Adar R, Pocino M, Sharon N. Inhibitory activity of cranberry juice on adherence of Type I and Type P fimbriated escherichia coli to eukaryotic cells. Antimicrobial Agents and Chemotherapy 1989;33(1):92-8. 14. Brown D. Herbal prescriptions for better health. Rocklin, CA. Prima Publishing 1996:349. 15. Howell AB, Vorse N, Der Maderosian a. Inhibition of the adheeence of P-fimbriated Escherichia coli to uroepithelial-all surfaces by proanthocyanidin extracts from cranberries. N Eng J Med.1998;339:1005-6. 16. Dietary Supplement Information Bureau. www.content.intramedicine.com: Cranberry. 17. Healthnotes, Inc.2001. www.healthnotes.com: Cranberry 18. Stothers LA. A randomized placebo controlled trial to evaluate naturopathic cranberry products as prophylaxis against urinary tract infection in women. Presented at: Am Urological Association 2001 Annual Meeting; June 2-7,2001; Anaheim, California. Publ ID:318

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Dandelion (taraxacum officinale) General Features Dandelion is a member of the compositae family and is closely related to chicory. 1 It is commercially grown in Europe and the U.S., as the leaves and roots are used in herbal supplements, which are primarily intended to improve digestion and flow of fat, bile, and cholesterol through the liver and gallbladder, in certain health conditions.9

Principle Active Constituents The principle active constituents responsible for Dandelion’s medicinal effects are its bitter properties that stem from the presence of sesquiterpene lactones of the eudesmanolide and germacranolide type, which are unique to Dandelion leaves and roots. Dandelion is also a good source of the prebioic inulin, as well as choline.9

Clinical Application and Mechanism of Action Liver and Gallbladder Conditions Studies in humans and laboratory animals show that Dandelion root enhances flow of bile, fat and cholesterol through the liver and gallbladder, which may improve conditions such as liver congestion or fatty liver (secondary to alcohol abuse or poor diet), bile duct inflammation, hepatitis, gallstones, and jaundice. 2,3,4,9

Mechanism of Action The mechanism of action is twofold. The active constituents: increase bile production and flow to the gallbladder (cholerectic effect) increase contraction of the gallbladder, releasing stored bile (cholagogue effect) to the intestinal tract. The high choline content of Dandelion root may also be an important aspect of Dandelion’s ability to influence bile flow.5

Dosage and Standardized Grade 1. 3 – 5 gms of dried root, by infusion or decoction, three times daily 2. 5 – 10 ml of tincture from the root (1:5, 24% ethanol), three times daily 6 3. 250 – 500 mg, powdered solid extract (4:1) 5

Adverse Side Effects, Toxicity and Contraindications Dandelion toxicity testing reveals that it is very non-toxic even when taken at high doses for considerable lengths of time.1,8 Dandelion supplementation should be used with caution in cases of occlusion of the bile ducts and/or gallbladder empyema, gallstones, and paralytic ileus, and requires medical follow-up in these cases.6 Otherwise, it is believed to be quite safe, with no side effects other than the occasional allergic reaction, which is most likely to occur in subjects who are allergic to related plants such as, chamomile and yarrow. 10

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Drug-Nutrient Interactions Diuretic Drugs - do not use in conjunction with diuretic drugs, as Dandelion may potentiate the diuretic effect due to its high potassium content. 7,8

Hobbs C. Taraxacum officinale: a monograph and literature review. In: Eclectic dispensatory. Portland: OR. Eclectic Medical Publications 1989. 2. Faber K. The dandelion taraxacum officinale. Pharmazie 1958;13:423-36. 3. Susnik F. Present state of knowledge of the medicinal plant taraxacum officinale weber. Med Razgledi 1982;21:323-8. 4. Bohm K. Choleretic action of some medicinal plants. Arzneimittel-Forsch 1959;9:276-378. 5. Murray M. The healing power of herbs. 2nd edition. Prima Publishing 1995:86-91. 6. Bradley P. British herbal compendium. Bournemouth. BHMA 1992:239. 7. Houghton P. Bearberry, dandelion, and celery. The Pharmaceutical Journal 1995;225:272-3. 8. Hirono I, et.al. Safety examination of some edible plants, part 2. Journal of Environmental Pathology Toxicology and Oncology 1977;1:72-4. 9. Healthnotes, Inc.2001. www.healthnotes.com: Dandelion. 10. Natural Products Encyclopedia. www.consumerslab.com: Dandelion

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59 Meschino Health Comprehensive Guide to Herbs

Devil’s Claw General Features Devil’s Claw is a native plant of southern Africa. It’s unusual name stems from the herb’s fruits, which seem to be covered with numerous small hooks. The secondary storage roots, or tubers of the plant are used for medicinal purposes.1 Decoctions of dried roots have been taken as a tea by indigenous peoples for a variety of digestive and rheumatic conditions.2 It was introduced to Europe by Mehnert and became so popular that in 1976, it was estimated that 30,000 arthritis patients in the United Kingdom alone were using it.3

Principle Active Constituents a. Iridoid glycosides: harpogide, harpogoside, and procumbide b. Phenolic acids: chlorogenic acid, cinnamic acid c. Flavonoids N.B. Harpogoside appears to be the constituent of greatest scientific research interest for arthritis and related musculoskeletal problems.4

Clinical Application and Mechanism of Action Arthritis and Joint Inflammatory Conditions Devil’s Claw has been reputed to have anti-inflammatory and anti-rheumatic properties.2,5,6,7 It is commonly used in the management of many inflammatory joint diseases including osteoarthritis, rheumatoid arthritis and gout. 5,6,7 Experimental evidence demonstrates that the aqueous extracts of Devil’s Claw possesses anti-inflammatory activity 8,9and may be equivalent to that of phyenylbutazone according to one experimental study. 10 However, its mode of action has not been determined, as it does not appear to directly block the synthesis of pro-inflammatory prostaglandins.11,12,19 A standardized grade of Devil’s Claw improved arthritic symptoms, with marked improvement in pain (89%), range of motion (84%), and time needed to reduce stiffness (86%), in a trial involving 43 patients. 13 A double-blind study also revealed Devil’s Claw’s value in reducing low back pain.14 Other trials have not shown a benefit from the use of Devil’s Claw supplementation in arthritic cases.15,16

Dosage and Standardized Grade Arthritis and Joint Inflammation: 200 - 500 mg, three times daily as a single agent (standardized grade containing 35% harpagoside content (iridoid glycoside).4,12,13,19

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Adverse Side Effects, Toxicity and Contraindications Devil’s Claw is considered a safe herb to use at recommended doses. Infrequent reports of slight digestive upset have been reported in various studies in a small number of patients. On a theoretical level, Devil’s Claw is considered a classic bitter, which increases gastric acid secretions to aid in digestion. As such, patients with active ulcers should avoid its use, although no formal evidence indicates that Devil’s Claw has exacerbated peptic ulcers in available human studies.4

Drug-Nutrient Interactions Bleeding Disorders - Devil’s Claw has been shown to potentiate the anti-coagulant effects of warfarin and possibly the platelet inhibitor drug known as Ticlopidine, used to prevent stroke and to treat intermittent claudication and other conditions. In one patient Devil’s Claw was associated with purpura (bleeding under the skin) when taken concurrently with warfarin.17,18 Thus, Devil’s Claw should not be taken concurrently with anticoagulant drugs such as, warfarin, coumadin, and aspirin.17

1. 2. 3. 4. 5. 6.

Tyler VE. The honest herbal. 3rd ed. Binghamton, NY. Pharmaceutical Products Press 1993:111-2. Weiss R. Herbal medicine. Beaconsfield. Beaconsfield Press 1988:362. Grahame R, Robinson B. Devil’s Claw (Harpagophytum Procumbens): pharmacological and clinical studies. Ann Rheum Dis 1981;40:632. Boon H, Smith M. The botanical pharmacy. Quarry Health Books 2000:92-6. Bradley P. British herbal compendium. Bournemouth. BHMA 1992:239. Chevallier A. The encyclopedia of medicinal plants. London. Reader’s Digest 1996:336.

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61 Meschino Health Comprehensive Guide to Herbs

7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Hoffman D. Holistic herbal. Rockport, MA. Element Books 1996:256. Soulimani R, Younos C, Mortier F, Derrieu D. The role of stomachal digestion on the pharmacological activity of plant extracts, using as an example of harpagophytum procumbens. Canadian Journal of Physiology and Pharmacology 1994;72(12):1532-6. Lanhers M, Fleurentin J, Mortier F, et.al. Anti-inflammatory and analgesic effects of an aqueous extract of harpagophytum procumbens. Planta Medica 1992;58:117-23. Newall C, Anderson L, David Phillipson J. Herbal medicines: a guide for health care professionals. London. The Pharmaceutical Press 1996:296. Whitehouse L, Znamirowska M, Paul C. Devil’s Claw (Harpagophytum Procumbens): no evidence for anti-inflammatory activity in the treatment of arthritic disease. Canadian Medical Association Journal 1983;129:249-51. Moussard C, Alber D, Toubin M, Thevenon N, Henry J. A drug used in traditional medicine, Harpagophytum Procumbens: no evidence for NSAID-like effect on whole blood eicosanoid production in humans. Prostaglandins Leukotrienes and Essential Fatty Acids 1992;46:283-6. Pinget M, Lecomte A. The effects of Harpagophytum Capsules (Arkocaps) in degenerative Rheumatology. Medecine Actuelle 1985;12:65-7. Chrubasik S, et.al. Effectiveness of Harpogophytum Procumbens in treatment of acute low back pain. Phytomed 1996;3:1-10. Whitehouse LW, et.al. Devil’s Claw (Harpagophytum Procumbens): no evidence for anti-inflammatory activity in the treatment of arthritic disease. Can Med Assoc J 1983;129:249-51. Grahame R, et.al. Devil’s Claw (Harpagophytum Procumbens): pharmacological and clinical studies. Ann Rheum Dis 1981;40:632. Healthnotes Online. Healthnotes, Inc. 2000. Shaw D, et al. Traditional remedies and food supplement: a 5-year toxicological study. Drug Safety 1997:17(1991-1995):342-56. Dietary Supplement Information Bureau. www.content.intramedicine.com: Devil’s claw.

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62 Meschino Health Comprehensive Guide to Herbs

Echinacea (Purple Coneflower) General Features Echinacea is a wildflower that is native to North America, although the majority used in herbal supplements comes from cultivated plants. It is a perennial herb, whose medical ingredients are found in the whole plant, including the root and aerial portions. It is primarily used as a short-term supplement to arrest the onset of a cold or flu (upper respiratory tract infection) in the early stages, or as means to shorten the duration of these self-limiting conditions.1,6,7

Principle Active Constituents a) Echinacoside - a compound composed of caffeic acid, a caffeic acid derivative (similar to catechol), glucose and rhamnose, all attached to a central glucose molecule. Other caffeic acid derivatives important to the pharmacology of Echinacea include cichoric acid, chlorogenic acid and cynarin. A significant degree of Echinaceaâ&#x20AC;&#x2122;s immune modulating properties are attributable to the presence of echinacoside. b) Polysaccharides â&#x20AC;&#x201C; a number of immunostimulatory polysaccharides have been isolated including inulin (Echinacea root contains ~ 20% inulin), which has been shown to stimulate the alternate complement pathway, enhancing the movement of white blood cells into areas of infection. Arabinogalactan has been shown to increase interferon, tumor necrosis factor and interleukin-1. c) Various Flavonoids 1,6,7,8

Clinical Application and Mechanism of Action 1. Immunostimulation a) Inulin stimulates alternative complement pathway of the immune system, which has been shown to enhance the action of white blood cells to fight infection and other pathogens. b) Echinacea enhances T cells production of interferon and other immune potentiators. The result is enhanced T cell replication, macrophage activity, antibody binding, and increased numbers of circulating neutrophils. c) The non specific T cell activation by Echinacea also increases activity of natural killer cells. d) Echinacea enhances macrophage phagocytosis and stimulates macrophages to produce a number of immunepotentiating compounds (i.e. tumor necrosis factor, interferon, and interleukin-1). e) Echinacea Inhibits hyaluronidase enzyme, which is normally secreted by microorganisms in an attempt to breakdown tissue barriers between cells ( known as the cement substance, ground substance or proteoglycans), enabling the microorganism to more easily spread and invade new cells. 2,3,4,5,6,7 2.

Therapeutic Application Treatment of Upper Respiratory Tract Infections (URI)- a review of 16 clinical trials, involving a total of 3396 patients, provided evidence that Echinacea can abort a cold or flu (upper respiratory tract infection) in the early stages and/or shorten the duration and severity of upper respiratory tract infections in a significant number of cases. 9 In one study involving 80 individuals, it was shown that Echinacea shortened the duration of cold symptoms from 6 days on average, compared to 9 days in the placebo group. 10 However, there is insufficient evidence to suggest that Echinacea can prevent colds and related URI, if taken prophylactically over a long period of time (e.g., throughout the winter). Studies examining this possible benefit have mostly reported negative results in that Echinacea has not demonstrated an ability to reduce the number of URI, colds or flus in clinical trials where

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it has been tested as a preventive agent in this regard . 11 Thus, at this time Echinacea is not recommended as a supplement to be taken for long periods, but is rather used most effectively as a short-term intervention to rally the immune system during the early (prodromal) stages of an upper respiratory tract infection. 1,6,7 Best Variety: Some experts suggest that Echinacea Purpurea is the best variety because it provides the greatest range of active compounds and has the greatest level of clinical research support. 1

Dosage and Standardized Grade Upper Respiratory Tract Infection - as an agent to help arrest the onset, or to help shorten the duration and minimize the severity of the common cold or flu, taking 300 mg of Echinacea every two hours for the first day of illness, then 300 mg three times per day for the duration of symptoms is a common practice. If taken as a capsule or caplet the standardized extract should contain 3.5 percent or greater echinacoside content and not less than 2.4% soluble beta1,2 d-5 fructofuranosides, per 300 mg tablet or capsule. 6 Authorâ&#x20AC;&#x2122;s Note: Anecdotal evidence suggests that many people take much higher doses of Echinacea at the beginning of cold symptoms and during the cold cycle. It is not uncommon to encounter individuals using doses as high as 900 mg of Echinacea every two hours at the outset of a cold, and maintaining this level of intake until the symptoms begin to subside. Fortunately, Echinacea appears to be generally safe, even when taken in very high doses, as indicated below.

Adverse Side Effects, Toxicity and Contraindications Echinacea is regarded as being generally safe, even when taken at high doses. It has not been found to cause any toxic effects and reported side effects of high dose supplementation are infrequent and usually limited to minor gastrointestinal symptoms, and increased urination. 12,13 Some minor allergic symptoms have also been reported. In Australia, one survey found that 20% of allergy-prone individuals were allergic to Echinacea upon testing. On rare occasions severe allergic reactions have occurred with Echinacea supplementation, some of them life threatening. 6,7,14

Other concerns are based upon the long-term administration of Echinacea and the possibility of over-stimulating the immune system in at risk individuals. As such, Echinacea should not be used by people with autoimmune disorders (Lupus, Rheumatoid Arthritis, etc.) and patients with multiple sclerosis, as there is evidence to show that it may trigger or aggravate such conditions. 15 A reported case also implicated the use of Echinacea in triggering recurrent episodes of erythema nodosum, an inflammatory condition that involves tender nodules under the skin. 16 As prolonged use of Echinacea may over-stimulate immune function and trigger underlying or hidden pathologies, the daily use of Echinacea for long periods as may occur in patients with impaired immune function (i.e., chronic fatigue), should not exceed eight weeks. The customary cycle of use in these cases is as follows: After one week of abstaining from Echinacea supplementation patients can begin another eight week cycle of supplementation, followed by one week off and so on.1 Thus, a primary concern of long-term use of Echinacea is rooted in the risk of sustained immune system enhancement, which may trigger some auto destructive consequences (i.e., attacking healthy body tissues, reawakening of dormant herpes viruses and/or, triggering autoimmune reactions). 1

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Drug-Nutrient Interactions a. Immunosuppressive Drugs – Echinacea counters the effects of these drugs and should not be used concurrently.17,18 b. Corticosteroid Medications – Echinacea may counter the effects of these drugs in patients with autoimmune conditions and should not be taken concurrently.19

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Murray MT. The Healing Power of Herbs. 2nd ed. Prima Publishing, 1995 Luetigg B, et.al. Macrophage activation by the polysaccharide arabinogalactan isolated from plant cell cultures of echinacea purpurea. J Nati Cancer Inst 1989;81:669-75. Tubaro A, et.al. Anti-inflammatory activity of a polysaccharide fraction of echinacea angustifolia root. J Pharm Pharmacol 1987;39:567-9. Roesier, J, et.al. Application of purified polysaccharides from cell cultures of the plant echinacea purpurea to mice medicates protection against systematic infections with listeria monocytogenes and candida albicans. Int J Immunopharmacol 1991;13:27-37. Brauning B, et.al. Echinacea purpurea radix for strengthening the immune response in flu-like infections. Z Phytother 1992;13:7-13. Healthnotes, Inc.2001.www.healthnotes.com: Echinacea. Dietary Supplement Information Bureau. www.content.intramedicine.com: Echinacea Duke JA. Handbook of phytochemical constituents of GRAS herbs and other economic plants. Boca Raton, FL: CRC Press, 1992. Melchart D, Linde K,Fisher P, et al. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev. 2000; (2): CDOOO530 Schulten B, Bulitta M, Ballering-Bruhl B, et al. Efficacy of Echinacea purpurea in patients with a common cold. A placebo-controlled, randomized, double-blind trial. Arzneimittelforschung. 2001; 51 (7): 563-8. Barrett B, Vohmann M, Calabrese C. Echinacea for upper respiratory infection. J Fam Pract. 1999; 48 (8): 628-35. Schultz V Hansel R, Tyler VE. Rational Phytotherapy: A Physicians’ Guide to Herbal Medicine. 3rd ed. Berlin, Germany: SpringerVerlag; 1998: 276 Parnham MJ. Benefit-risk assessment of the squeezed sap of the purple coneflower (Echinacea pupurea) for long-term oral immunostimulation. Phytomedicine. 1996; 3: 95-102.

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14. Mullins RJ, Heddle R. Adverse reactions associated with Echinacea: the Australian experience. Ann Allergy Asthma Immunol. 2002; 88: 42-51 15. Natural Products Encyclopedia. www.consumerslab.com: Echinacea. 16. Soon SL, Crawford RI. Recurrent erythema nodosum associated with Echinacea herbal therapy. J Am Acad Dermatol. 2001; 44:29899. 17. Vomel VT. Effect of a nonspecific immunostimulant on the phagocytosis of erythrocytes and the Ink by the reticulohistocyte-sytem in the isolated, perfused liver of rats of various ages. Arzneim Forsch/Drug Res. 1984; 34: 691-95 18. See DM, et al. In vitro effects of Echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients. Immunopharmacology. 1997; 35 (3): 229-35. 19. Bauer R. Echinacea Drugsâ&#x20AC;&#x201D;effects and active ingredients. Z Arztl Fortbild. (Jena). 1996; 90 (2): 111-15.

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Ephedra General Features Various Ephedra species of plants are found throughout the world and grow in desert or arid regions. Ephedra sinica, also known as Ma Huang, is probably the best-known Ephedra species, but there are many others. They are erect, branching shrubs whose stems and branches contain alkaloids, of which 40-90 percent is the stimulant known as ephedrine and the remaining alkaloids being primarily pseudoephedrine and norpseudoephedrine. 1,2,3 Western medicine’s interest in Ephedra began in 1923, with the discovery that ephedrine possessed a number of pharmacological effects. Ephedrine was synthesized for pharmaceutical purposes in 1927 and since then both ephedrine and pseudoephedrine have been used extensively in over-the-counter cold and allergy medications.4 In 1973, more than 20 million prescriptions contained either ephedrine or pseudoephedrine.1

Principle Active Constituents 1.

Ephedrine Ephedrine has similar pharmacological action as epinephrine, but is less potent. Ephedrine is also absorbed more slowly than epinephrine, but is longer acting with more sustained effects on the brain and central nervous system, but again is much less potent.4 Both ephedrine and pseudoephedrine cross the blood brain barrier resulting in stimulation of the nervous system.11 The physiological effects of ephedrine are similar to those of epinephrine and include:      

Increases blood pressure Increases cardiac output Increases heart rate Increases blood flow to the heart, brain, and skeletal muscle Decreases blood flow to the intestinal tract and kidneys Relaxation of bronchial muscles and uterine muscles 4

Pseudoephedrine Pseudoeohedrine also relaxes bronchial muscles like Ephedra, but exerts weaker effects on the heart and central nervous system. Therefore, it is often recommended in the treatment of chronic asthma instead of ephedrine.4

Clinical Application and Mechanism of Action Weight Loss Aid Ephedra has been shown to increase the metabolic rate and encourage the release of fatty acids from adipose tissue to the bloodstream, where they may be taken up and used as a metabolic fuel by skeletal muscle and other tissues. Ephedra acts as a sympathetic nervous system stimulant, enhancing the release of adrenaline and providing a direct thermogenic effect. 5,6 The thermogenic effect can be enhanced by methylxanthines (i.e., caffeine) and salicylates. As such, combinations of these ingredients have been used in studies with athletes and have been shown to produce ergogenic performanceenhancing effects. 7,8,9

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For weight loss patients, most of the studies have used a combination of 20 mg of ephedrine and 200 mg of caffeine, three times daily. Although significant weight loss results have been achieved using this approach (i.e., 36 lbs of weight loss in 24 weeks compared to 29 lbs in the placebo group), health practitioners and consumers should be aware of the dangerous side effects that can result (see Adverse Side Effects and Toxicity) from the use of ephedrine or Ephedra-containing supplements.7

Dosage Range and Standardized Grade Weight Loss Aid As a weight loss aid, a common dosage is 12.5 – 25.0 mg of ephedrine, taken twice or three times per day. Most Ephedra species (i.e., Ephedra sinica or Ma Huang) are 1 – 3 percent alkaloid content, but a 10 percent standardized extract is now available. Therefore, the dosage of a 10 percent alkaloid content (Ma Huang) extract would be 125 to 250 mg, three times daily.1

Adverse Side Effects, Toxicity and Contraindications As reported by the FDA (U.S.) Special Nutritionals Adverse Event Monitoring System, 17 percent of all adverse reactions related to dietary supplements were a result of Ephedra-containing products in 1998 (more than 800 reports). The list of adverse side effects include:            

Nervousness Insomnia Irritability Psychosis Headache Dizziness Seizures Stroke Premature ventricular contractions Increased blood pressure Myocardial infarction (heart attack) Sudden death 10,12,13

The Food and Drug Administration advisory review panel on non-prescription drugs recommended that ephedrine not be taken by patients with heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlarged prostate or by patients taking antihypertensive or antidepressant drugs. 1 Other contra-indications include anxiety, glaucoma, pheochromocytoma.14

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Drug-Nutrient Interactions Ephedra-containing products should not be used concurrently by patients taking the following medications:            

Caffeine containing drugs Cardec DM Epinephrine containing drugs Nadolol Pheneizine Phenylpropanolamine 15 Monoamine oxidase inhibitors (MAO-inhibitors) Antidepressants Digoxin – digitalis Antihypertensive drugs Guanethidine 16 Any Oral or Inhaled Anti-asthmatic medication 17,18

1. 2. 3. 4. 5. 6.

Murray M. The Healing Power of Herbs (2nd edition), Prima Publishing 1995:108-115 Chang HM and But PP. Pharmacology and Applications of Chinese Materia Medica, Vol.2, Teaneck, NJ: World Scientific Publishing, 1987 Duke JA. Handbook of Medicinal Herbs, Boca Raton, FL; CRC Press, 1985 Gilman AG, Goodman AS, and Gilman A. The Pharmacologic Basis of Therapeutics, New York: Macmillan, 1980 Lee T, et.al. Adrenomimetic Drugs in Craig C, Stitzel R, eds., Modern Pharmacology (4 th edition), New York;Little, Brown and Company 1994:907 Astrup A, et.al.. The Effect of Chronic Ephedrine Treatment on Substrate Utilization, the Sympatho-Adrenal Activity, and Expenditure During Glucose-induced Thermogenesis in Man, Metabolism 1986;35:260-265

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7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Astrup A, et.al.. Pharmacology of Thermogenic Drugs, AM J Clin Nutr 1992;55(1):246S-248S. Astrup A, et.al. The Effect and Safety of an Ephedrine / Caffeine Compound Compared with Ephedrine, Caffeine, and Placebo in Obese Subjects on an Energy Restricted Diet, Int J Obesity 1992;16:269-277 Dulloo AG, et.al. The Thermogenic Properties of Ephedrine / Methyxanthine Mixtures; Human Studies, Int J Obesity 1986;10:467481 Colgan M. Optimum Sports Nutrition, Advanced Research Press 1993, 454-455 McNeill JR, Interactions Between Herbal and Conventional medicines, Can J Cont Medical Educ 1999;11(12):97-110 Nightingale SL. From the Food and Drug Administration, JAMA 1996;275(20):p1534 Kikutani T. Contrary Views on Chinese Herbal Drugs and Side Effects, Int J Oriental Med 1990;15(4):184-188 Blumenthal M, et.al. The Complete German Commission E Monographs: Therapeutic Guide to Herbal medicine, Austin, Texas;American Botanical Council 1998:p685 Healthnotes Online, Healthnotes, Inc. 2000 Blumenthol M, et.al.(eds.) The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines, Boston, MA;Integrative Medicine Communication 1998:125-126 Faurshou M, et al. {The bronchodilating effect of ephedrine tablets in bronchial asthma}. Ugeskr Laeger 1993;155(46):3784-5 Laitinen LA, et al. A comparison of the bronchodilator action of pseudoephedrine and ephedrine in patients with reversible airway obstruction. Eur J Clin Pharmacol 1982;23(2):107-9

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Feverfew General Features Feverfew is a member of the sunflower family with the richest source of active constituents found within its leaves. The leaves of the plant contain a unique group of sesquiterpene lactones (85% of which is parthenoloide), which some studies suggest are its primary bioactive agent. Feverfew supplementation has demonstrated an ability to help reduce the frequency, and severity of migraine headaches is some individuals and this is its best-known therapeutic application for which it has gained immense popularity.6,8

Principle Active Constituents Parthenolide has been considered the primary active constituent, although one study showed that a high parthenolideyielding supplement was no more effective than a placebo tablet, in a Dutch study of 50 migraine sufferers. This study has cast some doubt as to what bioactive agent present in Feverfew is the one that provides migraine prevention and relief. As such, some authorities suggest using a whole herb Feverfew supplement rather than one that is standardized to yield a high level of parthenolide. Parthenolide represents 85% of the sesquiterpene lactone content of Feverfew , which are the most unique bioactive agents discovered thus far in the leaf of the plant.1,7

Clinical Application and Mechanism of Action 1. Migraine headaches Feverfew extracts inhibit the manufacture of compounds that promote inflammation, including prostaglandins, leukotrienes, and thromboxanes at the initial stages of a migraine headache, in a similar fashion as cortisone (inhibits phospholipase enzymes not the cyclo-oxygenase enzyme). As such, it blocks the first step of prostaglandin and related eicosanoid synthesis, which involves the activation of fatty acids from the cell membrane phospholipid structure. Due to this action, Feverfew also inhibits platelet aggregation, and vasoconstriction by limiting the synthesis of other eicosanoids such as thromboxane A2. All of these physiological outcomes may help to abort migraine headaches and contains other inflammatory conditions (i.e., arthritis, fever). 2,3,4

A number of well-designed clinical trials have demonstrated that Feverfew supplementation can reduce the frequency of migraine headaches if taken on a preventive basis each day by migraine sufferers. The Nottingham trial involving 59 migraine patients showed a 24% reduction in number of migraine headaches in an eight-month placebo-controlled crossover trial. 4 The clinical studies by Palevitch et al, and Prusinki et al, also demonstrated success in reducing migraine frequency in human subjects with a strong history of migraine headaches. 8, 9 As noted above, a Dutch study reported no benefit from the use of a Feverfew extract over placebo tablets in migraine sufferers. 7 A recent review in the Cochrane Database Systematic Review, by Pittler et al, concludes that the majority of trials suggest a beneficial effect of Feverfew compared with placebo, but the efficacy of Feverfew for the prevention of migraine has not been established beyond a reasonable doubt. 10

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2. Rheumatoid arthritis Due to its anti-inflammatory effects, the traditional use of Feverfew has also included the management of rheumatoid arthritis. A double-blind study testing this application provided encouraging results, however this should be regarded as preliminary evidence only. 5

Dosage and Standardized Grade Migraine Prevention and Maintenance: 25 – 75 mg of Feverfew , taken two to three times per day. To Abort a Migraine Attack: 1,000 – 2,000 mg may be necessary at the onset of an acute attack. Arthritis: Clinical trials have used a daily dosage of 76 mg of Feverfew . Based upon some evidence, using a standardized grade containing capsules or tablets with a parthenolide concentration of 0.4 to 0.7 % may be a consideration. As such, the daily dosage of parthenolide should yield at least 250 mcg. 6,8,11

Adverse Side Effects, Toxicity and Contraindications Among the many thousands of English citizens who commonly use Feverfew for the above stated medicinal purposes, there have been no reports of serious toxicity, which is also supported by animal experiments. 12 At recommended levels of intake Feverfew extract may produce minor side effects, such as gastrointestinal upset and nervousness in a small percentage of patients. 11 Parthenolide exhibits anti-platelet clotting properties and can potentially lead to a bleeding disorder in patients with a history of capillary or vascular fragility. As such, it should be use with caution in these individuals. 13 Chewing the leaves of the Feverfew plant may result in apthous ulcerations or exudative dermatitis from external contact, in sensitive individuals.6 Drug-Nutrient Interactions Anticoagulant Medications (e.g., coumadin, warfarin) – Feverfew may potentiate the anti-clotting effects of these drugs, increasing the risk of a bleeding disorder. Thus, appropriate patient monitoring of prothrombin time (INR) must accompany the concurrent use of Feverfew and anti-coagulant medications. 14,15

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Heptinstall S, et.al., Parthenolide Content and Bioactivity of Feverfew (Tanaceum Parthenuim (L.) Schultz-Bip), Estimation of Commercial and Authenticated Feverfew Products, J Pharm Pharmacol 44, 1992, 391-395. Heptinstall S, et.al., Extracts of Feverfew Inhibits Granule Secretion in Blood Platelets and Polymorphonuclear Leukocytes, Lancet 1, 1985, 1971-1074. Johnson ES, et.al., Efficacy of Feverfew as Prophylactic Treatment of Migraine, Br Med J 291, 1985, 569-573. Murphy JJ, Heptistall S, and Mitchell JRA, Randomized Double-blind Placebo-controlled Trial of Feverfew in Migraine Prevention, Lancet ii, 1988, 189-192. Pattrick M, et.al., Feverfew in Rheumatoid Arthritis: A Double-blind, Placebo-controlled study, Ann Rheum Dis 48, 1989, 547-549. Murray MT, The Healing Power of Herbs (2nd edition), Prima Publishing, 1995. De Weerdt CJ, Bootsma HRP, Hendricks H. Herbal medicines in migraine prevention. Randomized double-blind, placebo-controlled crossover trial of a feverfew preparation. Phytomedicine. 1996; 3: 225-230. Dietary Supplement Information Bureau. www.content.intramedicine.com: Feverfew Palevitch D, Earon G, Carasso R. Feverfew (Tanacetum parthenium) as a prophylactic treatment for migraine: a double-blind placebo-controlled study. Phytother Res. 1997; 11: 508-511. Pittler MH, Vogler BK, Ernst E. Feverfew for preventing migraine ( Cochrane Review). Cochrane Database Syst Rev. 2000; (3): CDOO2286. Healthnotes, Inc.2001. www.healthnotes.com: Feverfew. Newall C, Anderson LA, Phillpson JD. Herbal Medicines: A Guide for Health-Care Professionals. London, England: Pharmaceutical Press; 1996: 120. McNeill JR. Interactions between herbal and conventional medicines. Can J CME. 1999; 11 (12): 97-110. Groenewegen WA, et al. A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on human platelet activity in-vitro. J Pharm Pharmacol. 1990; 42 (8): 553-57. Biggs MJ, et al. Platelet aggregation in patients using feverfew for migraine. Lancet. 1982; 2 (8301): 776.

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Flaxseed and Flaxseed Powder General Features Flaxseeds are a rich source of secoisolariciresinol diglycoside (SLD) and other mammalian lignan precursors. Flaxseed contains 800-times more of these mammalian lignan precursors than is found in any other food (i.e. beans, nuts). The presence of SLD and related lignan precursors as well as its rich alpha-linolenic acid (omega-3 fat) content makes Flaxseed a very unique dietary supplement providing a broad range of health-promotion effects. The consumption of Flaxseed or processed Flaxseed (i.e. muffin or bread) has been shown to significantly raise blood levels of the mammalian lignans enterolactone and enterodiol in a dose-dependent manner. Enterolactone and enterodiol are produced in the colon by the action of bacteria on SLD.1,4 Both enterolactone and enterodiol act as phytoestrogens and can thus, bind to estrogen receptors on breast (and other reproductive tissues) cells and inhibit certain enzymes (i.e., aromatase enzyme in adipose tissue, also known as estrogen synthase) 2 These, and other synergistic effects have made Flaxseed a target for breast cancer research. Other Flaxseed attributes have stimulated research to examine its potential benefits in the prevention of cardiovascular disease, cancer (i.e. breast, prostate, colon), osteoporosis and the management of menopausal symptoms. 3,4

Principle Active Constituents

a. Mammalian Lignan Precursors In particular: Secoisolariciresinol and matairesinol. These are converted into the mammalian lignans, enterolactone and enterodiol by colonic bacteria. Enterolactone and enterodiol are phytoestrogens and exhibit other functions (i.e. antioxidants). b. Alpha-Linolenic Acid (an Omega-3 fat) The amount of alpha-linolenic acid in Flaxseed Powder is far less than in flaxseed oil (see flaxseed oil, alphalinolenic acid), which is more likely to provide more significant health-promotion effects related to Omega-3 fat consumption (e.g., anti-inflammatory effects) c. Fiber Soluble and insoluble fiber 4,5,6

Clinical Application and Mechanism of Action 1. Cancer Prevention and Support  Experimental Evidence - Enterolactone and enterodiol have been shown to exhibit the following anti-cancer functions on an experimental basis: • Compete with estradiol for nuclear binding estrogen binding sites in rat uteri • Inhibit growth of estrogen-sensitive breast cancer cell lines • Inhibit angiogenesis of cancer cells • Inhibit aromatase enzyme, reducing the synthesis of estrone hormone in adipose tissue • Decrease aberrant crypt and foci in rat colonic epithelium • Inhibit epithelial cell proliferation in rat mammary gland • Decrease tumor size in promotion stage of breast cancer in animal studies 5 • Reduced colon cancer development with concurrent intake of Flaxseed in carcinogen-induced colon cancer experiments with rats 4 www.meschinohealth.com

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• • • • • • •

Provide antioxidant protection 7 Lifetime exposure and gestational exposure to Flaxseed lignans induces cancer prevention structural changes to mammary glands and endocrine changes consistent with a reduced risk of breast cancer development in animals 12 Induce cancer cell differentiation Inhibition of tyrosine kinase and DNA topoisomerase – two key enzymes that determine the rate of cell division 8 Anti-mitotic effect 4 Reduction of plasma insulin-like growth factor-1 levels (IGF-1) in rats. Higher IGF-1 blood levels is associated with an increased risk of breast cancer in some human studies 9 Reduction of pulmonary metastasis of melanoma cells and inhibit the growth of metastasic tumors that formed in the lungs of mice 10 Human Evidence - Enterolactone and enterodiol have been shown to exhibit the following anti-cancer functions in human studies: Antiproliferative effect on the breast, similar to that of other selective estrogen receptor modulators, such as tamoxifen and raloxifen 11 Stimulate production of sex hormone-binding globulin (SHBG), decreasing levels of free unbound sex hormones 12 Decrease the synthesis of 16-alpha hydroxyestrone and increase the synthesis of 2 hydroxyestrone. 13 A higher 2 hydroxyestrone to 16-alpha hydroxyestrone ratio (urinary metabolites) has been shown to be related to a decreased risk of breast cancer in women. This is a suggested “chemoprotective effect”. 14 Breast cancer patients excrete very low levels of lignans compared with non breast cancer subjects 4 Vegetarian women are known to have a lower incidence of breast cancer and exhibit higher blood levels of mammalian lignans 15 Improvement in cystic mastalgia, a potentially precancerous condition in women 16 Increased or longer luteal phase, increased progesterone to estradiol ratios during the luteal phase, fewer anovulatory cycles, and a decreased tendency to ovarian dysfunction; all of which are linked to a reduced risk of breast cancer in women 4 Cyclical Mastalgia In a double blind placebo-controlled study by Plu-Bureau et al, they demonstrated that patients ingesting the flaxseed muffin (25gm Flaxseed ) reported a significant improvement in breast pain reduction compared to the placebo group, during the three consecutive menstrual cycle duration of the trial. Results were attributed to the antiestrogen effects of Flaxseed lignans. 16

Cholesterol Lowering and Other Effects on Reducing Cardiovascular Disease Animal studies originally suggested that Flaxseed intake had a hypocholesterolemic effect, that is due to its soluble fiber concentration, not to its alpha-linolenic acid content.16 In human trials including men and postmenopausal women with high blood cholesterol levels, Flaxseed Powder or Flaxseed supplementation in various forms has been shown to reduce total cholesterol (approximately 7-10 percent), reduce LDL-cholesterol (approximately 15 percent), reduce lipoprotein (a) (Lp(a)) concentrations by approximately 7 percent. Lp(a) is emerging as an important risk factor for cardiovascular disease as it increases

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clotting behaviour of platelets, cholesterol deposition in the artery wall and it oxidizes LDL-cholesterol, making it very atherogenic. Flaxseed supplementation is the only dietary factor shown to reduce Lp(a) to date. Estrogen replacement therapy reduces Lp(a) levels, but cholesterol lowering drugs (i.e. statin drugs) do not 17,18,19 Flaxseed lignans inhibit the cholesterol-7-alpha hydroxylase and acyl CoA cholesterol transferase enzymes, involved in cholesterol synthesis, thus reducing total cholesterol. 24 1. Chronic Renal Failure and Renal Disease In Lupus Animal and human studies indicate that a diet rich in soy based protein and isoflavones, and/or Flaxseed lignans retard the development and progression of chronic renal disease. The protective effect is considered to be due to effects on cell growth and proliferation, extracellular matrix synthesis, reduced oxidative stress and inflammation reduction 20 In humans (and animals) Flaxseed supplementation has demonstrated renoprotective effects in human lupus nephritis, with significant delay in the onset of proteinuria, and preservation of the glomerular filtration rate (GFR) and renal size 5. Bone Density and Menopausal Symptom Support Preliminary evidence in women suggests that the phytoestrogen influence of enterolactone and enterodiol (from Flaxseed supplementation) has a positive effect on bone density and menopausal symptoms (i.e. hot flashes) 11 6. Prostate Cancer Protective Effect Flaxseed lignans interfere with steroid metabolism and bioavailablity in a fashion that is linked to reduced prostate cancer risk. They also inhibit enzymes such as tyrosine kinase and topoisomerase, which initiate the cellular proliferation rate. Epidemiological studies link the above endocrine and molecular events with up to an 80 percent reduction in risk of prostate cancer 22 7. Constipation Human studies reveal that Flaxseed supplementation improves laxation 5 It appears that Flaxseed intake increases fecal excretion of bile acids, increasing laxation and reducing the conversion of bile acids to cholesterol in the liver; thereby lowering blood cholesterol 23,5

Dosage Ranges 1. 2. 3.

General Health and Cholesterol Lowering: 25â&#x20AC;&#x201C;50 gms of ground flaxseeds per day (unground seeds are significantly less bioavailable in regards to their lignan precursors content) 1, 13,14,17,18,19 Cyclical Mastalgia: 25 gm per day of ground Flaxseed Powder1,13,14,16 Female Menopausal Support: 25-50 gm per day of ground Flaxseed Powder13,14

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Adverse Side Effects and Toxicity Ground Flaxseed is extremely non-toxic. It is well tolerated according to human trails with no significant side effects, other than the occasional report of mild abdominal discomfort 5,16,23,24 Drug-Nutrient Interactions There are no well-known drug-nutrient interactions for ground Flaxseed , Flaxseed Powder or Flaxseed -containing products 1,16,25

References: Pregnancy and Lactation i. ii. iii. iv. v. vi. vii. viii. ix. x. xi. xii. xiii. xiv. xv. xvi. xvii. xviii. xix.

Encyclopedia of Nutritional Supplements. Murray M. Prima Publishing 1998. Reavley NM. The New Encyclopedia of Vitamins, Minerals, Supplements, and Herbs. Evans and Company Inc. 1998. The Healing Power of Herbs (2nd edition). Murray M. Prima Publishing 1995. Boon H and Smith M. Health Care Professional Training Program in Complementary Medicine. Institute of Applied Complementary Medicine Inc. 1997. Nesbitt PD et al. Human metabolism of mammalian lignan precursors in raw and processed flaxseed. Am J Clin Nutr 1995;69(3):549-55 Huthcins AM et al. Flaxseed influences urinary lignan excretion in a dose-dependent manner in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2000;9(10):1113-8 Tham DM et al. Clinical Review 97 : Potential health benefits of dietary phytoestrogens : a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab 1998;83(7):2223-35 Zeigler J. Just the Flax, Maâ&#x20AC;&#x2122;am: Researchers Testing Linseed. J Natl Cancer Instit 1994;86(23):1746-8 Cunnane SC et al. Nutritional attributes of traditional flaxseed in healthy young adults. Am J Clin Nutr 1995;61(1):62-8 Prasad K et al. Reduction in hypercholesterolemia atherosclerosis by CDC-flaxseed with very low alpha-linolenic acid. Atherosclerosis 1998;136(2):367-75 Kitts DD et al. Antioxidant activity of the flaxseed lignan secoisolariciresinol diglycoside and its mammalian lignan metabolites enterodiol and enterolactone. Mol Cell Biochem 1999;202(1-2):91-100 Kurzer MS et al. Dietary Phytoestrogens. Annu Rev Nutr 1997;17:353-81 Richard SE et al. Plasma insulin-like growth factor-1 levels in rats are reduced by dietary supplementation of flaxseed or lignan secoisolariciresinol diglycoside. Cancer Lett (Ireland) 2000;161(1):47-55 Li D et al. Dietary supplementation with secolariciresinol diglycoside (SDG) reduce experimental metastasis of melanoma cells in mice. Cancer Lett 1999;142(1):91-96 Brzzinski A, Debi A. Phytoestrogens: the natural selective estrogen receptor modulators? Eur J Obstet Gynecol Reprod Biol 1999;85(1):47-51 Tou JC, Thompson LU. Exposure to flaxseed or its lignan component during different developmental stages influences rat mammary gland structures. Carcinogenesis 1999;20(9):1831-5 Haggans CJ et al. Effect of flaxseed consumption on urinary estrogen metabolites in postmenopausal women. Nutr Cancer 1999;33(2):188-95 Haggns CJ et al. The effect of flaxseed and wheat bran consumption on urinary estrogen metabolism in premenopausal women. Cancer Epidemiol Biomarkers Prev 2000;9(7):719-25 Thompson LU et al. Antitumorigenic effect of mammalian lignan precursor from flaxseed. Nutr Cancer 1996;26:159-65

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xx. xxi. xxii. xxiii. xxiv. xxv. xxvi. xxvii. xxviii. xxix.

