Comphensive Guide to Accessory Nutrients and Essential Oils by James Meschino

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Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils

2 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Table of Contents ABOUT THE MESCHINO HEALTH COMPREHENSIVE GUIDE TO ACCESSORY NUTRIENTS AND ESSENTIAL OILS ........................... 4 MESCHINO HEALTH NATURAL HEALTH ASSESSMENT ...........................................................ERROR! BOOKMARK NOT DEFINED. COENZYME Q10 (UBIQUINONE) ................................................................................................................................................. 6 CREATINE................................................................................................................................................................................ 11 DEHYDROEPIANDROSTERONE (DHEA) .................................................................................................................................... 17 DIGESTIVE ENZYMES ............................................................................................................................................................... 21 DIMETHYLAMINOETHANOL (DMAE) ....................................................................................................................................... 26 (DEANOL)................................................................................................................................................................................ 26 DOCOSAHEXAENOIC ACID (DHA) (FISH OIL) (SEE ALSO EPA) ................................................................................................... 29 EICOSAPENTAENOIC ACID (EPA) (FISH OIL) (SEE ALSO DHA) ................................................................................................... 31 FLAXSEED OIL AND ALPHA-LINOLENIC ACID ............................................................................................................................ 34 GAMMA-LINOLENIC ACID (GLA).............................................................................................................................................. 36 GAMMA-ORYZANOL ............................................................................................................................................................... 39 GLUCOSAMINE SULFATE ......................................................................................................................................................... 41 GLUTAMINE ............................................................................................................................................................................ 45 GRAPE SEED EXTRACT AND RELATED PROCYANODOLIC OLIGOMERS (PYCNOGENOL) ............................................................ 49 5-HYDROXYTRYPTOPHAN (5-HTP) .......................................................................................................................................... 51 INDOLE-3-CARBINOL ............................................................................................................................................................... 54 LIPOIC ACID (THIOCTIC ACID) .................................................................................................................................................. 58 L-LYSINE.................................................................................................................................................................................. 60 MALIC ACID ............................................................................................................................................................................ 62 MELATONIN ............................................................................................................................................................................ 64 MODIFIED CITRUS PECTIN....................................................................................................................................................... 68 METHYLSULFONYL METHANE (MSM) ..................................................................................................................................... 72 N-ACETYLCYSTEINE (NAC) ....................................................................................................................................................... 76 PHOSPHATIDYLSERINE ............................................................................................................................................................ 79 POLICOSANOL (SACCHARUM OFFICINARUM) ......................................................................................................................... 81 PREBIOTICS (FOS AND OTHER OLIGOSACCHARIDES) ............................................................................................................... 86 PROBIOTICS ............................................................................................................................................................................ 89 PSYLLIUM (PSYLLIUM HUSK FIBER OR PSYLLIUM SEED) .......................................................................................................... 93 QUERCETIN ............................................................................................................................................................................. 98 S-ADENOSYLMETHIONINE (SAM) ........................................................................................................................................... 101

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3 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils SHARK CARTILAGE ................................................................................................................................................................ 105 SOY AND SOY EXTRACT......................................................................................................................................................... 108 JAMES MESCHINO DC, MS,ND .............................................................................................................................................. 108 TAURINE ............................................................................................................................................................................... 112 TRIMETHYLGLYCINE (BETAINE) ............................................................................................................................................. 116

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4 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

About the Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils 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 Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

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 Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Coenzyme Q10 (Ubiquinone) General Features CoQ10 is an essential component of the electron transfer system in the mitochondria. More specifically, it functions to shuttle hydrogen electrons from NAD to cytochrome b, facilitating the release of energy required to recouple ADP with inorganic phosphate in the synthesis of ATP. As such, CoQ10 is an integral part of the bioenergetic system that enables cells to produce adequate amounts of ATP through aerobic pathways. ATP is the primary fuel required to power the bodyâ&#x20AC;&#x2122;s metabolic reactions, maintain optimal function of cells and sustain life. A deficit in ATP synthesis can compromise any number of energy-dependent cellular functions and hasten the onset of dysfunction and if severe enough, cell death. Although the body can synthesize CoQ 10, deficiency states of CoQ10 tend to exist and are associated with various health conditions. Moreover, supplementation studies with CoQ 10 have been shown to effectively treat and sometimes reverse a number of these conditions. There is evidence that a decline in CoQ10 synthesis occurs with aging, predisposing individuals to a number of CoQ10 deficiency-related disorders and diseases. Professor F.L. Crane and his colleagues at the University of Wisconsin first discovered CoQ 10 in 1957. Since then, Dr, Karl Folkers at the University of Texas (Austin) is most responsible for the ongoing research on CoQ10.1-4 Coenzyme Q10 is also a fat soluble antioxidant, which has been shown to reduce oxidation of LDL-cholesterol and the mitochondrial DNA.5,6 CoQ10 supplementation has been shown to modulate immune system function, enhancing levels of immunoglobulin G (IgG), in the serum of patients provided with 60 mg CoQ10 per day.7 The average person may consume about 5 mg per day of CoQ 10 from foods, with the main sources being meat, fish, soybeans and some vegetable oils. Clinical Coenzyme Q10 studies have involved daily supplemental intake levels ranging from 60 mg to 300 mg per day; far greater than food alone can provide.8