Gross PE et al. Effect of dietary flaxseed in women with cyclical mastalgia. Program and abstract of the 23rd Annual San Antonio Breast Cancer Symposium. Dec 6-9 2000; San Antonio Texas. Abstract 153. Breast Cancer Res Treat. 2000;64:49 Arjmandi BH et al. Whole flaxseed consumption lowers serum LDL-cholesterol and lipoprotein (a) concentrations in postmenopausal women. Nutr Res 1998;18:1203-14 Jenkins DJA et al. Health aspects of partially defatted flaxseed, including effects on serum lipis, oxidative measures, and ex vivo androgen and progestin activity : a controlled cross over trial. Am J Clin Nutr 1999;69(3):395-402 Flaxseed Lowers Cholesterol. Nutr Science News 1998;3(11):575 Velasquez M et al. Dietary Phytoestrogens : A possible role in renal disease prtection. Am J Kidney Dis 2001;37(5):1056-68 Clark WF et al. A novel treatment for lupus nephritis : lignan precursor derived from flaxseed. Lupus 2000;9(6):429-36 Denis L et al. Diet and its preventive role in prostate disease. Eur Urol 1999;35(5-6):377-87 Chen WJL et al. Hypocholesterolemic effects of soluble fibers. In Kritchevsky D, Yahouny GD, eds. Dietary Fiber: basic and clinical aspects. New York: Plenum Press, 1986:275-89 Sanghui A et al. Inhibition of rat liver cholesterol 7-alha hydroxylase and acyl CoA : cholesterol acyl transferase activities by enterodiol an enterolactone. In Kritchevsky D, ed. Proceedings of the Symposium on Drugs Affecting Lipid Metabolism. New York: Plenum Press, 1984:311-322 Healthnotes Online. Healthnotes Inc. 2000. www.healthnotes.com: Flaxseed

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Garlic (Allium sativum) General Features Garlic is a member of the lily family and is a perennial plant composed of individual cloves enclosed in a white skin. It has been cultivated for more than 5,000 years in the Middle East and is an important part of Chinese Traditional Medicine. Within the bulb are contained its medicinal ingredients. These sulfur-containing active constituents have been shown to provide a multitude of health benefits, from preventing the common cold to reducing cancer risk. However, the available scientific evidence indicates that Garlicâ&#x20AC;&#x2122;s most established health benefit is related to the prevention of cardiovascular disease. 1,40,41

Principle Active Constituents The active constituents in Garlic are a mixture of sulfur-containing compounds, many of which are derived from allicin. These include: Diallyl sulfide Diallyl trisulfide Methyl allyl trisulfide Methyl allyl disulfide S-allyl cysteine (SAC) Ajoene 1

Clinical Application and Mechanism of Action 1. Cancer Prevention Studies Laboratory studies involving chemically induced cancers in animals suggest that Garlic compounds may inhibit certain cancers, such as breast, colon, skin, uterine, esophageal and lung cancer. Mechanisms: Modification of Phase I and Phase II liver detoxification enzymes by diallyl sulfide. Diallyl sulfide has been shown to speed up the detoxification of various carcinogens by increasing the Phase I and Phase II detoxification enzyme systems in the liver and intestinal cells Increased glutathione concentrations and increased activity of the glutathione-S-transferase enzyme by allyl methyl trisulfide and processed Garlic. Glutathione is a vital intracellular antioxidant and is also directly involved with the detoxification of many hazardous biochemical agents. Inhibits the initiation and promotion phases of carcinogenesis induced by 7, 12-dimethyl-benz(a)anthracene (DMBA). Inhibits synthesis of N-nitroso compounds in human studies (5 grams of fresh crushed Garlic has been shown to block N-nitrosoproline formation). Many nitrosamine products are classified as carcinogens and thus, Garlic may act to help prevent cancer by limiting their formation and concentration levels in various tissues. Consistent with this finding is the fact that Garlic consumption is associated with decreased risk of esophageal, stomach, and colon cancer in human observational studies (epidemiological evidence). Enhances DNA repair enzyme activity. Inhibits tumor proliferation

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1. The quantity of S-allyl cysteine (SAC) present in various Garlic preparations has been shown to correlate with the ability of these preparations to inhibit in-vivo formation of DNA adducts resulting from DMBA treatment. Other nutrients enhance the protective effects of Garlic in cancer studies. These nutrients include selenium and vitamin A. The pungent odor of Garlic is caused mainly by allicin. Allinase enzyme within Garlic converts alliin into allicin upon damage or crushing of Garlic cells. The crushing process brings allinase enzyme into contact with alliin allowing this reaction to occur. Thus, S-allyl-L-cysteine sulphoxide (alliin) decomposes into the reactive intermediate allyl sulphenic acid, two molecules of which spontaneously condense to form diallyl thiosulphinate (allicin). Allicin compromises 6575% of the total thiosulphate concentration of Garlic preparations.2,3,4,5,6,7,8,9,10,11,12,13,14,15 2. Cardiovascular Studies Studies reveal that Garlic has a beneficial effect on blood lipids, blood pressure, blood coagulation, and LDL oxidation. In one study, 432 individuals who had suffered a heart attack were given either Garlic oil extract or no treatment over a period of 3 years. The results showed a significant reduction of second heart attacks and about a 50% reduction in death rate among those taking Garlic.42 Mechanisms: Lowering of total cholesterol by 10-12% or by 9%, on average (meta-analysis of controlled studies– Warshafsky S) has been established, with the equivalent of one-half clove Garlic daily, delivering 4,000 mcg of allicin. Garlic compounds may block absorption of cholesterol or the re-absorption of bile from the gut, or inhibit the action of HMG CoA reductase enzyme, according to experimental studies. All of these biological actions would produce a decline in blood cholesterol levels. Garlic may also raise HDL-cholesterol levels. Lowering of blood pressure in hypertensive patients by 20-30 mm Hg systolic pressure and 10-20 mm Hg diastolic pressure (study by Foushee OB) has also been demonstrated. However, it is not clear at this time if Garlic supplementation can consistently help to lower blood pressure to any appreciable degree. Decreased platelet stickiness – Ajoene, a self-condensation product, is as potent as aspirin as an anti-coagulant agent, and its activity is enhanced by two breakdown products which are also present in Garlic. (Rose KO, et.al. Neurosurgery 26:880-882, 1990). Garlic also increases fibronolytic activity significantly, dissolving blood clots (Chutani SK and Legnani C) and improving blood flow. Decreased LDL oxidation – 600 mg per day of a Garlic preparation yielding 7.8 mg of alliin for two weeks reduced LDL-oxidation by 34 percent compared to controls. (Phelps S, et.al.)16,17,18,19,20,21,22 Reduced LDL-cholesterol oxidation is associated with a lower risk of developing atherosclerosis and heart disease. 3. Antimicrobial Activity Garlic has been shown to have significant antibacterial, antifungal, anti-helmintic (anti-parasite) and antiviral properties, however, it should not be used as a replacement for antimicrobial or anti-parasite medications.23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39 One intervention trial did show that taking Garlic each day during the winter months reduced the frequency of colds (upper respiratory tract infections) by two-thirds compared to those receiving the placebo.43

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Dosage and Standardized Grade As allicin is considered the parent compound of most of Garlic’s beneficial agents, preparations should be standardized to contain 4,000-5,000 mcg of allicin per dosage. This is approximately the amount contained within one fresh large Garlic clove (4g). As a rule, 10 mg of alliin yields a total allicin potential of 4,000 mcg. Clinical trials have used 600 – 900 mg (delivering 5,000 – 6,000 mg of allicin potential) of Garlic extract per day, in divided doses to obtain a variety of therapeutic outcomes as related to cardiovascular health and the prevention of the common cold. 44

Adverse Side Effects, Toxicity and Contraindications Garlic may cause gastrointestinal irritation, flatulence, and heartburn in sensitive individuals. Some people have slow Phase II sulfation detoxification enzymes in liver, which may produce an intolerance to Garlic consumption. 40 Experimantal and prospective studies reveal that Garlic preparations are very non-toxic in humans and animals. However, when large doses of raw Garlic are ingested, it may cause stomach upset, heartburn, nausea, vomiting, diarrhea, flatulence, facial flushing, rapid heart rate, and insomnia. As Garlic’s active constituents are potent blood thinners (anti-coagulants), Garlic supplements should be avoided prior to surgery, immediately after surgery and childbirth, to prevent excessive hemorrhage and blood loss . 45 In a single case report, an elderly man ingesting 2,000 mg of Garlic (4 cloves) daily for an undetermined period of time, developed a spontaneous epidural hematoma. There was no concurrent intake of any anti-coagulant or anti-inflammatory medication in this case. 46

Drug-Nutrient Interactions Anticoagulant Medications (e.g., Aspirin, Coumadin, Warfarin, Heparin, Plavix Ticlid and Trental): Garlic preparations are known to potentiate the effects of these drugs and may lead to a bleeding disorder and thus, Garlic products should not be combined with these drugs, without the attending physician’s consent and proper monitoring of prothrombin time (INR). 47,48 Saquinavir: Garlic may decrease blood levels of this drug, thus altering the activity and dose requirement for this drug. 49

Garlic preparations may also potentiate the effects of hypolipidemic and antihypertensive medications, helping to lower the dose requirement and side effects of these drugs. 50,51,52

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Boon H and Smith M, Health Care Professional Training Program in Complementary Medicine, Institute of Applied Complementary Medicine Inc., 1997. Sparnins VL, Barany G, Wattenberg LW, Effects of Organosulfur Compounds from Garlic and Onions on Benz(a)pyrene-induced Neoplasia and Glutathione S-transferase Activity in the Mouse, Carcinogenesis 9, 1988, 131-134. Shenoy NR, Choughuley AS, Inhibitory Effect of Diet Related Sulphydryl Compounds on the Formation of Carcinogenic Nirtosamines, Cancer Lett 65, 1992, 227-232. Lin X-Y, Liu JZ, Milner JA, Dietary Garlic Suppresses DNA Adducts Caused by N-nitroiso Compounds, Carcinogenesis 15, 1994, 349-352. Lin X-Y, Liu JZ, Milner JA, Inhibition of 7, 12-dimethylbenz(a)-anthracene Induced Mamary Tumors and DNA Adducts by Garlic Powder, Carcinogenesis 13, 1992, 1847-1851. Ip C, Lisk DJ, Stoewsand GS, Mammary Cancer Prevention by Regular Garlic and Selenium-enriched Garlic, Nutr Cancer 7, 1992, 279-286. Wargovich MJ, Woods C, Eng VWS, Stephens LC, Gray KN, Chemoprevention of Nitrosomethylbenzylamine-induced Esophageal Cancer in Rats by the Thioether, Diallyl Sulfide, Cancer Res 48, 1988, 6872-6875. Amagase H, Milner JA, Impact of Various Sources of Garlic and their Constituents on 7, 12-dimethyl-benz(a)anthracene Binding Tomamary Cell DNA, Carcinogenesis 14, 1993, 1627-1631. Brady JF, Wang MH, Hong JY, et.al., Modulation of Rat Hepatic Microsomal Monooxygenase Enzymes and Cytotoxicity by Diallyl Sulfide, Toxicol Appl Pharmacol 108, 1991, 342-354. Mei X, Lin X, Liu J, et.al., The Blocking Effect of Garlic on the Formation of N-nitrosoproline in Humans, Acta Nutrimenta Sinica 11, 1989, 141-145. Schaffer EM, Liu JZ, Green J, Dangler CA, Milner JA, Garlic and Associated Allyl Components Inhibit N-methyl-N-nitrosourea Induced Rat Mamary Carcinogenesis, Cancer Lett 102, 1996, 199-204. Choy YM, Kwok TT, Fung KP, Lee CY, Effect of Garlic, Chinese Medicinal Drugs and Amino Acids on Growth of Ehrlich Ascites Tumor Cells in Mice, Am J Clin Med 11, 1983, 69-73. Sundaram SG, Milner JA, Impact of Organosulfur Compounds in Garlic on Canine Mamary Tumor Cells in Culture, Cancer Lkett 74, 1994, 85-90. Sundaran SG, Milner JA, Diallyl Disulfide Inhibits the Proloiferation of Human Colon Tumor Cells in Culture, Biochim Biophys Acta 13, 15, 1996, 15-20. Sundaran SG, Milner JA, Diallyl Disulfide Suppresses the Growth of Human Colon Tumor Cell Xenographs in Athymic Nude Mice, J Nutr 126, 1996, 1355-1361. Warshafsky S, et.al., Effect of Garlic on Total Serum Cholesterol: A Meta-analysis, Ann Intern Med 119, 1993, 599-605.

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17. Block E, et.al., Journal of the American Chemical Society 106, 1984, 8295-8296. 18. Rose KO, et.al., Neurosurgery 26, 1990, 880-882. 19. Foushee DB, Ruffin J and Baberjee U, Garlic as a Natural Agent for the Treatment of Hypertension: A Preliminary Report, Cytobios 34, 1982, 145-162. 20. Chutani SK and Bordia A, The Effect of Fried Versus Raw Garlic on Fibrinolytic Activity in Man, Atherosclerosis 38, 1981, 417-421. 21. Legnani C, et.al., Effects of Dried Garlic Preparation on Fibrinolysis and Platelet Aggregation in Healthy Subjects, ArzneimittelForsch 43, 1993, 119-121. 22. Phelps S and Harris WS, Garlic Supplementation and Lipoprotein Oxidation Susceptibility, Lipids 28, 1993, 475-477. 23. Adetumbi MA and Lau BH, Allium Satibum (garlic) – A Natural Antibiotic, Med Hypothesis 12, 1983, 227-237. 24. Koch HP, Garlicin – Fact or Fiction?, Phytother Res 7, 1993, 278-280. 25. Hughes BG and Lawson L, Antimicrobial Effects of Allium Sativum L (Garlic), Allium Ampeloprasum L (Elephant Garlic) and Allium, Cepa L (Onion), Garlic Compounds and Commercial Garlic Supplement Products, Physiother Res 5, 1991, 154-158. 26. Huddleson IF, et.al., Antibacterial Substances in Plants, J Am Vet Med Assoc 105, 1944, 394-397. 27. Cavallito CJ and Bailey JH, Allicin, the Antibacterial Principle of Allium Sativum, I Isolation, Physical Properties and Antibacterial Action, J Am Chem Soc 66, 1944, 1950-1951. 28. Sharma VD, et.al., Antibacterial Property of Allium Sativum Linn: In Vivo and In Vitro Studies, Indian J Exp Biol 15, 1977, 466-468. 29. Elnima El, et.al., The Antimicrobial Activity of Garlic and Onion Extracts, Pharmazie 38, 1983, 747-748. 30. Amer M, Taha M, And Tosson Z, The Effect of Aquenous Garlic Extract on the Growth of Dermatophytes, Int J Dermatol 19, 1980, 285-287. 31. Moore GS and Atkins RD, The Fungicidal and Fungistatic Effects of an Aqueous Garlic Extract on Medically Important Yeast-like Fungi, Mycologia 69, 1977, 341-348. 32. Sandhu DK, Warraich MK, and Singh S, Sensitivity of Yeasts Isolated from Cases of Vaginitis to Aqueous Extracts of Garlic, Mykosen 23, 1980, 691-698. 33. Prasad G and Sharma VD, Efficacy of Garlic (Allium Sativum) Treatment Against Experimental Candidiasis in Chicks, Br Vet J 136, 1980, 448-451. 34. Hunan Hospital, Garlic in Cryptococcal Meningitis: A Preliminary Report of 21 Cases, Chin Med J 93, 1980, 123-126. 35. Fromtling R and Bulmer G, In Vitro Effect of Aqueous Extract of Garlic (Allium Sativum) on the Growth and Viability of Cryptococcus Neoformans, Mycologia 70, 1978, 297-405. 36. Vahora SB, Rizwan M, and Khan JA, Medical Uses of Common Indian Vegetables, Planta Medica 23, 1973, 281-393. 37. Bastidas GJ, Effect of Ingested Garlic on Necator Americanus and Ancylostoma Canium, Am J Trop Med Hyg 18, 1969, 920-923. 38. Nagai K, Experimental Studies on the Preventive Effect of Garlic Extract Against Infection with Influenza Virus, Jpn J Infec Dis 47, 1973, 321. 39. Wever ND, et.al., In Vitro Virucidal Effects of Allium Sativum (Garlic) Extract and Compounds, Planta Medica 58, 1992, 417-423. 40. Murray MT, The Healing Power of Herbs (2nd edition), Prima Publishing, 1995. 41. Natural Products Encyclopedia. www.consumerslab.com: Garlic 42. Bordia A. Garlic and coronary heart disease. The effects of garlic extract therapy over three years on the reinfarction and mortality rate. Dtsch Apoth Ztg. 1989; 129 (suppl 15): 16-17. 43. Josling P. Preventing the common cold with a garlic supplement: a double-blind, placebo-controlled survey. Adv Ther. 2001; 18 (4): 189-193. 44. Healthnotes, Inc.2001 www.healthnotes.com: Garlic. 45. Natuarl Products Encyclopedia. www.consumerslab.com: Garlic. 46. McNeill JR. Interactions between herbal and conventional medicines. Can J CME. 1993; 11 (12): 97-110 47. Kiesewetter H et al. Effect of garlic on platelet aggregation in patients with increased risk of Juvenile Ischaemic Attack. Eur J Clin Pharmacol 1993;45(4):333-6 48. Rose KD, Croissant PD, Parliament CF, Levin MB. Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic ingestion: a case report. Neurosurgery. May 1990;26(5):880-2 49. Piscitelli SC, Bursein AH, Welen N, Gallicano KD, Falloon J. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clinical Infectious Diseases. Jan 15 2002;34. Published on line Dec 5 2001. Accessed at: http://www.journals.uchicago.edu/CID/journal/issues/v34n2/010586.abstract.html 50. Steiner M et al. A double-blind crossover study in moderately hypercholesterolemic men that compared the effect of aged garlic extract and placebo administraion on blood lipids. Am J Clin Nutr 1996;64(6):866-70 51. Koscielny J et al. The antiatherosclerotic effect of allium sativum. Atherosclerosis May 1999;144(1):237-49 52. Fogarty M. Garlic’s potential role in reducing heart disease. Br J Clin Pract 1993;47(2):64-5

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Ginger General Features Ginger is native to southern Asia and has been used as food and medicine in many areas of the world for millennia. 16 The knotted and branched rhizome, commonly called the “root” is the portion of Ginger used for culinary and medicinal purposes. 1,13,16 Ginger’s modern day use dates back to the early 1980’s when a scientist named D. Mowrey noticed that the Ginger-filled capsules reduced his nausea during an episode of flu. 16

Principle Active Constituents The rhizome of the plant contains approximately 1 – 4% volatile oils, which are the aromatic constituents (zingiberene and bisabolene) that are responsible for Ginger’s characteristic odor and taste. Its more pungent constituents are known as gingerols and shogaols, which are the agents credited with Ginger’s anti-nausea and anti-vomiting effects. The gingerols are a collective group of aromatic ketones. The pungent principles are thought to be the most pharmacologically active components of Ginger.1,17

Clinical Application and Mechanism of Action 1. Motion Sickness, Nausea, and Vomiting Ginger is thought to act directly on the intestinal system to reduce nausea. 18 This is in contrast to anti-nausea medications that act on the brain and inner ear.19 Its action has been shown to partially inhibit the excessive gastric motility characteristics of motion sickness. 13 Several studies have demonstrated that Ginger supplementation can be effective to control motion sickness, nausea, and vomiting. In one study involving women with morning sickness, 250 mg of Ginger powder was taken four times per day and was shown to be very effective in a trial of 27 patients, during the early stages of pregnancy. However, several animal studies have demonstrated that Ginger can cause mutagenic changes in vitro and thus, Ginger is contraindicated during pregnancy within the traditional Chinese medical model and as reported in the German Commission E Monographs. Its safety during pregnancy is still in question. Current thinking suggests that a pregnant woman should not exceed a daily dose of 1,000 mg of Ginger, used for a short time interval, and she must seek clearance from her attending physician prior to starting this supplementation regime. 1,2,3,4,5 Other studies have also provided convincing evidence of Ginger’s anti-nausea (anti-emetic) effects. A double-blind placebo-controlled trial of 79 Swedish naval cadets showed that 1 gm of Ginger could decrease nausea and vertigo at sea. 20,4 Another double-blind trial aboard a ship showed that Ginger was equally as effective as various medications (cinnarizine, cinnarizine with domeperdone, cyclizine, dimehydrinate with caffeine, meclozine with caffeine, and scopolamine) in controlling seasickness, in a large study of 1,489 individuals. 21 In another study of 60 passengers aboard a ship, 500 mg of Ginger taken every 4 hours was shown to be as effective as the drug dimenhydrinate at 100 mg, every 4 hours, as a means to control nausea and vomiting (seasickness). 22 A study comparing Ginger to the drug dimenhydrinate, and a placebo, also showed that Ginger was an effective means to reduce nausea and vomiting. 2,23 In general, most, but not all, studies have shown Ginger to be effective as an anti-nausea and anti-vomiting intervention.13,14,15,16 It has even been used successfully in some cases to reduce nausea and vomiting in patients recovering from surgery and patients receiving chemotherapy treatment. 24,25

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2. Anti-inflammatory Effects in Arthritis Ginger has been shown to posses anti-inflammatory properties and has been effective in several small studies to control pain and inflammation in patients with a variety of arthritic and musculoskeletal inflammatory conditions. 10,26 Experimental investigations suggest that Ginger inhibits the synthesis of pro-inflammatory prostaglandins, by inhibiting both the cyclo-oxygenase and 5-lipoxygenase enzymes. 7,8,9,10 It also has antioxidant properties and contains protease enzymes, which may add to its anti-inflammatory properties. 13 In a study of 56 patients (28 with rheumatoid arthritis, 18 with osteoarthritis and10 with muscular discomfort), Ginger supplementation was effective in reducing pain and inflammation in three-quarters of the arthritis patients and all of the patients with muscular discomfort. No adverse side effects were reported in these patients who were followed for up to 2.5 years. 10 Experimental evidence is strong to illustrate the anti-inflammatory activities of Ginger. 1,2,3,4,5 An interesting side note is that in contrast to anti-inflammatory drugs (aspirin, ibuprofen, COX-2 inhibitors and other non steroidal anti-inflammatory medications) that are known to cause erosion and ulceration (sometimes internal bleeding) of the intestinal tract, Ginger has been shown to protect the stomach from the damaging effects of alcohol, non steroidal anti-inflammatory drugs and, may help prevent peptic ulcers. 27 3. Migraines Ginger may also help to prevent the recurrence of migraines due to its anti-inflammatory and anti-platelet aggregation properties.1 However, greater substantial evidence exists for the herb feverfew as a daily preventive supplement for migraine prevention (see Feverfew in this document).

Dosage and Standardized Grade 1. Motion sickness, Nausea and Vomiting: 1-2 gms per day of dry powdered Ginger or Ginger capsules (e.g., 500 mg, 2â&#x20AC;&#x201C;4 times per day) for nausea, vomiting, motion sickness has been used successfully. This is equivalent to approximately 10 grams or one-third of an ounce of fresh Ginger root (1/4 inch slice). The most current research suggests that Ginger should be standardized to contain at least 5% gingerols per dose and/or 4% volatile oils. 13,14,15,16

2. Arthritis and Musculoskeletal Inflammatory Conditions: Studies show that if used as a sole anti-inflammatory intervention that the daily dosage can range from 1,000 mg to 4,000 mg per day, based upon the dose required to reduce symptoms. 13,26

Adverse Side Effects, Toxicity and Contraindications Side effects from Ginger supplementation are rare when taken at recommended doses, and include heartburn and intolerance to the taste of Ginger. At 6 gms per day, Ginger may cause GI irritation to an empty stomach due to increased exfoliation of gastric epithelial cells. This could lead to ulcer formation if taken at a high dose for an extended period.13,14,15,16 It is not advisable at this time for pregnant women to use Ginger without their physicianâ&#x20AC;&#x2122;s consent, to reduce symptoms of morning sickness as recent experimental studies have indicated that Ginger may produce mutagenic changes in DNA. 14 In otherwise healthy individuals, Ginger has been shown to be very non-toxic13 Ginger has been shown to inhibit blood coagulation in experimental studies, but no evidence of this effect has been found in humans, as indicated by a number of European studies. 9,28,29

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Drug-Nutrient Interactions Anticoagulant Medications (e.g., Aspirin, warfarin, coumadin, heparin, Plavix, Ticlid, Trental): As test tube experiments show that Ginger may reduce platelet clotting it may potentiate the activity of anticoagulant drugs, although no evidence of an anti-clotting effect for Ginger has been found in humans. Nevertheless, the patientâ&#x20AC;&#x2122;s prothrombin time (INR) should be monitored if Ginger is to be taken concurrently with any anti-coagulant drug, to guard against a potential bleeding disorder. 30,31,32

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Boon H and Smith M, Health Care Professional Training Program in Complementary Medicine, Institute of Applied Complementary Medicine Inc., 1997. Mowrey D and Clayson D, Motion Sickness, Ginger, and Psychophysics, Lancet I, 1982, 655-657. Stewart JJ, et.al., Effects of ginger on Motion Sickness Susceptibility and Gastric Function, Pharmacology 42, 1991, 111-120. Grontved A, et.al., Ginger Root Against Seasickness â&#x20AC;&#x201C; A Controlled Trial on the Open Sea, Acta Otalaryngol 105, 1988, 45-49. Fischer-Rasmussen W, et.al., Ginger Treatment of Hyperemesis Gravidarum, Eur J Obstet Gynecol Reprod Biol 38, 1990, 19-24. Bone ME, et.al., Ginger Root-a New Antiemetic: The Effect of Ginger Root on Postoperative nausea and Vomiting After Major Gynecological Surgery, Anaesthesia 45, 1990, 669-671. Kiuchi F, et.al., Inhibition of Prostaglandin and Leukotriene Biosynthesis by Gingerols and Diaryheptanoids, Chem Pharm Bull 40, 1992, 387-391. Kuichi F, Shibuyu M, and Sankawa U, Inhibitors of Prostaglandin Biosyntheses from Ginger, Chem Pharm Bull 30, 1982, 754-757. Srivastava KC, Isolation and Effects of Some Ginger Components on Platelet Aggregation and Eicosanoid Biosyntheses, Prostaglandin Leurotrienes Med 25, 1986, 187-198. Srivastava KC and Mustafa T, Ginger (Zingiber Officinale) and Rheumatice Disorders, Med Hypotheses 39, 1992, 342-348. Srivastava KC and Mustafa T, Ginger (Zingiber Officinale) in Rheumatism and Muscoloskeltel Disorders, Med Hypotheses 39, 1992, 342-348. Mustafa T and Srivastava KC, Ginger (Zingiber Officinale) in Migraine Headaches, J Ethnopharmacol 29, 1990, 267-273. Murray MT, The Healing Power of Herbs (2nd edition), Prima Publishing, 1995.

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14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.

Healthnotes, Inc.2001 www.healthnotes.com: Ginger Dietary Supplement Information Bureau. www.content.intramedicine.com: Ginger Natural Products Encyclopedia. www.consumerslab.com: Ginger Tyler VE. Herbs of Choice: the Therapeutic Use of Phytomedicinals. Binghampton, NY: Pharaceutical Products Press 1994: 39-42 Holtmann S, Clarke AH, Scherer H, Hohn M. The anti-motion sickness mechanism of ginger. A comparative study with placebo and dimenhydrinate. Acta Otolaryngol (Stockh) 1989;108:168-74 Holtmann S, Clarke AH, Scherer H et al. The anti-motion sickness mechanism of ginger. Acta Otolaryngol 1989;108:168-74 Bradley PR (ed.). British Herbal Compendium, vol 1. Bournemouth, Dorset, UK: British Herbal Medicine Association, 1992:112-4 Schmid R, Schick T, Steffen R et al. Comparison of seven commonly used agents for prophylaxis of seasickness. J Travel Med 1994;1:203-6 Riebenfeld D, Borzone L. Ranomized double-blind study comparing ginger (ZintonaW) and dimenhydrinate in motion sickness. Healthnotes Rev 1999;6:98-101 Tyler VE. Herbs of Choice: The Therapeutic Use of Phytomedicinals. New York, NY: Pharmaceutical Products Press; 1994:p42 Phillips S, Hutchinson S, Ruggier R. Zingiber officinale (ginger) â&#x20AC;&#x201C; An antiemetic for day case surgery. Anaesthesia 1993;48:715-7 Meyer K, Schwartz J, Craer D, Keyes B. Zingiber officinale (ginger) used to prevent 8-Mop associated nausea. Dermatol Nursing 1995;7:242-4 Srivastava KC, Mustafa T. Ginger (Zingiver officinale) in rheymatism and musculoskeletal disorders. Med hypotheses December 1992;39(4):342-8 al-Yahya MA, Rafatullah S, Mossa JS et al. Gastroprotective activity of finger in albino rats. Am J Chinese Med 1989;17:51-6 Srivastava KC. Effects of aqueous extracts of onion, garlic and ginger on platelet aggreagation and metabolism of arachidonic acid in the blood vascular system: in vitro study. Prostaglandins Leukoit Med 1984;13:227-35 Srivastava KC. Effect of onion and ginger consumption on platelet thromboxane production in humans. Prostaglandins Leukot Essent Fatty Acids 1989;35:183-5 Suekawa M et al. Pharmacological studies on Ginger. I. Pharmacological actions of pungent constitutents, (6)-gingerol and (6)shogaol. J Pharmacobiodyn 1984;7(11):836-48 Guh JH et al. Antiplatelet effect of gingerol isolated from zingiber officinalte. J Pharm Pharmacol 1995;47(4):329-32 Bordia A, Verma SK, Srivastava KC. Effect of ginger (Zingiber officinale Rosc.) and fenugreek (Trigonella foenumgraecum L.) on blood lipids, blood sugar and platelet aggregation in patient swith coronary artery disease. Prostaglandins Leukot Essent Fatty Acids. May 1997;56(5):379-84

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Ginkgo Biloba General Features Ginkgo Biloba is a deciduous tree that lives as long as 1,000 years and may grow to a height of 100-122 feet. Extracts from the leaves are used medicinally.1 It is the world’s oldest living tree species, traceable back 300 million years.1,38 Presently, ginkgo is the most wisely prescribed herb in Germany, reaching a total prescription count of over 6 million in 1995. German physicians consider it to be as effective as any other drug treatment for Alzheimer’s disease and other severe forms of memory and mental function decline. 38 Principle Active Constituents Ginkgo flavones  Ginkgolides and bilobalide – terpene molecules unique to ginkgo. Ginkgo Biloba extract is standardized to contain 24 percent flavonoid glycosides, as these molecules represent a convenient analytical reference group. The three major back bone flavonoids include: Quercetin Kaempferol Isorhamnetine It also contains other flavonoid components such as proanthocyanidins. The ginkgolides and bilobalides account for 6% of Ginkgo Biloba Extract.1,2

Clinical Application and Mechanism of Action 1. Age-related Mental Decline and Memory Impairment A large number of well-controlled clinical trials have established that Ginkgo Biloba extract is an effective intervention in the management of Age-related Cognitive Decline (ARCD) and other conditions involving memory loss. A review of this evidence was reported in Lancet in 1992, which noted that of 40 double-blind controlled trials evaluating the efficacy of Ginkgo Biloba Extract, eight of these trials were rated of good quality, involving a total patient population of 1,000 subjects. Seven of the eight studies showed very good results and the authors of the article indicated that the evidence was strong enough to conclude that Ginkgo Biloba Extract is an effective treatment for ARCD. Most studies reported since 1992 have supported this conclusion, both in people with Alzheimer’s disease and other patients with age-related memory impairment. 38 A placebo-controlled study published in the Journal of the American Medical Association in 1997, involving over 300 patients with Alzheimer’s disease, revealed that Ginkgo Biloba Extract significantly improved patient outcomes compared to the placebo group. This was the first North American study using Ginkgo Biloba, which has helped to establish Ginkgo as a credible intervention for Alzheimer’s patients and other cognitive-impaired subjects, in the mind of some members of the medical community. In this study, Ginkgo Biloba Extract taken at 40 mg, three times daily, was shown to stabilize a large number of Alzheimer’s patients, improving the cognitive performance and the social functioning of demented patients during a 6-month to one -year period. 30 A 1998 quantitative analytical review of ginkgo studies, published in the Archives of Neurology, reported that Ginkgo Biloba Extract exhibits a small, but significant effect within a 3 – 6 month treatment course, using 120 – 240 mg per day, on objective measurements of cognitive function in Alzheimer’s disease. According to this review, Ginkgo Biloba Extract has not shown any significant adverse side effects in formal trials, but there are two case reports of bleeding complications (e.g.,sub-dural hematoma) with the use of ginkgo. 31 www.meschinohealth.com

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2. Prevention of Memory Loss and Enhanced Memory in Healthy Subjects Several recent studies have evaluated the ability of ginkgo to prevent age-related memory loss, and to enhance the memory of otherwise healthy young subjects. A 30 day double-blind placebo-controlled study, following 50 healthy men and women (18 – 40 years of age ), demonstrated that 120 mg per day of Ginkgo Biloba Extract resulted in significant improvement in some measures of memory function. A double-blind study of 26 subjects found that a single dose of 120 mg of Ginkgo Biloba Extract improved short-term memory, especially in people over 50 years of age. In a double-blind placebo-controlled crossover trial involving 20 individuals aged 19 – 24 years, a one time dose of Ginkgo Biloba Extract at 120, 240, or 360 mg resulted in improvement of mental-performance, most dramatically in one test that measured ability to rapidly perform attention-related tasks. A smaller trial involving eight subjects (25 – 40 years of age) found some improvement in short-term memory with a single dosing of Ginkgo Biloba Extract at 60 mg, but not at lower levels of intake. However, not all studies with younger patients have shown an improvement in memory function and larger, more long-term trials are required before Ginkgo can be recommended with confidence for this application. 38 Mechanism of Action Experimental evidence has suggested that the active constituents in Ginkgo Biloba are able to improve memory and other aspects of cognitive function via the following actions: Decreased Platelet Aggregation – Due to its antioxidant effects, increased synthesis of prostacyclin and antagonism of platelet-activating factor (PAF), Ginkgo Biloba Extract has been shown to improve blood flow to deeper centers of the brain, allowing a greater concentration of nutrients to reach these brain cells. This appears to have important considerations in cases of cognitive impairment due to cerebral vascular insufficiency. Decreased Lipid Peroxidation of Cellular Membranes of Red Blood Cells (which carry oxygen) and Nerve Cells (enhancing depolarization capacity and transmission of impulses) - Brain cells contain the highest percentage of unsaturated fatty acids in their membranes than any other cells in the body. This makes them extremely susceptible to free radical damage as unsaturated fatty acids contain double bonds, which are easily broken by free radicals in search of an electron. Ginkgo Biloba Extract, through its antioxidant capabilities, has been shown to prevent free radical damage to these structures, blocking lipid peroxidation and preserving the integrity of nerve cell membranes. This may help preserve or improve the transmission of nerve impulses from one nerve cell to the next, enabling better communication to occur among brain cells. Improves Synthesis and Turnover of Brain Neurotransmitters, and Normalizes Acetylcholine Receptors in the Hippocampus (the area of the brain most affected by Alzheimer’s disease) – Evidence exists to show that Ginkgo Biloba Extract can enhance the synthesis of the memory chemical acetylcholine, and improve its ability to relay important chemical signals to other nerve cells in key areas of the brain that are affected in Alzheimer’s disease, and ARCD. Vasodilation Action – Ginkgo Biloba Extract has been shown to cause the release of endothelium-derived relaxing factor (EDRF) and prostacyclin (a beneficial prostaglandin). The release of these bioactive agents within the body results in increased blood circulation and nutrient delivery to brain cells. 3 - 21 Direct Stimulation of Nerve Cell Activity – Recent evidence suggests that like other drugs used for the treatment of dementia, Ginkgo Biloba Extract appears to directly stimulate nerve cell activity and in various ways protects nerve cells from further injury. 38

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1. Senile Macular Degeneration and Diabetic Retinopathy Preliminary studies indicate that Ginkgo Biloba Extract may be beneficial in the management of macular degeneration and diabetic retinopathy. 22, 38 Ginkgoâ&#x20AC;&#x2122;s antioxidant properties and its ability to improve blood flow through the tiny blood vessels in the macular region of the eye, may be of value in preserving vision in these patients. 22 Other synergistic nutrients for this condition include the antioxidants, Vitamin E, Vitamin C, Beta-carotene and zinc, the herbal agent bilberry, and the accessory nutrient grape seed extract (see details in related sections of this document). 2. Peripheral Artery Insufficiency (i.e., intermittent claudication due to atherosclerosis) Due to its ability to improve microcirculation, Ginkgo Biloba Extract has been shown to improve blood flow, and reduce pain (pain-free walking distance), in at least 10 studies involving patients with peripheral vascular insufficiency. 23 A review the American Journal of Medicine (2000) indicates that eight double-blind placebo-controlled trials, provide evidence that Ginkgo can significantly increase pain-free walking distance in these patients. 38 3. Altitude Sickness Exposure to high altitudes and cold conditions can cause vertigo, insomnia, shortness of breath, headache, as well as pain and numbness in the extremities. A single double-blind study of 44 mountain climbers demonstrated that 160 mg per day of Ginkgo Biloba Extract helped prevent many of these symptoms upon expedition in the Himalayan mountain range. 38 4. Vertigo (dizziness) 70 patients suffering from vertigo were given 160 mg of Ginkgo Biloba Extract daily or a placebo for three consecutive months. Results showed that the group given Ginkgo had a 47% recovery rate as compared to 18% in the placebo group. 38 5. Premenstrual Syndrome A single study showed that 160 mg of Ginkgo Biloba significantly reduced major symptoms of PMS, especially breast pain and emotional disturbances, compared to placebo, in a two-month trial involving 143 women, who were 18â&#x20AC;&#x201C;45 years of age. 38 6. Male Impotence Due to its ability to increase microcirculation of peripheral blood vessels Ginkgo Biloba Extract has been use successfully in a number of small trials as a treatment for male impotence resulting from impaired blood flow (e.g., diabetes and atherosclerosis). 29 It may also reveres the side effects of male impotence and failure to reach orgasm, associated with the use of certain antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRI), according to one preliminary trial. 38

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Dosage and Standardized Grade The standardized grade of Ginkgo Biloba Extract is 24 percent flavone glycosides, and 6 percent terpenes or ginkgolides. As a rule, 40 mg tablets are most popular. The following daily dosages are commonly used: 1. Early memory loss and signs of impaired mental cognition: 40 mgs, 2-3 times per day 2. General prevention of vascular insufficiency and brain function: after 40 to 50 years of age – 40 mg, once per day 3. Peripheral artery disease: 40 mg, 3-4 times per day 4. Prevention of altitude sickness: 40 mg, 4 times per day 5. PMS: 80 mg, twice per day 6. Macular degeneration: 40 mg, 3 –4 times per day 7. Vertigo (of non-organic origin): 160 mg, twice per day

1,2,22,29,38

Adverse Side Effects, Toxicity and Contraindications Ginkgo Biloba Extract is considered to be relatively safe. Extremely high doses have been given to animals for extended periods without evidence of toxicity or untoward side effects. Of the nearly 10,000 patients followed in various ginkgo trials thus far, reports of side effects have been few, and include gastrointestinal discomfort, headaches, dizziness, and allergic skin reactions. However, Ginkgo Biloba Extract is a proven anticoagulant and through this action, it may increase the risk of internal bleeding in the brain and other cranial regions. To date, there have been two case reports linking the use of Ginkgo Biloba to bleeding disorders, including a patient presenting with a subdural hematoma (bleeding in the skull) and another with hyphema (spontaneous bleeding in the iris chamber). As such, ginkgo should not be used by those with known bleeding disorders (e.g., hemophilia), or during the period before or immediately after surgery, and prior to labor or after delivery. 29, 31 32, 38 To avoid possible dizziness some authorities suggest that one should limit the single dose of Ginko Biloba Extract to 40 mg tablets. To avoid insomnia produced by the vasodilation effect of Ginko Biloba Extract, do not take it at night. It is best to take it in divided doses in the morning, at lunch, mid afternoon and/or early evening. 29

Drug-Nutrient Interactions 1. Anticoagulants – Ginkgo is known to potentiate the effects of anticoagulant drugs and bleeding disorders in the brain and cranial vault have been reported in humans. As such, Ginkgo should not be taken concurrently with anticoagulants, including aspirin, coumadin, warfarin, plavix, ticlid, trental etc. 32,33,34,35,38 2. Non Steroidal Anti-Inflammatory Drugs (NSIADs) – Ginkgo may increase the risk of bleeding disorders associated with the use of NSAIDs, and thus should not be taken concurrently with these medications. 36 3. Monoamine Oxidase Inhibitors ( MAO- inhibitors) – Ginkgo may potentiate the action of MAO-inhibitor antidepressant drugs, and thus should not be taken concurrently with these medications. 37

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

DeFeudis FV (ed.), Ginkgo Biloba Extract (Egb 761): Pharmacological Activities and Clinical Application, Elsevier, Paris, 1991. Funfgeld EW (ed.), Rokan (Ginkgo Biloba): Recent Results in Pharmacology and Clinic, Sringer Verlag, NY, 1988 Kleijenen J, Knipshcild P. Ginkgo Biloba. Lancet 1992;340:1136-9 Kleijenen J, Knipschild P. Ginkgo Biloba for cerebral insufficiency. Br J Clin Pharmacol 1992;34:352-8 Schaeffler VK, Reeh PW. Double-blind study of the hypoxia-protective effect of a standardized ginkgo biloba preparation after repeated administration in healthy volunteers. Arzneimittel-Forsch 1985;35:1283-6 Chatterjee SS, Gabard B. Studies on the mechanism of action of an extract of ginkgo Biloba, A drug for the treatment of ischemic vascular diseases. Naunyn-Schmiedeberg’s Arch Pharmacol 1982;320(R52) Le Poncin et al. Effect of ginkgo biloba on changes induced by quantitative cerebral microembolization in rats. Arch Int Pharmacodyn Ther 1980;243:-44 Karcher L, Zagerman P, Kriedlstein J. Effect of a n extract of ginkgo biloba on rat brain energy metabolism in hypoxia. NaunynSchmiedeberg’s Arch Pharmacol 1984;327:31-5 Koltai M et al. Platelet activating factor (PAF): A review of its effects, antagonists and ossible future clinical implications (Part I). Drugs 1992;42(1):9-29 Koltain M et al. Platelet activating factor (PAF): A review of its effects, antagonists and possible future clinical implications (Part II). Drugs 1991 42(2):174-204 Schmidt U, Rabinovici K, Lande S. Einfluss eines ginkgo biloba specialekstraktes auf doe befomdlickeitbeizerebraler onsufficiziens. Muench Med Wochenschr 1991;133(suppl I):S15-18 Bruchert E, Heinrich SE, Ruf-Kohler P. WirksamkeitvonL11370bei. Alterenpatienten mit himleistungsschwache: multizentrishe doppelblindstudie des fachverbandes deutscher allegemeinaezte. Muench Med Wochenschr 1991;133(Suppl 1):S9-114 Meyer B. Etude multicentrique randomisee a double insu face au placebo due traitment des acouphenes per l’extrait de ginkgo biloba. Presse Med 1986;15:1562-4 Taillandier J et al. Traitment des troubles du vidillissement cerebral pal L’extrait ginkgo biloba. Presse Med 1986;15:1583-7 Haguenauer JP et al. Traitment des troubles de l’equilibre par l’extrait ginkgo biloba. Presse Med 1986;p1569-72 Vorberg G, Schmidt U, Schenk N. Wirsamkeit eines neuen ginkgo biloba ekstraktes bei 100 patienten mi zerabraler insuffiziens. Herg Geffasse 1989;9:936-41 Eckmann F, Himleistungsstorungen – Behandlung mit ginkgo biloba extract. Forsch Med 1990;108:557-60 Wesnes K et al. A double-blind placebo-controlled trial of tanakan in the treatment of idiopathic cognitive impairment in the elderly. Hum Psychopharmacol 1987;2:159-69

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19. Gessner B, Voelp A, Klasser M. Study of the long-term action of a ginkgo biloba extract on vigilance and mental performance as determined by means of quantitative measurements. Arzneimittel Forsch 1985;35:1459-65 20. Hofferberth B. Effect of ginkgo biloba extract on neurophysiological and psychometric measurement sin patients with cerebroorganic syndrome â&#x20AC;&#x201C; A double-blind study versus placebo. Arzneimittel-Forsch 1989;39:918-22 21. Hindmarch I, Subhan Z. The psychopharmacological effects of ginkgo biloba extract in normal healthy volunteers. Int J Clin Pharmacol Res 1984;4:89-93 22. Lanthony P, Cosson JP. Evolution de la vision des couleurs dand la retinopathie diabetique debutante traitee par extrait de ginkgo bilova. J Fr Ophtalmol 1988;11:671-4 23. Schneider B. Ginkgo biloba extract in peripheral arterial diseases: Meta-analysis of controlled clinical studies. Arzneimittel-Forsch 1992;42:428-36 24. Thomson GL et al. A clinical trial of ginkgo biloba extract in patients with intermittent claudication. Int Angiol 1990;9:75-8 25. Saudreau F et al. Efficacy of ginkgo biloba extract in the treatment of lower limb obliterative artery disease at stage III of the fontaine classification. J Mal Vasc 1989;14:177-82 26. Rudofsky VG. The effect of ginkgo biloba extract in cases of arterial occlusive disease: A randomized placebo controlled doubleblind crossover study. Forsch Med 1987;105:397-400 27. Bauer U. Ginkgo biloba extract in the treatment of arteriopathy of the lower limbs: Sixty-five week study. Presse Med 1986;15:1546-9 28. Bauer U. Six-month double-blind randomized clinical trial of ginkgo biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency. Arzneimittel Forsch 1984;34:716-21 29. Murray MT. The Healing Power of Herbs (2nd ed.) Prima Publishing 1995 30. LeBars PL et al. A placebo-controlled double-blind randomized trial of an extract of ginkgo biloba for dementia. North American EGB Study Group. JAMA 1997;278(16):1327-32 31. Oken BS et al. The efficacy of ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurology 1998;55(11):1409-15 32. Braquet P. Anti-anaphylactic properties of BN 52021: A potent platelet activating factor antagonist. Advances in Experimental Medicine and Biology 1987;215:215-33 33. Braquet P et al. Ethnopharmacology and the development of natural PAF antagonists as therapeutic agents. J Ethnopharmacol. April 1991;32(1-3):135-9 34. Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of ginkgo biloba extract. N Engl J Med. April 10 1997;336(15):p1108 35. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology. June 1996;46(6):1775-6 36. Kleijnen J et al. Ginkgo biloba. Lancet 1992;340(8828):1136-9 37. White HL et al. Extracts of ginkgo biloba leaves inhibit monoamine oxidase. Life Sci 1996;58(16):1315-21 38. Natural Product Encyclopedia. www.consumerslab.com:Ginkgo Biloba

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Ginseng General Features Asian Ginseng is a member of the Araliaceae family, which also includes the closely related American Ginseng and less similar Siberian Ginseng. The root of the plant is used for medicinal purposes, preferably from plants older than six years of age. There are three distinct types of Ginseng in the commercial market: 1. Panax Ginseng (Asian, Chinese, Korean Ginseng) 2. Siberian Ginseng (Eleuthero Ginseng) 3. American Ginseng (Panax quinquefolius, Canadian Ginseng) Panax Ginseng is the most widely used and most extensively studied species of Ginseng. Primarily the roots of the plant are used for medicinal purposes with standardized extracts available containing up to 5 percent ginsenoside content, in a high quality root extract product. Ginsenosides, which are triterpenoid saponins, vary between Panax, and American Ginseng. There are at least 13 different ginsenosides, some occurring more in one type of Ginseng than the other, or not at all as is sometimes the case. At this time, insufficient research exists to determine which type of Ginseng or ginsenoside complex is best suited to treat or prevent specific health conditions. However, studies reveal that the most consistent and reliable results occur when using high-quality extracts, standardized for active constituents. Siberian Ginseng contains seven eleutherosides (A-G), not ginsenosides.