Supplementation Studies and Clinical Applications 1. Cardiovascular Disease Biopsy results from heart tissue in patients with various cardiovascular diseases (especially congestive heart failure) show a deficiency in CoQ10 in 50 to 75 percent of cases. Low blood levels of CoQ10 are also a consistent finding in the majority of these patients.9-12 Supplementation studies with patients suffering from various cardiomyopathies (i.e. ischemic cardiomyopathy, dilated cardiomyopathy, heart valve disorders) and congestive heart failure have demonstrated significant improvement in heart function (according to the New York Heart Association functional scale) in a high percentage of cases. Many patients in these studies have been able to reduce the number of cardiac drugs required (1-3 medications reduced in 43 percent of CoQ10 supplemented patients in one study of 424 patients, over an eight year period). Heart function parameters monitored have included left ventricular wall thickness, mitral valve inflow slope, and fractional shortening.13,14,15 Congestive Heart Failure - Several controlled studies using Coenzyme Q10 supplementation in patients with congestive heart failure have demonstrated significant improvement in cardiac ejection fraction, reduced shortness of breath, and increased muscle strength. Other studies have demonstrated increased stroke volume and cardiac index, improved survival and improved quality of life, in general. Of great significance is the fact that when patients discontinue CoQ 10 supplementation, cardiac function deteriorates. Thus, CoQ10 needs to be a lifelong intervention in these cases.16,17,18 www.meschinohealth.com

7 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils Angina - A small study has shown that CoQ10 supplementation can reduce angina episodes and nitroglycerine use and improve treadmill exercise tolerance. Larger trials are required to substantiate this data.19 Hypertension - Several studies have provided evidence that CoQ10 supplementation can lower systolic and diastolic blood pressure (i.e. systolic 164-146, diastolic 98-86) in hypertensive patients. Improved blood cholesterol levels also occurred in one study, with a rise in HDL and a reduction in total cholesterol from 229.9 mg/dl to 213.3 mg/dl.18-22 2. Periodontal Disease Several intervention trials involving patients with periodontal disease have revealed that CoQ 10 supplementation can be useful in reversing the condition to various degrees.23,24 3. Aerobic Exercise Performance A study of 25 cross-country skiers has provided preliminary evidence that CoQ10 supplementation may improve exercise performance in endurance athletes.25 Sedentary individuals have also demonstrated improvement with work capacity, oxygen consumption, fat burning and oxygen transport after beginning an exercise program. The group supplemented with CoQ 10 demonstrated greater improvement in these aerobic parameters compared to the placebo group, in a 4-8 week trial period.26 Dosage Ranges 1. Cardiovascular Conditions: typical dosage is 50-60 mg, three times per day. Large doses (up to 300 mg) may be needed in severe heart disease. Some studies use a dosage of 2 mg CoQ 10 for each kilogram of body weight. 2. Periodontal Disease: 50 mg per day has been used in clinical trials 3. Exercise Performance Studies: 60 mg per day27

Toxicity and Contraindications Coenzyme Q10 is well tolerated, and no serious adverse effects have been reported with long-term use.27

Drug-Nutrient Interactions 1. Warfarin CoQ10 supplementation has been shown to antagonize the anti-coagulant effects of warfarin, requiring dose adjustment. 2. Beta-Blockers and HMG CoA Reductase (statin) drugs for cholesterol lowering are known to inhibit the endogenous synthesis of CoQ10. CoQ10 supplementation can compensate for this inhibition effect and is indicated as a concurrent therapy when these drugs are in use (100 mg of CoQ10 per day is recommended in these cases). 3. Psychotropic Drugs Coenzyme Q10 supplementation has been shown to reduce the cardiac side effects of phenothiazines and tricyclic antidepressant drugs. 4. Chemotherapy Q10 supplementation can mitigate the cardiac side effects and cardiotoxicity of the chemotherapy drug known as adriamycin (100 mg per day of CoQ10 supplementation). Even children with lymphoblastic leukemia or non-Hodgkin lymphoma realized this benefit compared with the placebo group.28-34 5. Anticoagulants

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8 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils As noted above, there are reported cases of CoQ 10 countering the action of warfarin. Thus, the physician prescribing warfarin may need to adjust the warfarin dose if CoQ10 is to be used and therefore must be consulted.34,35 The following drugs may reduce the bodyâ&#x20AC;&#x2122;s levels of CoQ10: 1. Orlistat: reduces CoQ10 absorption.36 2. Beta blockers: decreases CoQ10 synthesis.37 3. Biguanides: decreases CoQ10 synthesis.38 4. Clondine: decreases CoQ10 synthesis.39 5. Gemfibrozil: (cholesterol-lowering drug).40 6. Haloperidol: decreases CoQ10 synthesis.41 7. HMG-CoA Reductase inhibitors: decreases CoQ10 synthesis.42 8. Hydralazine: decreases CoQ10 synthesis.37 9. Methydopa: decreases CoQ10 synthesis.39 10. Phenothiazines: decreases CoQ10 synthesis.41 11. Sulfonylureas: some of these drugs decrease CoQ10 synthesis (acetohexamide, glyburide, tolazamide).38 12. Thiazide Diuretics: decrease CoQ10 synthesis.39 13. Tricyclic Antidepressants: decrease CoQ10 synthesis.41

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

Folkers K, Yamamura Y, editors. Biomedical and clinical aspects of coenzyme Q. Vol 1. Amsterdam: Elsevier/North-Holland Biomedical Press; 1977. Yamamura Y, Folkers K and Ito Y, editors. Biomedical and clinical aspects of coenzyme Q. Vol 2. Amsterdam, Holland; Elsevier/NorthHolland Biomedical Press; 1980. Folkers K, Yamamura Y, editors. Biomedical and clinical aspects of coenzyme Q. Vol 3. Amsterdam: Elsevier/North-Holland biomedical Press; 1981. Folkers K, Yamamura Y, editors. Biomedical and clinical aspects of Coenzyme Q. Vol 4. Amsterdam: Elsevier Science Publ; 1984. Frei B, Kim MC, Ames BN. Ubiquinenol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sce 1990;87:4879-83. Weber C, Jakobsen TS, Mortensen SA, Paulsen G, Holmer G. Effect of dietary coenzyme Q10 as an antioxidant in human plasma. Mol Aspects Med 1994;15(Suppl):97S-102S. Folkers K, et al. Increase in levels of lgG in serum of patients treated with coenzyme Q10. Res Commun Chem Pathol Pharnacol 1982;38:335. Reavely N. New encyclopedia of vitamins, minerals, supplements and herbs. New York: Evans M and Company, Inc.; 1998. p. 353-61. Kitamura N, Yamaguchi A, Otaki M, Sawatani O, Minoji T, Tamura H, et al. Mycocardial tissue level of coenzyme Q10 in patients with cardiac failure. In: Folkers K, Yamamura Y, editors. Biomedical and Clinical Aspects of Coenzyme Q, Vol 4. Amsterdam, Holland: Elsvier Science,Publ; 1984. p. 243-52. Littarru GP, Ho L, Folkers K. Deficiency of coenzyme Q10 in human heart disease, Part II. Int J Vit Nutr Res 1972;42:413. Folkders K, et al. Evidence for a deficiency of coenzyme Q10 in human heart disease. Int J Vit Res 1970;40:380. Folkers K, Vadhanavikit S, Mortensen SA. Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10. Proc Natl Acad Sci 1985;82:901. Langsjoen H, Langsjoen P, Langsjoen P, Willis R, Folkers K. Usefulness of coenzyme Q10 in clinical cardiology: A long-term study. Mol Aspects Med 1994;1(Suppl):165S-75S.