Principle Active Constituents 1. Triterpenoid Glycosides (saponins), which are known as ginsenosides, and include: RO, Rb1, Rb2, Rb3, Rc, Rd, Re, Rf, 20-gluco-Rf, Rg1, and Rg2, R91, Ra2, Rh1, Rh4. These are found in Korean and American Ginseng only. Korean Ginseng contains significant concentrations of Rb1, Rb2, Rc, Re and Rg1. American Ginseng contains primarily Rb1 and Re, and does not contain Rb2, Rf or in some instances Rg1. 2. Eleutherosides (A-G) â&#x20AC;&#x201C; found only in Siberian Ginseng Eleutherosides are a collection of specific coumarins, lignans, phenylpropanoids, polysaccharides, sterols, triterpenes and miscellaneous compounds.1, 2 Siberian Ginseng is considered to be a milder type of Ginseng compared to Panax Ginseng 2

Clinical Application and Mechanism of Action As there is considerable overlap in the clinical use of the three types of Ginseng they are presented here collectively: 1. Adaptogen There is some suggestion that Panax Ginseng has the ability to increase both ascorbic acid and cholesterol stores in the adrenal gland, while decreasing the 17-ketosterol and increasing ACTH excreted in the urine. An increase in plasma ACTH and corticosteroids following administration of Ginseng is well documented. These features may explain its use as a substance to help restore homeostasis under periods of stress and its use as an anti-fatigue 3, 4, 5, 6, 7, 8 supplement and general tonic.2, An adaptogen is thought to work in a non-specific manner, helping to re-establish balance and homeostasis at a physiological level.

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In Russia, Siberian Ginseng is used by deep sea divers, mine and mountain rescue workers, soldiers, factory workers, cosmonauts, and athletes primarily for its perceived ability to increase endurance and promote the bodyâ&#x20AC;&#x2122;s ability to tolerate stressful conditions.9 Studies with Panax Ginseng suggest that anti-fatigue effects may be mediated by stimulation of nerve impulses, direct affect on the hypothalamus-pituitary-adrenal axis, glycogen sparing in exercising muscle, and improved oxygen utilization. In animal studies, lower lactic acid and pyruvic acid levels in the blood were noted upon exercise, compared to the placebo group â&#x20AC;&#x201C; indicating a glycogen â&#x20AC;&#x201C; sparing effect through increased fatty acid oxidation during exercise.1, 2 These effects may be beneficial for endurance athletes and weight loss patients employing an exercise program. 10, 11, 12 A few studies have noted a performance-enhancing effect with the use of Panax Ginseng.12 2. Immunostimulating Effects In general, all three types of Ginseng demonstrate an ability to enhance immune system function. In particular Panax Ginseng appears to enhance antibody response, increase natural killer cell activity, stimulate macrophage activity, stimulate lymphocytes in vitro, stimulate the reticuloendothelial system, increase proliferation of T cells and B cells, and increase the production of interferon. 1, 2, 13, 14, Both Panax Ginseng and Siberian Ginseng have demonstrated enhanced immune function in placebo-controlled, double blind studies, including significantly higher antibody litres and natural killer activity levels in the Panax Ginseng study.15, 20 However, it should be noted that at high doses there is in vitro evidence that Ginseng may inhibit some immune functions, including lymphocyte proliferation.16, 17, 18, 19 Based upon the available research in this area, some authorities suggest that Ginseng supplementation is appropriate for chronic fatigue syndrome, HIV-infection, to combat infections or to help restore immune function from a compromised state.1, 2, 21 3. Female Reproductive Tissue Support Ginsenosides exert an estrogen-like action on the vaginal epithelium, which can prevent atrophic vaginal changes associated with menopause.22 It should be noted that breast tenderness can be a side effect of Ginseng use in women, which disappears when Ginseng is discontinued.23 N.B.: Black cohosh also maintains the vaginal epithelium without risk of this side effect (see Black Cohosh in this document) 4. Male Reproductive Tissue Support Panax Ginseng has been shown to increase sperm count and motility in men, as well as increasing plasma total and free testosterone, dihydrotestosterone, follicle stimulating hormone and leutinizing hormone. 24 An in vitro study suggests that it may relax the corpus cavernosum by releasing nitric oxide, which facilitates an erection. 25, 31 5. Type II Diabetes Panax and American Ginseng have demonstrated an ability to reduce fasting and post prandial blood glucose levels in type II diabetic patients. Its effects may alter the need or the dose of hypoglycemic medications and therefore, should only be used in this instance with knowledge of the attending physician.26, 27 6. Protection from Radiation Damage In experimental studies Ginseng has been shown to offer some protection against harmful radiation. 2 In particular, Siberian Ginseng is noted for its ability to provide protection in animals subjected to both single exposure and longterm x-ray radiation. Rats given the Siberian Ginseng have been shown to survive twice or three times as long compared to rats not given Siberian Ginseng, in radiation studies.28, 29

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Although no human trials in North America are available, Siberian Ginseng is thought to be useful as an adjunctive treatment for those undergoing radiation treatment for a variety of cancerous conditions. 1 Preliminary studies in Russia indicate that the use of Siberian Ginseng in people undergoing chemotherapy and radiation therapy for cancer has been of benefit in reducing side effects and aiding in bone marrow recovery. 30 N.B.: Note that Reishi Mushroom Extract and Astragalus are also known to reduce side effects from radiation treatment (see details in related sections of this document)

Dosage and Standardized Grade 1. Immune Stimulation (Chronic Fatigue Syndrome, weakened immune status):100-500 mg per day in divided doses (std to 4-8 percent ginsenoside content) – Panax Ginseng is considered to be the best choice for this purpose. 1, 2 For Siberian Ginseng – consider 100-200 mg per day in divided doses (20:1 extract)1 2. Weight Loss or Ergogenic Athletic Aid: 200 mg per day in divided doses (Panax Ginseng std to 4-8 percent ginsenoside content)32 3. General Anti-Stress Support: 100-200 mg per day (Panax Ginseng std to 4-8 percent ginsenoside content)33 4. Postmenopausal Support for Women: 100-500 mg per day in divided doses. (std to 4-8 percent ginsenoside content – Panax Ginseng)1 5. Male Infertility and Erectile Dysfunction: 100-500 mg per day in divided doses (std to 4-8 percent ginsenosides content – Panax Ginseng)1 6. Type II Diabetes and Syndrome X: 200 mg per day (100 mg, twice daily with meals) (std to 4-8 percent ginsenoside content – Panax Ginseng)1 N.B. Must consult the attending physician prior to Ginseng use in these cases 7. Adjunct to Chemotherapy or Radiation Treatment: Siberian Ginseng 300-400 mg per day in divided doses (20:1 extract)21 N.B. Long-term Ginseng supplementation usually involves a cycling effect with a two to three week non-use period, every 30 to 60 days1, 2

Adverse Side Effects and Toxicity 1. Panax Ginseng: The most common side effects include insomnia,diarrhea, skin eruptions, vaginal bleeding and breast tenderness. “Ginseng Abuse Syndrome” may exist in which over stimulation from Ginseng may cause hypertension, restlessness, nervousness, euphoria, insomnia, diarrhea and skin eruptions – from overuse. This description has been criticized due to the fact that most studied subjects also ingested high levels of caffeine.1 2. Siberian Ginseng: The most common side effects include insomnia, irritability, melancholy, anxiety Patients with rheumatic heart disease have reported pericardial pain, headaches, palpitations, and elevations in blood pressure.2 3. American Ginseng: The most common side effects include insomnia and irritability21

Contraindications and Precautionary Measures for all Forms of Ginseng Ginseng should not be given in the following cases: Hypertension Acute illness and fever Insomnia – (not to be taken at night by these individuals) Asthma

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Emphysema Cardiac disorders Patients suffering from mania, schizophrenia Insulin dependent diabetes mellitus Fibrocystic Breast Desease1,2,33 Caution must be exercised when administering Ginseng supplements: to type II diabetics as an adjunct to chemotherapy or radiation therapy1, 2, 33 at the same time as caffeine-containing beverages due to potential over stimulation effects. 21, 38

Drug-Nutrient Interactions Ginseng is contraindicated in patients on the following medications: 1. Drugs affecting brain neurotransmitters, especially monoamine oxidase inhibitors (MAO-inhibitors): Ginseng can potentiate the drug effect leading to headache, euphoria, Central Nervous System stimulation and tremors, mania symptoms.34 2. Phenobarbital 5 3. Warfarin – Ginseng has been shown to antagonize the clotting effects of warfarin, altering the prothrombin time or INR.35, 36 4. Ticlopidine – a platelet-inhibiting drug. Similar effects on clotting due to Ginseng intake may counter effect of this drug, used by patients with intermittent claudication or to prevent stroke.21 5. Digoxin or Digitalis – Ginseng has been shown to elevate serum levels of digoxin, potentiating the drugs effect on the heart.35, 37 This occurred in one case and no clear relationship exists, but caution should be exercised. 37 N.B.: Several studies performed in various countries have repeatedly shown that a high percentage of commercially available Ginseng supplement products do not meet the label claim for the amount of Ginseng, ginsenosides or active constituents they claim to possess. Furthermore, several cases of athletes consuming adulterated Ginseng products (i.e. ephedrine, pseudoephedrine) have occurred in which athletes have incurred doping charges against them and disqualification.39, 40, 41, 42, 43 As such, it is recommended that Ginseng products used for the intended purposes mentioned here, have available to health practitioners and consumers, “certificate of analysis” on each new batch of product formulated, to ensure potency and purity of the product.39-43 High quality Ginseng raw materials are expensive and thus may encourage some manufacturers to use inferior grades or to adulterate their products with cheaper ingredients (e.g., ephedra, caffeine) to simulate the anti-fatigue, performance-enhancing effects of Ginseng. Use with caution with patients on anti-asthmatic and antihypertensive drugs, as Ginseng may potentiate the effects of these drugs. As such, appropriate patient monitoring under these conditions is recommended.11,19

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19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.

Boon H, Smith M. The Botanical Pharmacy. Quarry Health Books 2000:180-99 Murray M. The healing Power of Herbs. Prima Publishing 1995:265-79, 314-20 Chang H, But P. Pharmacology and Applications of Chinese Materia Medica. World Scientific, Philadelphia PA 1986:p773 Teegarden R. Chinese Tonic Herbs. Japan Publishing Inc NY 1985:p197 Bensky D, Gamble A. Chinese Herbal Medicine Materia Medica. Eastland Press, Seattle WA 1986:p556 Fulder SJ. Ginseng and the hypothalmic-pituitary control of stress. American Journal of Chinese Medicine 1981;0:112-8 Hiai S, Yokoyama H Oura H. Features of ginseng saponins-induced corticosterone secretion. Endocrinologia Japonica 1979;26:737-40 Hiai S, Yokoyama H, Oura H, Kawashima Y. Evaluation of corticosterone secretion-inducing effects of ginsenosides and their prosapogenins and sopogenins. Chemical and Pharmaceutical Bulletin 1983;31:168-74 Fulder S. The drug the builds Russians. New Science 1980;21:576-9 Avakian EV et al. Effect of panax ginseng on energy substrates during exercise. Fed Proc 1980;39:287 Avakian EV et al. Effect of panax ginseng extract on erergy metabolism during exercise in rats. Planta Medica 1984;50:p151 McNaughton L et al. A comparison of Chinese and Russian ginseng as ergogenic aids to improve various factets of physical fitness. Int Clin Nutr Rev 1989;9:32-7 See DM, Broumand N, Sahl L, Tilles JG. In vitro effects of Echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients. Immunopharmacology 1997;35(3):229-35 Liu J, Wang S, Liu H et al. Stimulatory effect of saponins from Panax ginseng on immune function of lymphocytes in the elderly. Mechanisms of Ageing and Development 1995;83(1):43-53 Bohn B, Nebe CT, Birr C. Flow-cytometric studies with Eleutherococcus senticosus extract as an immunomodulatory agent. Arzneimittelforschung 1987;37(10):1193-6 Jie YH, Cammisuli S, Baggiolini M. Immunomodulatory effects of Panax ginseng C.A. Meyer in the mouse. Agents and Actions 1984;15:386-91 Yun TK, Yun YS, Han IW. Anti-carcinogenic effect of long-term oral administration of newborn mice exposed to various chemical carcinogens. Cancer Detection and Prevention 1983;6:515-25 Yeung HW, Cheung K, Leung KN et al. Immunopharmacology of Chinese medicine. I. Ginseng-induced immuno suppression in virus infected mice. American Journal of Chinese Medicine 1982;10:44-54 Kang M, Yoshimatsu H, Oohara A et al. Ginsenoside Rg1 modulates ingestive behavior and thermal response induced by interleukin-1 beta in rats. Physiology and Behaviour 1995;57(2):393-6

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38. Scaglione F, Cattaneo G, Alessandria M, Cogo R. Efficacy and safety of the standardized Ginseng extract G115 for potentiating vaccination against the influencza syndrome and protection against the common cold. [Published erratum appears in Drugs Exp Clin Res 1996;22(6):p338]. Drugs Under Experimental and Clinical Research 1996;22(2):65-72 39. Healthnotes Online. Healthnotes Inc. 2000; www.healthnotes.com: Ginseng 40. Punnonen R, Lukola A. Oestrogen-like effects of ginseng. British Mecial Journal 1980;281:p1110 41. Palmer BV, Montgomer ACV, Monteiro JC. Ginseng and mastalgia. [Letter] British Medical Journal 1978;1:p1284 42. Salvati G, Genovesi G, Marcellini L et al. Effects of Panax Ginseng: C.A. Meyer, Saponins on male fertility. Panminerva Med 1996;38(4):249-54 43. Chen, X, Lee TJ. Ginsenosides-induced nitric oxide-mediated relaxation of the rabbit corpus cavernosum. British Journal of Pharmacology 1995;115(1):15-8 44. Sotaniemi EA, Haapakoski E, Rautio A. Ginseng therapy in non-insulin-dependent diabetic patients. Diabetes Care 1995;18(10):1373-5 45. Vukson V et al. American ginseng reduces postprandial glycemia in nondiabetic subjects and subjects with type 2 diabetes mellitus. Arch Int Med 2000;160:1009-1013 46. Farnsworth NR, Kinghorn AD, Soejarto D, Waller DP. Siberian ginseng (Eleuthrococcus sentricosus): Current status as an adaptogen. In: Wagner H, hikino H, Farnsworth NR, eds. Economic and Meidicinal Plant Research. Academic Press Orlando FL: 1985:155-215 47. Ben-Hur et al. Effect of Panax ginseng and Eleutherococcus S. on survival of cultural mammalian cells after ionizing radiation. Am J Chin Med 1981;9:48-56 48. Kupin VI et al. Stimulation of the immunological reacitivty of cancer patients by eleutherococcus extract. Vopr Onkol 1986;32:21-6 [in Russia] 49. Salvati G et al. Effects of Panax ginseng C.A. Meryer saponins on male fertility. Panminerva Med 1996;38:249-54 50. Colgan M. Optimum Sports Nutrition. Advanced Research Press 1993:p310 51. Brown DJ. Herbal Prescriptions for Better health. Prima Publishing Rocklin CA 1996;129-38 52. Miller LG. Herbal Medicinals: Selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158(20):2200-11

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Goldenseal (Hydrastis Canadensis) General Features Goldenseal is a perennial member of the buttercup family, whose rhizome is the part used for medicinal purposes. 1 It is most frequently used for its anti-microbial properties to help fight infections and infestations. 2

Principle Active Constituents Alkaloids, including isoquinoline alkaloids such as berberine, which are thought to have anti-microbial properties.2

Clinical Application and Mechanism of Action 1. Antimicrobial In vitro studies have shown berberine to be effective against a large number of bacteria including members of Bacillus sp, Streptococcus sp, Staphylococcus sp, Klebsiella spp, Proteus spp, Corynebacterium diptheria, Enterobacter aerogenes, Salmonella typhi, Vibrio cholerae, Shigella boydii, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Escherichia coli and Xanthomonas citri. It is also active against a wide range of fungi, and using chick embryos, berberine at a dose of 0.5 mg per egg offered protection from Chlamydia trachomatis. This action was comparable to that afforded by a dose of 1 mg of sulphadiazine per egg.2 Berberine sulfate has been shown to prevent the adherence of streptococci to host cells, which may explain its antibiotic properties.2 Berberine has also been shown to activate macrophages, which engulf and destroy bacteria. 3 Berberine has been shown to have an antipyretic effect (lowers fever) in rats 4 and has been used historically for this purpose by certain populations. Thus, berberine may offer complementary support in the treatment of infections of the mucous membranes (oral cavity, throat, sinus, bronchi, genitourinary tract and gastro-intestinal tract.5 Goldenseal is often used to treat the common cold, either alone or in combination with Echinacea. 6 Authorâ&#x20AC;&#x2122;s Note: Due to insufficient evidence, Goldenseal should not be assumed to be a substitute for antibiotic therapy. 2. Liver Disorders Berberine has been shown to stimulate the secretion of bile and bilirubin. Studies with patients suffering from chronic cholecystitis (inflammation of the gallbladder) demonstrated improvement in clinical symptoms, a decrease in bilirubin levels, and an increase in the bile volume of the gallbladder. The oral doses of 5 to 20 mg of berberine, three times per day before meals, produced these results within 24-48 hours.5

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Dosage and Standardized Grade As no established protocols exist for the treatment of mucous membrane infections, the following guide may serve to provide the body with additional anti-microbial support: 250-500 mg (three times daily) of a powdered extract capsule (caplet), standardized to 4:1 or 8-12 percent alkaloid content.5

Adverse Side Effects, Toxicity and Contraindications Berberine has been shown to be very non-toxic in rat studies.5 It should be used with caution n cases of hypertension.7 Possible adverse effects include the fact that in high doses Goldenseal has been noted to cause: oral and pharyngeal irritation, nausea, vomiting, diarrhea, paresthesia, dizziness, nose bleeds, skin irritation, convulsions, hypotension, and death from respiratory or cardiac paralysis. However, the lack of adverse reactions reported from the widespread use of Goldenseal in many countries suggests that these potential reactions may be exaggerated. 2 Death from berberine poisoning has occurred but, generally speaking, it is unlikely to produce any serious adverse reactions at a dose at or below 1,500 mg per day. 9 However, patients with congestive heart failure, cardiac arrythmia (irregular heart beat) or high blood pressure should not take Goldenseal without proper monitoring by their physician as Goldenseal has been shown to prolong the duration of ventricular action potentials and increase vasodilation. It also has anti-arrhythmia effects on the heart and increases the cardiac synthesis of ATP through its inotropic properties. 8 As well, jaundiced individuals should not use Goldenseal. 10

Drug-Nutrient Interactions 1. Paclitaxel: The efficacy of this chemotherapy drug is diminished by the ingestion of Goldenseal and therefore, should not be taken concurrently with this medication. 11 2. Tetracycline and Doxycycline: Berberine has been shown to reduce the absorption of tetracycline and possibly other antibiotics in one study, and appears to diminish the antibiotic effect of tetracycline against cholera. Thus, it may not be wise to use Goldenseal concurrently with antibiotic therapy. 12

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Leung AY, Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics, John Wiley & Sons: New York, 5252, 1980, 189-190. 2. Boon H and Smith M, Health Care Professional Training Program in Complementary Medicine, Institute of Applied Complementary Medicine Inc, 1997, 204-207. 3. Kumazawa T, et.al., Activation of Peritoneal Macrophages by Berberine Alkoloids in Terms of Induction of Cytostatic Activity, Int J Immunopharmacol 6, 1984, 587-592. 4. Sabir M, et.al., Further Studies on Pharmacology of Berberine, Indian J Physiol Pharmacol 22, 1978, 9-23. 5. Murray M, The Healing Power of Herbs (2nd edition), Prima Publishing, 1995, 162-172. 6. Kumazawa Y, et.al., Activation of Peritoneal Macrophages by Berberine Alkaloids in Terms of Induction of Cytostatic Activity, Int J Immunopharmacol 6, 1984, 587-592. 7. Mills S, The Essential Book of Herbal Medicine (2nd edition), London: Penguin Publishing, 1991, 677. 8. Lau CW, Yao XQ, Chen ZY et al. Cardiovascular actions of berberine. Cardiovasc Drug Rev. 2001; 19 (3): 234-44. 9. Principles and Practice of Phytotherapy. Mills S and Bone K. Churchill Livingstone Publishers. 2000: 294-295. 10. Chan E. Displacement of bilirubin from albumin by berberine. Biol Neonate. 1993; 63 (4):201-208. 11. Lin HL et al. Berberine modulates expression of Mdr1 gene product and the response of digestive tract cancer cells to paclitaxel. Br J Cancer. 1999; 81 (3): 416-22. 12. Healthnotes, Inc. 2001. www.healthnotes.com: Goldenseal

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Gotu Kola (Centella asiatica) General Features Gotu Kola grows in tropical, swampy areas in various countries in the Middle East, the south of Africa, Eastern Europe, and Central Asia. The roots and leaves are used medicinally. 15,16 There is good supporting evidence that Gotu Kola, like Horsechestnut and Grape Seed Extract, is an effective intervention for chronic venous insufficiency when taken orally. It has also shown a positive effect in preventing keloid scar formation if taken prior to surgery, and it may be helpful in the treatment of enlarged scars. Applied topically, Gotu Kola has been shown to be effective in the treatment of burns and wounds, 1,17 although some experimental evidence suggests that it may be carcinogenic to skin cells when applied in this topical form. 18

Principle Active Constituents The primary active constituents are saponins (triterpenoids), which include asiaticoside, madecassoside, and madasiatic acid. These saponins, unique to Gotu Kola, have been shown to prevent excess scar formation by inhibiting the over-production of collagen at the wound site. The same constituents are also associated with promoting wound healing and they have been shown to increase the cement substance (ground substance or glycosaminoglycans) between cells and collagen fibers, forming a more effective seal in cases of chronic venous insufficiency and possibly other blood vessel leakage conditions. 15,16

Clinical Application and Mechanism of Action 1. Chronic Venous Insufficiency and Varicose Veins There is significant evidence for the use of Gotu Kola in the treatment of varicose veins and venous insufficiency. 17 At least four well designed clinical trials (a mix of placebo controlled, double blind and one open trial) have provided convincing evidence that Gotu Kola Extract (standardized grade) is able to improve vein function, reduce leg swelling and heaviness, and improve pain and discomfort, in a large percentage of these cases compared to the placebo groups. Moreover, two of the studies demonstrated a dose-dependent relationship, in that a higher dosage resulted in greater improvement than the lower dosage. 19, 20,21,22 A 1992 review of Gotu Kola studies (published in Minerva Cardioangiol), concluded that when taken orally, using a standardized grade extract, it provides a dose-related improvement in venous insufficiency symptoms, reducing foot swelling, ankle edema, and fluid leakage from veins. 23 Studies suggest that Gotu Kola Extract may improve structure and function of connective tissue in the body, helping to strengthen veins and possibly reducing symptoms of other connective tissue disorders, such as scleroderma and dermatitis. 24 2. Increases Formation of Glycosaminoglycans.1 By increasing the synthesis of glycosaminoglycans, Gotu Kola Extract may further strengthen the walls of veins and other blood vessels, in addition to its above noted effects on the collagen protein of connective tissue. 1

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3. Keloids and Other Connective Tissue Abnormalities There are numerous clinical reports and preliminary studies that suggest that Gotu Kola Extract can be useful in the treatment of keloid scars, anal fissures, periodontal disease, scleroderma, cellulite, and liver cirrhosis. 24,25 Experimental evidence has shown that the saponin constituents of Gotu Kola are able to stimulate the maturation of the scar by production of type I collagen, with a resulting decrease in the inflammatory reaction and myofibrinoblast production. 26 The net result is a scar that is less thick, more fine in its appearnce, and more visually acceptable in the mind of patients. Some authorities promote the use of Gotu Kola as part of a scar and keloid management program.26 Overall, there is a growing body of evidence that suggest that Gotu Kola Extract is an appropriate intervention for cellulite, keloid prevention and management, and may be useful in the treatment of a variety of connective tissue disorders. 2,3,4,5,6,7,8,9,10,11,12,13,17 For the prevention of keloid scars, Gotu Kola Extract is usually taken for 3 months prior to surgery, and for another 3 months afterwards. 17 4. Topical Application in Wound Healing and Burn Management Animal studies demonstrate that a Gotu Kola Purified Extract, containing high concentrations of asiaticoside, can enhance wound healing. 17 One preliminary trial in human subjects showed that Gota Kola Extract helped the healing of infected wounds (unless they had reached the bone level). 27 A significant number of studies originating in France have also shown that the topical application of Gotu Kola Extract can help heal various types of wounds. 28

Dosage and Standardized Grade Standardized Extracts of Gotu Kola contain up to 100% total triterpenoid content, usually broken down in the following percentages: asiatic acid (29-30%), asiaticoside (40%), madecassic acid (29-30%), and madecassoside (1-2%). For most conditions, including venous insufficiency, varicose veins, keloid or scar prevention or treatment, and treatment of other connective tissue disorders (e.g scleroderma) the usual oral dosage is 60 mg, twice per day. 15,16,17

Adverse Side Effects, Toxicity and Contraindications Gotu Kola has been shown to be very non-toxic when taken orally. It rarely causes any side effects other than the occasional allergic skin rash. Topical applications may cause contact dermatitis 1 and as noted earlier experimental studies on animals suggest that the topical application may act as a carcinogen to skin cells. 18

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Drug-Nutrient Interactions There are no well-known drug-nutrient interactions for Gotu Kola.

15, 16

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Bourguigon D, Study of the Action of Titrated Extract of Centella Asiatica, Gaz Med Fr 82, 1975, 4579-4583. Bonnett GF, Treatment of Localized Cellulitis with Asiaticoside Madecassol, Prog Med 102, 1974, 109-110. Grosshans E and Keller F, Cellulite: Reality or Imposter?, J Med Strasbourg 14, 1983, 563-567. Keller F and Grosshans E, Cellulities: Reality or Fraud? Med Hyg 41, 1983, 1513-1518. Tenailleau A, On 80 Cases of Cellulities Treated with the Standard Extract of Centella Asiatica, Quest Med 31, 1978, 919-924. Carraro Pereira I, Treatment of Cellulitis with Centella Asiatica, Folha Med 79, 1979, 401-404. Guarnerio F, et.al., Treatment of Hemorrhoids with Centella Asiatica, G Ital Angiol 6, 1986, 46-52. Benedicenti A, Galli D, and Merlini A, The Clinical Therapy of Periodontal Disease: The Use of Potassium Hydroxide and the WaterAlcohol Extract of Centella Asiatica in Combination with Laser Therapy in the Treatment of Severe Periodontal Disease, Parodontol Stomatol 24, 1985, 11-26. Castellani C, et.al., Asiaticoside and Cicatrization of Episiotomies, Bull Fed Soc Gynecol Obstet 18, 1966, 184-186. Collonna dâ&#x20AC;&#x2122;Istria J, Research on the Healing Action of Madecassol in Cervical and Laryngeal Surgery After Ionizing Radiations, J Fr Otorhinolaryngol 19, 1970, 507-510. Oâ&#x20AC;&#x2122;Keeffe P, A Trial of Asiatiocoside on Skin Graft Donor Areas, Br J Plast Surg 27, 1974, 194-195. Pignataro O and Teatini GP, Clinical Research on the Cicatrizing Action of Madecassol in Comparison of Oropharyngeal Mucosa, Minerva Med 56, 1965, 2683-2686. Rui R, et.al., Clinical Study of Madecassol in Otorhinogoly, J Med Lyon 47, 1966, 693-706. Sevin P, Some Observations on the Use of Asiaticoside (Madecassol) in General Surgery, Prog Med (France) 90, 1962, 23-24. Murray MT, The Healing Power of Herbs (2nd edition), Prima Publishing. Healthnotes, Inc. 2001.www.healthnotes.com: Gotu Kola. Natural Products Encyclopedia. www.consumerslab.com: Gotu Kola Laerum OD, Iversen OH. Reticuloses and epidermal tumors in hairless mice after topical skin application sof cantharidin and asiaticoside. Cancer Res 1972;32:1463-9

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19. Belcaro GV, Grimaldi R, Guildi G. Imrovement of capillary permeability in patients with venous hypertension after treatment with TTFCA. Angiology 1990;41:533-40 20. Belcaro FV, Rulo A, Grimaldi R. Capillary filtration and ankle edema in patients with venous hypertension treated with TTFCA. Angiology 1990;41:12-8 21. Cesarone MR, Laurora G, De Sactis MT et al. The microcirculatory activity of Centella asiatica in venous insufficiency. A double-blind study [translated from Italian]. Minerva Cardioangiol 1994;42:299-304 22. Pointel JP, Boccalon H, Cloarec M et al. Titrated extract of Centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. Angiology 1987;38:46-50 23. Cesarone MR, Laurora G, De Sanctis MT et al. Activity of Centella asiatica in venous insufficiency [in Italian: English abstract]. Minerva Cardioangiol 1992; 40:137-43 24. Kartnig T. Clinical applications of Centella asiatica (L.) Urb. Herbs Spices Med Plants 1988;3:145-73 25. Bosse JP, Papillon J, Frenette G et al. Clinical study of a new antikeloid agent. Ann Plat Surg 1979;3:13-21 26. Widegerow AD, Chait LA, Stals R, et al. New innovations in scar management. Aesthetic Plast Surgery. 2000;24 (3):277-34. 27. Morisset R, Cote NG, Panisset JC et al. Evaluation of the healing activity of hydrocotyle tincture in the treatment of wounds. Phytother Res 1987;1:117-21 28. Kartnig T. Clinical application sof Centella asiatica 9L) Urb. In Herbs, Spices and Medicinal Plants: Recent Advances in Botany, Horticulture and Pharmacology, vol.3 Craker LE, Simon JE (eds.) Oryx Press Phoenix, AZ 1986:145-73

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Gugulipid (Gum Guggul) General Features Gum Guggul or Gugulipid is derived from the mukul myrrh tree, which is native to India. Upon injury, the tree exudes a yellowish gum resin known as Gum Guggul, Gugulipid or Guggulu. The trees are tapped during the winter to acquire these oleoresin compounds that have been used extensively by Ayurevedic (Indian medical system) physicians for centuries to treat a wide variety of disorders. 1,11.The most scientifically proven application for the use of Gugulipid pertains to its ability to lower blood cholesterol, triglycerides, and improve the LDL to HDL-cholesterol ratio in patients with hypercholesterolemia and related lipid disorders. 1, 11, 12

Principle Active Constituents Guggul contains resin, volatile oils, and gum. The extract isolates ketonic steroid compounds known as guggulsterones. Guggulsterones have been shown to be the active constituent in Guggul that account for its cholesterol and triglyceride lowering effects. 1,13, 14

Clinical Application and Mechanism of Action 1.

High Cholesterol and/or Triglycerides Gugulipid was granted approval in India for marketing as a lipid-lowering drug in June 1986. Studies show that it lowers total cholesterol, LDL –cholesterol, while elevating HDL–cholesterol levels. (Agarwal RC, 1986 and Nityanand S, 1989). It appears that guggulsterones increase the uptake of LDL –cholesterol from the blood by the liver. Studies in humans demonstrate that guggulsterone can produce a cholesterol reduction of 14-27%, in 4-12 weeks, and a 22-30% drop in blood triglyceride levels, in patients with hypercholesterolemia and/or hypertriglyceridemia. A striking feature is its lack of toxicity. Unlike other cholesterol lowering drugs, the administration of Gugulipid has not revealed any significant side effects, liver damage or toxicity, in human or animal studies to date.2,3,4,5,6,7,8,9,11,12 At least three well-controlled double-blind trials have shown that the oral administration of 75 – 100 mg of guggulsterone per day can significantly lower cholesterol and triglycerides, and improve the LDL to HDL-cholesterol ratio, in a manner that is associated with a reduced risk of heart disease and related cardiovascular disorders. One of these trials tested Gugulipid against the cholesterol lowering drug clofibrate, in a study involving 228 hypercholesterolemic patients. Results showed that the standardized grade of Gugulipid was equal in its effects to clofibrate in its ability to lower cholesterol levels and improve the lipid profile. 6,8,15 Experimental evidence indicates that guggulsterone lowers cholesterol, in part, by enhancing the uptake of excess serum LDL-cholesterol particles by the liver. This is accomplished through receptor-mediated endocytosis, located on the surface of the liver cell membranes. Rat liver exhibits up to an 87% increase in binding sites for human 1251- LDL with exposure to guggulsterones. Studies such as these imply that guggulsterones increase the catabolism of LDL-cholesterol as a primary mechanism through which it acts to lower blood cholesterol levels. 9 Of note is the fact that experimental studies reveal that Gugulipid also reduces oxidation of LDL-cholesterol via its antioxidant properties which may further provide protection against cardiovascular disease, as oxidized LDLcholesterol (modified LDL-cholesterol) has been shown to get deposited in the artery wall (narrowing blood vessels) to a much greater extent than non-oxidized LDL-cholesterol lipoproteins. 16 Gum Guggul has also been shown to reduce the stickiness of blood platelets, which is another biological action associated with reduced risk of cardiovascular disease. 17

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2. Anti-inflammatory Effects In experimental animal models, Gum Guggul demonstrates one-fifth the anti-inflammatory potency as hydrocortisone and the equivalent anti-inflammatory potency as phyenylbutazone and ibuprofen.10 In Ayurevedic medicine Gum Guggul has been used for this purpose, but no well-controlled trials on humans are available to firmly establish its application in the treatment of arthritic and other inflammatory joint conditions. 11,13 3. Acne The lipid lowering effect of Gum Guggul may help to control cystic acne, according to one of its traditional applications by Ayruvedic practitioners. One small clinical trial reported in 1994, tested Gum Guggul against the antibiotic drug tetracycline for the treatment of cystic acne. The results showed that Gum Guggul compared favorably in its effects to outcomes realized by patients treated with tetracycline. 18

Dosage and Standardized Grade 1. To Lower Cholesterol and/or Triglyceride Blood Levels: 25 mgs of guggulsterone three to four times per day has been used successfully. If using a 5% guggulsterone content product, this translates into a dose of 500 mgs of Gugulipid, three to four times per day. Often, a 2.5% grade of guggulsterone content product is all that is available and thus, two 500 mg capsules of Gugulipid, taken three to four times per day is necessary to yield the therapeutic dosage of guggusterone. 1,11,12,13 2. Acne: 500 mg, taken twice per day (standardized grade of 2.5% guggulsterone content). 18

Adverse Side Effects, Toxicity and Contraindications In clinical studies, Gugulipid has not display any significant untoward side effects or produced adverse effects on liver function. Nor has it shown any adverse effects on kidney function, blood cell counts and appearance, heart function, or blood chemistry. This is in sharp contrast to many lipid-lowering drugs that are known to create various consequential side effects, especially in regards to liver function. Animal studies also reveal that Gum Guggul is extremely non toxic.1,12 On rare occasions, Gum Guggul supplementation may cause minor gastrointestinal distress, skin rash, diarrhea and nausea. 11,13

Drug-Nutrient Interactions 1. Hypolipidemic Drugs: Gum Guggul may potentiate the cholsesterol lowering and triglyceride-lowering effects of these medications, enabling the attending physician to lower the dose or eliminate the need for these drugs, and in doing so, reduce the likelihood of side effects from these medications. 19,20,21 2. Anticoagulant Drugs: Gum Guggul may potentiate the effects of these drugs, and thus, proper patient monitoring of prothrombin time (INR) should be adhered to if Gum Guggul is used concurrently with anticoagulants such as, aspirin, warfarin, coumadin, plavix etc. 22 3. Thyroid Medications: Some studies suggest that Gum Guggul may stimulate the thyroid gland, which in turn, may alter the dosing requirement of thyroid medications. 23,24 4. Gum Guggul may reduce the absorption of the following drugs if taken at the same time: 5. Propranol 25 6. Calcium Channel Blockers (e.g, Diltiazem) 26

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Murray MT, The Healing Power of Herbs (2nd edition), Prima Publishing, 1995. Satyavati GV, A Primising Hypolipidaemic Agent from Gum Guggul (Commiphora Wightii), Econ Med Plant Res 5, 1991, 47-82. Nityand S and Kapoor NK, Hypocholesterolemic Effect of Commiphora Mukul Resin, Indian J Exp Biol 9, 1971, 376-377. Kuppurajan K, et.al., Effect of Gugglu on Serum Lipids in Obese Hypercholesterolemic and Hyperlipidemic Cases, J Assoc Physicians India 26, 1978, 367-371. Malhotra SC, Ahuja MMS, and Sundaram KR, Long Term Clinical Studies on the Hypolipidaemic Effect of Commiphora Mukul (Guggulu) and Clofibrate, Indian J Med Res 65, 1977, 390-395. Verna SK and Bordia A, Effect of Commiphora Mukul (Gum Guggulu) in Patients of Hyperlipidemia with Special Reference to HDL â&#x20AC;&#x201C; cholesterol, Indian J Med Res 87, 1988, 356-360. Agarwal RC, et.al., Clinical Trial of Gugulipid a New Hypolipidemicagent of Plant Origin in Primary Hyperlipidemia, Indian J Med Res 84, 1986, 626-634. Nityanand S, Srivastava JS, and Asthana OP. Clinical Trials with Gugulipid, a New Hypolipidaemic Agent, J Assoc Physicians India 37, 1989, 321-328. Singh V, et.al., Stimulation of Low Density Lipoprotein Receptor Activity in Liver Membrane of Guggulsterone Treated Rats, Pharmocol Res 22, 1990, 37-44. Sharma JN and Sharma JN, Commparison of the Anti-inflammatory Activity of Commiphora Mukul (an indigenous drug) with those Pfhenylbutazone and Ibuprofen in Experimental Arthritis Induced by Mycobacterial Adjuvant, Arzneimittel-Forsch 27, 1977, 1455-1457. Dietary Supplement Information Bureau. www.content.intramedicine.com: Guggul. Natural Health Products Encyclopedia. www.consumerslab.com: Guggul. Healthnotes, Inc.200.www.healthnotes.com: Guggul Satyavati GV. Gum guggul (Commiphora mukul) â&#x20AC;&#x201C; The success of an ancient insight leading to a modern discovery. Indian J Med 1988;87:327-35 Singh RB, Niaz MA, Ghosh S. Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. Cardiovasc Drugs Ther 1994;8:659-64 Singh K, Chander R, Kapoor NK. Guggulsterone, a potent hypolipidaemic, prevents oxidation of low density lipoprotein. Phytother Res 1997;11:291-4 Mester L, Mester M, Nityanand S. Inhibition of platelet aggregration by guggulu steroids. Planta Med 1979;37:367-9 Thappoa DM, Dogra J. Nodulocystic acne: oral gugulipid versus tetracycline. J Dermatol 1994;21:729-31 Satyavati GV et al. Experimental studies on the hypocholesterolemic effect of commiphora mukul. Indian J Med Res 1969;57(10):1950-62

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20. Nityanand S et al. Clinical trials with gugulipid. A new hypolipidaemic agent. J Assoc Physicians India 1989;37(5):323-8 21. **Satyavati GV et al. Guggulipid: a promising Hypolipidemic agent from gum guggul (Commiphora Wightii). Econ Med Plant Res 1991;5:48-82 22. **Satyavati GV et al. Guggulipid: a promising Hypolipidemic agent from gum guggul (Commiphora Wightii). Econ Med Plant Res 1991;5:48-82 23. Tripathi YB et al. Thyroid stimulatory action of (Z)-Guggulsterone: mechanism of action. Planta Med 1988;54(4):271-7 24. Panda S, Kar A. Gugulu (Commiphora mukul) induces triiodothyronine production: possible involvement of lipid peroxidation. Life Sci 1999;65(12):PL137-41 25. **Dalvi SS et al. Effects of gugulipid on bioavailability of diltiazem and propranolol. J Assoc Physicians India 1994;42(6):454-5 26. **Dalvi SS et al. Effects of gugulipid on bioavailability of diltiazem and propranolol. J Assoc Physicians India 1994:42(6):454-5

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Hawthorn (Crataegus oxyacantha) General Features Hawthorn is a spiny shrub or tree, and is a member of the crataegus family. It has been used medicinally since ancient times and during the first century, Roman physicians used Hawthorn as a drug to treat a variety of heart and cardiovascular conditions. During the Middle Ages Hawthorn was used for the treatment of congestive heart failure (dropsy), an application that has proven to be valid according to modern day evidence-based research. 1,11,12,13,14

Principle Active Constituents Hawthorn flowers, berries, and leaves contain flavonoid compounds that appear to account for its positive effects on cardiac function. These flavonoids account for the red color of Hawthorn berries. The flavonoids found in Hawthorn include olgomeric procyanidins (OPCs), vitexin, vitexin 4 – 0 – rhamnoside, quercetin, and hyperoside. Standardized extracts of Hawthorn are usually validated by their vitexin and procyanidin content, which ensure that sufficient levels of flavonoids are present to yield the desired outcomes on cardiovascular health.11,12, 13,14 Hawthorn flower extract is the primary compound used medicinally and is particularly rich in the following flavonoids: Quercitin Quercitin-3-galactoside Vitexin Vitexin-4-rhamnoside In addition to proanthocyanidins, Hawthorn extract also contains cardiotonic amines, which include: Phenylethylamine Methoxyphenylamine Tyramine Isobutilamine 1,2,3

Clinical Application and Mechanism of Action Cardiovascular Effects: Angina: Dilation of Coronary Vessels - Evidence exists to show that Hawthorn extract may improve coronary artery blood flow and strengthen the contractions of the heart muscle. This has lead to findings that Hawthorn extract can benefit patients with a history of angina by preventing or reducing angina attacks and improving other indices of cardiovascular function, according a small number of clinical trials. 4,5,6,7,8,15, 16 Congestive Heart Failure: Hawthorn increases cyclic AMP (adenosine monophosphate) in the Myocardium (heart muscle) due to its effects on inhibiting the enzyme phosphodiesterase, which breaks down cyclic AMP (cAMP). The oral administration of Hawthorn extract results in higher myocardial concentrations of cAMP in patients suffering from various cardiomyopathies (heart conditions). As cAMP can be further phosphorylated to ADP (adenosine diphosophate) and then to ATP (adenosine triphosphate-the energy source used by the heart muscle to pump blood through the system), higher myocardial concentrations of cAMP enables the heart muscle to pump more efficiently. The net result is an increase in the heart muscle’s force of contraction. This effect has been shown to be of great benefit for patients with congestive heart failure, who by definition, have a weakened heart muscle. A number of wellcontrolled clinical trails have demonstrated that Hawthorn extract can reverse many cases of congestive heart failure via its inotropic effect (increasing the amount of available energy) on cardiac muscle. 9,10,11.

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High Blood Pressure: Inhibits Angiotensin – Converting Enzyme (acting as an ACE-inhibitor) – by inhibiting the angiotensin-converting enzyme Hawthorn extract reduces the conversion of angiotensin I to angiotensin II, which is a potent constrictor of blood vessels and stimulates adrenal production of aldosterone. Thus, in a similar fashion to ACE-inhibitor drugs, Hawthorn extract has been shown to exert a blood pressure lowering effect. However, Hawthorn has been shown to have a modest effect on lowering blood pressure in hypertensive patients relative to more powerful ACE-inhibitor medications. In one study, systolic blood pressure dropped from 205 to 148 mm Hg, but other studies have shown a more modest reduction in blood pressure (e.g., systolic decline from 160 – 150 mm Hg, diastolic decline from 89 – 84 mm Hg) with Hawthorn extract supplementation. 7,11,15 Clinical trials show that Hawthorn extract can be an effective adjunct to the lowering of high blood pressure, but its hypotensive effects often require two to four weeks to manifest themselves. Hawthorn does not further lower blood pressure in subjects who demonstrate normal blood pressure, but rather selectively appears to reduce blood pressure only in hypertensive individuals. 23 Thus, the cardiovascular conditions that may be responsive to Hawthorn include congestive heart, angina, and high blood pressure. In particular, Hawthorn has a long history of use in the treatment of congestive heart failure. Congestive Heart Failure Clinical Trials: At least 8 double-blind, placebo-controlled trials, involving a total of more than 400 participants, have shown that Hawthorn extract is an effective intervention for mild to moderate congestive heart failure. 17 One study, involving more than 200 patients, found that Hawthorn extract was helpful in more severe congestive heart failure cases. 18 Even in more severe cases of congestive heart failure patients receiving high dose Hawthorn extract reported improvement in subjective symptoms ( shortness of breath, fatigue, etc.) as well as objective improvement in exercise capacity. 18 A comparative study has indicated that Hawthorn extract is about as effective as low dose captopril, a drug commonly used to treat congestive heart failure. 19 Hawthorn appears to act in a similar manner as other cardiac glycoside drugs, such as digoxin and digitalis, which exert an inotropic effect on the myocardium; enhancing ATP production through bioenergetic pathways. Studies reveal that Hawthorn provides similar benefits as these drugs, and exhibits a much safer profile. Digoxin and related cardiac glycoside prescription drugs increase the strength of the heart pump, but also increase the likelihood of dangerous arrhythmias. This occurs because these drugs shorten the refractory period between heartbeats (the period in which the heart can not contract between beats), which increases the chances of premature beats arising from areas outside or inside the heart’s natural pacemaker. In turn, this disturbs the necessary synchronized and rhythmic contraction pattern that the heart muscle must follow to perform its function properly. The result is the development of cardiac arrhythmia, which can be life threatening. It is well documented that digoxin and related drugs have a narrow index of safety for this reason. In contrast to this, Hawthorn extract is able to strengthen the heart muscle, and has been shown to lengthen the refractory period between heartbeats, which reduces the likelihood of developing cardiac arrhythmias. As well, Hawthorn exhibits much lower toxicity than digoxin and is reported to have an enormously large range of safety, in regards to daily dosage (a number of studies have used doses as high as 600 mg per day with no significant side effects reported). 20,21,22, 13, 15 The major precautionary note pertains to the fact that it is not known if Hawthorn can be used safely with other cardiac glycoside drugs or with other medications (usually ACE- inhibitors) that are now more commonly prescribed in the treatment of congestive heart failure. 13 Some authorities suggest that Hawthorn’s effects are synergistic to the biological actions of cardiac glycoside drugs and ACE-inhibitors, indicating that they can be used concurrently as long as the attending physician is able to monitor patient response and adjust the dosing of these drugs accordingly. 15 From an historical standpoint, Hawthorn has been used alone and in combination with other cardiac glycoside drugs in the management of congestive heart failure.11, 15

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Anti- Aging: (Author’s Note) Hawthorn may be an important herb in the prevention of cardiovascular disease and agerelated cardiac decline leading to the development of congestive heart failure. Studies demonstrate that after the age of 35- 40 the heart muscle appears to make less ATP energy in a certain percentage of individuals. This has been shown to result from a marked reduction in Coenzyme Q10 synthesis, which is required to maximize the conversion of ADP to ATP. Theoretically, supplementation with both Coenzyme Q10 and Hawthorn extract may help to stave off age-related declines in ATP production, due to their known inotropic effects on heart muscle. Many practitioners involved in anti-aging medicine subscribe to this practice and recommend these supplements on a preventive basis to their patients over 40 – 50 years of age. (see also Coenzyme Q10 in this document).

Dosage and Standardized Grade 1. Hawthorn flower extract should be standardized to contain 18 - 20 percent procyanidins or 2 –5% flavonoid content, of which at least 1.5% is the flavonoid vitexin. 11,12,13,14,15 2. Congestive Heart Failure: In a 1993 study of 30 patients with congestive heart failure 80 mg of standardized Hawthorn extract taken twice per day for eight weeks showed a statistically significant improvement in heart function vs. the placebo. There were no side effects (Leuchtgens H, 1993). Blood pressure was also mildly reduced. 10 However, other studies have used 300 – 600 mg of Hawthorn extract, three times per day, and have shown good results in cases of congestive heart failure without generating any side effects. Thus, the dosage range for this application is vast, ranging from 80 to 600 mg, two to three times per day, and is based upon the severity of the condition; as more severe congestive heart failure has been shown to respond better to higher doses. 11,12,13,14,15 3. Angina: 180 mg per day (e.g., 60 mg, three times per day) 15 4. High Blood Pressure: 100 – 250 mg, one to three times per day 23 5. Anti- Aging: For general prevention purposes 70-100 mg of standardized Hawthorn extract may be appropriate after age 40 – 50 1,2,3,4,5,6,7

Adverse Side Effects, Toxicity and Contraindications Hawthorn is regarded as being very safe. The German Commission E lists no known risks, contraindications, or drug interactions with Hawthorn. Animals given very large doses of Hawthorn extract have not shown any signs of toxicity. In clinical trials with congestive heart failure and other cardiovascular patients, reported side effects have been rare, consisting of stomach upset and occasional allergic skin reaction.1,13,14,15

Drug-Nutrient Interactions Hawthorn may potentiate the action of the following drugs, and therefore, requires appropriate physician monitoring if taken concurrently with these medications. This is extremely important in the case of digitalis, digoxin and other cardiac glycoside drugs, as it is plausible that a drug nutrient interaction of this nature could lead to life threatening consequences. Interactions of concern include: 1. Digitalis, digoxin and other cardiac glycoside medications 24 2. Antiarrhythmic Medications 25 3. Anti-hypertensive Medications: As Hawthorn extract is known to lower high blood pressure to some degree, it may work synergistically with a variety of antihypertensive drugs, reducing the required dosage of the drug. 26, 27

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Petkov V, Plants with Hypotensive, Antiatheromatous and Coronarodilating Action, Am J Clin Med 7, 1979, 197-236. Wagner H, Bladt S, and Zgainski EM, Plant Drug Analysis, Springer-Verlag, New York, 1984, 166 & 178-179. Ammon HPT, Handel M, Crataegus, Toxicology and Pharmacology, I Toxicity, Planta Medica 43, 1981, 105-120, II Pharmacodynamics, Planta Medica 43, 1981, 209-239, III Pharmacodynamics and Pharmacokinetics, Planta Medica 43(4), 1981, 313-322. Mavers VWH, and Hensel H, Changes in Local Myocardial Blood Flow Following Oral Administration of a Crataegus Extract to Nonanesthetized Dogs, Arzneimittel-Forsch 24, 1974, 783-785. Roddewig VC, and Hensel H, Reaction of Local Myocardial Blood Flow in Non-anaesthetic Dogs and Anesthetized Cats to Oral and Parental Application of Crataegus Fraction (Ologomer Procyanidins), Arzneimittel-Forsch 27, 1977, 1407-1410. Rewerski VW, et.al., Some Pharmacological Properties of Oligometric Procyanidin Isolated from Hawthorn (Crataegus Oxyacantha), Arzneimittel-Forsch 17, 1967, 490-491. Uchida S, et.al., Inhibitory Effects of Condensed Tannins on Angiotensin Converting Enzyme, Jpn J Pharmacol 43, 1987, 242-245. Blesken R, Crataegus in Cardiology, Forschr Med 110, 1992, 290-292. Oâ&#x20AC;&#x2122;Connoly VM, et.al., Treatment of Cardiac Performance (NYHA Stages I to II) in Advanced Age with Standardized Crataegus Special Extract, Forschr Med 104, 1986, 805-808. Leuchrgens H, Crataegus Special Extract WS 1442 in NYHA II heart failure. A Placebo Controlled Randomized Double-blind Study, Forschr Med 111, 1993, 352-354. Murray MT, The Healing Power of Herbs (2nd edition), Prima Publishing, 1995. Dietary Supplement Information Bureau.www. content.intramedicine.com: Hawthorn Natural Products Encyclopedia. www.consumereslab.com: Hawthorn Healthnotes, Inc. 2001. www.healthnotes.com: Hawthorn Principles and Practice of Phytotherapy. Mills M and Bone K. Churchill Livingstone.2000: 444-445 Wagner H et al. Cardioactive Drugs IV. Cardiotonic amines from crataegus oxyacantha. Planta Medica 1982;45:99-101 Weihmayr T, Ernst E. Therapeutic effectiveness of crataegus. Forschr Med 1996;114:27-9 Tauchert M. Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in patients with chronic stable New York heart Association class-III heart failure. Am Heart J 2002;143(5):910-5 Tauchert M, Siegel G, Schulz V. Hawthorn extract as plant medication for the heart; a new evaluation of it therapeutic effectivenss [translated from German]. MMW Munch Med Wochenschr. 1994;136(suppl 1):S3-S5 Popping S, Rose H, Ionescu I et al. Effect of a hawthorn extract on contraction and energy turnover of isolated rat cardiomyocytes. Arzneimittelforschung 1995;45:1157-61

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21. Joseph G, Zhao Y, Klaus W. Pharmacolgic action profile of crataegus extract in comparison to epinephrine, amirinone, milrinone and digoxin in the isolated perfused guinea pig heart [in German; English abstract]. Arzneimittelforschung 1995;45:1261-5 22. Schulz V, Hansel R, Tyler VE. Rational Phytotherapy: A Physicianâ&#x20AC;&#x2122;s Guide to Herbal medicine. 3 rd ed. Berlin, Germany, Springer-Verlag 1998:91-4 23. Murray M, Pizzonro J. Encylopedia of Natural Medicine (2nd ed) Prima Publishing 1997:524-35 24. Petkov V. Plants and hypotensive, Antiatheromatous and coronarodilatating action. Am J Chinese Med 1979;7:197-236 25. Wagner H et al. Cardioactive Drugs IV. Cadiotonic amines from crataegus oxyacantha. Planta Medica 1982;45:99-101 26. Uchida S et al. Inhibitory effects of condensed tannins on agiotensin converting enzyme. Jap J Pharmacol 1987;43(2):242-6 27. Taskov M. On the coronary and cardiotonic action of crataemon. Acta Physiol Pharmacol Bulg 1977;3(4):53-7

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Horsechestnut seed (Aesculus hippocastanum) General Features The Horsechestnut tree is native to Asia and Northern Greece, but is now cultivated in many areas of Europe and North America and is mainly grown as an ornamental tree in parks and gardens. Unlike true chestnuts, the seeds (nuts) of the Horsechestnut are not edible, but an extract containing active ingredients from the seed has been used for a few centuries in Germany for the treatment of chronic venous insufficiency. In fact, in Germany more prescriptions are written for the oral, standardized Horsechestnut extract as a treatment for chronic venous insufficiency, than for any other drug or supplement.1,2,3,4 Numerous clinical trials have documented the efficacy of Horsechestnut supplementation in the treatment of chronic venous insufficiency and related circulatory problems. 1

Principle Active Constituents The major active constituents are considered to be saponins, referred to as escin, which is a complex and unique mixture of over thirty individual pentacyclic triterpene diester glycosides. Other key constituents include flavonoids, sterols and lipids.1,4,5,6,7,8,9

Clinical Application and Mechanism of Action 1. Chronic Venous Insufficiency Chronic Venous Insufficiency is an imprecise term, which refers to the impairment of venous return, usually from the legs, and often involves edema (swelling), leg pain, fatigue and/or heaviness upon standing or walking, and possibly skin discoloration.1,7,9,10,11,12 Other terms used to describe the same condition include deep vein incompetence, peripheral venous incompetence and early stage varicose veins. 1,4 This condition has been reported to affect 10-15% of men and 20-25% of women.9 Numerous clinical trials have shown that the oral administration of the standardized grade of Horsechestnut seed can effectively treat chronic venous insufficiency in a large percentage of cases. Many double-blind, placebo-controlled studies reveal that it has proven to be effective on a consistent basis and can outperform the use of compression stockings, which are often used in the management of this condition. Studies reveal that Horsechestnut supplementation objectively improves venous tone, without arterial constriction or a rise in blood pressure. It has been shown to reduce leg volume in these patients versus the placebo group, and has outperformed use of support stockings in regards to this outcome. Overall, patients consistently report reduced leg pain, swelling, heaviness, pain, and fatigue with the use of Horsechestnut seed extract.1,4,7,9,10,11,12,13,14,15 As for the mechanism of action, the escin component (triterpene saponins) of Horsechestnut extract acts by reducing capillary permeability to water, essentially helping to seal off the escape of water out of veins into the extravascular space. It has also been shown to improve tone of connective tissues within veins and block the breakdown of ground substance (proteoglycans), which provides important structural integrity to veins. Horsechestnut seed ingredients have been shown to inhibit the enzymes that breakdown these important proteoglycans and to inhibit lysosomal enzymes and hyaluronidase enzyme, which are both known to break down tissue structure. Horsechestnut seed extract has also been shown to possess antioxidant properties. The combination of these effects accounts for the ability of this supplement to reduce localized edema and inflammation, increase venous pressure and flow, reduce venous deformity and distension, and reduce leg, ankle and foot circumference in afflicted individuals and in healthy subjects studied during a 15-hour air flight, who fared better in these measurements than did the placebo group.1,6,8

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2. Prevention of Deep Vein Thrombosis Following Surgery Over a 3-year period, a controlled trial of 4,176 patients with thrombosis, lung infarction or lung embolism investigated prophylactic treatment for deep vein thrombosis and embolism arising from surgery. Patients received an intravenous injection of Horsechestnut extract (10 ml per day), strophantin or digitalis, Vitamin B complex and Vitamin C or a similar injection without Horsechestnut extract for 4 days prior to surgery and continuing for up to 7 days after the operation. Horsechestnut significantly reduced the incidence of deep vein thrombosis following surgery compared to the control group and other patients.1 3. Other Potential Applications These may include cerebral edema following cranial fractures and trauma, haemorrhoids, varicose veins (early stages), carpal tunnel syndrome 1,6 and possibly as a supplement to help prevent hemorrhage in diabetic retinopathy, and to support the small blood vessels in the macula of the eye in certain eye conditions. 4. Topical Application A topical gel containing 1.4-2% escin (triterpene glycoside) content has been used successfully to help treat chronic venous insufficiency, hematoma, contusions, non-penetrating wounds and sports injuries involving edema.1,4

Dosage and Standardized Grade 1. Chronic Venous Insufficiency (and other related venous and vascular problems mentioned above): The usual dosage is 200 mg, 2-3 times per day (standardized to 40% escin content).1 Other references cite a daily dosage of 300 mg, 2-3 times per day (standardized to 50 mg: 16%-21% triterpene glycosides calculated as anhydrous escin per dose).7,9,16,17 2. Topical Application: Gels and lotions containing 1.4% to 2% Horsechestnut seed extract are available commercially for topical use.1,4

Adverse Side Effects, Toxicity and Contraindications Horsechestnut has been shown to be very non-toxic in numerous animal studies.1 The American Medical Association published a noteworthy review article of Horsechestnut in the Archives of Demalology, highlighting the evidence to support the use of this supplement in cases of chronic venous insufficiency. In regards to reported side effects, the researchers indicate that minor side effects occurred in 0.95 to 3% of subjects taking Horsechestnut seed extract in the various studies that met the inclusion criteria. These minor side effects included stomach upset, calf spasm, dizziness, nausea, headache, itching, and allergic skin reactions.12 Overall, side effects from Horsechestnut seed extract are mild and infrequent 11 and patient tolerance is regarded as excellent, by some researchers. 6 However, based on reports of worsening of kidney function in patients with existing kidney disease who received intravenous escin, this supplement should be avoided by anyone with known kidney disease.18.19 Patients with liver disease or bleeding disorders are also best to avoid this supplement, according to some health experts. 20,21 Topically, Horsechestnut has been associated with rare allergic skin reactions, and should not be applied to broken or ulcerated skin, as the saponin content acts as an irritant to these raw tissues. 1

Drug-Nutrient Interactions Anticoagulant Medications (Warfarin, Coumadin Aspirin, etc.) - Experimental evidence suggests that Horsechestnut seed extract may potentiate the effects of anticoagulant drugs. However, there are no reports of bleeding disorders in humans to date, in subjects using Horsechestnut seed extract with or without concurrent anticoagulant therapy.

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Practitioners and patients should be mindful of this potential interaction, but it is not considered to be a contraindication to the use of Horsechestnut seed extract at this time.22,23,24

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Mills S, Bone K. Principles and Practice of phytotherapy. Churchill Livingstone 2000;Horsechestnutseed:448-55 Schulz V et al. Rational Phytotherapy. Berlin:Springer-Verlag;1998:129-38 Chandler RF. Horse chestnut. Canadian Pharm J 1993;Jul/Aug:297-300 Dinsdale, M. Horse Chestnut. Better Nutriiton, Feb2000;62(2):32 Guillaume M, Padioleau F. Venotonic effect, vascular protection, anti-inflammatory and free radical scavenging properties of horse chestnut extract. Arzneim-Forsch Drug Res 1994;44:25-35 Sirtori, CR. Aescin: pharmacology, pharmacokinetics and therapeutic profile. Pharmacol Res 2001 Sep;44(3):183-93 Herbal Help for Tired Swollen Legs. Environmental Nutrition, Jun2001;24(6):p7 Brunner F, Hoffmann C, Schuller-Petrovic S. Responsivemenss of human varicose saphenous veins to vasoactive agents. Br J Clin Pharmacol 2001 Mar;51(3):219-24 Bone, Kerry. Phytotherapy Review & Commentary: Horse-chestnutâ&#x20AC;&#x201D;A safe and effective vein treatment. Townsend Letter for Doctors & Patients, May2000;202:p152 Pittler, MH, Ernst E. Horse chestnut seed extract for chronic venous insufficiency. Cochrane Database Syst Rev 2002;(1):pp.CD003230 Pittler MH, Ernst E. Horse-chestnut seed extract for chronic venous insufficiency. A criteria-based systematic review. Arch Dermatol 1998 Nov;134(11):1356-60 Morien, K. Horse Chestnut Effective in Chronic Venous Insufficiency. HerbalGram, Winter 99;45:p22 Koch R. Comparative study of Venostasin and Pycnogenol in chronic venous insufficiency. Phytotherapy Res 2002 Mar;12(Suppl 1):S1-5 Rothkopf M, et al. New findings on the efficacy and mode of action of the horse chestnut saponins escin. Arzneim-Forsch/Drug Res 1976;26(2):225-35 **Guillaume M et al. Veinotonic effect, vascular protection, anti-inflammatory and free radical scavenging properties of horse chestnut extract. Arzneim-Forsch/Drug Res 1994;44(1):25-35 Tyler, VE. Herbs of Choice: The Terapeutic Use of Phytomedicinals. Binghampton, NY; Pharmaceutical Products Press, 1994:112-3

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17. Blumental M, Busse WR, Goldberg A et al. (eds.) The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston, MA: Integrative Medicine Communications, 1988:148-9 18. Hellberg K, Ruschewski W, de Vivie R. Medikamentoes bedingtes post-operatives Nierenversagen nach herzchirugischen. Eingriffen. Thoraxchirurgie 1975;23:396-9 19. Wilhelm K, Feldmeier C. Postoperative und posttraumatische Oedemprophylaxe und-therapie. Laborchemische Untersuchungen ueber die Nierenvertraeglichkeit von beta-Aescin. Med Klin 1975;70:2079-83 20. Newall CA, et al. Herbal Medicines: A Guide for Health Care Professionals. London: The Pharmaceutical Press 1996:166-7 21. Heck AM et al. Potential interactions between alternative therapies and warfarin. Am J health Syst Pharm, Jul2000;57(13):1221-7 22. Heck AM, DeWitt BA, Lukes AL. Am J Helath Syst Pharm 2000 Jul 1;57(13):p1221-7;Quiz p1228-30 23. Akopov SE et al. Mechanisms of platelet-induced angioplastic reactions: Potentiation of calcium sensitivity. Can J Physiol Pharmacol. Jul 1997;75(7):849-52 24. Dworschak E et al. Medical activities of aesculus hippocastaneum (Horse-chestnut) Saponins. Adv Exp Med Biol 1996;404:471-4

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Huperzine A General Features Huperzine A is an extract from a club moss (from the Lycopodiaceae family) that has been used for centuries in Chinese folk medicine for a variety of conditions. In modern times Huperzine A research has focused on its ability to raise brain levels of the memory chemical acetylcholine, hence its potential role in the treatment and prevention of Alzheimer’s Disease, dementia and other cases of memory and learning impairment. 1, 2

Principle Active Constituents Huperzine A or HupA is a specific alkaloid compound that is found in very low concentrations in the moss where it occurs naturally at only a 1% concentration. Thus, when used therapeutically, Huperzine A is given as a concentrated extract. Commercially available extracts contain up to 95% HupA concentration.1,2,3 HupA was first synthesized in 1990, which has helped to increase its availability in the marketplace.3

Clinical Application and Mechanism of Action 1. Alzheimer’s disease and Dementia In a double-blind trial with Alzheimer’s disease patients, the group given 200 mcg of Huperzine A, twice per day for eight weeks demonstrated significant improvement in memory, cognitive and behavioural functions. 7 Huperzine A has been used successfully in a clinical setting with approximately 100,000 Alzheimer’s and dementia patients in China.3 At Beijing’s Institute of Mental Health, Huperzine A was tested against fodine in 101 patients with benign senescent forgetfulness (age-related memory impairment). After four weeks of supplementation, 70% of the group receiving Huperzine A showed significant improvement in their memory as measured by memory quotient (MQ). An additional 111 Alzheimer’s patients were also included in the study. Overall, the group receiving HupA demonstrated a 10% improvement in the memory quotient over the four-week test period, and significant improvement in other measures of cognitive function. Side effects occurred in only 3% of these patients, with the most frequent side effects involving dizziness and gastrointestinal symptoms. 4 In a study done at Zhejiang Medical University in Shanghai, 103 patients with Alzheimer’s disease were given 200 mcg of HupA per day or a placebo. After eight weeks, 58% of those receiving HupA showed marked improvement in mental function, compared to 36% in the placebo group.2 In another double-blind study, the administration of Huperzine A at 100-150 mcg two to three times per day, was shown to be more effective than the drug piracetam in a trial involving patients with age-related cognitive decline.8 Animal research shows that Huperzine A has a greater ability to preserve acetylcholine levels than may be available through the use of some prescription drugs that act as acetylcholinesterase inhibitors. 9.10 2. Learning Enhancement Animal studies show that Huperzine A supplementation provides animals with memory-enhancement and a broad range of improved cognitive behaviors.5 There is some suggestion that Huperzine A supplementation in otherwise normal individuals can enhance memory and recall ability as well as learning capacity. In a small controlled trial of adolescent middle school students, the administration of 100 mcg of Huperzine A two times per day, was shown to be effective in improving memory and learning performance over a four week period. Although no side effects were reported, the researchers caution that this was a high dose of Huperzine A for subjects with no apparent signs of acetylcholine deficiency and the long term safety of such a practice needs to be established before young, healthy individuals should ingest doses in this range in an attempt to boost their learning capacity.11

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Biological Action HupA is rapidly absorbed by the brain where it acts as a potent, reversible and selective inhibitor of the enzyme acetylcholinesterase, which breaks down the memory chemical acetylcholine. By inhibiting this enzyme, brain concentrations of acetylcholine are increased, thereby facilitating improvements in memory and learning capacity. A hallmark feature of Alzheimer’s disease is reduced concentrations of acetylcholine in specific areas of the brain involved with memory and other cognitive functions. Huperzine A supplementation appears to help increase acetylcholine levels in Alzheimer’s patients in cases where the condition has not yet advanced to the point where brain cells are permanently damaged. Studies show that Huperzine A provides a longer acting effect than the drugs tacrine and doneprizil, which are used in Alzheimer’s disease, and it also appears to produce fewer side effects. This is due to the fact that only very small doses of Huperzine A are required due to its high specificity for the acetylcholinesterase enzyme. As such, HupA is under intensive investigation as a viable intervention in the prevention and treatment of Alzheimer’s disease, dementia, and other conditions involving learning and memory impairment.1,4,5,6 Further, it has recently been reported that HupA also reduces neuronal death (death of nerve cells) caused by glutamate (glutamate toxicity results in seizures associated with exposure to nerve gas), suggesting that HupA may act to protect brain cells from various types of degenerative damage and chemical insults. The dual bio-activities (preserving acetylcholine and protecting nerve cells) make HupA an attractive agent to study as a potentially important therapeutic agent for Alzheimer’s disease.1

Dosage and Standardized Grade 1. Alzheimer’s disease:150 to 200 mcg, one to two times per day in divided doses 2,12 2. Early Memory Loss: 50 to 150 mcg one to two times per day in divided doses 3,12 3. General Brain Support (after age 45-50): Consider 25 to 50 mcg per day

Adverse Side Effects, Toxicity and Contraindications Huperzine A inhibits the breakdown of acetylcholine by reversibly inhibiting the enzyme acetylcholinesterase. This gives rise to the potential to increase acetylcholine levels to toxic levels, if the dosage is too high. 1,13 Excessive levels of acetylcholine in the brain can result in cholinergic syndrome, which manifests as a slowing of the heart rate (bradycardia), contraction of the pupil of the eye (miosis), sweating, increased movement of intestinal tract contents (hyperperistalsis), as well as wheezing, excessive salivation, urinary incontinence and excessive discharge of mucus from the air passages of the lungs (bronchorrhea).14 To date, none of the human trials using Huperzine A have produced cholinergic syndrome in any subject. However, the potential for this to occur remains plausible and thus, dosage recommendations should be strictly adhered to and patients and practitioners should closely monitor response to the use of this bioactive agent.15 Side effects are rare at recommended doses, but may include dizziness and gastrointestinal symptoms. 4,8,10

Drug-Nutrient Interactions Acetylcholinesterase Inhibitors, such as Donepezil and Tacrine - These drugs also inhibit the breakdown of acetylcholine and therefore, the addition of Huperzine A may potentiate their effects, increasing the likelihood of developing cholinergic syndrome as a serious side effect. 17,18 These drugs on their own are noted for the side effects of vomiting, excess saliva and tear production, and increased sweating, which indicate their tendency to over stimulate the cholinergic system.15

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Bai DL, et al. Huperzine A, a potential therapeutic agent for treatment of Alzheimer’s disease. Curr Med Chem, Mar2000;7(3):355-74 Dworkin N. Restoring memory. Psychology Today, Jul/Aug00;32(4):p28 Pirisi, Angela. Plant wisdom: Memory moss. Yoga Journal, 08/31/1999;147:p95 McCaleb R. Huperzia looks promising for improving memory. HerbalGram, 10/31/1995;35:p14 Tang XC. Huperzine A (shuangyiping): A promising drug for Alzheimer’s disease. Chung Kuo Yao Li Hsueh Pao, Nov1996;17(6):481-4 Ashani Y, Peggins JO, Doctor BP. Mechanism of inhibition of cholinesterases by huperzine A. Biochem Biophys Res Commun, 1992:184:719-26 Xu SS, Gao, ZX, Weng Z et al. Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer’s disease. Chung Kuo Yao Li Hsueh Pao, 1995;16:391-5 Wang Z, Ren G, Zhao Y et al. A double-blind study of huperzine A and piracetam in patients with age-associated memory impairment and dementia. In: Kanba S, Richelson E (eds.) Herbal Medicines for Nonpsychiatric Diseases. Tokyo: Seiwa Choten Publishers, 1999:39-50 Cheng DH, Tang XC. Comparative studies of huperzine A, E2020, and tacrine on behavior and cholinesterase activites. Pharmacol Biochem Behav, 1998;60:377-86 Cheng DH, Ren H, Tang XC. Huperzine A, a novel promising acetylcholinesterase inhibitor. Neuroreport, 1996;8:97-101 Sun QQ, Xu SS, Pan JL, et al. Huperzine-A capsules enhance memory and learning performance in 34 pairs of matched adolescent students. Acta Pharmacol Sin, 1999;20:601-3 Qian BC, Wang M, Zhou ZF, et al. Pharmacokinetics of tablet huperzine A in six volunteers. Chung Kuo Yao Li Hsueh Pao, 1005;16:396-8 Huperzine A for memory enhancement? NCRHI Newsletter, 04/30/2000;23(2):3-4 [Pharmacist’s Letter] Current Medical Diagnosis and Treatment. 33rd Annual Revision, 1994. Lange Medical Books. Appleton and Lange:p1323 2001 Healthnotes, Inc. www.healthnotes.com: Huperzine A Skolnick AA. Old Chinese herbal medicine used for fever yields possible new Alzheimer disease therapy. JAMA, Mar1997;277(10):p776 Cheng DH et al. Huperzine A, a novel promising acetylcholinesterase inhibitor. Neuroreport, Dec1996;8(1):97-101 Liu J, et al. Inhibitory effects of huperzine B on cholinesterase activity in mice. Chung Kuo yao Li Hsueh Pao, Feb1999;20(2):141-4

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Kava (Piper methysticum) General Features Natives of the South Pacific have used a nonalcoholic drink made from Kava root as a ceremonial and social drink for centuries. Kava was valued for its mellowing effects and to encourage socializing by these native groups. It has been cultivated over the years for such purposes by Pacific Islanders as first reported by Captain James Cook on his historic voyages through the South Seas. The Kava beverage first causes a numbing and astringent effect in the mouth, followed by a relaxed sociable state where fatigue and anxiety are lessened. Eventually a deep restful sleep ensues from which one is said to awaken the next morning refreshed and without symptoms of a hangover. Excess intake can produce a stupor and dizziness, a condition described as Kava abuse. 26 In 1966, European scientists interested in Kava’s sedative and intoxicant effects isolated its kavalactone constituents, which have been found to produce sedative, pain-killing, and anticonvulsant properties. Kava is a member of the pepper family and its rootstock or rhizome (underground stem) is used for medicinal purposes. Its most well defined application is in regards to its ability to reduce feelings of anxiety and as a natural sedative. 1, 9,10, 11

Principle Active Constituents Kava-lactones, also known as Kava-pyrones – these consist of fat soluble resins such as dihydrokavain, which have been found to produce sedative, painkilling and anticonvulsant effects. Other Kava-lactones include kavain, methysticin, and dihydromethysticin. 1, 9, 12,13,14.

Clinical Application and Mechanism of Action 1. Anxiety Kava-lactones have been shown to have natural sedative properties by influencing GABA (gamma amino benzoic acid) receptors, in a similar fashion as does benzodiazepines (e.g, valium), but appears to modulate the limbic system emotional processes rather than affect parts of the brain affected by benzodiazepines. 15, 16The limbic system is the primitive part of the brain that controls our emotions and survival instincts. 10 At least six, well-designed, clinical studies have provided evidence that Kava extract can be an effective intervention in the management of anxiety, from non organic causes (e.g., not appropriate for anxiety secondary to hyperthyroidism). These studies have tested Kava extract against placebo, against hormone replacement therapy in the treatment of anxiety associated with menopausal symptoms, and against common drugs used to treat anxiety, such as oxazepam, bromazepam, and other standard benzodiazepines. In one of the smaller trials, involving 52 anxiety patients, 81% of the subjects treated with Kava extract rated the treatment as very good or good. In the study of menopausal women, the Kava group reported better overall relief from anxiety than did the groups given hormone replacement therapy or placebo. When tested head-to-head against anti-anxiety drugs from the class of benzodiazepines, the Kava group reported the same level of improvement as provided by these proven medications. In total, these studies have followed more than 400 patients and suggest that Kava is an effective intervention for the treatment of anxiety from non-organic causes. However, Kava’s anti-anxiety effects may not manifest themselves until the eight week of continuous supplementation, although some studies indicate a benefit along these lines within the first week of treatment. The German Commission E states that Kava is useful for relieving “states of nervous anxiety, tension, and agitation”. 17,18,19,20,21,22,23,24,11

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Of special note is the fact that unlike benzodiazepines, Kava does not seem to impair reaction time or alertness when taken in divided doses throughout the day for the treatment of anxiety, at recommended intake levels. 2. Insomnia Kava is known to have sedative effects at specific levels of intake, which have prompted its use as a natural treatment for insomnia. This effect is also considered to be mediated through its influence of the limbic system. 10 In one placebo-controlled study of 12 healthy volunteers Kava extract was shown to improve the ability to fall asleep at a dose of 300 mg per day (yielding 210 mg of Kava-lactone content). It also lengthened the deep sleep phase and shortened the wakeful phases in sleep, according to EEG recordings (electro-encephalogram). These effects are looked upon favorably compared to effects on sleep induced by benzodiazepines and barbituate drugs. Kava administration also increased the density of sleep spindles, an effect, which is comparable to medical sedative drugs. 26

Dosage and Standardized Grade Kava extract should be standardized to contain a set percentage of Kava-lactone content. High-yielding products contain 70% Kava-lactone content as a rule 1. Anxiety (mild to moderate cases) – 45-70 mg Kava-lactones, three times daily. Up to 240 mg per day of Kava-lactone intake has been used for this purpose. The total daily dose should not exceed 300 mg. 9,10,11,26 2. Insomnia – 180—210 mgs of Kava-lactones one hour before bed time.1,2,3 According to the German Commission E monograph Kava should not be taken for more than three months without the advice of a physician. 27

Adverse Side Effects, Toxicity and Contraindications Liver Damage: Over the years there has been some suggestion that Kava use may induce liver damage in long-term users, as evidenced by the yellowing of the skin that occurs in some Kava users. 28 However, this was considered to be a skin reaction by many authorities and concern about liver injury was not strongly considered. As such, Kava was generally regarded as a safe supplement until recently. 27 However, in November 2001, German authorities reported 24 cases of liver damage associated with the use of Kava in Germany. Liver problems included hepatitis, liver failure, and cirrhosis. Of these, one person died and three required a liver transplant. 29 The 1998 edition of the German Commission E Monographs does not mention liver disease in its discussion of Kava’s side effects. 27 Since that publication date, four case reports of Kava-induced liver toxicity have appeared in medical journals. In two of these cases, severe liver failure resulted in the need for a liver transplant. 30,31,32,33 Of interest is the fact that in most, but not all of these cases, patients were taking other medications, which are known to cause liver damage as an established side effect. This may imply that Kava potentiated the liver-damaging effects of these drugs in these cases and that the use of Kava in the absence of such medications may not pose the same degree of risk of liver injury. 34 However, some of the cases of Kava-related liver disease cannot be explained by the concomitant use of other drugs. 9

Other investigations have implicated Kava as an agent that can produce liver injury. A survey of the aboriginal community in Australia revealed that heavy Kava users were at higher risk of developing liver damage, as evidenced by laboratory studies, than were non- users and occasional users of Kava. Risk of liver injury was directly related to the amount of Kava consumed. 35 In Germany, Canada and the United States, governments are have considered banning the use of Kava, due to reports from Europe indicating that taking Kava at recommended intake levels can induce severe liver injury, even

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in occasional users. At this time, Kava is still available without a prescription in many parts of the world, but experts suggest that individuals seek appropriate monitoring of liver enzymes by their physician if they intend to use this herbal agent on any level of frequency. Anyone with pre-existing liver disease or taking other drugs known to cause liver damage, or consuming alcohol on a regular basis, should avoid the use of Kava altogether. 11 On December, 18, 2001 the Food and Drug Administration (FDA) in the United States informed health care practitioners that it was launching an investigation to determine if Kava supplementation poses a health threat to human health. The agency noted that German and Swiss health authorities had reported approximately 25 cases of serious liver toxicity, related to Kava consumption. This initial communication was to serve as a data-gathering tool and was not issued as a warning or alert. “ Although there are currently no published reports of liver toxicity in the U.S., the FDA has indicated that it has received adverse event reports through its MEDWATCH system that potentially links Kava to liver damage.” 41 Other Side Effects: Long-term use (few months to a year) can produce Kava dermopathy (scali skin eruptions) on the palms, soles, forearms, back and shins. High doses (7310 gms per week) may decrease serum albumin, protein, urea, bilirubin, platelet count and lymphocyte count.1,2,3,4 Kava may temporarily turn skin yellow, create mild gastrointestinal disturbances, induce an allergic skin reaction, such as a rash and/or produce pupil enlargement in long-term users. 28,36,37 Short-term Kava studies (4 –7 weeks) at usual intake doses have not shown any significant side effects other than the occasional report of gastrointestinal upset or skin rash. 38 Acute Dystonic Reactions: Kava should not be use by individuals who have had acute dystonic reactions, which consist of spasms in the muscles of the neck and movements of the eyes. These problems are related to the neurotransmitter dopamine, according to popular beliefs, and are typically caused by antipsychotic drugs, which affect dopamine. Kava may trigger these reactions in patients with a known history of dystonic reactions. 40

Drug-Nutrient Interactions Kava supplementation is reported to potentiate the effects of the following medications leading to excess sedation and thus, should not be taken concurrently: Sedative medications ( benzodiazepines)42, 43 Alprazolam – a reported case possibly lead to coma in a patient combining Kava with this drug. 44 Antidepressant drugs 42 Diphenydramine – an over-the-counter drug that induces sedation

41,42

Alcohol – some reports suggest that Kava can increase alcohol’s damaging effects to the heart, nervous system, liver, immune system, kidneys and other organs. It is advisable not to combine Kava intake with the consumption of alcohol. 48,49,50

Antipsychotic drugs – Kava may increase risk of dystonic reactions if combined with these drugs. 11 Levodopa – patients with Parkinson’s disease taking levodopa should avoid Kava as Kava’s effects on the dopamine system may reduce the effectiveness of levodopa. 11

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Singh Y, Kava: An Overview, J Ethnopharmacol 37, 1992, 13-45. Holm E, et.al., Studies on the Profile of the Neurophysiological Effects of D.L.-kavain: Cerebral Sites of Action and Sleep-WakefulnessRhythm in Animals, Arzneimittel-Forsch 41, 1991, 673-683. Lindenberg D and Pitule-Schodel H, D, L-kavain in Comparison with Oxazepam in Anxiety Disorders. A Double-blind Study of Clinical Effectiveness, Forschr Med 108, 1990, 49-50, 53-54. Kinzler E, Kromer J, and Lehmann E, Clinical Efficacy of a Kava Extract in Patients with Anxiety Syndrome: Double-blind Placebo Controlled Study Over 4 Weeks, Arzneimittel-Forsch 41, 1991, 584-588. Warnecke G, Neurovegetative Dystonia in the Female Climacteric. Studies on the Clinical Efficacy and Tolerance of Kava Extract WS 1490, Forschr Med 109, 1991, 120-122. Norton SA and Ruze P, Kava Dermopathy, J Am Acac Dermatol 31, 1994, 89-97. Ruze P, Kava-induced Dermopathy: A Niacin Deficiency, Lancet 336, 1990, 1442-1445. Mathews JD, et.al., Effects of the Heavy Usage of Kava on Physical Health: Summary of a Pilot Survey in an Aboricinal Community, Med J Aust 148, 1988, 548-555. Healthnotes, Inc. 2001. www.healthnotes.com: Kava Dietary Supplement Information Bureau. www.content.intramedicine.com: Kava Natural Product Encyclopedia. www.consumerslab.com: Kava Meyer HJ, Kretzschmar R. Kawa pyroneâ&#x20AC;&#x201D;a new kind of substance group of central muscle relaxants of the mephenesin type [translated from German]. Klin Wochenschr 1966;44:902-3 Klohs MW, keller F, Williams RE et al. A chemical and pharmacological investigation of Piper methysticum Forst. J Med Pharm Chem 1959;1:95-103 Bruggemann VF, Meyer HJ. Studies on the analagesic efficacy of the kava constituents dihydrokavain (DHK) and dihydromethysticin (DHM) [in German; English abstract]. Arzneimittelforschung 1963;13:407-9 Jussofie A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology (Berl) 1994;116:469-74 Boonen G, Haberlein H. Influence of genuine kavapyrone enantiomers on the GABAA binding site. Planta Med 1998;64:504-6 Volz HP, Kieser M. Kava-kava extract WS 1490 versus placebo in anxiety disordersâ&#x20AC;&#x201D;a randomized placebo-controlled 25-week outpatient trial. Pharmacopsychiatry 1997;30:1-5 Kinsler E, Kromer J, Lehmann E. Effect of a special kava extract in patientw with anxiety-,tension-, and excitation states of non-psychotic genesis. Double blind study with placebos over 4 weeks [translated from German]. Arzneimittelforschung 1991;41:584-8

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19. Warnecke G, Pfaender H, Gerster G et al. Efficacy of an extract of kava root in patients with climacteric syndrome. A double blind study with a new mono-preparation [translated from German]. Z Phytother 1990;11:81-6 20. Warnecke G. Psychosomatic disorders in the female climacterium, clinical efficacy and tolerance of kava extract WS 1490 [translated from German]. Fortschr Med 1991;109:119-22 21. Malsch U, Klement S. Randomized placebo-controlled double-blind clinical trial of a special extract of kava roots (WS 1490) in patients with anxiety disorders of non-psychotic origin [abstract]. Eur Phytojournal [serial online]. 2000;1. Available at:http://www.escop.com/issue_1. Accessed May 10, 2001 22. Woelk H, Kapoula O, Lehri S et Al. The treatment of patients with anxiety. A double blind study: dava extract WS 1490 versus benzodiazepine [translated from German]. Z Allg Med 1993;69:271-7 23. Cropley M, Cave Z. Effect of kava and valerian on physiological responses to psychological stress assessed under laboratory conditions [abstract]. FACT 2001;6:76 24. De Leo V, la Marca A, Morgante G et al. Evaluation of combining kava extract with hormone replacement therapy in the treatment of postmenopausal anxiety. Maturitas 2001;39:185-8 25. Munte TF, Heinze HJ, Matzke M, Steitz J. Effects of oxazepam and an extract of kava roots (Piper methysticum) on event-related potentials in a word-recognicition task. Pharmacoelctroencephalog 1993;27:46-53 26. Principles and Practice of Phytotherapy. Mills S and Bone K. Churchill Livingstone. 2000: 456-58 27. Blumenthal M, Busse WR, Goldberg A et al. (eds.) The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston MA: Integrative Medicine Communications 1998:156-7 28. Jappe U, Franke I, Reinhold D, Golinick HPM. Sebotropic drug reaction resulting from kava-kava extract therapy: A new entity? J Amer Acad Dermatol 1998:38:104-6 29. Stafford, Ned. Germany may ban kava kava herbal supplement. Reuters Nov.19 2001 30. Escher M, Desmeules J, Giostra E, Mentha G. Hepatitis associated with kava, a herbal remedy for anxiety. BMJ 2001;322:p139 31. Kraft M, Spahn TW, Menzel J et al. [Fulminant liver failure after administration of the herbal antidepressant Kava-Kava.] Dtsch Med Wochenschr 2001;126:970-2 [in German]. 32. Strahl S, Ehret V, Dahm HH, Maier KP. [Necrotizing hepatitis after taking herbal remedies.] Dtsch Med Wochenschr 1998;123:1410-4 [in German] 33. Russmann S, Lauterburg BH, Helbling A. Kava hepatotoxicity. Ann Intern Med 2001;135:68-9 [letter] 34. Information provided by the German Federal Institute for Drugs and Medical Devices. 35. Mathews JD, Riley MD, Fejo L et al. Effects of the heavy usage of kava on physical health: summary of a pilot survey in an aboriginal community. Med J Aust 1988;148:548-55 36. Schmidt P, Boehncke WH. Delayed-type hypersensitivity reaction to kava-kava extract. Contact Derm 2000;42:363-4 37. Blumenthal M, Busse WR, Goldberg A et al (eds.) The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston MA: Integrative Medicine Communications 1998:156-7 38. Schulz V, Hansel R, Tyler VE. Rational Phytotherapy: A Physicianâ&#x20AC;&#x2122; Guide to Herbal Medicine. 3 rd ed. Berlin, Germany: SpringerVerlag;1998:p71 39. Schelosky L, Raffauf C, Jendroska K et al. Kava and dopamine antoginism [letter]. J Neurol Neurosurg Psychiatry 1995;58:639-40 40. National Nutritional Foods Association Update. December 21, 2001. Kava safety concerns raised. 41. Jussofie A et al. Kavapyrone enriched extract from piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology (Berl). Dec 1994;116(4):469-74 42. Klohs MW. Chemistry of Kava. Psychopharmacol Bull 1967;4(3):p10 43. Almeida JC et al. Coma from the health food store: Interaction between Kava and Alprazolam. Ann Intern Med Dec1996;125(11):940-1 44. Jamieson DD et al. Positive interaction of ethanol and kava resin in mice. Clin Exp Pharmacol Physiol Jul1990;17(7):509-14 45. Cantor C. Kava and alcohol. Med J Aust Nov1997;167(10):p560 46. Herberg KW. Effect of Kava-special extract WS 1490 combined with ethyl alcohol on safety-relevant performance parameters. Blutalkohol Mar1993;30(2):96-105

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Licorice (Glycyrrhiza Glabra) General Features Licorice is a perennial shrub, whose roots and underground horizontal stems called rhizomes are used medicinally. 1 Licorice originated in the Mediterranean and Middle East, where it has been used as flavoring agent since at least 500 B.C. 22 Most of the Licorice candy available in North America today contains no Licorice, but rather is flavored with anise oil. 21 When taken in high enough amounts (two to three weeks, at a dose of 1,000 mg of glycyrrhizin content) the glycyrrhizin constituent of Licorice produces effects similar to those of the hormone aldosterone, causing fluid retention, increased blood pressure, and loss of potassium. 23, 24 Thus, the long-term use of Licorice products containing glycyrrhizin can result in serious side effects and requires appropriate monitoring by a health professional. Some Licorice products used for the treatment of stomach ulcers and canker sores have the glychrrhizin removed and are referred to as de-glycrrhizinated Licorice (DGL). These products are not associated with the same adverse side effects noted for whole Licorice products or Licorice extracts containing glycrrhizin. 23 As Licorice is known to produce anti-inflammatory effects, contains phytoestrogens, regulates adrenal hormones, stimulates antibody production, stimulates mucous production in the esophagus, and provides antioxidant protection to liver cells, this herb has been used therapeutically for a vast number of health conditions over the years by alternative practitioners. 22, 1 However, the risk of serious side effects from the use of Licorice makes this herbal supplement (with the exception of DGL) a less desirable natural intervention for many conditions than the use of other herbal agents that are known to provide similar health benefits, without risk of serious adverse reactions. 22,23,24

Principle Active Constituents 1. Terpenoids: these include glycyrrhizin (also called glycyrrhizinic or glycrrhizic acid), which yields glycrrhetinic acid (also called Glycyrrhetic or glycrretic acid), as well as other terponoids. Terpenoids are steroid-like compounds that can affect steroid function in the body and, may also account for some of Licorice’s phytoestrogen effects on certain tissues.1 2. Flavonoids and Isoflavonoids: these provide the antioxidant properties and some of the phytoestrogen properties of Licorice products. The flavonoids found in Licorice also participate in the healing of peptic ulcers, a proven application for DGL.1 3. Coumarins: the presence of these constituents, increase the chance of developing photo-sensitivity–induced dermatitis, and possibly bleeding disorders (internal bleeding), due to their effects on inhibiting platelet aggregation.1,22

Clinical Application and Mechanism of Action 1. Premenstrual Syndrome (PMS) Licorice contains phytoestrogens (isoflavones and glycyrrhetinic acid), which have the ability to influence estrogen metabolism. Phytoestrogens generally have 1/20 and 1/100 the potency of the body’s estrogen. 1,2 PMS symptoms have been associated with an increased estrogen to progesterone ratio. 1 Licorice supplementation has been shown to improve symptoms of PMS, likely through its effects on toning down the influence of endogenous (produced in the body) estrogens, on breast, uterine and other tissues. 1,2,3 However, other herbal agents such as Black Cohosh and Chasteberry extract are also effective agents in the management of PMS and do not impose the same degree of adverse side effects associated with the use of Licorice. As such, they may be wiser choices for the management of PMS (see Black Cohosh, Soy Isoflavones and Chasteberry in this document)

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2. Anti-inflammatory Effects Licorice produces a cortisol – like action, which inhibits the formation of certain inflammatory compounds. Glycyrrhetinic acid may also have a direct anti-inflammatory action by selectively inhibiting the classical complement cascade.1 To date, there have been no well-designed human trials demonstrating the efficacy of Licorice in the management of arthritis or other inflammatory conditions. Other herbal agents such as curcumin, white willow extract, boswellia, and ginger, have been used in clinical trials for these purposes with good success, and may therefore be more reliable interventions for these problems. (see details for each of these herbal agents in this document) 3. Liver Support and Protection Glycyrrhizin has been shown to be an effective treatment in the management of viral hepatitis. 1 In-vitro studies demonstrate that it protects the liver from damage caused by chemical toxins such as carbon tetrachloride, likely through the inhibition of the cytochrome P-450 enzyme system conversion of CCI4 to CCI3.1 The flavonoid content of Licorice has also been shown in experimental studies to protect liver cells from free radical damage through its antioxidant effects. 22 At present there are no well-designed human trials to demonstrate how useful Licorice might be in the management and treatment of liver conditions, whereas, natural agents such as N-acetylcysteine, Reishi Mushroom Extract, Milk Thistle, Dandelion and Trimethylglycine (Betaine) have been shown to be effective in clinical trials with patients suffering from various liver disorders. (see details for each of these natural agents in this document) 4. Peptic Ulcers In an attempt to reduce the side effects of Licorice, de-glycyrrhizinated Licorice (DGL) was developed. The flavonoid content of Licorice has been shown to exert a number of health-promoting effects to the alimentary tract by affecting parietal cell acid secretion, gastric mucosal prostaglandin production, and possibly the inhibition of Helicobacter pylori bacteria growth. For these reasons DGL has been tested as a treatment for peptic ulcers, and the available studies suggest it has healing properties for gastric (stomach) and duodenal ulcers. 26 Taken as a chewable tablet, Caved-S or Ulcedal have demonstrated remarkable success in treating gastric and duodenal ulcers. The results are comparable to the ulcer medications cimetidine and ranitidine commonly used in the treatment of gastric ulcers. Furthermore, these chewable Licorice tablets were shown to be equally, or more effective as these standard ulcer drugs in regards to preventing ulcer recurrence (one year follow-up). It appears that these tablets must mix with saliva in order to be effective, thus, swallowing Licorice capsules is ineffective in ulcer treatment.1,2 Chewing de-glycyrrhizinated Licorice chewable tablets may be seen as an effective complementary means of treating gastric and duodenal ulcers. DGL appears to stimulate the normal defense mechanisms that prevent ulcer formation. Specifically, DGL improves and enhances the quality and quantity of the protective coating that lines the intestinal tract, increases the life span of the intestinal cells, and improves blood supply to the intestinal lining. 13 Scientific evidence suggests that Licorice-derived compounds, other than glycchrizin, have the effect of raising the local concentration of those prostaglandins that promote mucus secretion and cell proliferation (through inhibition of 15- hydroxyprostaglandin dehydrogenase and delta-13-prostaglandin reductase) in the stomach, leading to the healing of ulcers. 29 DGL has been shown to be more cost-effective than Tagamet or Zantac, costing 85 percent less for a month’s supply.13

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As an aside, it should be kept in mind that modern day medicines are now able that target the Helicobacter pylori bacteria, which is a principal cause of ulcers; an effect that may not occur through the use of DGL alone (test tube studies show that DGL also kills the Helicobacter pylori bacteria, but it is not proven in-vivo). Hence, DGL may be viewed as a good complementary medicine in the treatment of peptic ulcers, in this regard. 24 Finally, a preliminary study suggests that DGL might help prevent ulcers caused by the use of aspirin and other non steroidal anti-inflammatory drugs (e.g., ibuprofen), and thus may be considered as a prophylactic intervention, by patients taking these medications for prolonged periods. 24 5. Canker Sores De-glycyrrhizinated Licorice chewable tablets may also speed the healing of apthous ulcers (canker-sores), although there is less evidence for this application than for its effects on treating and preventing peptic ulcers 14 For this purpose, DGL (200 mg) is mixed with warm water and swished in the mouth for three minutes, and then expelled. 23 (see also Reishi Mushroom Extract in this document) 6. Eczema, Psoriasis and Other Skin Conditions With topical application, glycyrrhetinic acid produces an effect similar to hydrocortisone, and has been used with some success in the treatment of eczema and psoriasis.15 An extract of Licorice, called liquiritin, has been used as a treatment for melasma, a pigmentation disorder of the skin. One study showed a 70% improvement rating when this cream was applied twice daily for four weeks, compared to only 20% improvement in the placebo group. 25 Licorice creams and gels can also be applied directly to herpes sores, and may help to speed the healing of these lesions. 25

Dosage and Standardized Grade PMS and Anti-Inflammatory Applications: Consider a solid (dry powdered) extract (4:1) capsule containing 250-500 mg, taken three times per day. (standardized to 12 â&#x20AC;&#x201C; 20% glycrrhizin content) 2, 22,23 Peptic Ulcers: Studies have used DGL chewable tablets (250 - 380 mg), two to four tablets between meals, or 20 minutes before meals. Normally an 8-16 week course is utilized for therapeutic purposes. DGL tablets should contain no more than 1 â&#x20AC;&#x201C; 2% glycrrhizin content. 23, 27 Canker Sores (Apthous ulcers): Mix 200 mg of DGL with warm water and swish in mouth for three minutes, several times per day. 23,28

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Adverse Side Effects, Toxicity and Contraindications A major drawback to the use of Licorice is that doses of more than 3 gms of Licorice root daily (or doses as low as 100 mg of glycyrrhin) have caused hypertension, sodium and water retention, hypokalemia, and suppression of the rennin â&#x20AC;&#x201C; aldosterone- angiotensin system.16,17 Low serum potassium (hypokalemia), resulting from the use of Licorice, has resulted in cardiac arrhythmias and ECG abnormalities. These changes are thought to occur as a result of general depression of the rennin - aldosterone â&#x20AC;&#x201C; angiotensin system, and together constitute pseudo (hyper) aldosteronism. 1 As such, patients with high blood pressure or an existing cardiovascular disorder, renal failure, or liver disease should be extremely cautious with Licorice use.1 Licorice has also been shown to reduce testosterone levels in some men by inhibiting enzymes involved in testosterone synthesis, and therefore should be avoided by men combating impotence, infertility, or decreased libido. 30

As a result of these common side effects, long-term use of Licorice extract or whole Licorice supplementation should only be undertaken if prescribed by a qualified health professional, who is able to monitor side effects, including certain parameters of the blood chemistry profile. 23, 29 Licorice may also interfere with hormone replacement therapy and hypoglycemic therapy. 18 It inhibits or enhances the activity of prednisone, and should not be used in conjunction with a vast number of medications, as outlined below. 1,19 The following side effects are common at doses of 400 mg or more of glycyrrhizin per day: 13 - Hypertension - Sodium and water retention - Excessive potassium excretion (hypokalemia) - Cardiac Arrhythmias - Amenorrhea - Hyperprolactemia (with possible infertility) 13 - Several deaths have resulted from the ingestion of Licorice products.1 The Dutch Nutrition Information Bureau suggest that no more than 200 mg of glycyrrhizin should be consumed daily.20 According to the German Commission E Monographs, Licorice is contraindicated in the following conditions: cholestatic liver disorders, liver cirrhosis, hypertension, hypokalemia, severe kidney insufficiency and pregnancy, as well as in cases of edema or congestive heart failure. 29

Drug-Nutrient Interactions Licorice supplementation (excluding DGL) has been shown to cause electrolyte imbalances in some individuals and thus, its use is contraindicated in patients on the following medications: Digoxin and Digitalis 1, 18, 31,32 Laxatives 33,34 Lithium 35, 36 Licorice has also been reported to alter the effectiveness of the following drugs and thus, its use is contraindicated in patients on the following medications: Antihypertensive drugs Diuretics 37,38

37, 38

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Corticosteroid drugs (e.g., predisone): Licorice can either potentiate or inhibit the effects of predisone and other coricosteroid drugs. 35,36 Nitrofurantoin: Licorice increases the absorption and blood levels of this drug. 41 Anticoagulants: Licorice has been shown to increase risk of a bleeding disorder if taken concurrently with warfarin or coumadin. 37,38 Side Note As noted earlier, most of the Licorice candy available in North America is flavoured with anise oil, not Licorice.21 Authentic Licorice candy contains between 0.26 mg/g and 7.9 mg/g of glycyrrhizin; while medicinal Licorice products range from 0.30 mg/g to 47.1 mg/g of glycyrrhizin.22 Authorâ&#x20AC;&#x2122;s Note: Generally speaking, a number of other herbal agents can be used more safely for PMS, as antiinflammatory agents and for liver support, in place of Licorice. The most useful role of Licorice appears to be for the treatment of peptic ulcers through the use of chewable DGL tablets, which do not produce the side effects associated with other Licorice supplement products.20

1. 2. 3. 4.

Boon H and Smith M. Health Care Professional Training Program In Complementary Medicine, Institute of Applied Complementary Medicine Inc 1997:227-235. Murray MT. The Healing Power of Herbs, Rocklin CA; Prima Publishing 1992:246 Newall CA, Anderson LA, Phillipson JD. Herbal Medicines:A Guide For Health Care Professionals, London;The Pharmaceutical Press 1996:296. Kroes BH, Beukelman CJ, van den Berg AJ, Wolbink GJ, van Dijk H, Labadie RP.Inhibition of Human Complement by Beta-glycyrrhetinic Acid, Immunology 1997;90(1):115-120

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5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

Suzuki H, Ohta Y, Takino T, Fugisawa Kea.Effects of Glycyrrhizin on Biochemical Tests in Patients with Chronic Hepatitis: Double-blind Trial, Asian Medical Journal 1984;26:423-438 Kiso Y, Tohkin M, Hikino H, et.al., Mechanisms of Antihepatotoxic Activity of Glycyrrhizin, I. Effect on Free Radical Generation and Lipid Peroxidation, Planta Medica 1984;50:298-302 Morgan AG, McAdam WAF, Pacsoo C, Darnborough A. Comparison between Cimetidine and Caved-S in the Treatment of Gastric Ulceration, and Subsequent Maintenance Therapy, Gut 1982;23:545-551 Glick L. Deglycyrrhizinated Liquorice for Peptic Ulcer, Lancet 1982;2:p 817 Tewari SN, Wilson AK. Deglycyrrhizinated Liquorice in Duodenal Ulcer, Practitioner 1972;210:820-825 Kassir ZA. Endoscopic Controlled Trial of Four Drug Regimens in the Treatment of Chronic Duodenal Ulceration, Irish Medical Journal 1985;78:153-156 Murray M. The Healing Power of Herbs (2nd edition), Prima Publishing 1995:228-239 Das SK, Gulati AK, and Singh VP. Deglycryrrhizinated Liquorice in Aphthous Ulcers, J Assoc Physicians India 1989;37:p647 Evans FQ. The Rational Use of Glycyrrhetinic Acid in Dermatology, Br J Clin Pract 1958;12:269-279 Sharaf A and Goma N. Phytoestrogens and Their Antagonism to Progesterone and Testosterone, J Endocrinol 1965;31:289-290 Stormer FC, Reistad R, and Alexander J. Glycyrrhizic Acid in Liquorice â&#x20AC;&#x201C; Evaluation of Health Hazard, Fd Chem Toxicol 1993;31303-312 Biglieri EG. My Engagement with Steroids: A Review-Steroids 1995;60(1):52-58 Schleimer RP. Potential Regulation of Inflammation in the Lung by Local Metabolism of Hydrocortisone, American Journal of Respiratory Cell and Molecular Biology 1991;4:166-173 Chandler RF. Glycyrrhiza Glabra In: De Smet PAGM, Keller K, Hansel R, Chandler RF, eds, Adverse Effects of Herbal Drugs, Volume 3 ed., New York: Springer 1997:67-87 Tyler V, The Honest Herbal (3rd edition), Binghampton, New York: Pharmaceutical Products Press 1993:p375 Spinks EA, Fenwick GR. The Determination of Glycyrrhizin in Selected UK Liquorice Products, Food Additives and Contaminants 1990;7:769-778 Dietary Supplement Information Bureau. www.content.intramedicine.com:Licorice Healthnotes, Inc. 2001. www.healthnotes.com:Licorice Natural Products Encyclopedia. www.consumerslab.com:Licorice Rees, WD, Rhodes J, Wright JE et al. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gatroenterol 1979;14:605-7 Amer M, Metwalli M. Topical liquiritin improves melasma. Int J Dermatol 2000;39:299-301 Blumenthal M, Busse WR, Goldberg A et al. (eds.) The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston, MA: Integrative Medicine Communications 1998:161-2 Bardhan KD, Cumberland DC, Dixon RA, Holdsworth CD. Clinical trial of deglycyrrhizinised liquorice in gastric ulcer. Gut 1978;19:779-82 Das SK, Das V, Gulati AD, Singh VP. Deglycyrrhizinated licorice in aphthous ulcers. J Assoc Physicians India 1989;37:p647 Mills S, Bone K. 30 Principles and Practice of Phytotherapy. Churchill Livingstone:465 â&#x20AC;&#x201C; 478 Armanini D, Palermo M. Reduction of serum testosterone in men by licorice. N Engl J Med 1999;341:p1158 Farese RV et al. Licorice-induced hyperminarlocorticoidism. New England J Med 1991;325:1223-7 DeSmet P et al. Adverse Effects Of Herbal Drugs I. Berlin, Springer-Verlag 1992:97-104 Epstein MT et al. Effect of eating liquorice on the rennin-angiotensin-aldosterone axis in normal subjects. Br Med J 1977;1:488-90 Takeda R et al. Prolonged pseudoaldosteronism induced by glycyrrhizin. Endocrinology Japan 1979;26(5):541-7 Gibson MR. Glycyrrhiza in Old and New Perspectives. Lloydia 1978;41(4):348-54 MacKenzie MA et al. The Influence of Glycyrrhetinic Acid on Plasma Cortisol and Cortisone in healthy Young Volunteers. J Clin Endocrin Metab 1990;70:1637-43 Hatano T et al. Phenolic constituents of licorice III. Structures of glicoricone and licuforanone, and inhibitory effects of licorice constituents on monoamine oxidase. Clin Pharm Bull 1988;36:2090-7 Mahram GH et al. A further contribution to the triterpenoid constituents of glycyrrhiza glabra. Planta Medica 1989;55:p629

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Milk Thistle (Silybum Marianum) General Features Milk Thistle has been used medicinally for several thousand years. 1 Medical use of Milk Thistle can be traced back to the well-known 17th century pharmacist Nicholas Culpeper, who cited the use of Milk Thistle as a medicinal agent for opening “obstruction” of the liver and spleen, and recommended it for the treatment of jaundice. 46 The Greeks and the Romans also noted its ability to protect against and repair certain liver conditions. Scientific investigation into the use of liver-related conditions began in the 1960’s, with the isolation of silymarin (a combination of flavonolignans) from the ripe seeds. It is essentially the silymarin content of Milk Thistle extract, which has been shown to provide its medicinal effects, especially in regards to the treatment and prevention of various liver conditions. 42, 46 In 1986, the German Commission E approved an oral extract of Milk Thistle standardized to 70% crude silymarin content as a treatment for liver disease. 47

Principle Active Constituents Silymarin – Silymarin is a mixture of flavonolignans consisting chiefly of silibinin, silidianin, and silicristin. Silibinin is the silymarin component that yields the greatest degree of biological activity and is largely responsible for the benefits attributed to silymarin Milk Thistle extracts are usually standardized to contain 70 to 80 percent silymarin content 2,6, 46,47

Clinical Application and Mechanism of Action Mechanism of Action Extensive investigation into the biological activities of silymarin have uncovered the following mechanisms of action: 1. Antioxidant Function: Silymarin has been shown to be at least ten times more potent in its antioxidant activity than 2,3,4,5,6 vitamin E, in the liver, stomach, and intestine. Experimental evidence reveals that silymarin protects animals from liver damage upon exposure to diverse toxic chemicals, such as carbon tetrachloride, ethanol, galactosamine and amanita phalloides or its toxins – a very lethal agent from the toadstool mushroom. 2,3,4,5,6,7,8,9 2. Increases Liver Glutathione: Silymarin increases liver glutathione content by over 35 percent in healthy human subjects and by over 50 percent in rats. In the liver, glutathione participates in both phase I and phase II detoxification processes, facilitating the detoxification of a wide range of hormones, drugs and chemicals. Glutathione also acts as an intracellular antioxidant that protects cells against dangerous free radicals from various sources. 3,4,5,9,10,11,12 In many liver and immune-related diseases, glutathione liver concentrations are depleted permitting faster advancement of liver damage and disease progression. The ability of Milk Thistle to help restore liver glutathione levels is considered to be a primary means by which silymarin has been shown to be an effective treatment for various liver diseases. 46,47,48 3. Inhibits the formation of pro-inflammatory leukotrienes (eicosanoids): This effect may help to control swelling and inflammation from various types of mechanical and chemical insults. 13,14 4. Stimulates Protein Synthesis: Silibinin stimulates RNA polymerase A (also known as polymerase I) and DNA synthesis, which in turn increase the synthesis of ribosome proteins and thus, stimulates cell development. This ultimately increases the regenerative capacity of liver cells and results in the production of new liver cells to replace the damaged old ones. As such, silymarin has been shown to aid in the repair of liver cells that have been damaged by various microorgamisms, alcohol, and other damaging chemicals. However, silymarin has not been shown to have a stimulatory effect on malignant liver tissue. 6,15,16,10,17 www.meschinohealth.com

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5. Competitive Binding with Some Toxins: Silymarin appears to compete with amanita phalloides â&#x20AC;&#x201C; based toxins (from toadstool (deathcap) mushrooms) for a receptor on the cell membrane. Under experimented conditions, silymarin prevents death in animals exposed to these very lethal liver toxins when given prior to the amanita phalloides toxins, or within 10 minutes after exposure to these toxins. 10,7,8,18 6. Increased Superoxide Dismutase Concentrations: Silymarin has been shown to increase the concentrations of superoxide dismutase â&#x20AC;&#x201C; a very powerful intracellular antioxidant, which quenches the superoxide anion (a very 19 aggressive damaging and reactive, free radical oxygen species). Clinical Applications: (Primarily The Treatment of Various Liver Conditions) 1. Cirrhosis: Patients with liver damage due to excess alcohol consumption have shown improvement in laboratory, and liver biopsy assessment after silymarin treatment. Another study revealed improved survival in patients with cirrhosis who were treated with silymarin versus placebo, in a 4-year study involving 87 patients. 20,21,22 A doubleblind, placebo-controlled study involving 106 Finnish soldiers with alcoholic liver disease revealed that treatment with Milk Thistle produced improvement in regards to a reduction in liver enzyme blood levels and histological improvement of liver cells, as evidenced by liver biopsy samples in 29 subjects. 49 Two other studies have provided similar evidence 50, 51, although not all studies performed to date have demonstrated these types of positive results in alcoholic liver disease. 52,53 2. Chronic Viral Hepatitis and Acute Hepatitis: Most, but not all, studies have shown the effectiveness of silymarin in treating both acute and chronic hepatitis. 10,23,24,47 In the majority of these studies improvement in bilirubin levels and liver serum enzymes have been documented, and a reduction in abdominal discomfort, fatigue, and improved appetite have been reported in patients treated with silymarin. To date the majority of successful clinical trials have administered silymarin intravenously (I.V.) and therefore, the applicability of these findings to the oral ingestion of silymarin is not completely known. 10,23,24,25 However, one recently completed, well-designed clinical trial showed that the oral intake of Milk Thistle (yielding 240 mg per day) decreased blood levels of AST, ALT, and gammaglutamyltransferase (GGT) in a study of 20 patients with chronic viral hepatitis. These are all known to be important liver enzyme blood tests that are highly correlated with the degree of liver damage. 23 3. Protection from Chemical Toxins: Animal studies reveal that Milk Thistle extract protects the liver from a variety of toxins including alpha-amanitin and phalloidin (both from the extremely poisonous Deathcap or Toadstool mushroom), carbon tetrachloride, thioacetamide, DL-ethionine, phenothiazines acetaminophen and ethanol 10,26,27,28,29,47 (alcohol). Several human studies have shown that silymarin can reverse certain instances of liver damage induced by alcohol consumption (treated subjects demonstrated improved values for amino transferase (AST) and alanine aminotransferase (ALT) in blood testing). There was also a trend in the concentrations of total and conjugated 10,30 serum bilirubins in the silymarin group, compared to the controls. Another study with patients taking the psychotropic drugs phenothiazines or butyrophenones, demonstrated that silymarin decreased liver damage induced by these drugs and decreased serum levels of malondialdehyde (MDA), which is a biomarker for the production of free radicals. 31 However, a study examining the protective role of Milk Thistle in Alzheimerâ&#x20AC;&#x2122;s patients taking the drug tacrine, failed to show that Milk Thistle could prevent the liver inflammation that is known to be a side effect of this medication. 54 4. Enhance Detoxification: For general support of liver detoxification in anti-aging medicine silymarin has been shown to significantly increase liver concentrations of glutathione, increase solubility of bile and provides additional antioxidant support to liver cells. As such, it is recommended by anti-aging and holistic practitioners as supplement that may help to slow the biological processes of aging and exert a number of health-promoting effects that are consistent with principles of disease prevention practices. 10,32,11,12

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5. Psoriasis: A number of reports suggest that silymarin may be of value in the treatment of psoriasis, likely due to its ability to inhibit the synthesis of pro-inflammatory leukotrienes and improve the liverâ&#x20AC;&#x2122;s capacity to detoxify foreign compounds and contaminants. Some evidence suggests that certain bioactive agents absorbed in the intestinal tract, that escape detoxification by the liver and intestinal mucosal cells, may trigger inflammatory reactions involved in the exacerbation of skin conditions, such as psoriasis. 33,34 This application, however, requires further substantiation, according to certain authorities. 47 6. Sluggish Liver or Minor Hepatic Insufficiency: This term is usually used by European physicians and American Naturopaths to describe a myriad of symptoms involving aching beneath the ribs, fatigue, unhealthy skin appearance, general malaise, constipation, allergies, premenstrual syndrome, and/or chemical sensitivities, for which Milk Thistle has been recommended. 55

Dosage and Standardized Grade Most Milk Thistle products are standardized to 70 to 80 percent silymarin content. Thus, a 200 mg (70% silymarin extract) tablet contains 140 mg of silymarin. 35,36, 46, 47,48 a. Liver Conditions: for the liver conditions mentioned above a dosage of 140 mg of silymarin, three times daily is often used.

30, 46,47,48

After 8-12 weeks improvement should occur, allowing a reduction to 140 mg twice per day.

b. Psoriasis: 140 mg of silymarin, three times daily.

c. Therapeutic Detoxification Support: 140 mg of silymarin, twice daily.

Adverse Side Effects, Toxicity and Contraindications Milk Thistle is extremely non-toxic and side effects are rare. It increases bile flow and thus, may cause mild diarrhea in some individuals. 39,40,41 A study of 2,637 subjects reported in 1992 showed a low incidence of side effects, limited mainly to mild gastrointestinal disturbance. On rare occasions more severe abdominal discomfort has occurred. 56,57

Drug-Nutrient Interactions There are no known adverse drug interactions reported for milk thistle. However, as it stimulates liver detoxification pathways it may potentially speed up the metabolism of some drugs. Thus, practitioners should closely monitor patients on concurrent medications. 42,43,44,45 Milk Thistle may reduce the liver damage or side effects of certain medications, and thus its concurrent administration with the following medications may be advisable: Acetaminophen Anesthetics Chemotherapy Clofibrate Halopersidol Metronidazole Pravastatin Tacrine43

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Foster S. Milk Thistle. Silybum marianum. Houston, TX: American Botanical Council;1997:p7 Awang D. Milk thistle. Can Pharm J 1993;422:403-4 Wagner H. Antihepatotoxic flavonoids. Plant Flavonoids in Biology and Medicine: Biochemical, Pharmacological, and SturctureActivity Relationships (Cody V, Middleton E, Harbourne jV, eds.) Alan R. Liss, New York 1986:p545-58 Adzet T. Polyphenolic compounds with biological and pharmacological activity. Herbs Spices Med Plants 1986;1:167-84 Hikino H, Kiso Y, Wagner H, Fiebig. Antihepatotoxic actions of flavanolignans from silybum marianum fruits. Planta Medica 1984;50:248-50 Wagner H. Plant constituents with antihepatotoxic activity. Natural Products as Medicinal Agents (Beal JL and Reinhard E, eds.) Hippokrates-Verlag, Stuttgart, Germany 1981 Vogel G et al. Protection against Amanita phalloides intoxication in beagles. Toxicol appl Pharm 1984;73:355-62 Vogel G et al. Studies on pharmacodynamics, site and mechanism of action of silymarin, the anti-hepatotoxic principle from Silybum marianum (L.) Gaert. Arzneimittel-Forsch 1975;25:179-85 Valenzuela A et al. Silymarin protection against hepatic lipid peroxidation induced by acute ethanol intoxication in the rat. Biochem Pharm 1985;34:2209-12 Hikino H, Kiso Y. Natural products for liver diseases. Economic and Medicinal Plant Research 1988;2:39-72 Valenzuela A, Aspillaga M, Vial S, Guerra R. Selectivity of silymarin on the increase of the glutathione content in different tissues of the rat. Planta Medica 1989;55:420-2 Campos R, Garrido A, Guerra R, Valenzuela A. Silybin dihemisuccinate protects against gluta thione depletion and lipid peroxisation induced by acetaminophen in rat liver. Planta Medica 1989;55:417-9 Fiebrich F, Koch H. Silymarin, an inhibitor of prostaglandin synthetase. Experientia 1979;35:148-50 Fiebrich F, Koch H. Silymarin, an inhibitor of prostaglandin synthetase. Experientia 1979;35:150-2 Sonnenbichler J et al. Stimulatory effect of silibinin on the DNA synthesis in partially hepatectomized rat livers: Non-response in hepatoma and othr malignant cell lines. Biochem Pharm 1986;35:538-41 Sonnenbichler J, Zetl I. Biochemical effects of the flavonolignan silibinin on RNA, protein and DNA synthesis in rat livers. Plant Flavonoids in Biology and Medicine: Biochemical, Pharmacological, and Structureâ&#x20AC;&#x201C;Activity Relationships (Cody V, Middleton E, and Harbourne JB, eds.) Alan R. Liss, New York 1986:319-31 Magliulo P, Carosi G, Minoli L, Gorini S. Studies on the regenerative capacity of the liver in rats subjected to partial hepatectomy and treated with silymarin. Arzneimittelforschung 1973;23:161-7 Desplaces A et al. The effects of silymarin on experimental phalloidin poisoning. Arzneimittel-Forsch 1975;25:89-96

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19. Muzes G, Deak G, Land I et al. Effect of the bioflavonoid silymarin on the in vitro activity and expression of superoxide dismutase (SOD) enzyme. Acta Physiologica Hungarica 1991;78(1):3-9 20. Schopen RD, Lange OK: Therapy of hepatoses, Therapeutic use of silymarin. Med Welt 1970;21:691-8 21. Ferenci P et al. Randomized controlled trial of silymarin treatment in patients with cirrhyosis of the liver. J Hepatol 1989;9:105-13 22. Deak G et al. Immunomodulator effect of silymarin therapy in chronic alcoholic liver diseases. Orv Hetil 1990;131:p1291-2 p1295-6 23. Buzzelli G, Moscarella S, Giusti A et al. A pilot study on the liver protective effect of silybin-phosphatidylcholine complex (IdB1016) in chronic active hepatitis. International Journal of Clinical Pharmacology Tehrapy and Toxicology 1993;31(9):456060 24. Lirussi F, Okolicsanyi L. Cytoprotection in the nineties: Experience with ursodeoxycholic acid and silymarin in chronic liver disease. Acta Physiologica Hungarica 1992;80(1-4):363-7 25. Berenguer J et al. Double-blind trial of silymarin versus placebo in the tratment of chronic hepatitis. Muench Med Wochenschr 1971;119:240-60 26. Weiss RF. Herbal Medicine. Gothenburg, Sweden: Ab Areanum 1988:362 27. Hruby C. Silibinin in the treatment of deathcap fungus poisoning. Forum 1984;6:23-6 28. Faulstich II, Jahn W, Wieland T. Silybin inhibition of amatoxin uptake in the perfused rat liver. Arzneimittelforshung 1980;30(1):452-4 29. Tuchweber B, Sieck R, Trost w. Prevention of silybin of phalloidin-induced acute hepatotoxicity. Toxicology and Applied Pharmacology 1979;51:265-75 30. Salami HA, Sarna S. Effect of silymarin on chemical, functional and morphological alterations of the liver. Scandinavian Journal of Gastroenterology 1982;17:517-21 31. Palasciano G, Portincasa P, Palmieri V et al. The effect of silymarin on plasma levels of malondialdehyde in patients receiving longterm treatment with psychotropic drugs. Current Therapeutic Research 1994;55(5)537-45 32. Nassauto G et al. Effect of silibinin on biliary lipid composition. Experimental and clinical study. J Hepatal 1991;12:290-95 33. Kock HP et al. Silymarin: Potent inhibitor of cyclic AMP phosphodiesterase. Meth Find Exp Clin Pharm 1985;7:409-13 34. Weber G et al. The liver, a therapeutic target in dermatoses. Med Welt 1983;34:108-11 35. Blumenthal M, Brusse WR, Goldber A et al. The Complete German Commission E Monographs. Austin, TX: American Botanical Council 1998:p685 36. Health care professional training program in complementary medicine. Boon H and Smith M. Institute of Applied Complementary Medicine Inc. 1997:241-5 37. Wagner H et al. The chemistry of silymarin (silybin), the active principle of the fruits of silybum marianum (L.). Gaertn ArzneimForsch Drug Res 1968;18:688-96 38. Brown DJ. Herbal Prescriptions for Better Health. Rocklin, CA:Prima Publishing 1996:151-8 39. Murray MT. The Healing Power of herbs. Rocklin, CA:Prima Publishing 1992:p246 40. Brown D. Silymarin educational monograph. Townsend Newsletter for Doctors 1994;136:1282-5 41. Tyler VE. Herbs of Choice. The Therapeutic Use of Phytomedicinals. Binghamton, NY: Pharmaceutical Products Press 1994:p209 42. The Botanical Pharmacy. Quarry Health Books2000. Boon H and Smith M:250-4 43. Beckmann-Knopp S, Rietbrock S, Weyhenmeyer R et al. Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes. Pharmacol Toxicol Jun2000;86(6):2506 44. Venkataramanan R, Ramachandran V, Komoroski BJ et al. Milk Thistle, a herbal supplement, drecreases the activity of CYP3A4 and uridine disphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos Nov2000;28(11):1270-3 45. Zhao J et al. Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: Implications in cancer chemoprevention. Carcinogenesis Nov1999;20(11):2101-8 46. Healthnotes Online. Healthnotes Inc, 2000. www.healthnotes.com: Milk Thistle 47. Natural Products Encyclopedia. www.consumerslab.com: Milk Thistle 48. Dietary Supplement Information Bureau. www.content.intramedicine.com: Thistle 49. Salmi HA, Sarna S. Effect of silymarin on chemical, functional and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 1982;17:517-21 50. Feher J, Desk G, Muzes G et al. Liver protective action of silymarin therapy in chronic alcoholic liver diseases [in Hungarian]. Orv hetil 1989;130:2723-7 51. Fintelmann V, Albert A. Proof of the therapeutic efficacy of LegalonW for toxic liver illnesses in a double-blind trial [translated from German]. Therapiewoche 1980;30:5589-94 52. Trinchet JC, Coste T, Levy VG et al. Treatment of alcoholic hepatitis with silymarin. A double-blind comparative study in 116 patients [translated from French]. Gastroenterol Clin Biol 1989;13:120-4 53. Bunout D, Hirsch SB, Petermann MT et al. Controlled study of the effect of silymarin on alcoholic liver disease [translated from Spainch]. Rev Med Chil 1992;120:1370-5

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54. Allain H, Schuck S, lebreton S et al. Aminotransferase levels and silymarin in de novo tacrine-treated patients with Alzheimerâ&#x20AC;&#x2122;s disease. Dement Geriatr Cogn Disord 1999;10:181-5 55. Giannola C, Buogo F, Forestiere G et al. A two-center study on the effects of silymarin in pregnant women and adult patients with so-called minor hepatic insufficiency [in Italian]. Clin Ther 1985;114:129-35 56. Albrecht M, Frerick H, Kuhn U et al. Therapy of toxic liver pathologies with Legalon [in German]. Z Klin Med 1992;47:87-92 57. Adverse Drug Reactions Advisory Committee. An adverse reaction to the herbal medication in milk thistle (Silybum marianum). Med J Aust 1999;170:218-9

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Muira Puama (Potency Wood) General Features This is one of the best-known herbs for treating erectile dysfunction and is used to enhance libido in both men and women. This shrub, native to Brazil, has been used traditionally as an aphrodisiac and nerve-stimulant in South American folk medicine.1 The British Herbal Pharmacopoeia recommends this herb in the treatment of impotence. 4

Principle Active Constituents Unknown

Clinical Application and Mechanism of Action 1. Erectile Dysfunction A 1990 study conducted at the Institute of Sexology in Paris, France, demonstrated that 62 percent of men reawakened their libido and 51 percent of men reversed erectile failure problems in 262 subjects, who initially complained of lack of sexual desire and inability to attain or maintain an erection. Results occurred within two weeks of beginning therapy with Muira Puama supplementation, at a daily dosage of 1000-1500 mg per day. 2 2. Female Libido Enhancement A unique blend of Muira Puama combined with Ginkgo Biloba (herbal VX) was assessed in 202 healthy women complaining of low sex drive. After one month of treatment with Herbal VX, 65 percent of women reported statistically significant improvements in frequency of sexual desires, sexual intercourse, and sexual fantasies, as well as in satisfaction with sex life, intensity of sexual desires, excitement of fantasies, ability to reach orgasm, and intensity of orgasm. A double-blind study is planned to further substantiate these results.3

Dosage and Standardized Grade Erectile Dysfunction â&#x20AC;&#x201C; 1000 â&#x20AC;&#x201C; 1500 mg per day, in divided doses, if used as a single agent (Standardized to 6:1 extract from Muira Puama root). 2

Adverse Side Effects, Toxicity and Contraindications Muira Puama is well tolerated and no significant side effects have been noted. non-toxic at therapeutic doses. 4

1,2,3

Drug-Nutrient Interactions There are no well-known drug-nutrient interactions for Muira Puama at this time.

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1,4

Muira Puama is reported to be

140 Meschino Health Comprehensive Guide to Herbs

1. 2. 3. 4.

Duke JA. Handbook of Medicinal Herbs (Boca Raton: CRC Press) 1985 Wyanberg J. Aphrodisiacs: Contribution to the clinical validation and use of ptychopetalum guyanna (murira puama) â&#x20AC;&#x201C; presented at The First International Congress on Ethnopharmacology. Strasber, France June 5-9, 1990 Waynberg J, Brewer S. Effects of herbal VX on libido and sexual activity in premenopausal and postmenopausal women. Adv Ther 2000;17(5):255-62 British Herbal Pharmacopoeia. British Herbal Medicine Association. West York, England, 1983:132-133

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Picrorhiza General Features Picrorhiza is a perennial plant, whose roots and rhizomes have been used for thousands of years in Indian traditional medicine. It grows high in the Himalayan mountains. 1,2 Picrorhizaâ&#x20AC;&#x2122;s most important use is in the treatment and prevention of liver conditions, whereby many of its protective influences appear to be similar to those exhibited by the herb milk thistle (see milk thistle in this document). 2 It may also benefit asthma sufferers, and patients with rheumatoid arthritis or a skin condition known as vitiligo. 1,2 There have a limited number of double-blind, placebo-controlled trials performed with Picrorhiza, but several open trials have provided preliminary evidence to support the positive outcomes revealed by animal and test tube studies. As such, it is difficult to make definitive statements about its clinical use, although its long history of use in Indian traditional medicine and recently performed clinical trials indicate that it is very non toxic and is associated with only occasional mild side effects. 1,2

Principle Active Constituents Iridoid Glycosides, including glycoside picroside-1, kutkoside, androsin, and apocynin. 2 A standardized preparation from roots of picrorhiza, which have been tested in preclinical studies, is a mixture of iridoid glycosides containing at least 60% picroside-1, and kutkoside in the proportion 1:1.5, and is known as Picroliv (Sabinsa Corporation). 3

Clinical Application and Mechanism of Action Liver Health Animal and laboratory studies strongly suggest that Picrorhiza may protect liver cells via four physiological mechanisms: 1. Picrorhiza extract stimulates growth of and regeneration of damaged liver tissues in a similar manner to the silymarin flavonoid from milk thistle. 4 2. Picroriza extract may be able to protect the liver from viral hepatitis infection and dose-dependent toxic agents such as alcohol and acetaminophen. 5,6,7,8 Rat liver was shown to be protected against the damaging effects of thioacetamide, galactosamine and carbon tetrachloride, when treated concurrently with Picrorhiza extract, under experimental conditions. 5 Mice injected with carbon tetrachloride showed significantly less liver damage upon concurrent treatment with picrorhiza, and rats subjected to daily high intake of alcohol ingestion developed significantly less liver damage than animals given the same amount of alcohol without concurrent intake of pirorhiza extract. 6,8 3. Picrorhiza extract may produce anti-inflammatory effects, helping to contain liver damage.2 4. Picrorhiza extract has been shown to act as an antioxidant in the liver, reducing liver cell damage from uncontrolled propagation of free radicals. 9 It may also help liver cells restore their intracellular glutathione stores after injury from infection of free radical insult. Glutathione is an extremely important intracellular antioxidant in liver cells and directly participates in the detoxification of many potentially dangerous chemicals that are filtered through the liver each minute of our lives. 9

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Human Studies 4. Viral Hepatitis In a study of 37 patients with chonic viral hepatitis B, who received picrohriza extract and 23 patients with chronic viral hepatitis B, who received the placebo, 59% of those treated with picrohriza extract showed no sign of the viral antigen 15 to 20 days after the course of treatment. In the placebo group, only one subject demonstrated this outcome. The treatment group received a dose of 200 mg of Picrorhiza extract daily for 30 days. 10 A second clinical trail demonstrated that Picrorhiza extract, plus a variety of minerals, was also successful in treating a series of cases of acute viral hepatitis, in a study performed in India, and a number of similar reports have appeared in Indian medical literature over the years. 1,11 In a randomized, double-blind placebo controlled trial in patients diagnosed with acute viral hepatitis (HBsAG negative). Patients receiving 375 mg of Picrorhiza root powder, three times per day for 2 weeks (n= 15) demonstrated significantly lower blood levels of the liver enzymes known as SGOT, SGPT as well as bilirubin, compard to the placebo group (n= 18). In the Picrorhiza treatment group, bilirubin levels returned to normal values in 27.44 days, on average, compared to 75.9 days in the group given the placebo. 7 5. Asthma Two preliminary trials indicate that picorhiza may improve breathing ability in asthma patients and reduce the severity of the condition. 12,13 This may be related to the ablitiy of picrorohiza extract to reduce inflammation in the lungs and related air passageways. 14 However, a double-blind follow-up study failed to show a benefit in asthmatic sufferers. 15 6. Rheumatoid Arthritis Animal studies indicate that Picrorhiza extract can decrease joint inflammation. 16 A single open trial suggested that Picrorhiza extract may reduce symptoms of rheumatoid arthritis to a limited degree. 17 7. Vitiligo Picrorhiza extract appears to modulate the immune system in such a way as to produce a beneficial effect on the benign skin condition called vitiligo, which has been shown to result from a hyperactive immune system. Vitiligo is characterized by irregular, pigment-free skin patches. 18 In a preliminary trial, Picrorhiza extract, in combination with the drug methoxsalen, was shown to hasten recovery from vitiligo faster than the combination of methoxsalen and sun exposure alone. 19

Dosage and Standardized Grade Therapeutic Dose For Above Conditions â&#x20AC;&#x201C; 250 â&#x20AC;&#x201C; 350 mg, twice or three times daily (standardized to 4% - 10% kutkin content) 2

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Adverse Side Effects, Toxicity and Contraindications Picrorhiza extract is considered very safe and only mild and infrequent side effects are associated with its use, which include loose stools and colic. 1,11

Drug-Nutrient Interactions 1. Diabetic Hypoglycemic Drugs – animal studies indicate that Picrorhiza may affect blood sugar, which may alter the dose requirement of diabetic hypoglycemic medications. Thus, proper patient monitoring is advised. 20 2. Anticoagulant Drugs (warfarin, coumadin, aspirin etc.) – as picrorihza has been shown in animal studies to inhibit platelet aggregation to some degree, it may potentiate the action of other anticoagulant drugs. Thus, proper patient monitoring is advised with respect to prothrombin time (INR). 14 3. Immunosuppressive Medications – experimental studies indicate that Picrorhiza may stimulate the immune system and thus, may counter the effects of immunosuppressive drugs. 18,21

1. 2. 3. 4. 5. 6. 7.

Healthnotes, Inc. 2001. www.healthnotes.com: Picrorhiza Dietary Supplement Information Bureau. www.content.intramedicine.com: Picrorhiza Sabinsa Corporation product Manual: Picroliv Singh V, et al. Effect of picroliv on protein and nucleic acid synthesis. Indian J Exp Biol Jan1992;30(1):68-9 Visen PK, et al. Curative effect of picroliv on primary cultured rat hepatocytes against different hepatotoxins: an in vitro study. J Pharmacol Toxicol Methods Oct1998;40(3):173-9 Santra A et al. Prevention of carbon tetrachloride-induced hepatic injury in mice by picrorhiza kurrooa. An in vitro study. J Pharmacol Toxicol Methods Oct1998;40(3):173-9 Vaidya AB, et al. Picrorhiza kurroa (Kutaki) Royle ex Benth as a hepatoprotective agent—Experimental and clinical studies. J postgrad Med Dec1996;42(4):105-8

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8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

Rastogi R, et al. Picroliv protects against alcohol-induced chronic hepatotoxicity in rats. Planta Med Jun 1996;62(3):283-5 Chander R, et al. Effect of picroliv on glutathione metabolism in liver and brain of mastomys natalensis infected with plasmodium berghei. Indian J Exp Biol Aug1992;30(8):711-4 Thygarajan SP, et al. Effect of Phyllanthus amcrus on chronic carriers of hepatitis B virus. The Lancet 1988 Oct1:764-6 Chaturvedi GN, Singh RH. Jaundice of infectious hepatitis and its treatment with an indigenous drug. Picrorhiza kurrooa [sic]. J Res Ind Med 1966;1:1-13 Rajaram D. A preliminary clinical trial of Picrorrhiza kurroa in brochial asthma. Indian J Pharmacol 1975;7:95-6 Shan BK, Kamat SR, Sheth UK. Preliminary report of use of Picrorrhiza kurroa root in bronchial asthma. J Postgrad Med 1977;23:118-20 Dorsch W et al. Antiasthmatic effectgs of picrorhiza kurroa: Androsin prevents allergen- and PAF-induced brochial obstruction in guinea pigs. Int Arch Allergy Appl Immunol 1991;95(2-3):128-33 Doshi VB, Shetye VM, Mahashur AA, Kamat SR. Picrorrhiza kurroa in bronchial asthma. J Postgrad Med 1983;29:89-95 Hart BA, Simons JM, Knaan-Shanzer S, et al. Antiarthritic activity of the newly developed neutrophil oxidative burst antagonist apocynin. Free Rad Biol Med 1990;9:127–31 Langer JG, Gupta OP, Atal CK . Clinical trials on Picrorhiza kurroa. Ind J Pharmacol 1981;13:98–103 [review] Atal CK, et al. Immunomodulating agents of plant origin I:Preliminary Screening. J Ethnopharmacol Nov1986;18(2):133-41 Bedi KL, Zutshi U, Chopra CL, Amla V. Picrorhiza kurroa, an Ayurvedic herb, may potentiate photochemotherapy in vitiligo. J Ethnopharmacol 1989;27:347–52 Joy KL, et al. Anti-diabetic activity of picrorrhiza kurroa extract. J Ethnopharmacology Nov1999;67(2):143-8 Sharma ML, et al. Immunostimulatory activity of picrorhiza kurroa leaf extract. J Ethnopharmacol Feb1994;41(3):185-92

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Pygeum (Pygeum africanum) General Features Pygeum africanum is an evergreen tree native to Africa. The bark of the tree is used by the natives of tropical Africa as a treatment for urinary disorders. European scientists were so impressed with reports of pygeum’s therapeutic benefits in these cases, they set out to discover which active constituents were responsible for these effects. They discovered that the bark contains fat-soluble compounds that are responsible for pygeum’s beneficial effects in the treatment of benign prostatic hyperplasia (BPH). Pygeum extract has also been shown to enhance the secretions of the prostate and bulbourethral glands, both in terms of quantity and quality. 1

Principle Active Constituents 1. Pentacyclic terpenes: which have an anti-edema effect or decongestion effect (reduce swelling) 2. Phytosterols (sterolic triterpenes): mostly beta-sitosterol and beta-sitosterone, which are shown to reduce the build up of pro-inflammatory prostaglandins. 3. Esters of ferulic acid bound to n-tetracosanol and n-docosanol: which indirectly controls testosterone activity in the prostate in a manner that reduces BPH. 1,31

Clinical Application and Mechanism of Action Benign Prostatic Hyperplasia (BPH) Mechanism of Action: The various active constituents in Pygeum extract appear to work synergistically to reverse BPH. The esters of ferulic acid reduce serum prolactin levels. Prolactin increases the uptake of testosterone by the prostate gland and its subsequent conversion to DHT (dihydrotestosterone) via the 5 alpha-reductase enzyme. In turn, a build up of DHT in the prostate increases the rate of cell division to an excessive degree, increasing the number of cells and mass of the prostate gland, which often results in BPH. 2,3,4 Pygeum extract also exerts a systemic cholesterol-lowering effect and reduces the intra-prostatic cholesterol content. 5 Breakdown products of cholesterol accumulate in prostate tissue, which may affect the development of BPH or prostate cancer. 4 These metabolites of cholesterol initiate degenerative changes of prostate cells, which can lead to enlargement and other degenerative changes. Interestingly, drugs that lower blood cholesterol (e.g., statin drugs) have been shown to favourably influence BPH and reduce the formation of damaging cholesterol metabolites. 1 The sterolic fraction of Pygeum extract (Phytosterols) helps to prevent testosterone accumulation within the prostate and has been shown to reduce inflammation by preventing the intraprostatic formation of pro-inflammatory prostaglandin series – 2. 5,6 Numerous studies indicate that Pygeum extract is effective in reducing the clinical symptoms of BPH. used in conjunction with Saw Palmetto extract 1 and Stinging Nettle (urtica dioica). 31

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7-30,

and is often

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Clinical Studies: At least ten double-blind, clinical trials, involving more than 600 men with BPH, have shown that Pygeum extract is an effective natural agent in the treatment of this condition. Most trials lasted 45 to 90 days and results generally showed a significant reduction in nighttime urination, urinary frequency, and residual urine volume, as well as a stronger urine stream, in men with diagnosed BPH. Pygeum extract is more popular in France and Italy, than in Germany.32 The exact mechanism as to how Pygeum works is no fully understood, but it does not appear to block the conversion of testosterone to dihydrotestosterone by inhibiting the 5-alpha reductase enzyme, which is the action of the drug finesteride and likely the therapeutic action of some natural agents such as Saw Palmetto, Stinging Nettle and Genistein (soy-derived isoflavone). Rather, Pygeum is thought to reduce prostate inflammation and congestion, and has been shown to inhibit other prostate growth factors linked to BPH. 1,33,34

Dosage and Standardized Grade Benign Prostatic Hyperplasia â&#x20AC;&#x201C; 100 mg, twice daily (standardized to 12 -14 percent triterpenes and 0.5% n-docosanol content) is a popular dosage of Pygeum used in the treatment of benign prostatic hyperplasia, but half of this daily dosage has also been used with success in some studies. 1,32

Adverse Side Effects, Toxicity and Contraindications Extensive animal studies reveal that Pygeum is non-toxic even at extremely high doses (i.e. 8gm/kg). It is well tolerated in BPH human trials with infrequent side effects reported, which include mild gastrointestinal distress, ranging from nausea to stomach pain. 1,35

Drug-Nutrient Interactions There are no well-known drug-nutrient interactions for Pygeum Africanum.

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.

Murry M. The Healing Power of Herbs. Prima Publishing 1995:286-93 Muntzing J et al. Direct and indirect effect of docosanol, the active principle in Tadenan, on the rat prostate. Invest Urol 1979;17:176-80 Thieblot L. Preventive and curative action of Pygeum africanum extracts on experimental prostatic adenoma in the rat. Therapie 1975;26:575-80 Hinman F. Benign Prostatic Hyperplasia. Springer-Verlag, NY 1983 Bombardelli E. Methods, composition and compounds for the tratment of prostatic adenoma. European Patent Appl 8330491.3, June 10, 1985 Marcoli M. Anti-inflammatory and antiedemigenic activity of extract of Pygeum africanum in the rat. New Trends Androl Sci 1985;1:89 Guillemin P. Clinical trials of V1326, or Tadenan, in prostatic adenoma. Med Pract 1970;386:75-6 Lange J, Muret P. Clinical trial of V1326 in prostatic disease. Medicine 1970;11:2807-11 Wemeau L, Delmay J, Blankaert J. Tadenan in prostatic adenoma. Vie Medicale January 1980:585-8 Viollet G. Clinical experimentation of a new drug from prostatic adenoma. Vie Medicale June, 1970:3457-8 Lhez A, Leguevague G. Clinical trials of a new lipid-sterolic complex of vegetal origin in the tratment of prostatic adenoma. Vie Medicale December 1970:5399-5404 Thomas JP, Rouffilange F. The action of Tadenan in prostatic adenoma. Rev Int Serv 1970;43:43-5 Huet, JA. Prostatic disease in old age. Med Intern 1970;5:405-8 Rometti A. Medical treatment of prostatic adenoma. La provence medicale 1970;38:49-51 Gallizia F, Gallizia G. Medical treatment of benign prostatic hypertrophy with a new phytotherapeutic principle. Recent Med 1972;9:461-8 Durval A. The use of a new drug in the treatment of prostatic disorders. Minerva Urol 1970;22:106-11 \Pansadoro V, Benincasa A. Prostatic hypertrophy:Results obtained with Pygeum africanum extract. Minerva Med 1972;11:119-44 Zurita EI, Pecorini M, Cuzzoni G. Treatment of prostatic hypertrophy with Pygeum africanum extract. Rev Bras Med 1984;41:364-6 Maver A. Medical therapy of the fibrous-adematose hypertrophy of the prostate with a new vegetal substance. Minerva Med 1972;63:2126-36 Bongi G. Tadenan in the treatment of prostatic adenoma. Minerva urol 1972;24:129-39 Doremieux J, Masson JC, Bollack C. Prostatic hypertrophy, clinical effects and histological changes produced by a lipid complex extracted from Pygeum africanum. J med Strasbourg 1973;4:253-257 Del Valio B. The use of a new drug in the treatment of chornic prostatitis. Minerva Urol 1974;26:81-94 Colpi G, Farina U. Study of the activity of chloroformic extract of Pygeum africanum bark in the treatment of urethral obstructive syndrome caused by non-cancerous prostapathy. Urologia 1976;43:441-8 Donkervoort T et al. A clinical and urodynamic study of Tadenan in the treatment of benign prostatic hypertrophy. Urology 1977;8:218-25 Dufour B, Choquenet C. Trial controlling the effects of Pygeum africanum extract on the functional symptoms of prostatic adenoma. Ann Urol 1984;18:193-5 Legramandi C, Ricci-Barbini V, Fonte A. The importance of Pygeum africanum in the treatment of chronic prostatitis void of bacteria. Gaz Medica Ital 1984;143:73-6 Ranno S et al. Efficacy and tolerability in the treatment of prostatic adenoma with Tadenan 50. Progresso Medico 1986;42:165-9 Frasseto G et al. Study of the efficacy and tolerability of Tadenan 50 in patients with prostatic hypertrophy. Progresso Medico 1986;42:4952 Bassi P et al. Standardized extract of Pygeum africanum in the treatment of benign prostatic hypertrophy. Minerva Urol 1987;39:45-50 Barlet A et al. Efficacy of Pygeum africanum extract in the medical therapy of urination disorders due to benign prostatic hyperplasia: Evaluation of objective and subjective parameters. A placebo-controlled double-blind multicenter study. Wien Klin Wochenschr 1990;102:667-73 Healthnotes Online. Healthnotes Inc, 2000;www.healthnotes.com:Pygeum Natural Product Encyclopedia. www.consumerslab.com:Pygeum Andro MC, Riffaud JP. Pygeum africanum extrct for the treatment of patients with benign prostatic hyperplasia:a review of 25 years of published experience. Vurr Ther Res 1995;56:796-817 Yablonsky F, Nicolas V, Riffaud JP et al. Antiproliferative effect of Pygeum africanum extract on rat prostatic fibroblasts. J Urol 1997;157:2381-7 Bombardelli E, Morazzoni P. Prunus africana (Hook, f.)Kalkm. Fitoterapia. 1997;68:205-18

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Red Clover (Trifolium pratense) General Features Interest in the physiological effects of phytoestrogens (plant-based estrogen) found in many plants first arose in Australia, during the 1940â&#x20AC;&#x2122;s, when it was observed that sheep grazing on various species of clover became infertile. It was several decades later, when results from epidemiological studies suggested that the dietary consumption of soy products might have a protective role in breast cancer. Subsequent research indicates that much of this protective effect appears to be related to the presence of isoflavones, which also possess phytoestrogen activity. Studies have shown that supplementation with soy isoflavones can help reduce hot flashes and related menopausal symptoms, favorably modulate hormonal levels in premenopausal women, increase levels of sex hormone-binding globulin (SHBG), which is deemed to be a favorable effect for protection against reproductive cancers, and help reduce risk of coronary heart disease in women. Soy isoflavones have also been shown to inhibit the aromatase enzyme in fat tissue, which converts androstenedione to estrone hormone. Higher levels of estrone hormone are associated with increased breast cancer risk and thus, isoflavones may provide additional protection from breast cancer by reducing circulating estrone levels via the inhibition of aromatase enzyme (estrogen synthase). To date a significant number of studies have evaluated the potential therapeutic and preventive effects of soy isoflavones on reproductive organ diseases in women and men, bone density and osteoporosis, cardiovascular disease, and the management of menopausal symptoms, premenstrual syndrome, fibrocystic breast disease, uterine fibroids and endometriosis (see soy in this document). The positive results from many of these investigations have sparked the interest of researchers, who are presently exploring the health benefits that may be available from the isoflavones contained within red clover. 1

Principle Active Constituents Red Clover is a rich source of isoflavones and is known to contain all four isoflavones, which include genistein, diadzein, formononetin, and biochanin A. The predominant isoflavones in soy include genistein and diadzein. Formononetin can be converted into diadzein, which in turn can be metabolized to equol by bowel bacteria. Equol has substantially more estrogenic activity than either diadzein or formononetin. Thus, the composition and concentration of the bacterial flora of the large bowel is an important determinant of how efficiently an individual can synthesize equol (the most powerful phytoestrogen) and thereby be influenced by its physiological effects. Studies show that there is great variation in the absorption rate of isoflavones, in general, from one person to the next. Isoflavones occur as flavone glycosides in soy, Red Clover and other plant foods. As such, the gut bacteria must first split the carbohydrate molecule away from the isoflavone to convert it to its free, aglycone form (without attachment to a carbohydrate). The aglycone form is then absorbed into the body and is able to exert its phytoestrogen effects on target tissues. (e.g., breast, endometrium, prostate gland, bone etc.). It has been shown that subjects with fewer gut bacteria (possibly from treatment with antibiotics or other causes) have less ability to absorb phytoestrogens for this reason and that absorption rates can vary from 13% to 35% depending upon the status of the individual gut microflora. Therefore, in some cases it may be wise to provide an individual with probiotic and/or prebiotic supplementation in order to restore, or further support, the gut microflora, and thereby increase the absorption of isoflavones from food and/or supplements. In general, it has been shown that between 30 to 70% of dietary isoflavones are converted to active metabolites by gut bacteria and are then able to get absorbed into the bloodstream, and exert their phytoestrogens effects on target tissues.1,2

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Clinical Application and Mechanism of Action 1. Prevention of Reproductive Organ Diseases In Women Although no long-term studies in humans exist to prove that Red Clover supplementation can prevent breast cancer and other female reproductive diseases, high intakes of soy are strongly associated with a significant reduction in risk. The chemical structure of phytoestrogens is very similar to the body’s own estrogens. Many reproductive cancers are known to result from, or be promoted by, over-stimulation by the body’s estrogen hormones, as well as from the use of hormone replacement therapy. Of great importance is the fact that isoflavones, which have only 1/1,000 to 1/10,000 the potency of estradiol (a potent estrogen made by the body), can bind to estrogen receptors and compete with estrogen in the human body. Isoflavones are a form of “selective estrogen receptor modifier” (SERM), which preferentially activate the beta estrogen receptors, dominant in the brain, bone and heart, yet show little affinity for the alpha estrogen receptor in breast and uterine tissue. This is similar to the effect of Tamoxifen, which is used as a drug to help prevent recurrence of estrogen receptor-positive breast cancer. Over-stimulation of alpha receptors from estradiol and estrone, tends to result in more rapid cell division and increased risk of breast cancer. Due to their greater affinity for beta receptors (including breast cells), isoflavones tend to slow the proliferation rate of breast cells, and breast cancer cells, in the presence of the body’s own estrogens. As such, isoflavones demonstrate, in experimental and animal models, features suggesting that they have real potential to prevent breast cancer (and other reproductive cancers), and may also be useful in containing and controlling existing reproductive cancers in certain cases. Intensive study is underway at this time to determine if this latter application is valid. Until this is clearly established, women should not take isoflavone supplements of any kind to help treat existing breast cancer or to help block the recurrence of breast cancer, without the consent of their attending physician.1,2,3 Although not as potent as estradiol, high intakes of phytoestrogens from food sources and isoflavone-containing supplements can increase blood levels of phytoestrogens to 1,000 times those of estradiol and other endogenous (made by the body) estrogens. Phytoestrogens compete with the body’s own estrogen for receptor sites (on the breast, bone, prostate, brain, cervix, etc.) and if endogenous levels are high, isoflavones have been shown to exhibit anti-estrogenic properties, toning down the dangerous over-stimulation effect of the body’s own estrogens. If endogenous estrogen levels are low (as occurs in menopause), isoflavones can produce estrogenic effects to help manage menopausal symptoms.7 2. Menopausal Symptoms A preliminary study involving 23 postmenopausal women by Lila Natchtigall (Gynecologist, N.Y.), showed that the use of 40 mg per day of Red Clover extract reduced the incidence of hot flashes by 50% during the 3-month period.4 A second open trial revealed that Red Clover extract (40 mg per day) resulted in significant improvement in night sweats and hot flashes.7 However, a group of researchers from George Washington University and Columbia University reviewed the scientific evidence for Red Clover in the management of menopause. Publishing their results in Menopause, the Journal of the North American Menopause Society, they found only two good clinical trials in which menopausal women were randomly given Red Clover extracts or a placebo for three months. Neither of the trials found Red Clover to be better than placebo for hot flashes or vaginal dryness, and found no benefit on blood cholesterol. As of December 2001, the Harvard Women’s Health Watch suggests that women would be better off spending their money on supplements that contain soy, not red clover, as soy has been shown to consistently improve menopausal symptoms and reduce high cholesterol levels in postmenopausal women, to a modest, but significant degree.4,5,6,7 By contrast, the use of hormone replacement therapy (HRT) has been shown to be very effective in managing menopausal symptoms, but is associated with a significant increase in risk of breast cancer. As a result, only 10-

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35% of postmenopausal women use it and half of those women discontinue HRT within a year, often due to side effects such as bleeding and breast pain or because of concerns about breast or uterine cancer, and thromboembolic disease. In fact, HRT is contraindicated in about 10% of postmenopausal women, including those who have a history of estrogen-dependent malignancy (breast cancer, uterine cancer, etc.), clotting disorders associated with estrogen use or active liver or thromboembolic disease. It is interesting to note that 85% of North American women experience hot flashes and other vasomotor changes during menopause, whereas a study of menopausal Thai women revealed that only 27% of these women experience these menopausal symptoms. A study of Japanese women noted a similar finding. Researchers believe that the higher intake of isoflavones in the traditional Asian diet accounts for the lower incidence of menopausal symptoms experienced by Asian women. This is further supported by migration studies that indicate that Asian women living in North America who abandon their traditional dietary patterns have a higher incidence of chronic and degenerative diseases, including hormone-dependent cancers, colon cancer, and cardiovascular disease compared with those who consume traditional Japanese diets. Other studies have shown that postmenopausal women with higher urinary excretion of isoflavones (a marker for higher intake and higher blood levels of isoflavones) demonstrate a significant reduction in hot flashes compared to women who excrete less than 2 mg of urinary isoflavones per day, on average (in women not using HRT).7 Authorâ&#x20AC;&#x2122;s Note: At this time, it appears that soy isoflavones and black cohosh provide the most reliable relief of menopausal symptoms and are also the safest natural interventions to use, regarding contraindications, side effects and drug-nutrient interactions. (See Soy and Black Cohosh in this document) 3. Bone Density and Osteoporosis Red Clover has been evaluated for its potential ability to support bone density through the effects of its phytoestrogen content. A one year trial (double-blind, placebo-controlled) involving 107 women showed that 40 mg of Red Clover extract decreased the rate of bone mineral density loss and bone mineral content reduction in the lumbar spine in pre and peri-menopausal women. No effect was seen in the hip or in urinary bone markers. Another study found that Red Clover extract supplementation increased bone mineral density in the proximal radius and ulna. 7,8 Studies using soy have also demonstrated a positive effect on bone density as well as the use of ipriflavone, a derivative of soy isoflavones.7 4. Cholesterol Lowering A review of the scientific literature revealed that three out of four clinical trials involving postmenopausal women found that Red Clover did not reduce high cholesterol or produce any significant changes to serum lipid levels. 6,9 By comparison, evidence supports the use of soy extract and soy foods as a natural cholesterol-lowering intervention.7,10 One study did show that Red Clover extract was able to increase HDL-cholesterol by 15 to 29% and reduce serum apolipoprotein B by 11.5-17% in postmenopausal women, after six months of treatment. These findings require verification.8

Dosage and Standardized Grade The most common therapeutic dosage of Red Clover extract yields 40 mg per day of Red Clover isoflavonoids.2,4,6,7,9

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Adverse Side Effects, Toxicity and Contraindications Red Clover is considered to be safe when taken in accordance with proper dosing guidelines. However, the presence of coumarins in Red Clover and Red Clover extract increases the potential for bleeding disorders, and thus, it should not be combined with anti-coagulant medications. Practitioners and patients should monitor response to the use of Red Clover for any increased bleeding or bruising tendencies. 5,11 Previous history of an estrogen-dependent or reproductive cancer requires that a patient seek clearance from their attending physician before using a phytoestrogen-containing supplement product, such as red clover.1,2,3

Drug-Nutrient Interactions Anti-coagulant Medications - The high coumarin content of Red Clover lends itself to an increase risk of bleeding disorders if combined with aspirin, warfarin, coumadin, heparin, Plavix (clopidogrel), Trental (pentoxifylline), or any other blood thinner.5,11

1. 2. 3.

4. 5. 6. 7.

Mills S and Bone K. Principles and Practice of Phytotherapy. Churchill Livingstone, Publisher:54-6;67-8 Medical Post, Oct 3, 2000: Isoflavones and Menopause Dornstauder E, Jisa E, unterrieder I, Krenn L, Kubelka W, Jungbauer A. Estrongenic activity of two standardized red clover extracts (Menoflavon) intended for large scale use in hormone replacement therapy. J Steroid Biochem Mol Biol 2001 Jul; 78(1):67-75 Gower T. New answers to menopause? Health Jan/Feb2002;16(1) p76 Robb-Nicholson C. By the way, Doctor: Does red clover work? Harvard Womenâ&#x20AC;&#x2122;s Health Watch Dec2001;9(4):p7 Fugh-Berman A, Kronenberg F. Red clover (Trifolium pratense) for menopausal women: current state of knowledge. Menopause 2001 Sep-Oct;8(5):333-7 Nachtigall LE. Isoflavones in the management of menopause. Total Health Jul/Aug2001;23(4):p26

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Clifton-Bligh PB, Baber RJ, Fulcher GR, Nery ML, Moreton T. The effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism. Menopause 2001 Jul-Aug;8(4):259-65 9. Howes JB, Sullivan D, Lai N, Nestel P, Pomeroy S, West L, et al. The effects of dietary supplementation with isoflavones from red clover on the lipoprotein profiles of post menopausal women with mild to moderate hypercholesterolaemia. Atherosclerosis 2000 Sep;152(1):143-7 10. Anthony MS, et al. Effects of soy isovlavones on atherosclerosis: potential mechanisms. Am J Clin Nutr Dec1998;68(6 Suppl):1390S-35S 11. Heck AM, DeWitt BA, Lukes Al. Potential interactions between alternative therapies and warfarin. Am J Health Syst Phar 2000 Jul 1;57(13):p1221-7;quiz p1228-30

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Reishi Mushroom Extract General Features Reishi Mushroom (Ganoderma lucidum) is called â&#x20AC;&#x153;the mushroom of immortalityâ&#x20AC;? in China and has been used in Oriental Medicine for over 2,000 years.1,2 In recent years its active ingredients have been the subject of intensive research regarding their apparent ability to help prevent or treat certain types of cancer, aid in the treatment of liver disease, HIV infection, acute or recurrent herpetic infections, high blood pressure, chronic bronchitis, allergies and asthma, and favorably modulate immune function.3 The Reishi Mushroom grows wild on decaying logs and tree stumps in the coastal provinces of China. The fruiting body of the mushroom is used medicinally. 4

Principle Active Constituents 1. Specific Polysaccharides: which occur in the form of Beta-D-glucans bound to amino acids. These agents are shown to possess immune-modulating and anti-cancer properties.3 2. Triterpene compounds known as ganoderic acids: which have been shown to lower blood pressure, reduce platelet stickiness and may decrease LDL-cholesterol.5 3. Other major active constituents: include sterols, coumarin and mannitol.5

Clinical Application and Mechanism of Action 1. Anti-Cancer Agent Animal cancer studies have shown a 50% tumor regression outcome with Reishi Mushroom Extract treatment (e.g., connective tissue cancer model in mice).6 Reishi Mushroom Extract is used by some cancer surgeons in Japan to treat cancer patients and significant anti-tumor and immunostimulation effects have been noted in many of these cases. 7 Polysaccharides from reishi mushrooms and from other types of folk-medicinal fungi are patented in Japan for use as immunomodulators in the treatment of cancer. They are combined with chemo- and radiotherapy and have demonstrated an ability to reduce side effects, increase the efficacy of treatments, and to accelerate recovery from disease.8,9 Studies from China have shown that Reishi Mushroom Extract potentiates the tumoricidal capacity of macrophages and T-cells.10,11 Reishi Mushroom Extract is known to have other immune modulating effects and antioxidant properties.12,13,14,15,16 Animal studies also show that the polysaccharide fraction of reishi mushrooms can induce apoptosis (programmed cell death of cancer cells) in leukemic cells and induce cellular differentiation in 40-45% of leukemic cells treated with reishi polysaccharides, demonstrating significant cancer treatment potential. These effects were primarily due to the increased secretion of anti-tumor cytokines (signaling agents) induced by Reishi Mushroom polysaccharides, namely TNF-alpha and IFN-gamma, and these two cytokines acted synergistically on the inhibition of leukemic-cell growth.17 In a related experiment, the D-glucan polysaccharide fraction of Reishi Mushroom was shown to produce dramatic tumor regression in a mice sarcoma study. In many animals, complete tumor regression occurred in the group injected with beta-D glucan fractions within a 5-week period. The study by Y. Sone et al, reported tumor inhibition rates of 90% and tumor regression in 75% of afflicted animals.18

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2. Immune System Enhancement (Bronchitis, Asthma, Allergies, Herpetic Conditions and HIV Infection) As noted above, Reishi Mushroom Extract modulates many components of the immunesystem, which in part, account for its apparent anti-tumor properties. Chronic bronchitis in the elderly has been shown to respond favorably to treatment using a concentrated Reishi Mushroom product in a trial involving 2,000 cases in China. This study demonstrated a better than 60% success rate. After several months of treatment there was a noted rise in the levels of immunoglobulin A in the sputum.10 Immunoglobulin A is the main immunoglobulin found in the respiratory tract. A deficiency is common in allergies,19 systemic lupus and rheumatoid arthritis.20 Reishi Mushroom Extract supplementation has been shown to help improve cases of asthma and allergies. Two constituents of Reishi Mushroom Extract, oleic acid and cyclooctasulfur were shown to inhibit the release of histamine, which is likely how it benefits asthmatic and allergic patients.10,21,22 A specific protein-bound polysaccharide component of Reishi Mushroom Extract known as GLhw-02 has been shown to possess potent anti-viral properties against herpes simplex virus type 1 and type-2 under experimental conditions.23 A small human trial demonstrated that Reishi Mushroom Extract reduced pain dramatically in two patients with postherpetic neuralgia and in two other patients with severe pain due to herpes zoster infection (shingles, which is caused by a herpes virus).24 Under experimental conditions, various ganoderic acids in Reishi Mushroom Extract have been shown to be active anti-HIV agents, showing an ability to reduce viral replication by 50% at conservative doses. 25 Combined with other Oriental herbs, reishi is currently used in treatments of AIDS-related complex, AIDS, and alone or in combination formulas to treat chronic fatigue syndrome.26,27,28 Finally, studies on male mice reveal that Reishi Mushroom Extract was effective in enhancing the recovery of cellular immunocompetence after gamma-ray irradiation. Reishi Mushroom supplementation significantly increased white blood cell count (leukocytes) and other parameters of immune function in these animals, 29 in a similar fashion as has been shown to occur with astragalus supplementation in patients treated with chemo- or radiation therapy. (See Astragalus in this document.) 3. Cardiovascular Health (High Blood Pressure and Reduced Platelet Aggregation) Two human controlled studies revealed that Reishi Mushroom Extract can reduce high blood pressure to a significant degree (systolic and diastolic), even in patients who had previously failed to respond to established anti-hypertensive medications.30,31 Animal studies reveal that Reishi Mushroom Extract reduces blood pressure through a central inhibition of sympathetic nerve activity, although it does not slow heart rate or induce a sedative effect in general. 32 Under experimental conditions, Reishi Mushroom Extract has a mild to moderate effect on reducing platelet aggregation, which may further help to decrease risk of cardiovascular disease. (33) It has also been shown to increase endurance, blood flow to the brain and to improve oxygenation of cells. As such, it aids energy production on a cellular level, which may improve cardiovascular health and is used to boost memory and intellectual capacity in some cultures,34 including success in a study of Alzheimerâ&#x20AC;&#x2122;s patients.35 4. Liver Protective Effects (Hepatoprotective Properties) Reishi is prescribed in China for the treatment of chronic and acute hepatitis.36 Various ganoderic acids in reishi mushrooms have strong antihepatotoxic properties,37 which under experimental conditions have been shown to protect liver cells from chemically-induced injury, including protection from the highly toxic and lethal substance, carbon tetrachloride.38,39

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Dosage and Standardized Grade Therapeutic Applications: Typically 250 mg, one to four times per day is used if taken as a single agent (standardized to 10-12.5% polysaccharide content).40 General Wellness: (immune, cardiovascular, liver support, etc.,) Consider 30-120 mg per day (standardized to 1012.5% polysaccharide content). Reishi Mushroom Extract should be taken with food or it may cause stomach upset and loose stools.41

Adverse Side Effects, Toxicity and Contraindications Side effects from Reishi Mushroom Extract supplementation are infrequent and include dizziness, dryness of the mouth, throat and nasal areas, stomach upset and loose stools. 41 Reishi Mushroom contains agents that may be allergins to some patients, although allergic reactions are rare.42 Note that there is no crossâ&#x20AC;&#x201C;sensitivity to the Reishi Mushroom if a person is allergic to the Button Mushroom or the commonly eaten white mushroom that is found in most grocery stores.35 In general, Reishi Mushroom has been shown to be very non-toxic in animal toxicity studies and in humans, even when used at high therapeutic doses.3

Drug-Nutrient Interactions When used at high therapeutic doses, Reishi Mushroom Extract has the potential to potentiate (enhance) the effects of the following types of medications, and thus requires proper patient monitoring: - Antihypertensive medications 43,44 - Hypoglycemic medications 45 - Anticoagulant medications (e.g. warfarin, coumadin) 46

Jong SC, et al. Medicinal benefits of the mushroom ganoderma. Adv Appl Microbiol 1992;37:101-34 Herbs to the Rescue. Nutrition News 30Nov92;V.XVI(11):p4

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3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

28. 29. 30. 31.

32. 33. 34.

Jones K. Reishi (Ganoderma): Longevity Herb of the Orient-Part 2. Townsend Letters for Doctors & Patients 20Nov92;112:1008-12 Leung AY, Foster S. Encyclopedia of Common Natural Ingredients Used in Foods, Drugs, and Cosmetics, 2nd ed. New York: John Wiley & Sons 1996:255-60 Hobbs C. Medicinal Mushrooms. Santa Cruz, CA., Botanica Press 1995:96-107 Ikekawa T, et al. Antitumor action of some basidiomycetes, especially phellinus linteus. Japan J Can Res 1968;59:p155157 Morishige F. Lecture 1988. In: Becoming healthy with reishi, III. Kampo I-YS, Toyo-Igaku Sha Co. Ltd. Tokyo:12-20 (trans.) Tsukagoshi S, et al. Krestin (PSK). Cancer Treat Rev 1984;11(2):131-135 Teikoku Chemical Industry Co. Ltd. 1982. Mushroom glycoproteins as neoplasm inhibitors. Japanese Patent No. 82 75,926 12May82; in Chem Abstr;97:p4431 1j Lingzhi. In Chang HM and But PP-H, eds. Pharmacology and Applications of Chinese Materia Medica, Vol I Singapore:World Scientific 1986:642-653 Nakashima S, et al.. Effect of polysaccharrides from ganoderma applanatum on immune responses I. Enhancing effect on the induction of delayed hypersensitivity in mice. Microbiol Immunol 1979;23(6):501-513 Li S-C, Pen T-S, Kang M. Shang Wu Printer, Shanghai 1933 (trans.) Liu B, Bau Y-S. Fungi Pharmacopoeia (Sinica). The Kinoko Company, Oakland, CA 1980:168-169 Lin JM, et al. Radical scavanger and antihepatotoxic activity of ganoderma formosanum, ganoderma lucidum and ganoderma neojaponicum. J Ethnopharmacol Jun 1995;47(1):33-41 Wang SY, Hsu ML, Hsu HC, Tzeng CH, Lee SS, Shiao MS, et al. The anti-tumor effect of ganoderma lucidum is mediated by cytokines released from activated macrophages and T lymphocytes. Int J Cancer 17Mar97;70(6):699-705 Lee JM, Kwon H, Jeong H, Lee JW, Lee SY, Baek SJ, et al. Inhibition of lipid peroxidation and oxidative DNA damage by Ganoderma lucidum [In Process Citation]. Phytother Res May 2001;15(3):245-9 Wang SY. The anti-tumor effect of ganoderma lucidum is mediated by cytokines released from activated macrophages and T Lymphocytes. Int J Cancer. May 1997;70(6):699-705 Sone Y, et al. Structures and antitumor activities of the polysaccharides isolated from fruiting body and the growing culture of mycelium of ganoderma lucidum. Agr Biol Chem 1985;49:2641-53. Tizard IR. Immunology:An Introduction. Saunders, Philadelphia 1984:p94;p323 Hayward AR. Immune Deficiency Disease. In Allergic Diseases from Infancy to Adulthood. Bierman C. Warren and David S. Pearlman, eds. W.B. Saunders, 2nd ed 1988:34 Tasaka T, et al. Anti-allergic constituents in the culture medium of Ganoderma lucidum (I). Inhibitory effect of oleic acid on histamine release. Agents and Actions 1988;23(3/4):153-6 Tasaka T, et al. Anti-allergic constituents in the culture medium of ganoderma lucidum (II). Inhibitory effect of cyclooctasulpher on histamine release. Agents and Actions 1988;23(3/4):157-160 Lee SY. Eo, SK, et al. Antiherpetic activities of various protein bound polysaccarides isolated from ganoderma lucidum. J Ethnopharmacol. Dec 1999;68(1-3):175-81 Hijikata Y, et al. Effect of Ganoderma lucidum on Postherpetic Neuralgia. Am J Chin Med 1998;26(3-4):375-81 el-Mekkawy S, et al. Anti-HIV-1 and Anti-HIV-1-protease substances from ganoderma lucidum. phytochemistry. Nov 1998;49(6):1651-57 Willard T., Jones K. Reishi Mushroom. Sylvan Press, Issaquah, WA 1990 Cohen M. 1988. Paths to wholeness in HIV infection:A comprehensive approach. In AIDS, Immunity and Chinese Medicine. Proceedings of the ninth annual symposium of the Oriental Healing Arts Institute, 23Oct88, Long Beach, CA. B.C. Enger and E.R. Long, eds. O.H.A.I., Long Beach, CA 1989:92-102 Pers. Comm. Dharmananda, Ph.D, Institute of Traditional Medicine, Portland, OR, March 1992 Chen WC, Hau, DM, Lee, SS. Effects of ganoderma lucidum and krestin on cellular immunoceompetnece in gamma-ray-irradiated mice. Am J Chin Med 1995;23(1):71-80 Kammatsuse K, Kajiware N, Hayashi K. Studies on Ganaderma lucidum:I. Efficacy against hypertension and side effect. Yakugaku Zasshi 1985;105:531-3 Jin H, Zhang G, Cao X, et al. Treatment of hypertension by ling zhi combined with hyptensor and its effects on arterial, arteriolar and capillary pressure and microcirculation. In:Nimmi H, Xiu RJ, Sawada T, Zheng C (eds). Microcirculatory Approach to Asian Traditional Medicine. New York:Eslevier Science 1996:131-8 Lee SY. Cardiovascular effects of mycelium extract of ganoderma lucidum:inhibition of sympathetic outflow as a mechanism of its hypotensive action. Chem Pharm Bull (Tokyo) May 1990;38(95:1359-64 Su C. Potentiation of ganodermic acid S on prostaglandin E (1)-induced cyclic AMP elevation in human platelets. Thromb Res Jul 2000;99(2):135-45 Jong SC, et al. Medicinal benefits of the mushroom ganodermal. Adv Appl Microbiol 1992;37:101-34

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35. Sahley BJ. Reishi Mushroom, Healing Herb of the Future. MMRC Health Educator Reports;31Jan97:1-2 36. Tamura T, et al. Fermentation product as food for patients with liver failure. In Chem Abstr;108(13):110853m. 37. Hirotani M, et al. Ganoderic Acids T, S and R. New triterpenoids from the cultured mycelia of ganoderma lucidum. Chem Pharm Bull

1986;134(95):2282-5 38. Gong Z, Lin Z-B. The pharmacological study of lingzhi (Ganoderma lucidum) and the research of therapeutical principle of â&#x20AC;&#x153;Fuzheng

Gubenâ&#x20AC;? in traditional Chinese medicine. Pei-Ching I, Hseuh Y, Hseuh P 1981;13:6-10. (trans.)

39. Lin J-M, Lin C-C, et al. Radical scavenger and antihepatotoxic activity of Ganoderma formosanum, Ganoderma lucidum and

Gonoderma neo-japonicum. J Ethnopharm 1995;47:33-41 Hobbs C. Medicinal Mushrooms. Santa Cruz, CA:Botanica Press 1995;96-107 McGuffin M, ed. et al. Botanical Safety Handbook. Boca Raton, CRC Press1997:p55 Horner WE, et al. Basidiomycete Allergens:Comparison of three ganoderma species. Allergy. Feb 1993;48 (2):110-16 Lee SY. Cardiovascular effects of mycelium extract of Ganoderma lucidum:Inhibition of sympathetic outflow as a mechanism of its hypotensive action. Chem Pharm Bull. (Tokyo) May 1990;38(50):1359-64 44. Kanmatsuse K, et al. Studies on Ganoderma lucidum. I. Efficacy against hypertension and side effects. Yakugaku Zasshi Oct 1985;105(10):942-47 45. Hikino H, et al. Mechanisms of hypoglycemic activity of Ganoderan B:A glycan of Ganoderma lucidum fruit bodies. Planta Med Oct 1999;55(5):423-8 46. Tao J, et al. Experimental and clinical studies on inhibitory effect of Ganoderma lucidum on platelet aggregation. J Tongji Med Univ 1990;10(4):240-3 40. 41. 42. 43.

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Saw Palmetto (Serenoa Repens) General Features Saw Palmetto is a small palm tree, native to the southeast United States, that gives rise to berries which contain constituents that are used for medicinal purposes; most commonly the treatment of benign prostatic hyperplasia (BPH). More specifically, Saw Palmetto berries contain saturated and unsaturated fatty acids and sterols, including beta-sitosterol. Commonly referred to as Sabal by the European practitioners who heavily rely upon its therapeutic actions, the purified fat-soluble extract is used medicinally and contains up to 85 to 95 percent fatty acids and sterols. The Saw Palmetto berry itself contains only 1.5 percent fatty acid and sterols, thus it lacks sufficient quantities of these active constituents to be of clinical importance, unless large volumes are consumed.1-4 In the 1960â&#x20AC;&#x2122;s, French researchers discovered that by concentrating the fatty oils of Saw Palmetto berry into a standardized extract, they could greatly improve its therapeutic efficacy. 44 The principle therapeutic use of Saw Palmetto extract is for the treatment of benign prostatic hyperplasia. 3 However, due to its metabolic effects it may also be of value in the prevention of benign prostatic hyperplasia 5, prostate cancer 6, and in women, the treatment (and preventing recurrence ) of polycystic ovarian disease and hirsutism. 4 Saw Palmetto extract is an accepted medical treatment for BPH in France, Germany, Austria, Italy, New Zealand, and other European countries, and is the gold standard, in some of these countries, against which new prostate medications must prove themselves. 44

Principle Active Constituents Fatty acids and Sterols (including beta-sitosterol): These active constituents have been shown to inhibit the enzyme known as 5-alpha-reductase under experimental conditions. This enzyme converts testosteone to dihydrotestosterone within prostate cells. 3,4 These fatty acids and sterols have also been shown to reduce inflammation of the prostate and minimize the effects of androgens (e.g., testosterone), and estrogen, on the prostate gland. All of these effects appear to work synergistically to help treat and possibly prevent BPH, as men age. 45,46,47,48 Other constituents within Saw Palmetto extract (polysacchasides) may favorably modulate immune function as well. 49

Clinical Application and Mechanism of Action Benign Prostatic hyperplasia (BPH) In this condition, which affects the majority of men over their lifetime (50-60 percent by age 40-59 and 80% by age 80), Saw Palmetto extract has been shown to be very effective. 4 In a recent systematic review (Nov, 1998) of 18 randomized trials lasting 4 to 48 weeks, Ishani et al conclude, â&#x20AC;&#x153;the evidence suggests that serenoa repens improves urologic symptoms and flow measures compared with placebo. Serenoa repens produced similar improvement in urinary symptoms and (urine) flow compared to (the drug) finasteride, and is associated with fewer adverse treatment events. The long term effectiveness, safety and ability to prevent BPH complications are not knownâ&#x20AC;?. This review included a total of 2,939 men, who were treated for BPH. Compared to finesteride (a pharmaceutical drug used to treat BPH), Saw Palmetto extract (serenoa repens) produced similar improvements in urinary symptom scores and peak urine flow. 7 A large number of clinical trials have provided evidence that Saw Palmetto extract is effective in at least two-thirds of men suffering from BPH 4,8-21, sometimes outperforming the drug finasteride in head-to-head trials.12,42,21

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Some of these trials reveal that Saw Palmetto extract can actually shrink the size of the prostate gland, reversing prostate enlargement (exhibiting a type of anti-aging effect). 1,44 Mechanism of Action: The fatty acids and sterols (liposterolic extracts) derived from the Saw Palmetto berries appear to exert their therapeutic effects via the following mechanisms: a. Inhibit the intraprostatic conversion of testosterone to dihydrotestosterone (DHT), and inhibits DHTâ&#x20AC;&#x2122;s intracellular binding and transport.22,23 DHT is a more potent form of testosterone, which stimulates prostate cells (and prostate cancer cells) to multiply excessively, causing the prostate to enlarge. 4 The conversion of testosterone to DHT occurs via the 5 alpha-reductase enzyme. Saw Palmetto extract is a 5 alpha-reductase inhibitor under experimental conditions (the drug finasteride works via the same mechanism). 22,24,25,26,27,28 b. Androgen Receptor Blockade: Saw Palmetto extract blocks the effect of testosterone and DHT by binding to androgen receptors (blocking access of testosterone and DHT from entering prostate cells), and has been shown to block the translocation of the cytosol androgen receptor to the nucleus (blocks the transport of the cytosol receptor to the nucleus, thus blocking the androgenic effect on the nucleus of the cell).29,30,31,32,33 Saw Palmetto extract may also reduce the number of androgen receptors in the prostate cell membrane, an action shown to be mediated through the effect of Saw Palmetto extract on the nuclear DNA of prostate cells (inhibiting the genetic expression of androgen receptor synthesis and transport to the cell surface). This effect would also minimize the degree to which androgen hormones could influence the prostate gland. 45 c. Anti-Estrogenic Effects: Higher circulating estrogens in the male body (usually due to increased abdominal fat, as fat cells convert androstenedione to estrone hormone) has been shown to potentially contribute to BPH. Estrone inhibits the hydroxylation (breakdown or detoxification) and subsequent elimination of DHT. Hence, DHT can accumulate more easily within prostate cells. Saw Palmetto extract has been shown to significantly lower cellular (cytosol) and nuclear estrogen and progesterone receptors on the prostate gland in men suffering from BPH, compared to the placebo group. In the prostate gland, progesterone receptor activation is linked to increased estrogenic activity. It has been suggested that the anti-estrogenic effect of Saw Palmetto extract is a primary feature of its therapeutic effect on reducing BPH. 33 In a double-blind placebo-controlled study, it was shown that of the 35 men suffering from BPH who were treated with Saw Palmetto extract compared to placebo, biopsies of their prostate gland demonstrated a significantly lower number of estrogen and progesterone receptors after treatment with Saw Palmetto for 3 months. This implies that Saw Palmetto extract may also exert an anti-estrogen and anti-progesterone effect by reducing the available number of these receptors within the prostate cell membrane. 48 d. Anti-Inflammatory Effects: Saw Palmetto extract has been reported to inhibit both the cyclooxygenase and lipoxygenase enzyme pathways, which may provide an anti-inflammatory effect and partial relief of BPH symptoms. The conversion of arachidonic acid to pro-inflammatory prostaglandins (PG-2 series) and other related leukotrienes and eicosanoids, is catalyzed by the cyclooxygenase and 5-lipoxygenasase enzymes. 34 e. Phytoestrogen Effect - Saw Palmetto extract has been shown to compete with endogenous estrogens for receptor 35,36 sites.

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Polycystic Ovarian Disease and Hirsutism Saw Palmetto extract appears to have both anti-androgenic and anti-estrogenic effects. This may also be beneficial in cases of polycystic ovarian disease (both for treatment and prevention of recurrence) as well as for hirsutism , in 4 women. Prostate Cancer Treatment Some recent evidence suggests that Saw Palmetto extract may be a useful complementary intervention in cases of prostate cancer. Recently the Journal of Clinical Oncology reported that a Saw Palmetto extract formulation (also containing six other Chinese herbs) was able to markedly reduce PSA (Prostate Specific Antigen) levels in patients with advanced prostate cancer (n=32). Al least an 80 percent reduction in PSA levels occurred in patients with androgen-dependent prostate cancer (26 patients attained undectable or anorchid PSA levels) and a 50 percent reduction in PSA levels occurred in the androgen independent-prostate cancer patients. This study carried out at the Memorial Sloan-Kettering Cancer Center used Saw Palmetto dosages that were approximately three to nine times higher than typically used to treat BPH.Some recent evidence suggests that Saw Palmetto extract may be a useful complementary intervention in cases of prostate cancer. Recently the Journal of Clinical Oncology reported that a Saw Palmetto extract formulation (also containing six other Chinese herbs) was able to markedly reduce PSA (Prostate Specific Antigen) levels in patients with advanced prostate cancer (n=32). Al least an 80 percent reduction in PSA levels occurred in patients with androgen-dependent prostate cancer (26 patients attained undectable or anorchid PSA levels) and a 50 percent reduction in PSA levels occurred in the androgen independent-prostate cancer patients. This study carried out at the Memorial Sloan-Kettering Cancer Center used Saw Palmetto dosages that were approximately three to nine times higher than typically used to treat BPH. Adverse reactions to these high doses included pulmonary embolism, hypertriglyceridemia, allergic reactions, leg cramps, nausea, diarrhea, impotence, loss of libido, hot flashes, breast tenderness, and enlargement. However, researchers conclude that it is â&#x20AC;&#x153;generally well toleratedâ&#x20AC;?, but should not be routinely recommended to patients with a history of cardiovascular disease. 37

Dosage and Standardized Grade 1. Benign Prostatic Hyperplasia (BPH): Usual dosage is 160 mg, twice daily (std to 85-95 percent fatty acids and sterols), or 320 mg, twice per day (standardized to 45% fatty acids and sterols). 8-21 N.B.: This is equivalent to approximately 10 gms of crude berries.1 2. Prostate Cancer Support: Refer to Journal of Clinical Oncology 2000;18(21):3595-3603, article by Small E.J. et al. (dosage 3-9 times higher than for BPH). 37 3. Polycystic Ovarian Disease and Hirsutism: Consider the same dosage as used for BPH in men

Adverse Side Effects, Toxicity and Contraindications Detailed toxicology studies with Saw Palmetto extract carried out on various animals indicate that the extract has no toxic effects. At BPH treatment doses, Saw Palmetto extract is safe and no significant side effects have been noted. Gastrointestinal upset is rare, but occurs on occasion.17

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The FDA in the United States lists Saw Palmetto as a herb of unknown safety. However, in Germany and Austria more than 90 percent of BPH cases are treated by physicians with phytonutrient formulations (most of which contain Saw Palmetto extract).1, 38,41 A systematic review of the literature reveals that Saw Palmetto extract is associated with fewer adverse treatment events than is the drug finasteride, including a 1% occurrence of erectile dysfunction versus 5% for finasteride. 7 Saw Palmetto extract does not appear to affect serum levels of testosterone, Follicle-stimulating hormone or Luteinizing hormone. 39 Clinical trials have shown that Saw Palmetto extract is essentially non-toxic. In a 3-year study, only 34 of the 435 subjects using Saw Palmetto extract reported any side effect, which most commonly was mild gastrointestinal distress. 44

Drug-Nutrient Interactions Theoretically, Saw Palmetto extract may antagonize the effects of hormone replacement therapy and oral contraceptives in women, if they choose to use Saw Palmetto extract for polycystic ovarian disease or hirsutism. 1 However, no stated drug-nutrient interactions for Saw Palmetto exist at this time. 43, 44

1. 2. 3. 4. 5.

Newall CA, Anderson LA, phillipson JD. Herbal Medicines: A Guide for Health Care Professionals. London: The Pharmaceutical Press 1996:p296 Leung A, Foster S. Encyclopedia of Common Natural Ingredients used in Food, Drugs and Cosmetics. 2 nd ed. New york, NY: John Wiley and Sons 1996:p649 Awang DVC. Saw palmetto, African prune and stinging nettle for benign prostatic hyperplasia (BPG). Canadian Pharmaceutical Journal 1997; November:p37-44,p62 Murray MT. The healing Power of herbs. Rocklin, CA: Prima Publishing 1992:p246 Benign Prostatic Hyperplasia. Medical Post; Oct 17,2000

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6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.

Paubert-Braquet M, Richardson FO, Servent-Saez N et al. Effect of Serenoa repens extract (Permixon) on estradiol/testosterone-induced experimental prostate enlargement in the rat. Pharmacological Research 1996;34(3-4):171-9 Ishani W et al. Serenoa repens for benign prostatic hyperplasia (Cochrane Review Abstract) nov 6 1998;medscape.com Cirillo-Marucco E, Pagliarulo A, Tritto G et al. Extract of Serenoa repens (PermiconR) in the early treatment of prostatic hypertrophy. Urologia 1983;5:1269-77 Tripodi V, Giancaspro M, Pascarello M et al. Treatment of prostatic hypertrophy with Seronoa repens extract. Medical praxis 1983;4:41-6 Greca P, Volpi R. Experience with a new drug in the medical treatment of prostatic adenoma. Urologia 1985;52:532-5 Crimi A, Russo A. Serenoa repens for the treatment of the functional disturbances of prostate hypertrophy. Medical Praxis 1983;4:47-51 Braeckman J. The extract of Seronoa repens in the treatment of benign prostatic hyperplasia: A multicentre open study. Current Therap Research 1994;55(7):776-85 Romics I, Schmitz H, Frang D. Experience in treating benign prostatic hypertrophy with sabal serrulata for one year. International Urology and Nephrology 1993;25(6):565-69 Boccafoschi, Annoscia S. Compariosn of Serenoa repens extract with placebo by controlled clinical trial in patients with prostatic adenomatosis. Urologia 1983;50:1257-68 Emili E, Lo Cigno M, Petrone U. Clinical trial of a new drug for treating hypertrophy of the prostate (Permixon). Urologia 1983;50:1042-8 Champault G, Bonnard AM, Cauquil J, Patel JC. Medical treatment of prostatic adenoma. Controlled trial: PA 109 vs. placebo in 110 patients. Annales d’Urologe 1984;18:407-10 Tasc A, Barulli M, Cavazzana A et al. Treatment of obstruction in prostatic adenoma using an extract of Serenoa repens. Double-blind clinical test vs. placebo. Minerva Urologica E Nefrologica 1985;37:87-91 Vahlensieck WJ et al. Benign prostatic hyperplasia – Treatment with Sabal fruit extract. A treatment study of 1,334 patients. Fortschritte der Medizin 1993;111:323-6 Pannunzio E et al. Serenoa repens in the tratment of human benign prostatic hypertrophy (BPH). Journal of Urology 1987;137:p226A Adriazola Semino m et al. Symptomatic treatment of benign hypertrophy of the prostate. Arch Esp Urol 1992;45:211-3 Carraro JC, Raynaud JP, Koch G et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasis: A randomized international study of 1,098 patients. Prostate 1996;29:231-40 Carilla E et la. Binding of Permixon, a new treatment for prostatic benign hyperplasia, to the cytosolic androgen receptor in the rat prostate. J Steroid Biochem 1984;20:521-3 Sultan C et al. Inhibition of androgen metabolism and binding by a liposterolic extract of Serenoa repens B in human foreskin fibroblasts. J Steroid Biochem 1984;20:515-9 Briley M, Carilla E et al. Inhibitory effect of Permixon on testosterone 5-alpha-reductase activity of rat ventral prostate. British Journal of Pharmacology 1984;83(suppl):p401 Delos S, Iehle C, Martin PM, Raynaud JP. Inhibition of the activity of ‘basic; 5-alpha-reductase (type 1) detected in DU 145 cells and expressed in insect cells. Journal of Steroid Biochemistry and Molecular Biology 1994;48(4):347-52 Delos S, Carsol JL, Ghazarossian E et al. Testosterone metabolism in primary cultures of human prostate epithelial cells and fibroblasts. Journal of Steroid Biochemistry and Molecular Biology 1995;55(3-4):375-83 Iehle C, Delos S, Guirou O et al. Human prosatic steroid 5 alpha-reductase isoforms—a comparative study of selective inhibitors. Journal of Steroid Biochemistry and Molecular Biology 1995;54(5-6):273-9 Rhodes L, Primka RL, Berman C et al. Compariosn of Finasteride (Proscar), a 5a reductase inhibitor and various commercial plant extracts in in vitro and in vivo 5a reductase inhibition. The Prostate 1993;22:43-51 El-Sheikh MM, Dakkak MR, Saddique A. The effect of permixon on androgen receptors. Acta obstetrica et Gynecologica Scandinavica 1988;67:397-9 Ravenna L, Di Silverio F, Russo MA et al. Effects of the lipiosterolic extract of Serenoa repens (Permixon) on human prostatic cell lines. Prostate 1996;29(4):219-30 Wilson JD. The pathogenesis of benign prostatic hyperplasia. American Journal of Medicine 1980;68:745-55 Carilla E, Briley M, Fauran Fea. Binding of Permixon, a new treatment for prostatic benign hyperplsia, to cytosolic androgen receptor in rat prostate. Journal of Steroid Biochemistry 1984;20:521-3 Di Silverio F et al. Evidence that Serenoa repens extract displays antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy. Eur Urol 1992;21:309-14 Breu W, Hagenlocher M, Redl K et al. Anti-inflammatory activity of Sabal fruit extracts prepared with supercritical carbon dioxide, in vitro antagonists of cyclooxygenase and 5-lipoxygenase metabolism. Arzneimittelforschung 1992;42(4):547-51 Elghamry MI, Hansel R. Activity and isolated phytoestrogen of shrub palmetto fruits (Serenoa repens Small), a new estrogenic plant. Experientia 1969;25:828-9 Di Silverio F, D’Eramo G, Lubrano C et al. Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients. European Urology 1992;21:309-14

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37. Small EJ et al. Prospective trial of the herbal supplement PC-Spes in patients with progressive prostate cancer. JCO 2000;18(21):35953603 38. McPartland JM et al. Benign prostatic hyperplasia treated with saw palmetto:a literature search and an experimental case. J Am Osteop Assoc 2000;100(2):89-96 39. Casarosa C, Cosci di Coscio M, Fratta M. Lack of effects of a liposterolic extract of Serenoa repens on plasma levels of testosterone, FSH, and luteinizing hormone. Clinical Therapeutics 1988;10:585-88 40. Gerber GS et al. Saw palmetto (serenoa repens) in men with lower urinary tract symptoms: effects on urodynamic parameters and voiding symptoms. Urology 1998;51(6):1003-7 41. MacDonald A et al. Systematic review of cernilton for the treatment of benign prostatic hyperplasia. Br J Urol 1999;85:836-941 42. Sokeland J et al. A combination of Sabal and urtica extracts verus finasteride in BPH: a comparison of therapeutic efficacy in a one-year double-blind study. Urologe CA 1997;36:327-33 43. Healthnotes Online. Healthnotes Inc 2000. www.healthnotes.com: Saw Palmetto 44. Natural Product Encyclopedia. www.consumerslab.com: Saw Palmetto 45. Ravenna L et al. Effects of the lipidosterolic extract of serenoa repens (permixon) on human prostatic cell lines. Prostate 1996;29(4):21930 46. Delos S et al. Testosterone metabolism in primary cultures of human prostate epithelial cells and fibroblasts. J Steroid Biochem & Molecular Biol 1994;48(4):347-52 47. Paubert-Braquet M et al. Effect of serenoa repens extract (permixon) on estradiol/testosterone-induced experimental prostate enlargement in the rat. Pharmacol Res 1996;34(3):171-9 48. Di Silverio F et al. Evidence that serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients. European Urologv 1992;21(4):309-14 49. Wagner H et al. Immunostimulatin lactation of polysaccharides (heteroglycans) from higher plants. Arzneimittelforschung 1985;35(7):1069-75

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Shiitake Mushroom General Features Shiitake Mushroom (Lentinus edodes) has been used in traditional Chinese medicine for thousands of years, as is the case with reishi and maitake mushrooms. All of these mushrooms contain specific polysaccharides (e.g., beta glucans) that are known to modulate immune system activity and provide other health-promoting effects. Recently, researchers have begun to test Shiitake Mushroom in clinical trials with humans to help validate its traditional use in Chinese medicine and confirm its biological activity suggested by experimental studies.1 Shiitake mushrooms grow on the trunks and stumps of trees. They are native to many parts of Asia, but are now cultivated throughout the world (including the United States) for medicinal use. The fruiting body is used medicinally. 1,2

Principle Active Constituents The primary active constituent is reported to be a polysaccharide called lentinan, which is contained in Shiitake Mushroom preparations, referred to as Lentinus Edodes Mycelium Extract (LEM). Thus, commercially available LEM is a rich source of polysaccharides and lignans from the shiitake mushroom.2 Lentinan is a beta-glucan polysaccharide isolated from shiitake mushrooms, which has been used as the principle agent in recent human studies.3

Clinical Application and Mechanism of Action Experimental evidence has shown that a purified fraction of LEM, rich in shiitake lignans, stimulates the immune system by activating macrophage cells and increasing the proliferation of bone marrow cells, and it inhibits the cytopathic effects of HIV-1 virus in vitro.4,5 LEM has also shown that it increases lymphokine-activated killer (LAK ) cell activity by 42-56.9% in vitro (when combined with interleukin 2), which may be of importance in the complementary support of cancer therapy.6 1. AIDS (HIV â&#x20AC;&#x201C; Infection) M. Gordon et al, have administered lentinan or placebo to HIV patients using I.V. method, in three small phase I/II placebo-controlled trials. Overall, lentinan treatment produced an increase in the number of CD4 cells ( T-helper cells ) and, in some patients, neutrophil activity. In one of the studies lentinan was used in conjunction with didanosine, which proved to be effective in raising the CD4 count by 142/mm3 on average, over a twelve-month period. In contrast, there was a decrease in the CD4 count in those patients receiving the didanosine alone. There were no significant side effects in the lentinan treatment group in regards to anemia, leukopenia, pancreatitis or neuropathy. Based on these findings, these researchers recommend a larger, longer clinical trial of lentinan in combination with didanosine in HIV patients, free of opportune infection. 7 2. Cancer Treatment Support Several trials studying cancer patients have investigated the effects of lentinan as a cancer treatment support intervention. Repeated injections of lentinan have been shown to have beneficial effects on the immune systems of cancer patients.8,9,10,11,12 Two trials reported that lentinan injections prolonged life in people with a variety of advanced cancers.13,14 Another trial found that intravenous lentinan increased five-year survival rates in prostate cancer patients compared with those not given lentinan.15 It is not known whether or not oral consumption of Shiitake Mushroom extract would yield the same benefits as the injectable method used in these studies.

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3. Genital Warts Oral supplementation of lentinan has been shown to significantly reduce the recurrence rate of genital warts (condyloma acuminata). A preliminary trial involving a group of men and women with genital warts found that those who took 12.5 mg of lentinan per day for two months after laser surgery, had a recurrence rate of only 10.5% as compared to 47% in the group that did not receive the lentinan.16

Dosage and Standardized Grade The most current evidence suggests that Shiitake Mushroom extract or lentinan products should be standardized to 3.2% KS-2 polysaccharides per dose. Therapeutic applications typically have used 100-400 mg (standardized extract), three times per day, with food.1 Recommended intake of LEM is 1-3 grams, two to three times per day. Purified lentinan is considered a drug in Japan and is not currently available as an herbal supplement in North America.2

Adverse Side Effects, Toxicity and Contraindications Shiitake mushrooms have an excellent record of safety, but have been known to induce temporary diarrhea and abdominal bloating when used in high amounts. It is important to take this product with food.2

Drug-Nutrient Interactions 1. Immunosuppressive Medications (e.g., cyclosporin): As shiitake mushrooms and its extracts (e.g., LEM) are known to stimulate the immune system, they are contraindicated in cases where patients are taking immunosuppressive drugs.4,5 2. Didanosine: Shiitake Mushroom extract has been shown to enhance the efficacy of didanosine in HIV patients when administered intravenously, and thus should be considered for use in these cases.

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Dietary Supplement Information Bureau. Shiitake Mushroom. www.intramedicine.com. Dietary Supplement Education Alliance 2001 Healthnotes Inc. 2001. Shiitake Mushroom. www.puritan.com/healthnotes Gordon M, Bihari B, Goosby E, Gorter R, Greco M, Guralnik M, et al. A placebo-controlled trial of the immune modulator, lentinan, in hIVpositive patients: a phase I/II trial. J Med 1998;29(5-6):305-30 Suzuki H, et al. Immunopotentiating Substances in Lentinus edodes Mycelial Extract(LEM)-- Activation of Macrophage and Proliferation of Bone Marrow Cell. Nippon Shokakibyo Gakkai Zasshi. Jul1988;85(7):1430 Suzuki H, et al. Inhibition of the Infectivity and Cytopathic Effect of Human Immunodeficiency Virus by Water-soluble Lignin in an Extract of the Culture Medium of Lentinus edodes Mycelia (LEM). Biochem Biophys Res Commun. Apr1989;160(1):367-73 Li JF, et al. Study on the Enhancing Effect of Polyporus Polysaccharide, Mycobacterium Polysaccharide and Lentinan on Lymphokineactivated Killer Cell Activity in vitro. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih. Apr1996;16(4):224-26. Gordon M, et al. A Placebo-controlled Trial of the Immune Modulator, Lentinan, In HIV-positive Patients: A Phase I/II Trial. J Med. 1998;29(5-6):305-30 Miyakoshi H, Aoki T, Mizukoshi M. Acting mechanism of lentinan in human—II. Enhancement of non-specific cell-mediated cytotoxicity as an interferon inducer. Int J Immunopharmacol 1984;6:373–9. Arinaga S, Karimine N, Takamuku K, et al. Enhanced induction of lymphokine activated killer cell after lentinan administration in patients with gastric carcinoma. Int J Immunopharmacol 1992;14:535–9. Matsuoka H, Yano K, Seo Y, et al. Usefulness of lymphocyte subset change as an indicator for predicting survival time and effectiveness of treatment with the immunopotentiator lentinan. Anticancer Res 1995;15:2291–6. Miyakoshi H, Aoki T, Mizukoshi M. Acting mechanism of lentinan in human—II. Enhancement of non-specific cell-mediated cytotoxicity as an interferon inducer. Int J Immunopharmacol 1984;6:373–9. Arinaga S, Karimine N, Takamuku K, et al. Enhanced induction of lymphokine activated killer cell after lentinan administration in patients with gastric carcinoma. Int J Immunopharmacol 1992;14:535–9. Matsuoka H, Yano K, Seo Y, et al. Usefulness of lymphocyte subset change as an indicator for predicting survival time and effectiveness of treatment with the immunopotentiator lentinan. Anticancer Res 1995;15:2291–6. Matsuoka H, Seo Y, Wakasugi H, et al. Lentinan potentiates immunity and prolongs the survival time of some patients. Anticancer Res 1997;17:2751–6. Tari K, Satake I, Nakagomi K, et al. Effect of lentinan for advanced prostate carcinoma. Hinyokika Kiyo (Acta Urol Japon) Guangwen Y, Jianbin Y, Dongqin L et al. Immunomodulatory and therapeutic effects of lentinan in treating condyloma acuminata. CJIM 1999;5:190-2

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St. John’s Wort (Hypericum perforatum) General Features St. John’s wort is a perennial plant that is common to Europe and the United States (especially abundant in northern California and southern Oregon). It derives its unusual name from the fact that it tends to flower around the feast of St John. In Old English, a plant was known as a “wort”, hence the name St. John’s wort. The plant has a notable reputation throughout history as a treatment for emotional and nervous disorders. In the early 1900’s, German researchers began studying St. John’s wort, seeking to identify the physiological mechanisms through which it imparts its antidepressant effects. 1,12,13 As such, it has received a great deal of attention from the research community during the last century, making it one of the best-documented herbal agents. In Germany, St. John’s wort is the most commonly prescribed antidepressant, and is covered by the national health-care system for this application. 12 An abundance of evidence exists to support the use of St John’s wort in cases of mild to moderate depression. 1,12,13,14 Studies indicate that a standardized grade of this herbal product is at least as effective as any other type of antidepressant medication, and in general, produces fewer and milder side effects. 12 However, in cases of severe depression (major depression), where patients may feel suicidal, are unable to cope with daily life, or feel paralyzed by anxiety, and/or are incapable of getting out of bed, unable to sleep, uninterested in eating, St John’s wort is not an appropriate intervention. These cases require the attention of a trained specialist, possibly hospitalization, and it should be noted that St, John’s wort has been shown to be ineffective in trials involving this type of severely depressed patient. Furthermore, other medications (e.g., imipramine) have been shown to be effective in these cases, and may be required in order to save the person’s life. 12,15 In North America, the medial profession does not commonly recommend or prescribe St. John’s wort for mild to moderate depression, but rather rely on a variety of other drugs such as serotonin reuptake inhibitors, tricyclic antidepressants and MAO-inhibitors. It should be acknowledged that it is unsafe to use St John’s wort in conjunction with any other antidepressant drug, as St. John’s wort may potentiate the action of these medications on brain neurotransmitter levels, and produce potentially life-threatening side effects such as serotonin syndrome. A number of adverse reactions of this nature have been reported, and often involve a person self-medicating with St. John’s wort, without the knowledge of their attending physician, who has prescribed another antidepressant drug. 16,17,18

Principle Active Constituents Possibly Hyperforin and Flavonoids: The active constituents of St. John’s wort are found in the leaves and the flowers of the plant. For many years it was assumed that hypericicin and pseudohypericin acted similar to monoamine oxidase inhibitor (MAO-inhibitors) drugs and were responsible for its antidepressant properties via this action. 1,2 In recent years this has been shown to be invalid and evidence now exists to suggest that hyperforin and flavonoids from the leaves and flowers of the plant may be the real antidepressant agents. 13, 19,20,21 Yet, two double-blind studies using St. John’s wort extracts, containing low hyperforin content, found it to be effective in treating depression. 22,23 Test tube studies indicate that the active constituents (although not completely identified) in St. John’s wort extract act by inhibiting the reuptake of the neurotransmitters serotonin, norepinephrine, and dopamine and thus, increase brain levels of these important chemical messengers. 24

Clinical Application and Mechanism of Action 1. Mild and Moderate Depression The official German Commission E Monograph lists psychovegetative disturbances, depressive states, fear, and nervous disturbances as clinical indications for the use of St. John’s wort extract. At least 26 studies demonstrate that www.meschinohealth.com

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St. John’s wort is effective in the treatment of mild to moderate depression. 1,6,7,8,9 Symptoms of mild to moderate depression include depressed mood, lack of energy, sleep problems, anxiety, appetite disturbance, difficulty concentrating, poor stress tolerance and chronic irritability. Studies on St. John’s wort and other antidepressant drugs use the Hamilton Depression Index (HAM-D) to evaluate patient response. The HAM-D is a set of questions that can help establish the severity of depression and is a useful tool to track improvement through a rating scale system. An overview of all studies involving the use of St. John’s wort extract for mild to moderate depression reveals that it is effective in approximately 55% of cases. As with other antidepressants it usually requires up to 4–6 weeks to show a significant improvement in the patient’s symptoms. 12 St. John’s wort has been tested against placebo and against standard antidepressant drugs in a significant number of clinical trials, involving patients with mild to moderate depression. In double-blind placebo-controlled trials totaling more than 1,000 patients, St. John’s wort extract has shown that it can significantly reduce HAM-D scores when compared to placebo. 25 In one study HAM-D scores dropped by at least 50% in 70% of the subjects taking St. John’s wort (and in 24% of patients in the placebo group). 26 Not all studies have shown success however, but the same is true for prescription antidepressants that are in use today, such as sertraline, which in some studies has not shown a benefit. This is common in the area of depression where no real precise method is available to measure the benefit of an intervention, such as a blood test for a proven biomarker of disease progression or improvement. 27, 28 In general, the evidence to support the use of St. John’s wort for the treatment of mild to moderate depression appears to be as substantial as the use of other prescription drugs. 1,11,12,13,14 Short-term double-blind studies (6 – 8 weeks) testing St. John’s wort against fluoxetine (Prozac) demonstrated that St. John’s wort is equally, or more effective, than fluoxetine in treating patients with mild to moderate depression, and produced fewer and less severe side effects. 29,30 St John’s wort has also been shown to be as effective as sertraline (Zoloft) and imipramine in the treatment of moderate depression, in other head-to-head trials. 31,32 It should be noted once again that St. John’s wort does not represent a treatment option for severe depression, and that a study testing St. John’s wort against imipramine showed that imipramine was a more effective treatment for patients presenting with severe depression. 15 2. Anxiety and Insomnia In many of the studies testing St. john’s wort as a treatment for depression, many patients reported an improvement in anxiety and insomnia, associated with their depression. 12,14 3. Seasonal Affective Disorder (SAD) One small controlled trial showed that St. John’s wort was effective in the treatment of SAD. 33 This may be due to its ability to raise brain levels of serotonin. Further studies are required to substantiate this preliminary report. 34 4. Viral Infections St John’s wort demonstrates antiviral activity against herpes simplex type 1 and 2, influenza A and B and vesicular stomatitis virus. Thus, it may have application for patients with these problems, although no concrete statements can be made at this time.4,5

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Dosage and Standardized Grade The standardized grade of St. John’s wort contains 0.3% hypericin content. A few new products on the market are standardized to 2 –3% hyperforin content instead of hypericin. These are taken at the same dosage as products standardized to 0.3% hypericin. 11,12,13,14 Depression (Mild to Moderate): 300 mgs, three times per day with meals for mild to moderate depression. 1, 11,12,13,14 Note that the use of 600 mgs, three times per day with meals for severe depression did prove to be effective in a single trial, but the use of St. John’s wort in these cases is not widely accepted at this time. 1,11,12,13,14

Adverse Side Effects, Toxicity and Contraindications Animal studies do not suggest that St. John’s wort produces any significant toxicity, even when taken in large amounts. 34,38 In two human trials designed to record adverse side effects from the use of St. John’s wort, only 2.4% of the 3,250 study subjects reported side effects, which were primarily limited to mild stomach discomfort, allergic reactionsprimarily rash, fatigue, and restlessness. The second study revealed similar findings in a group of 313 users of St. John’s wort, over a one-year period. 35,36 Other infrequently reported adverse side effects include dizziness and excess sedation. 1 St. John’s wort has also been shown to speed up the detoxification of many drugs and thereby, alters dose requirement of these medications, as discussed below. 12 When taken alone (not concurrently with other antidepressants) St. John’s wort is not reported to produce any frequently encountered side effects 39, however, the following precautionary statements should be acknowledged: 1. St. John’s wort can produce a photosensitivity reaction resulting in skin rash upon exposure to sunlight. It is a rare side effect.10 This reaction is due to the presence of hypericin, a chemical that is a napthodianthrone compound. Patients using this product should avoid excessive exposure to direct sunlight, especially if they are fair-skinned.59 2. Originally, it was thought that patients should avoid foods with a high tyramine content (cheese, beer, pickled herring, and yeast) and drugs such as L-dopa and 5-hydroxytryptophan, due to the fact that hypericin was considered a MAO-inhibitor, and would thus, permit a dangerous rise in blood pressure if these agents were present at significant concentrations in the blood stream. This was later shown to be invalid and therefore, these restrictions and precaution no longer apply. 40,41,42 Note that if the tyramine ingested from these foods is not broken down in the intestinal tract by the MAO-A enzyme, then severe high blood pressure will result. 40,41,42

Drug-Nutrient Interactions Antidepressant drugs: St. John’s wort acts in the body like many other antidepressant drugs, and has been shown to potentiate their effects, producing dangerous and severe side effects. It is therefore recommended that patients not take St. John’s wort concurrently with any other antidepressants, including the following: - 5-hydroxytryptophan 43 - Serotonin re-uptake inhibitors (SSRIs) 44-50 - MAO-inhibitors 44-50 - Tricyclic antidepressants 44-50 - Resperine 51 - Barbituates and sedatives 51

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- Any attempt combine the use of St’ John’s wort with an antidepressant medication should be supervised by a physician, trained in this area.11 Medications that Cause Sun Sensitivity: St. John’s wort may increase the potential for certain medications such as Sulfa drugs, Feldene and Prevacid to produce photosensitivity reactions, resulting in a severe skin rash. This is most important for fair-skinned individuals, who are most vulnerable. In these cases, sun light exposure to the skin must be limited. 12 Alters the Rate of Detoxification of Other Drugs: St. John’s wort has been shown to alter the rate of detoxification of other drugs thereby altering their dose requirement and in cases where the therapeutic safety index is very narrow, as is the case with digitalis or digixon. These drug-nutrient interaction can potentially be very dangerous. Evidence of this nature exists to suggest that St. John’s wort should not be taken concurrently with the following drugs: - Digoxin and digitalis 52 - Theophylline 53 - Immunosuppressive drugs ( e.g., cyclosporin) 54 - Oral contraceptives- where it has caused breakthrough bleeding 55,56 - Anesthetic drugs- refrain form taking St. John’s wort seven days prior to surgery 57 - Protease inhibitors 58 - Hormone replacement therapy 55 Warfarin and Coumadin 56

1. 2. 3.

Boon H and Smith M, Health Care Professional Training Program in Complementary Medicine, Institute of Applied Complementary Medicine Inc., 1997. Suzuki O, et.al., Inhibition of Monoamine Oxidase by Hypericin, Planta Medica 50, 1984, 272-274. Holtz J, Demisch L, and Gollnick B, Investigations About Antidepressive and Mood Changing Effects of Hypericum Performatum, Planta Medica 55, 1989, 643.

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4. 5.

6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.

Schmidt U and Sommer H, St. John’s Wort Extract in the Ambulatory Therapy of Depression. Attention and Reaction Ability are Preserved, Forschr Med 111, 1993, 339-342. Johnson D, Effects of St. John’s Wort Extract Jarsin. Paper Presented at the 4 th International Congress on Phytotherapy, Munich, Germany, September 10-13, 1992. [Abstract SL53]; Woelk H, Multicentric Practice – Study Analyzing the Functional Capacity in Depressive Patients, Paper Presented at the 4th International Congress on Phytotherapy, Munich, Germany, September 10-13, 1992 [Abstract SL54]; Sommer H, Improvement of Phychovegetative Complaints by Hypericum, Paper Presented at the 4 th International Congress on Phytotherapy, Munich, Germany, September 10-13, 1992 [Abstract SL55] Schlich D, Brauckmann F, and Schenk N, Treatment of Depressive Conditions with Hypericum, Psychol 13, 1987, 440-444 Harrer G and Sommer H, Treatment of Mild/Moderate Depressions with Hypericum, Phytomed 1, 1994, 3-8 Lavie D, Antiviral Pharmaceutical Compositions Containing Hypericin or Pseudohypericin, European Patent Application No. 87111467.4, filed 8/8/87, European Patent Office, Publ. No. 0 256 A2. 1987, 175-177 Someya H, Effect of a Constituent of Hypericin Erectum on Inection and Multiplication of Epstein-Barr Virus, J Tokyo Med Coll 43, 1985, 815-826 Gulick R, et.al., Human Hypericism: A Photosensitivity Reaction to Hypericin (St. John’s Wort), Int Conf AIDS 8, B90, 1992. [Abstract PoB 3018] Murray MT, The Healing Power of Herbs (2nd edition), Prima Publishing, 1995 Natural Products Encyclopedia. www.consumerslab.com:St John’s Wort Healthnotes, Inc. 2001. www.healthnotes.com:St. John’s Wort Dietary Supplement Information Bureau. www.content.intramedicine.com: St. John’s Wort Vorbach EU, Arnoldt KH, Hubner WD. Efficacy and tolerability of St. John’s Wort extract LI 160 versus imipramine in patients with severe depressive episodes versus imipramine in patients with severe depressive episodes according to ICD-10. Pharmacopsychiatry 1997;30(suppl 2):81-5 DeMott K. St. John’s wort tied to serotonin syndrome. Clinical Psychiatry News 1998;26:p28 Gordon JB. SSRIs and St. John’s wort: Possible toxicity? Am Fam Physician 1998;57:p950, p953 Lantz MS, Buchalter E, Giambanco V. St John’s wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999;12:7-10 Holzl J, Demisch L, Gollnik B. Investigations about antidepressive and mood changing effects of Hypericum perforatum. Planta Med 1989;55:643. Chatterjee SS, Koch E, Noldner M, et al. Hyperforin with hypericum extract: Interactions with some neurotransmitter systems. Quart Rev Nat Med 1997;Summer:110. Calapai G, Crupi A, Firenzuoli F, et al. Effects of Hypericum perforatum on levels of 5-hydroxytryptamine, noradrenaline and dopamine in the cortex, diencephalon and brainstem of the rat. J Pharm Pharmacol 1999;51:723–8. Schrader E. Equivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol 2999;15:61-8 Schrader E, Meier B, Brattstrom A. Hypericum treatment of mild-moderate depression in a placebo-controlled study: a prospective, double-blind, randomized, placebo-controlled, multicentre study. Hum Psychopharmacol 1998;13:163-9 Müller WE, Rolli M, Schäfer C, Hafner U. Effects of hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry 1997;30(suppl):102–7 Kalb R, Trautmann-Sponsel RD, Kieser M. Efficacy and tolerability of hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. A randomized double-blind multicenter clinical trial. Pharmacopsychiatry 2001;34:96-103 Hansgen KD, Vesper J. Antidepressant efficacy of a high-dose hypericum extract [translated from German]. MMW Munch Med Wochenschr 1996;138:29-33 Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St. John’s wort in major depression: a randomized controlled trial. JAMA 2001;285:1978-86 Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. John’s wort) in major depressive disorder: a randomized controlled trial. JAMA 2002;287:1807-14 Schrader E. Equivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol 2000;15:61-8 Harrer G, Schmidt U, Kuhn U, et al. Comparison of equivalence between the St. John’s wort extract LoHyp-57 and fluoxetine. Arzneimittelforschung 1999;49:289-96 Brenner R, Azbel V, Madhusoodanan S, et al. Comparison of an extract of hypericum (L1 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study. Clin Ther 2000;22:411-9 Philipp M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomized multcentre study of treatment for eight weeks. BMJ 1999;319:1534-9

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33. Martinez B, Kasper S, Ruhrmann S, et al. hypericum in the treatment of seasonal affective disorders. J Geriatr Psychiatr Neurol 1994;7(suppl 1):S29-33 34. Muller WEG, et al. Effects of Hypericum Extract on the Expression of Serotonin Receptors. J Geriatric Psychiatry and Neurology. 1994;7:S63-S64 35. Rayburn WF, Gonzalez CL, Christensen HD, et al. Effect of prenatally administered hypericum (St John’s wort) on growth and physical maturation of mouse offspring. Am J Obstet Gynecol 2001;184:191-5 36. Woelk H, Burkard G, Grunwald J. Benefits and risks of the hypericum extract LI 160: Drug monitoring study with 3,250 patients. J Geriatr Psychiatr neurol 1994;7(suppl 1):S34-8 37. Hubner WD, Arnoldt KH. St John’s wort: a one year treatment study [in German; English abstract]. Z Phytother 2000;21:306-10 38. Schulz V, Hansel R, Tyler VE. Rational Thytotherapy: A Physicians’ Guide to Herbal Medicine. 3 rd ed. Berlin, Germany: Springer-Verlag 1998:p56 39. De Smet PA, Nolen WA. St. John’s wort as an anti-depressant. BMJ 1996;3:241-2 40. Suzuki O, Katsumata Y, Oya M, et al. Inhibition of monoamine oxidase by hypericin. Planta Med 1984;50:272-4 41. Bladt S, Wagner H. Inhibition of MAO by fractions and constitutents of hypericum extract. J Geriatr Psychiatr Neurol 1994;7(suppl 1):S579 42. Thiede HM, Walper A. Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatr Neurol 1994;7(suppl 1):S546 43. Kahn RS, et al. L-5-hydroxytryptophan in the treatment of anxiety disorders. J Affect Disord Mar1985;8(2):197-200 44. Muller WE, et al. Effects of Hypericum Extract (LI 160) in Biochemical Models of Antidepressant Activity. Pharmacopsychiatry. 1997;30(Supp 2):102-07 45. Linde K, et al. St. John's Wort for Depression--An Overview and Meta-analysis of Randomised Clinical Trials. BMJ. 1996;313m:253-58 46. Demott K. St. John’s Wort Tied to Serotonin Syndrome. Clin Psychiatry News 1998;26:28. 47. Suzuki O, et al. Inhibition of Monoamine Oxidase by Hypericin. Planta Medica 1984;50:272-74. 48. Bladt S, et al. Inhibition of MAO by Fractions and Constituents of Hypericum Extract. J Geriatric Psychiatry and Neurology 1994;7:S57S59 49. Gordon JB. SSRIs and St.John's Wort: possible toxicity? Am Fam Physician Mar1998;57(5):950,953 50. Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999;12(1):7-10. 51. Okpanyi SN, et al. Animal experiments on the psychotropic action of a hypericum extract. Arzneimittelforschung Jan1987;37(1):10-3 52. Johne A et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum) Clin Pharmacol Ther Oct1999;66(4):338-45 53. Nebel A, et al. Potential metabolic interaction between St. John’s wort and Theophylline. Ann Pharmacother Apr1999;33(4):p502 54. Ruschitzka F, et al. Acute heart transplant rejection due to St. John’s wort. Lancet Feb2000;355(9203):548-9 55. Rey JM, et al. Hypericum perforatum (St John;s Wort) in depression: Pest or blessing? Med J Aust Dec1998;169(11-12):583-6 56. Yue Qy, Bergquist C, Gerden B. Safety of St. John’s wort (Hypericum perforatum), correspondence. Lancet 2000;355:576-7 57. Ernst E. Second thoughts about safety of St John’s Wort. Lancet Dec1999;354(9195):2014-6 58. Piscitelli SC, et al. Indinavir concentrations and St. John’s Wort. Lancet Feb2000;355(9203):547-8 59. Mills S, Bone K. Principles and Practice of Phytotherapy. Churchill Livingstone 2000:548-9

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Stinging Nettle or Nettle (Urtica Dioica) General Features Nettle resembles a noxious weed that can cause a pruritic rash upon contact with the skin. The aerial parts and the roots (rhizomes) of two species (Urtica dioica L. and Urtica urens L.) are used medicinally. 1,2,3,4 Stinging Nettle extract is commonly used in formulations to treat benign prostatic hyperplasia in many regions of Europe. 5,6 It may also have value in the management of arthritis symptoms, gout and the treatment of hayfever, but these applications are less well substantiated than its accepted use in the treatment of benign prostatic hyperplasia. 7,8,21,22,23

Principle Active Constituents - Flavonoids (Leaf) - Sterols – including beta-sitosterol and sitosterol –3 –D – glucoside (roots) - Lignans (roots) - Fatty acids (roots) 9 - Polysaccharides and Lectins 21 There is controversy as to which of the above constituents are most important in the treatment of BPH, arthritis, and allergic conditions. 21

Clinical Application and Mechanism of Action 1. Benign Prostatic Hyperplasia (BPH) Nettle is most commonly combined with other phytonutrients, such as Saw Palmetto, Pygeum Africanum and Betasitosterol, in the treatment of BPH.10,11,21,22 However, it has been used a singular treatment agent in at least two double-blind studies involving men with BPH. In these studies Nettle proved to be superior to placebo, but showed less impressive results than studies using Saw Palmetto, Pygeum and/or Cernilton. 12,13,22 Urtica extract has been shown to block the action of dihydrotestosterone (DHT). Like saw palmetto extract, Urtica extract appears to interact with the binding of DHT to cytosolic and nuclear receptors hence, decreasing the impact of DHT’s effect on the cell division rate of prostate cells. DHT tends to cause excessive cell division leading to BPH, if it builds up intraprostatically. 14 Other studies indicate that Urtica extract inhibits the binding of sex hormone-binding globulin to human prostatic tissue, thus, reducing excessive androgen stimulation to the gland. It may also inhibit the aromatase enzyme, which converts androstenedione to estrone hormone within fat tissue. Estrone hormone is linked to increased BPH symptoms and a build up of DHT in the prostate gland, as this form of estrogen decreases the hydroxylation (breakdown or detoxification) and elimination of DHT. 2,15 Experimental evidence has repeatedly shown that Urtica extract exerts anti-proliferative effects on human prostate cells as well as on human prostate cancer cells in in-vitro, and in-vivo animal studies. 16,17 Urtica dioica extract is also a weak inhibitor of the 5 alpha-reductase enzyme, which converts testosterone to dihydrotestosterone (DHT). 19 All of these biological mechanisms are beneficial in the treatment of BPH. Some authorities suggest that Nettle contains numerous biologically active chemicals that may influence the function of the prostate gland, interact with sex hormones, slow the growth of prostate cells, fight prostate cancer, and reduce inflammation. 22

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A number of open studies involving at least 15,000 men, although less reliable than double-blind placebo controlled studies, have also shown Nettle extract to be useful in the treatment of symptoms associated with BPH. 2. Hayfever (allergic rhinitis) A small study of 69 subjects demonstrated that Nettle supplementation reduced hayfever symptoms to a significant degree, under double-blind, placebo-controlled conditions. 25 3. Arthritis A small double-blind study, along with historical use of Nettle, suggests that by applying Stinging Nettle leaf topically over arthritic joints, symptoms of pain, swelling and stiffness may improve. 26

Dosage and Standardized Grade 1. BPH: As a single agent, Urtica dioica extract is usually taken at 300-600 mg per day, in divided doses. 18, 21 As part of a combination formula lower doses of Nettle extract are usually employed. 18 A 5:1 extract is commonly used therapeutically, consisting of an Urtica product standardized to 1-2% silica content. 23 2. Hayfever: 300 mg of Urtica extract, twice per day. 25

Adverse Side Effects, Toxicity and Contraindications Adverse side effects are rare. Infrequent reports of scanty urination, skin irritation, and gastric distress occur in some patients. 2,20 In one study involving 4,087 subjects who took 600 to 1,200 mg of Nettle root daily for 6 months, less than 1% reported mild stomach upset, and only 0.19% experienced allergic skin reactions (skin rash). 27

Drug-Nutrient Interactions There are no well-known drug nutrient interactions for stinging Nettle. Theoretically, Nettle may potentiate the effect of antihypertensive drugs and antagonize the effects of oral hypoglycemic drugs in type II diabetics, and possibly interact with sedative medications, but no clinical evidence exists to establish these interactions as a contraindication to the use of Urtica dioica at this time. 20,22

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Leung A, Foster S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs and Cosmetics. New York, NY: John Wiley and Sons 1996:p649 ESCOP. Urticae Radix/Nettle Root. In: ESCOP Monographs (Fascicule 2) Exeter: ESCOP 1996:p58 ESCOP.Urticae Folium/Herba (Nettle Leaf). In: ESCOP Monographs (Fascicule 4) Exeter: ESCOP 1997:p58 Weiss RF. Herbal medicine. Beaconsfield, England: Beaconsfield Publishers Ltd 1988:p362 Dreikorn K, Schonhofer P. Status of phytotherapeutic drugs in the treatment of benign prostatic hyperplasia. [German] Urologe A 1995;34(2):119-29 Buck A. Phytotherapy for the prostate. British Journal of urology 1996;78:325-36 Chrubasik S, Enderlein W, Bauer R, Grabner W. Evidence for antirheumatic effectiveness of herba urticae dioicae in acute arthritis: A pilot study. Phytomedicine 1997;4(2):105-8 Rand J. pilot study indicates that tewed herba urticae diocae may potentiate the effects of diclofenac in acute arthritis. Focus on Alternative and Complementary Therapies 1997;2(4):156-7 The Botanical Pharmacy. Quarry Health Books 1999. Boon H and Smith M:256-9 Schneider HJ, Honold E, Mashur T. Treatment of benign prostatic hyperplasia. Results of a surveillance study in the practices of urological specialists using a combined plant-based preparation. Forschritte der Medizin 1995;113:37-40 Harmann R, Mark M, Soldati F. Inhibition of 5 alpha reductase and aromatase by PHL-00801 (Prostatonin), a combination of PY102 (Pygeum africanum) and UR102 (Urtica dioica) extracts. Phytomedicine 1996;3(2):121-8 Belaiche P et al. Clinical studies on the palliative tratment of prostate adenoma with extract of urtica root. Phytother Res 1991;5:267-9 Romics I. Observations with Bazotion in the management of prostatic hyperplasia. Int Urol Nephrol 1987;19(3):293-7 Wagner H et al. Search for the anti-prostatic principle of stinging nettle (urtica dioica) roots. Phytomedicine 1994;1:213-24 Hyrb D, Khan M, Romas N, Rosner W. The effect of extracts of the roots of the the stinging nettle (Urtica dioica) on the interaction of SHBG with its receptor on human prostatic membranes. Planta Medica 1995;61:31-2 Konrad L et al. Antiproliferative effect on human prostate cancer cells by a stinging nettle root (urtica dioica) extract. Planta med 2000;66(1):44-7 Lichius JJ et al. Antiproliferative effect of a polysaccharide fraction of a 20% methanolic extract of stinging nettle roots upon epithelial cells of the human prostate (LNCaP) Pharmzie 1999;54(10):768-71 Pizzorno J, Murray M. Encyclopedia of Natural Medicine (2nd ed) Prima Health 1998:p762 Benign Prostatic Hyperplasia. Medical Post. Oct 17, 2000

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20. Newall C, Anderson L, Phillipson J. herbal medicines: A Guide for health Care professionals. London: The Pharmaceutical Press 1996:p296 21. Healthnotes, Inc 2001. www.healhnotes.com: nettle 22. Natural Products Encyclopedia. www.consumerslab.com: nettle 23. Dietary Supplement Information Bureau. www.content.intramedicine.com: Stinging Nettle 24. European Scientific Cooperative on Phytotherapy. Urticae radix. Exeter, UK: ESCOP, 1996-1997:4-5. Monographs on the uses of plant drugs, fascicule 2. 25. Mittman P. Randomized, double-blind study of freeze-dried Urtica dioica in the treatment of allergic rhinits. Planta Med 1990;56:44-7 26. Randall C, Randall H, Dobbs F et al. Randomized controlled trial of nettle sting for the treatment of base-of-thumb pain. J R Soc Med 2000;93:305-9 27. Shulz V, Hansel R, Tyler VE. Rational Phytotherapy: A Physicianâ&#x20AC;&#x2122;s Guide to Herbal medicine. 3 rd ed. Berlin, Germany: Springer-Verlag 1998:201-2

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Tribulus Terrestris (Puncture Vine) General Features Tribulus Terrestris is an annual plant, which has been commonly used in folk medicine for a number of purposes. 1 Most recently, it has been researched for its ability to reverse erectile dysfunction, enhance libido and as a treatment for angina pectoris.2,3 Tribulus Terrestris is a rich source of saponins, of which protodioscin has received a significant amount of attention in regards to sexual dysfunction issues.2,3

Principle Active Constituents Steroidal Saponins (Furanosterols)4,5

Clinical Application and Mechanism of Action 1. Erectile Dysfunction Tribulus Terrestris supplementation has been shown to reverse erectile dysfunction problems and improve or enhance sexual desire in men and women. 3,6 Evidence exists to demonstrate that protodioscin (saponin) from Tribulus Terrestris can be converted in the body to dehydro-epiandrosterone (DHEA), a precursor to the synthesis of testosterone and estrogen. 3 It is thought that Tribulus Terrestris can increase testosterone levels in men and estrogen levels in women.6 However, some evidence refutes this.7 An alternate explanation suggests that protodioscin (saponin) increases the release of nitric oxide from the arterial endothelium and nitrergic nerve endings in the region of the genitalia, facilitating increased blood flow to the corpus cavernosum.2 This effect appears to be more likely than the elevation of testosterone, as studies with body builders fail to demonstrate a rise in serum testosterone in these athletes after supplementation with Tribulus Terrestris.7 2. Angina Pectoris Tribulus Terrestris is known to dilate coronary arteries and improve angina pectoris in afflicted patients as demonstrated in a clinical and cross-over trial of 406 cases of angina pectoris. This appears to confirm the effect of protodioscin as a mediator to enhance the release of nitric oxide locally, dilating arteries and increasing blood flow through the coronary blood vessels of the heart as mentioned above. 8 This application requires cooperation with the attending physician.8

Dosage and Standardized Grade Erectile Dysfunction and Libido-Enhancement â&#x20AC;&#x201C; 250 mg (Standardized extract containing 40 percent saponins), three times daily is a common daily dosage in these cases. A daily dosage of up to 1500 mg per day has also been used safely.6

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Adverse Side Effects, Toxicity and Contraindications The LD 50 in rats is greater than 10 gm per kg of body weight. Tribulus Terrestris appears to be very safe at recommended doses with no major adverse side effects reported.6,8 Tribulus Terrestris should probably be avoided in cases of reproductive cancers (e.g., prostate, breast cancers)

Drug-Nutrient Interactions There are no well-known drug-nutrient interaction for tribulus terrestris. Authorâ&#x20AC;&#x2122;s Note: It is probably wise to not take it concurrently with other vasodilating agents such as nitroglycerine or sildenofil (viagra).

1. 2. 3. 4. 5. 6. 7. 8.

Arcasoy HB, et al. Effect of tribulus terrestris L. saponins mixture on smooth muscle preparations: a preliminary study. Boll Chim Farm 1998;137(11):473-5 Adaikan PG, et al. Proerectile pharmacological effects of tribulus terrestris extract on the rabbit corpus cavernosum. Ann Acad med Singapore 2000;29(1):22-6 Adimoelja A. Phytochemicals and the breakthrough of traditional herbs in the management of sexual dysfunctions. Int J Androl 2000;23(suppl 2):82-4 Selected Medicinal Plants of India. Chemexil 1992:323-5 Mahato S, et al. J Chem Soc, Perkin Trans 1981;1:2405 Wright J. Muscle and Fitness. Sept 1996;p140-2,p224 Brown GA, et al. Effects of anabolic precursors on serum testosterone concentrations and adaptations to resistance training in young men. Int J Sport Nutr Exerc Metab 2000;10(3):340-59 Wang B, et al. 406 cases of angina pectoris in coronary heart disease treated with saponins of tribulus terrestris. Zhong Xi Ti Jie he Z|a Zhi 1990;10(2):85-7

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Turmeric (Curcumin) General Features Turmeric is a member of the ginger family. It has been used historically as a major ingredient in curry powder (flavour) and for colouring (i.e. preparation of mustard). The medicinal portions of Turmeric are the primary and secondary rhizomes. It is used medicinally in both traditional Chinese medicine and in the traditional medicine of India; primarily as a treatment for a variety of inflammatory conditions and some other health problems. Turmeric contains 0.3-5.4 percent Curcumin content, which has been shown to be a primary active constituent for medicinal purposes. As such, standardized extracts of Turmeric have been developed that are in the range of 90-95 percent Curcumin content. These products delivery a considerable amount of Curcumin at doses much lower than would be required if a patient were to use Turmeric supplementation for an intended health purpose. 1,2

Principle Active Constituents 1. Curcumin: a phenylpropanoid derivative 2. Volatile oil components 1,2,3 N.B. Curcumin has an estimated bioavailablity of 65 percent after oral administration. 10

Clinical Application and Mechanism of Action 1. Arthritis and Inflammatory Joint Conditions Curcumin has been shown to inhibit the 5-lipoxygenase enzyme that gives rise to the formation of pro-inflammatory eicosanoids in neutrophils, in particular, leukotriene B4.4,5 It is also a potent antioxidant.6,7 Several clinical studies have reported Curcuminâ&#x20AC;&#x2122;s effectiveness in the treatment of rheumatoid arthritis. In a head to head trial against the powerful anti-inflammatory drug phyenylbutazone, patients using the Curcumin supplement fared equally as well as did those taking phyenylbutazone at a dosage of 300 mg per day in regards to joint swelling, walking speed and morning stiffening. In another study involving the post-operative inflammation model, 400 mg per day of Curcumin was shown to be as effective as 100 mg of phyenylbutazone.8,9 No side effects from Curcumin use were reported in these studies, whereas phyenylbutazone is known to be associated with a number of adverse side effects. 8,9 In India, Turmeric is used for a wide range of arthritic and muscular disorders.10 2. Cancer Treatment Support Although studies using Curcumin for cancer treatment have not been performed to date, a large body of evidence from animal and experimental evidence suggests that it may be of benefit. Curcumin has been shown to induce apoptosis (programmed cell death) in various cancer cell lines and animal tumor cells, and may inhibit angiogenesis (the growth of new blood vessels around cancer cells). In rats and mice, dietary Curcumin has demonstrated preventive activity against carcinogenesis in the skin, colon, forestomach, and duodenum. Curcumin blocks certain cyclosporine-resistant pathways of T-cell proliferation and thus may be a potential adjuvant immunosuppressive agent for the treatment of cancer. 10

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In vitro experiments have shown that Curcumin may inhibit the growth of estrogen positive human breast MCF-7 cells induced by a variety of carcinogens. This effect appears to be synergistic in combination with the soy isoflavonoid genistein.11

Dosage and Standardized Grade Arthritis and Joint Inflammatory Conditions: 400 mg Curcumin, three times daily if used as a solitary anti-inflammatory agent (std to 95 percent Curcumin content or greater). 2,8 To achieve this level of Curcumin from Turmeric, a Turmeric dosage of 8,000 to 60,000 mg would be required.2 Cancer Treatment Support: There are no human studies are available, but 400 mg of Curcumin, three times daily may be considered. However, the attending physician should be consulted in regards to all supplementation initiatives.

Adverse Side Effects, Toxicity and Contraindications In animal studies even extremely high doses of Turmeric or Curcumin have not produced evidence of toxicity, mortality or genetic damage.2 In human studies Turmeric and Curcumin appear to have no adverse effects. Prolonged use may occasionally result in gastrointestinal upset.2,12,13 Curcumin and Turmeric may also stimulate bile flow, which can potentially aggravate problems related to blockage of the common bile duct or gallstones.13

Drug-Nutrient Interactions Warfarin and Coumadin: Curcumin has been shown to inhibit cyclooxygenase enzyme in platelets, reducing platelet coaguability and has demonstrated fibrinolytic effects.5,14 For these reasons it is believed that it may potentiate the anticlotting effects of warfarin or coumadin, increasing the risk of a bleeding disorder, at a high dosage. There are no adverse events of this nature reported to date, but caution is recommended at this time. 15

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33.

Leung A. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. John wiley & Sons, New York 1980:p313-4 Ammon HPT, Wahl MA. Pharmacology of Curcuma longa. Planta Medica 1991;57:1-7 Sharma OP. Antioxidant properties of curcumin and related compounds. Biochem Pharmacol 1976;25:1811-25 Srivastava R. Inhibition of neutrophil response by curcumin. Agents and Actions 1989;28:298-303 Ammon HP, Safayhi H, Mack T, Sabieraj J. Mechanism of anti-inflammatory action sof curcumine and boswellic acids. Journal of Ethnopharmacology 1993;38(2-3):113-9 Selvam R, Subramanian L, Gayathri R, Angayarkanni N. The antioxidant activity of turmeric (Curcuma longa). Journal of Ethnopharmacology 1995;47(2):59-67 Osawa T, Sugiyama Y, Inayoshi M, Kawakishi S. Antioxidative activity of tetrahydrocurcuminoids. Bioscience Biotechnology and Biochemistry 1995;59(9):1609-12 Deodhar SD, Sethi R, Srimal RC. Preliminary studies on antirheumatic activity of curcumin (di-feruloyl methan). Indian Journal of Medical Research 1980;71:632-4 Satoskar RR, Shah SJ, Shenony SG. Evaluation of anti-inflammatory property of curcumin (di-feruloyl methane) in patients with postoperative inflammation. International Journal of Clinical Pharmacology Therapy and Toxicology 1986;24:651-4 Grant K, et al. Alternative Therapies: Turmeric. Am J Health-System Pharmacy 2000;57(12):1121-2 Verma SP, Salamone E, Goldin B. Curcumin and genistein, plant natural products, show synergistic inhibitory effects on the growth of human breast cancer MCF-7 cells induced by estrogenic pesticides. Biochemical and Biophysical Research Communications 1997;233(3):692-6 Shankar TNB, Shantha NV, Ramesh HP, et al. Toxicity studies on tumeric (Curcuma longa): Acute toxicity studies in rats, guinea pigs, and monkeys. Indian Journal of Experimental Biology 1980;18:73-5 Tyler VE. Herbs of Choice. The Therapeutic Use of Phytomedicinals. Binghampton NY: Pharmaceutical Products Press 1994:p209 Ammon HP, et al. Mechanism of anti-inflammatory actions of curcumine and boswellic acids. J Ethnopharmacol 1993;38(2-3):113-9 Heck A, et al. Potential interactions between alternative therapies and warfarin. Am J Health-Syst Pharm 2000;57(13):1221-7 Srivastava KC, et al. Curcumin, A major component of food spice turmeric (curcuma longa) inhibits aggregation and alters eicosanoids metabolism in human blood platelets. Prostaglandins Leukot Essent Fatty Acids. Apr1995;52(4):223-7 Srivastava V, et al. Effect of curcumin on platelet aggregation and vascular prostacyclin synthesis. Arzneim Forsch/Drug Res 1986;36:715-7 Healthnotes, Inc 2001. www.healthnotes.com: Turmeric Natural Products Encyclopedia. www.consumerslab.com: Turmeric Dietary Supplement Information Bureau. www.content.intramedicine.com: Turmeric Ammon HP, et al. Mechanism of anti-inflammatory actions of curcumin and boswellic acids. J Ethnopharmacol 1993;38:p113 Srivastava V, et al. Effect of curcumin on platelet aggregation and vascular prostacyclin synthesis. Arzneim Forsch/Drug Res 1986;36:715-7 Arora RB, Basu N, Kapoor V, Jain AP. Anti-inflammatory studies on Curcuma longa (turmeric). Ind J Med Res 1971;59:1289–95 Sreejayan N, Rao MNA. Free radical scavenging activity of curcuminoids. Arzneimittelforschung 1996;46:169–71 Ramirez-Boscá A, Soler A, Gutierrez MAC, et al. Antioxidant curcuma extracts decrease the blood lipid peroxide levels of human subjects. Age 1995;18:167–9 Srivastava R, Dikshit M, Srimal RC, Dhawan BN. Anti-thrombotic effect of curcumin. Thromb Res 1985;40:413–7 Mehta K, et al. Antiproliferative effect of curcumin (diferuloylmethane) against human breast tumor cell line. Anticancer Drugs Jun1997;8(5):470-81 Kawamori T, et al. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res Feb1999;59(3):597-601 Menon LG, Kuttan R, Kuttan G. Anti-metastatic activity of curcumin and catechin. Cancer Lett 1999;141:159–65 Thamlikitkul V, Bunyapraphatsara N, Dechatiwongse T, et al. Randomized double blind study of Curcuma domestica Val. For dyspepsia. J med Assoc Thai 1989;72:613-20 Rasyid A, Lelo A. The effect of curcumin and placebo on human gall-bladder function: an ultrasound study. Aliment Pharmacol Ther 1999;13:245-9 Lal B, Kapoor AK, Asthana OP, et al. Efficacy of curcumin in the management of chronic anterior uveitis. Phytotherapy Res 1999;13:318–22 Soni KB, et al. Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers. Indian j Physiol Pharmacol Oct1992;36(4):273-5

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34. Deshpande S, et al. Subchronic oral toxicity of turmeric and ethanolic turmeric extract in female mice and rats. Toxicology Letters 1998;95:183-93 35. Kandarkar SV, Sawant SS, Ingle AD, et al. Subchronic oral hepatotoxicity of turmeric in mice-histopathological and ultrastructural studies. Indian J Exp Biol Jul1998;36(7):675-9

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Uva Ursi (Bearberry) General Features Uva Ursi is a small evergreen shrub found in colder northern climates. It has red flowers and red berries, which bears like to eat, hence its alternate name bearberry. The active constituents, used medicinally, are found in its leaves. Today it is often used to help treat and/or prevent recurrent urinary tract infections, although no human trials confirming this effect have been published to date. 1,4

Principle Active Constituents Arbutin is the most active constituent, which typically comprises up to 10% (7-9 %) of the plant by weight. It is derived from the leaves of the plant for medicinal purposes. 5

Clinical Application and Mechanism of Action Urinary Tract Infections To be effective, the glycoside arbutin must be converted to hydroquinone in the urinary tract. In this form, arbutin and methylarbutin have been shown to produce a natural antibiotic effect in the urinary tract, but this effect requires an alkaline environment. Hence, diet is important to potentiate its effects (more vegetarian in nature). Other compounds in Uva Ursi help to increase alkalinity of the urine.1 As noted above, there are no well-designed human studies to confirm that Uva Ursi can alleviate urinary tract infections. Thus, it should not be used as a sole treatment in these cases, according to expert sources. 4,6 (See also Cranberry in this document)

Dosage and Standardized Grade Urinary Tract Infection: The German Commission E Monograph suggests 700-1,000 mgs of a standardized extract tablet or capsule (containing 20% arbutin content), taken three times daily.1,7

Adverse Side Effects, Toxicity and Contraindications Excess build up of hydroquinone can be toxic at 1 gm (equivalent to 0.5 ounces of fresh Uva Ursi leaves). Signs and symptoms of toxicity include tinnitus, nausea, vomiting, shortness of breath, cyanosis, convulsions, delirium and collapse. 3 The high tannin content may also produce cramping, nausea, or vomiting. 4

Drug-Nutrient Interactions There are no well known drug-nutrient interactions for Uva Ursi at this time. 4,8

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1. 2. 3. 4. 5.

6. 7. 8.

Leung A. Encylclopedia of common natural ingredients used in food, drugs, and cosmetics. New York: New York. John Wiley & Sons 1980:316-7. Merck Index. 10th Ed. Rahway, NJ. Merck & Co. 1983:796-7, 4721. Boon H and Smith M. The Botanical Pharmacy. Quarry Health Books. 1999: 304-307 Healthnotes, Inc. 2001 www.healthnotes.com: Uva ursi Matsuda H, Nakamura S, Tanaka T, Kubo M. Pharmacological studies on leaf of Arctostaphylos uva-ursi (L) Spreng. V. Effect of water extract from Arctostaphylos uva-ursi (L) Spreng (bearberry leaf) on the antiallergic and antiinflammatory activities of dexamethasone ointment. J Pharm Soc Japan 1992;112:673-7 Natural Products Encyclopedia. www.consumerslab.com: Uva ursi Blumenthal M, Busse WR, Goldberg A, et al. (eds.) The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston, MA: Integrative Medicine Communications 1998:224-5 Dietary Supplement Information Bureau. www.content.intramedicine.com: Uva ursi

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Valerian (valeriana officinalis) General Features There are more than 200 plant species belonging to the genus Valeriana, but the most common one, and the one used for medicinal purposes is Valeriana officinalis. 1,9 10 This plant grows wild all over Europe, but most of the Valerian used in consumer health products is cultivated. 10 The rootstock contains its active constituents, which are concentrated into health products used primarily for the treatment of insomnia and anxiety. 1,9,10 Scientific studies evaluating the effects of Valerian on humans began in the 1970â&#x20AC;&#x2122;s, which subsequently lead to its approval as a sleep aid by the Germanyâ&#x20AC;&#x2122;s Commission E Monograph in 1985. 9

Principle Active Constituents 1. Valepotriates (iridoid molecules) and valerenic acid. These compounds are exclusive to Valerian. 1 It now appears that valerenic acid is a possible active constituent, but not the valepotriates. 9 2. Volatile Oils 12

Clinical Application and Mechanism of Action Insomnia Valerian acts as a sedative in that its active constituents, which are not fully understood or known, are capable of binding to the same brain receptors as Valium and other benzodiazepine drugs. Central nervous system sedation is regulated by receptors in the brain known as GABA-A receptors (gamma amino butyric acid). Experimental test tube studies indicate that active constituents in Valerian may weakly bind to GABA-A receptors in the brain, producing a sedation effect. Human trials suggest that Valerian tends not to impair mental function or produce a morning hangover, and dependency has not been reported with its use. Studies have demonstrated improved sleep quality and insomnia relief. 1,2,3,9,11,12 Overall, studies suggest that Valerian improves sleep quality (more restful sleep), and the transition into sleep. However, it may not increase total sleep time. These findings arise from several double-blind trials, that provide evidence for Valerian as an effective treatment for individuals with mild to moderately severe insomnia. 2,3,4,13,14,15,16 A 28-day study, involving 121 subjects, showed that Valerian supplementation provided significant improvement in insomnia cases, compared to the placebo. 13 A 14-day trial, involving 78 elderly patients, also showed that Valerian supplementation provided significant improvement in insomnia cases, compared to placebo. As shown in other studies, it often takes a number of days before the effects of Valerian appear. As such, patients tend to report more consistent improvement in relief of insomnia after several days of Valerian supplementation (its effects are not immediate as would be the case for many drugs prescribed for this condition). 14 There is also convincing evidence from animal studies that Valerian produces a calming effect, as well as enhanced sleepiness, and reduced activity patterns. These studies provide important objective proof of Valerianâ&#x20AC;&#x2122;s natural sedative capabilities. 18,19,20,21 In head-to-head trials testing Valerian against the drug oxazepam (10 mg at bedtime) and bromazepam, Valerian supplementation demonstrated that it could provide equal relief for insomnia, as did these common sleep-aid medications. 15,16

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Anxiety Several preliminary studies indicate that Valerian may be an effective treatment in cases of uncomplicated anxiety (not linked to major depression) and it has been used for this problem historically and clinically, although more research is needed to better understand its application in this regard. 1,2,3,17 Dosage and Standardized Grade Insomnia: As a mild sedative, Valerian may be taken 30-45 minutes before retiring at the following dosage and standardized grade: Valerian extract, 200 –400 mg (standardized to 0.8% valerenic acids content) 8,11 Anxiety and Stress Reduction: 200 mg, twice per day (standardized to 0.8% valerenic acids content). 11

Adverse Side Effects, Toxicity and Contraindications Animal studies show that it takes enormously large doses of Valerian to produce any serious side effects, and in one suicide attempt, a human subject experienced no life threatening effects (stomach cramps, fatigue, chest tightness, tremors and light-headedness), after taking 20 gms of valerin (20-40 times the recommended dose). 22,23 There have been approximately 50 reported cases of overdose when subjects took a product called Sleep-Qik, containing Valerian as well as conventional medications, but no liver damage was noted. 24,25 Generally speaking, Valerian is considered to be safe and usually causes only mild gastrointestinal upset on rare occasions. It is on the GRAS list (generally recognized as safe) of the FDA. Some mild impairment to attention ability may occur for a couple of hours after intake, and thus, driving immediately after Valerian supplementation is not advised. However, Valerian is not reported to cause morning drowsiness when taken the night before. 9,10,11 If morning sleepiness does occur, simply reduce the dosage.1

Drug-Nutrient Interactions Valerian may potentiate the actions of the following medications and thus, it is considered to be prudent to not take Valerian concurrently with these drugs:    

Barbituates or Sedatives Antidepressants 27,28,29 Anti-anxiety medications Hypnotic drugs 33,34,35

26 30,31,32

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Houghton PJ. The biological activity of Valerian and related plants. J Ethnopharmacol 1988;22(2):121-42. Leathwood P, et.al.. Aqueous extract of Valerian root (Valeriana Officinalis L.) Improves sleep quality in man. Pharmacol Biochem Behav 1982;17:65-71. Bakderer G, Borbely AA. Effect of Valerian on human sleep. Pharmacol 1985;87:406-9. Leathwood PD, Chauffard F. Aqueous extract of Valerian reduces latency to fall asleep in man. Planta Medica 1985;54:144-8. Lindahl O, Lindwall L. Double blind study of a Velerian preparations. Pharmacol Biochem Behav 1989;32(4):1065-6. Dressing H, et.al.. Insomnia: are Valeriana/Melissa combinations of equal value to Benzodiazepine? Therapiewoche 1992;42:726-36. Leung A. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York, New York. John Wiley & Sons, 1980. Murray MT. The healing power of herbs. 2nd ed. Prima Publishing, 1995. Natural Products Encysclopedia www.consumerslab.com: Valerian Healthnotes, Inc. 2001 www.healthnotes.com: Valerian Dietary Supplement Information Bureau. www.content.intramedicine.com: Valerian Mennini T, Bernasconi P, Bombardelli E, et al. In vitro study on the interaction of extracts and pure compounds from Valeriana officinalis roots with GABA, benzodiazepine and barbiturate receptors. Fitoterapia 1993;64:291â&#x20AC;&#x201C;300 Vorbach EU, Gortelmeyer R, Bruning J. Therapy for insomniacs:effectiveness and tolerance of valerian preparations [translated from German]. Psychopharmakotherapie 1996;3:109-15 Kamm-Kohl AV, Jansen W, Brockmann P. Modern valerian therapy for nervous disorders in old age [translated from German]. Med Welt 1984;35:1450-4 Dorn M. Efficacy and tolerability of Baldrian versus oxazepam in non-organic and non-psychiatric insomniacs: a randomized, doubleblind, clinical, comparative study [translated from German]. Forsch Komplementarmed Klass Naturkeilkd 2000;7:79-84 Schmitz M, Jackel M. Comparative study for assessing quality of olife of patients with exogenous sleep disorders (temporary sleep onset and sleep interruption disorders) Kohnen R, Oswald WD. The effects of valerian, propranolol, and their combination on activation, performance and mood of healthy volunteers under social stress conditions. Pharmacopsychiatry 1988;21:447-8 Hendriks H, Bos R, Woerdenbag HJ, et al. Central nervous depressant activity of valerenic acid in the mouse. Planta Med 1985;1:28-31 Leuschner J, Muller J, Rudmann M. Characterisation of the central nervous depressant activity of a commercially available valerian root extract. Arzneimittelforschung 1993;43:638-41

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20. Krieglstein J, Grusla D. Centrally depressant components of valerian. However, valepotriates, valerenic acid, valeranone and the essential oil are ineffective [in German]. Dtsch Apoth Ztg 1988;128:2041-6 21. European Scientific Cooperative on Phytotherapy. Valerianae radix. Exeter, UK: ESCOP 1996-1997:3-4 Monographs on the Medicinal uses of Plant Drugs, Fascicule 4 22. Resecrans JA, Defeo JJ, youngken HW Jr. Pharmacological investigation of certain Valeriana officinalis L. extracts. J Pharm Sci 1961l50:240-4 23. Willey LB, Mady SP, Cobaugh DJ, et al. Valerian overdose: a case report. Vet Hum Toxicol 1995;37:364-5 24. Chan TY, Tang CH, Critchley JA. Poisoning due to an over-the-counter hypnotic, Sleep-Qik (hyoscine, cyproheptadine, valerian). Postgrad Med J 1995;71(834):227-8 25. Chan TY. An assessment of the delayed effects associated with valerian overdose [letter]. Int J Clin Pharmacol Ther 1998;36:569 26. Hendriks H, et al. Central nervous depressant activity of valerenic acid in the mouse. Planta Med Feb1985;1:28-31 27. Houghton PJ. The biological activity of valerian and related plants. J Ethnopharmacol 1988;22(2):121-42 28. Santos MS, et al. Synaptosomal GABA release as influenced by valerian root extract – involvment of the GABA carrier. Arch Int Pharmacodyn Ther 1994;327(2):220-31 29. Houghton PJ. The scientific basis for the reputed activity of valerian. J Pharm Pharmacol May 1999;51(5):505-12 30. Houghton PJ. The biological activity of valerian and related plants. J Ethnopharmacol 1988;22(2):121-42 31. Santos MS, et al. Synaptosomal GABA release as influenced by valerian root extract – involvment of the GABA carrier. Arch Int Pharmacodyn Ther 1994;327(2):220-31 32. Houghton PJ. The scientific basis for the reputed activity of valerian. J Pharm Pharmacol May1999;51(5):505-12 33. Houghton PJ. The biological activity of valerian and related plants. J Ethnopharmacol 1988;22(2):121-42 34. Santos MS, et al. Synaoptosomal GABA release as influenced by valerian root extract – involvment of the GABA carrier. Arch Int Pharmacodyn Ther 1994;327(2):220-31 35. Houghton PJ. The scientific basis for the reputed activity of valerian. J Pharm Pharmacol May1999;51(5):505-12

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Vinpocetine General Features Vinpocetine is a derivative of the Vinca minor (lesser periwinkle), which is native to many parts of Europe, where it grows in woods and thickets. The isolated active constituent known as ethyl apovincaminate was discovered in the late 1960’s and since that time has been studied and used as a natural agent to enhance blood flow to the brain, with particularly emphasis on its potential use in cerebral vascular insufficiency, dementia and ischaemic stroke.1,

Principle Active Constituents Vinpocetine is a synthetic ethyl ester of apovincamine, derived originally from the Vinca minor.3

Clinical Application and Mechanism of Action Vinpocetine has been shown to enhance blood flow to the brain, act as an antioxidant and protect brain cells from the neurotoxic effects of Abeta Proteins that are linked to the development of Alzheimer’s disease. Therefore, it is being explored as a preventive and therapeutic agent in regards to cerebral vascular insufficiency, ischaemic stroke (to prevent a recurrence), age-related dementia and Alzheimer’s disease.1,2,3,4 Vinpocetine has demonstrated good brain penetration, making it available to exert its bioactive effects on brain circulation and brain cells.1 1. Ischaemic Stroke The increase in the regional blood flow in response to Vinpocetine administration is well established and strengthened by new diagnostic techniques (e.g., transcranial Doppler technique etc.). Vinpocetine has been shown to increase brain circulation, mainly in the thalamus, basal ganglia and visual cortex. Multicenter, randomized, placebo-controlled clinical studies have proven Vinpocetine to be effective in patients with organic psychosyndrome. It has also been shown to be beneficial in redistributing regional blood flow and enhancing glucose supply of brain tissue in ischaemic post-stroke patients (using positron emission tomography studies).1 A small, but important study recruited 30 patients, who had suffered a stroke within the past 72 hours and were given either dextran or dextran plus Vinpocetine. After three months of follow-up, the group given the Vinpocetine showed a 30% reduction in risk of recurring stroke, as defined by the modified Barthel Index, and 60% as defined by the modified Ranking score, compared to the group given dextran alone.3 2. Chronic Cerebral Insufficiency Vinpocetine supplementation was given to forty-two patients with chronic cerebral dysfunction at a daily dosage of 10 mg, three times per day for 30 days. Compared to the forty-two patients given the placebo tablets (who also had chronic cerebral dysfunction), patients receiving the Vinpocetine treatment scored consistently better in all evaluations as measured by the Clinical Global Impression scale, the Sandoz Clinical Assessment-Geriatric scale, and the MiniMental Status Questionnaire. There were no serious side effects related to the ingestion of Vinpocetine. 5 3. Dementia and Alzheimer’s disease In a placebo-controlled, randomized double-blind, multi-center trial involving two hundred and three patients with mild to moderate organic psychosyndrome, including dementia, half of the participants were given Vinpocetine supplementation at 10 mg, three times daily or 20 mg, three times daily for 16 weeks versus the other half of the group who took the placebo pills three times per day. Statistically significant improvements were found in favour of the Vinpocetine group (at both dosages) compared to the placebo group. The Vinpocetine group demonstrated better objective scores on the Clinical Global Impression scale and in cognitive performance (SKT). Vinpocetine was also

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superior to placebo in ratings of the severity of illness. There were no serious side effects reported from the use of Vinpocetine and adverse events between Vinpocetine-treated patients and the placebo group were comparable, indicating no increased attributable risk from the use of Vinpocetine. 6 In regards to Alzheimer’s disease, experimental evidence has shown that Vinpocetine protects brain cells from the toxic effects of Amyloid beta-Protein (Abeta-Protein), which is the agent known to damage brain cells in the development of Alzheimer’s disease. Abeta-Protein induces free radical damage, which in turn, leads to severe damage to the energy factories (mitochondria ) of the cell, vital enzymes (especially those needed to produce the memory chemical, acetylcholine) and other cellular structures. Uncontrolled free radical damage of this nature can ultimately lead to brain cell death of affected neurons. Vinpocetine has been shown to quench (neutralize) free radicals produced by Abeta-Protein, reducing the oxidative damage (free radical) to brain cells under experimental conditions. It also has been shown to protect key respiratory chain complexes within the mitochondria (energy factories of the cell) that were exposed to Abeta-Protein. The researchers conclude that Vinpocetine can exert neuroprotective properties which might be of importance and contribute to its clinical efficacy in the treatment of Alzheimer’s disease or other neurodegenerative disorders in which oxidative stress is involved (e.g., Parkinson’s disease, Multiple sclerosis etc.) 7 As reviewed by CD Nicholson, “Vinpocetine attenuates cognitive deficits, reduces ischaemia-induced hippocampal cell loss and increases cerebral blood flow and glucose utilization. 8 Many scientists indicate that Vinpocetine’s ability to improve cognitive function is primarily due to its effects on enhancing blood flow to the brain, dilating blood vessels, supporting the proper function of red blood cells and reducing blood viscosity via its influence on reducing platelet stickiness.9,10,11

Dosage and Standardized Grade Cerebral Vascular Insufficiency, leading to cognitive dysfunction: 5 mg, 10 or 20 mg, three times per day 2,5,6 Dementia and Alzheimer’s disease: 5 mg, 10 or 20 mg, three times per day 2,5,6

Adverse Side Effects, Toxicity and Contraindications The available clinical studies do not indicate that Vinpocetine supplementation, when taken at recommended doses, produces any adverse side effects or toxicity.1,3,5,6 However, it is a powerful anti-coagulant and therefore, the possibility of a bleeding disorder in the brain or elsewhere in the body is a potential side effect that needs to be considered and the focus of future studies.4

Drug-Nutrient Interactions Anti-Coagulant Medications (e.g., Aspirin, Coumadin, Warfarin): Vinpocetine may potentiate the effects of these drugs increasing the risk of a bleeding disorder in the brain or elsewhere in the body. Thus, it is contraindicated in these cases, as is Ginkgo Biloba, which affects the brain in a similar fashion as Vinpocetine.4

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Bรถnรถczk P, Gulyรกs B, Adam-Vizi V, Nemes A, Kรกrpรกti E, Kiss B, et al. Role of sodium channel inhibition in neuroprotection: effect of vinpocetine. Brain Res Bull Oct2000;53(3):p245-54 2. Dietary Supplement Information Bureau: Vinpocetine. www.content.intramedicine.com. Dietary Supplement Education Alliance 2001 3. Feigin VL, Doronin BM, Popova TF, Gribatcheva EV, Tchervov DV. Vinpocetine treatment in acute ischaemic stroke: a pilot single-blind randomized clinical trial. Eur J Neurol Jan2001;8(1):p81-5 4. Kidd PM. A review of nutrients and botanicals in the integrative management of cognitive dysfunction. Alternative Medicine Review (ALTERN MED REV) Jun1999;4(3):144-61 5. Balestreri R, Fontana L, Astengo F. A double-blind placebo controlled evaluation of the safety and efficacy of Vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction. J Am Geriatr Soc 1987;35:425-30 6. Hindmarch I, et al. Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes. Int Clin Psychopharmacol 1991;6(1):31-43 7. Pereira C, Agostinho P, Oliveira CR. Vinpocetine attenuates the metabolic dysfunction induced by amyloid beta-peptides in PC12 cells. Free Radic Res Nov2000;33(5):p497-506 8. Nicholson CD. Pharmacology of nootropics and metabolically active compounds in relation to their use in dementia. Psychopharmacology (Berl) 1990;101:147-59 9. Burtsev EM, et al. [10-year experience with using Cavinton in cerebrovascular disorders]. Zh Nevropatol Psikhiatr Im S S Korsakova 1992;92(1):56-60 10. Tamaki N, et al. The effect of Vinpocetine on cerebral blood flow in patients with cerebrovascular disorders. Ther Hung 1985;33:13-21 11. Osawa M, Maruyama S. Effects of TCV-3B (Vinpocetine) on blood viscosity in ischemic cerebrovascular disease. Ther Hung 1985;33:712

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White Willow Bark (Salix spp) General Features The white willow tree is native to North America and central and southern Europe. Both the bark and leaves contain the active constituents (phenolic glycosides), although the bark has been used traditionally in the preparation of the medicinal white willow extract.1,2 Willow bark has been used as a treatment for fever and pain in China since 500 BC. One of the principle active constitutents in White Willow Bark is salicin or salicylic acid. Its discovery in the nineteenth century led to the development of aspirin, which is a synthetic version of this phenolic glycoside, known as acetylsalicylic acid (ASA), produced from the chemical modification of salicylic acid. 11,14 There are some distinct differences between the physiological action of ASA and salicin that indicate that salicin may be safer to use under certain conditions, as it does not impair blood clotting to the same degree as aspirin, and it does not appear to significantly irritate the stomach lining.12,13 The analgesic effects of white willow extract are slower to develop than that of ASA, but may last longer than the analgesic effects of aspirin. 15

Principle Active Constituents 1. Phenolic glycosides including salicin, salicortin, tremulacin and salireposide. 2. Other constituents include tannins, flavonoids and catechins.2,3,4,18

Clinical Application and Mechanism of Action 1. Anti-inflammatory and Pain Killer (Analgesic) Effects White Willow Bark (100 mg) in conjunction with other herbal agents has been shown to be effective in the management of osteoarthritis, with respect to reduced pain and improved joint function.5 The pharmacological action of willow appears to be largely determined by its salicin content, although other phenolic glycosides within white willow extract have also been shown to have anti-inflammatory properties. 6,7,18 The phenolic glycosides (including salicin) from white willow extract are slowly converted into active moieties (most notably salicylic acid), primarily in the liver and intestines, via a multiple stage process.7 Like aspirin, these active moieties inhibit the synthesis of inflammatory prostaglandin hormones that are involved in inflammatory conditions and the production of pain and fever. 1,7,17 However, as the phenolic glycosides in white willow extract are converted by the body slowly into various active anti-inflammatory moieties, the biological effect is, therefore, slower than conventional ASA use, but has been shown in some studies to have a longer duration of action. It should be noted that salicin, from White Willow Bark extract, does not irreversibly inhibit platelet aggregation in contrast to the effects of acetylsalicylic acid (ASA).7 Thus, white willow extract is not considered to be a strong anticoagulant and may therefore, be an acceptable alternative anti-inflammatory and pain killer medications in cases where the anticoagulant effects of ASA and other non steroidal anti-inflammatory drugs (eg., ibuprofen) are contraindicated. 7 Back Pain: A four week double-blind placebo-controlled trial, published in the American Journal of Medicine (2000), showed that white willow extract demonstrated almost a 40% success rate in regards to helping low back pain patients achieve a pain-free state, compared with only a 6% success rate in the placebo group. In this group of 210 low back pain patients, none of the white willow extract users reported any stomach pain or gastrointestinal intolerance of any type. One patient within the white willow extract group had an allergic reaction. 16

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Osteoarthritis: A double-blind placebo-controlled trial of 78 subjects with osteoarthritis of the knee or hip also showed that white willow extract was effective in decreasing pain and improving joint function compared to the placebo.1 2. Headache Some evidence suggests that White Willow Bark extract may be helpful in the treatment of certain headaches. 7,8,17

Dosage and Standardized Grade Arthritis, Back Pain, and Headaches: If taken as a single agent, a daily dose of salicin totaling 60 to 120 mg (taken in divided doses) is commonly recommended. 15 However, in the clinical trials cited above, daily doses as high as 120 to 240 mg of salicin were used successfully.11,15,16,17 Note that most standardized white willow products contain 15% salicin content, thus 100 mg of white willow extract at a standardized grade of 15%, salicin, would yield 15 mg of salicin. Often, White Willow Bark extract (100 mg, 15% standardized grade of salicin content) is combined with other antiinflammatory herbs for therapeutic use.5

Adverse Side Effects, Toxicity and Contraindications Due to the presence of salicin, some researchers suggest that White Willow Bark extract is contraindicated for conditions that also involve contraindications to ASA. These include asthma, diabetes, gout, haemophilia, hyperthrombinaemia, hepatic / renal disease, active peptic ulcer disease, glucose â&#x20AC;&#x201C; 6 â&#x20AC;&#x201C; phosphate dehydrogenase deficiency, individuals sensitive to aspirin and children under 12 years of age. 3 According to the Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines, the most well established contraindications include active peptic ulcers, gastritis, and children under 12 years of age. 9 When taken at standard doses (120 mg per day of salicin content), white willow extract is the equivalent of 50 mg of aspirin (a baby aspirin), which is a very small dose (one regular aspirin contains 300 to 320 mg of acetylsalicylic acid). As such, experts have concluded that other active constituents (eg., other phenolic glycosides) also play a role in the anti-inflammatory and pain-relieving effects associated with the use of white willow extract. 16 Like aspirin, white willow extract also provides an analgesic effect, helping to reduce pain. 11 Some occasional gastrointestinal upset and allergic reactions occur with the use of white willow extract, but the incidence of stomach upset and intestinal distress are significantly less than occurs with use of aspirin, which is notorious for is effects on causing erosion and ulcerations to the gastrointestinal tract.9,11,13 Nausea and headaches are also rare side effects associated with the use of white willow extract.7

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Drug-Nutrient Interactions White Willow Bark extract may interact with other drugs in a similar fashion as ASA, producing a negative health effect. Although no reports of White Willow Bark extract have been reported practitioners should be alerted to the following potential drug-nutrient interactions with salicin: Drug

Combined Effect

Acebutoiol

Decreased anti-hypertensive effect of acebutoiol

Adrenocorticoids (systemic)

Increased adrenocorticoid effect

Alendronate (biphosphanate)

Increased risk of stomach irritation if taken within 30 minutes of Alendronate

Allopurinol

Decreased allopurinol effect by increasing kidney resorption of uric acid

ACE Inhibitor

Decreased ACE inhibitor effect (angiotensin窶田onverting enzyme) anti-hypertensive drugs

Antacids

Decreased aspirin effect

Anticoagulants

Increased anti-coagulant effect (abnormal bleeding)

Anti-diabetic agents (oral)

Low blood sugar

Anti-inflammatory drugs (NSAIDs)

Risk of stomach, intestinal bleeding and ulcers

Bumetanide

Possible aspirin toxicity

Carteolol

Decreased anti-hypertensive effect of carteolol 3,1

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Bradley PR, et.al., British Herbal Compendium, Vol.1, Bournemouth, Dorset, UK, British Herbal Medicine Association 1992, 224-226 Meier B, et.al., Pharmaceutical Aspects of the Use of Willows in Herbal Remedies, Planta Medica, 54, 1988, 559-560. Newall C, Anderson L, Phillipson J, Herbal Medicines. A Guide for Health Care Professionals, London: The Pharmaceutical Press, 1996, 296. Meier B, et.al., Identifikation und Bestimmung Von Je Acht Phenolglykosiden in Salix Purpurea und Salix Daphnoides Mit Moderner HPLC, Pharmaceutica Acta Helvetica 60, 1985, 269-274. Mills SY, et.al., Effect of a Proprietary Herbal Medicine on the Relief of Chronic Arthritic Pain: A Double-blind Study, Br J Rheum, 35, 1996, 874-878. Tyler V, Herbs of Choice. The Therapeutic Use of Phytomedicinals, Binghampton: Pharmaceutical Products Press, 1994, 209. ESCOP, Salicis Cortex/Willow Bark, In: ESCOP Monograph Fascicule 4 Exeter, ESCOP, 58, 1997. Hoffmann D, Holistic Herbal, Rockport, CA: Element Books, 1996, 256. Blumenthal M, et.al., The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines, Boston, MA: Integrative Medicine Communications, 1998, 230. Griffith HW, Complete Guide to Non Prescription and Prescription Drugs, The Body Press / Perigee, 1998, 132-133. Natural Products Encylopedia. http://www.consumerslab.com/: White Willow Krivoy N, Pavlotsky E, Chrubasik S et al. Effect of Salicic cortex extract on human platelet aggregation. Planta med 2000;66:1-4 European Scientific Cooperative on Phytotherapy. Salicis cortex. Exeter UK: ESCOP; 1996-1997:p2. Monographs on the medicinal uses of plant drugs, fascicule 4. Foster S. 1010 Medicinal Herbs. Interweave Press, Loveland CO 1998:210-1 Healthnotes Inc. 2001. www.healthnotes.com: Willow Chrubasik S, Eisenberg E, Balan E et al. Treatment of low back pain exacerbations with willow bark extract: a randomized doubleblind study. Am J Med 2000;109:9-14 Schmid B, Ludtke R, Selbmann HK et al. Efficacy and tolerability of a standardized willow bark extract in patients with osteoarthritis: randomized, placebo-controlled, double blind clinical trial [translated from German.] Z Rheumatol 2000;59:314-20 Weiss RF. Herbal Medicine. Ab Arcanum, Gothenburg, Sweden 1988;31:p303

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Wild Yam (Dioscorea Villosa) General Features Wild yam (Dioscorea Villosa) is distinctly different from the vegetable often referred to as yam or the sweet potato vegetable.1,2 Wild yam is a perennial plant producing a large fibrous root stock. The roots are the part used medicinally and are a rich source of the steroidal saponins (based on the sapogenin diosgenin) including diosoin and dioscorin.1,2 Contrary to popular health claims, Wild yam roots do not contain and are not converted into progesterone or dehydroepiandrosterone (DHEA) in the human body. The confusion lies in the fact that yam saponins can be manipulated into progesterone by applying a laboratory pharmaceutical process. Thus, pharmaceutical-based progesterone is made from Wild yam, but the human body can not make this conversion on its own. Women who require progesterone replacement cannot use Wild yam or its steroidal saponins (sapogenin diosgenin-diosoin, dioscorin, dioscoretine) as a substitute. Of interest is the fact that Wild yam saponins can also be pharmaceutically converted into cortisone, estrogens and progesterone-like compounds. Once again, the human body is unable to make these conversions.3,4 Wild yam and Mexican yam refer to the same family of saponin yielding botanicals and the above information also applies to Mexican yam.8

Principle Active Constituents Steroidal saponins (based on the sapogenin diosgenin) including diosoin and dioscorin. 1,2

Clinical Application and Mechanism of Action Anti-Spasmodic and Anti-Inflammatory Although no well-designed trials have been performed, Wild yam is considered to be a strong antispasmodic and antiinflammatory with traditional use in rheumatic and arthritic patients as well as to treat dysmenorrhea. 1,2,5,6 Unfortunately, it is difficult to predict how effective Wild yam or its saponins are as an intervention to reduce muscle spasm and cramping. 2

Dosage and Standardized Grade Anti-spasmodic: 2-4 ml tincture, three times daily. Alternatively one or two capsules or tablets of the dried root, three times daily.

Adverse Side Effects, Toxicity and Contraindications Some people may experience nausea when taking large amounts of Wild yam. Generally, no major side effects or toxicity have been reported.2,7 As a precaution, it is probably best avoided by patients with hormone-dependent cancer (i.e., prostate, breast cancer).8

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Drug-Nutrient Interactions No well-known drug-nutrient interactions exist for Wild yam at this time.2,7

1. 2. 3. 4. 5. 6. 7. 8.

Hudson T. Wild yam, natural progesterone, unraveling the confusion. Townsend Letter for Doctors and Patients 1996;July:1257 Boon H, Smith M.The Botanical Pharmacy. Quarry health Books 2000:314-6 Araghiniknam M, Chung S, Nelson-White T, Eskelson C, Watson RR. Antioxidant activity of dioscorea and dehydroepian drosterone (DHEA) in older humans. Life Sciences 1996;59(11):147-57 Dollbaum C. Lab analyses of salivary DHEA and progesterone following ingestion of jaym-containing products. Townsend Newsletter for Doctors 1996;159:104 Chevalier A. The Encyclopedia of medicinal Plants. London: Readerâ&#x20AC;&#x2122;s Digest 1996:336 Hoffmann D. holistic Herbal. Rockport, CA: Element Books 1996:256 Healthnotes Online. Healthnotes, Inc 2000 Craddick J. Potential hazards of Mexican yam. Townsend Letter for Doctors and Patients 1996Aug/Sept:101