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9 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 14. Tsuyusaki T, Noro C, Kikawada R. Mechanocardiography of ischemic or hypertensive heart failure. In: Yamamura Y, Folkers K, Ito Y, editors. Biomedical and clinical aspects of coenzyme Q. Vol 2. Amsterdam, Holland; Elsevier/North-Holland Biomedical Press; 1980. p. 273-88. 15. Judy WV, Hall JT, Toth PD, Folkers K. Myocardial effects of co-enzyme Q10 in primary heart failure. In: Folkers K, Yamamura Y, editors. Biomedical and clinical aspects of Coenzyme Q. Vol 4. Amsterdam: Elsevier Science Publ; 1984. p. 281-90. 16. Langsjoen PH, Vadhanavikit S, Folkers K. Response of patients in classes III and IV of cardiomyopathy to therapy in a blind and crossover trial with coenzyme Q10. Proc Natl Acad Sci 1985;82:4240-4. 17. Morisco C, Trimarco B, Condorelli M. Effect of CoQ10 therapy in patients with congestive heart failure: A long-term multicenter randomized study. Clin Invest 1993;71(Suppl):134S-6S. 18. Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino G. Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure. CoQ10 Drug Surveillance Investigators. Mol Aspects Med 1994;15(Suppl):287S-94S. 19. Kamikawa T, Kobayashi A, Yamashita T, Hayashi H, Yamazaki N. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cariol 1985;56:247-51. 20. Digiesi V, Cantini F, Brodbeck B. Coenzyme Q10 in essential hypertension. Mol Aspects Med 1994;15(Suppl):257S-63S. 21. Langsjoen P, et al. Treatment of essential hypertension with coenzyme Q10. Mol Aspects Med 1994;15:265-72. 22. Digiesi V, Cantini F, Bisi G, et al. Mechanism of action of coenzyme Q10 in essential hypertension. Curr Thes Res 1992;51:668-72. 23. Nakamura R, Littrau GP, Folkers K, Wilkinson EG. Study of Co Q10 enzymes in gingiva from patients with periodontal disease and evidence for a deficiency of coenzyme Q10. Proc Natl Acad Sci 1974;71:1456. 24. Wilkinson EG, Arnold RM, Folkers K. Treatment of periodontal and other soft tissue diseases of the oral cavity with coenzyme Q10. In: Folkers K, Yamamura Y, editors. Biomedical and clinical aspects of coenzyme Q. Vol 1. Amsterdam: Elsevier/North-Holland Biomedical Press; 1977. p. 251-65. 25. Ylikoski T, Piirainen J, Hanninen O, Penttinen J. The effect of coenzyme Q10 on the exercise performance of cross-country skiers. Mol Aspects Med 1997;18(Suppl):283S-90S. 26. Vanfraechem JHP, Folkers K. Coenzyme Q10 and physical performance. In: Folkers K, Yamamura Y, editors. Biomedical and clinical aspects of coenzyme Q. Vol 3. Amsterdam: Elsevier/North-Holland biomedical Press; 1981. p. 235-41. 27. Murry M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 296-308. 28. Mortensen SA, Leth A, Agner E, Rohde M. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductate inhibitors. Mol Aspects Med 1997;18(Suppl):137S-44S. 29. Bargossi AM, Grossi G, Fiorella PL, Gaddi A, Di Giulio R, Battino M. Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductate inhibitors. Mol Aspects Med 1994;15(Suppl):187S-93S. 30. Hamada M, Kazarani Y, Ochi T, Ito T, Kokubu T. Correlatio between serum CoQ10 level and myocordiol contractility in hypertensive patients. In: Folkers K, Yamamura Y, editors. Biomedical and clinical aspects of Coenzyme Q. Vol 4. Amsterdam: Elsevier Science Publ; 1984. p. 263-70. 31. Judy WV, Hall JH, Dugan W, Toth PD, Folkers K. Coenzyme Q10 reduction in adriamycin cardiotoxicity. In: Folkers K, Yamamura Y, editors. Biomedical and clinical aspects of Coenzyme Q. Vol 4. Amsterdam: Elsevier Science Publ; 1984. p. 231-41. 32. Iarussi D, Auricchio U, Agretto A, Murano A, Giuliano M, Casale F, et al. Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: Control study in children with acute lyphhoblastic leukemia and non-Hodgkin lymphoma. Mol Aspects Med, 1994;15(Suppl):207S-12S. 33. Kishi T, Makino K, Okamoto T, Kishi H, Folkers K. Inhibition of myocardial respiration by psychotherapeutic drugs and prevention by coenzyme Q. In: Yamamura Y, Folkers K and Ito Y, editors. Biomedical and clinical aspects of coenzyme Q. Vol 2. Amsterdam, Holland; Elsevier/North-Holland Biomedical Press; 1980. Pg. 139–54. 34. Heck AM, Deweitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 2000;57(13):1221-30. 35. Landbo C, Almdal TP. Interaction between warfarin and coenzyme Q10. Ugeskr Laeger. 1998;160(22):3226-7. 36. Xenical (orlistat), Product Prescribing Information. Nutley, NJ: Roche Laboratories, Inc., Sept 2000. 37. Kishi T, Watanabe T, Folkers K. Bioenergetics in clinical medicine XV. Inhibition of coenzyme Q10-enzymes by clinically used adrenergic blockers of beta-receptors. Res Commun Chem Pathol Pharmacol. 1977;17(1):157-64. 38. Kishi T, Kishi H, Watanabe T, Folkers K. Bioenergetics in clinical medicine XI. Studies on coenzyme Q and Diabetes Mellitus. J Med 1976;7(3):307-21. 39. Kishi H, Kishi T, Folkers K. Bioenergetics in clinical medicine. III. Inhibition of coenzyme Q10-enzymes by clinically used anti-hypertensive drugs. Res Commun Chem Pathol Pharmacol 1975;12(3):533-40. 40. Aberg F, Appelkvist EL, Bröijersén A, Eriksson M, Angelin B, Hjemdahl P, et al. Gemfibrozil-induced decrease in serum Ubiquinone and alpha- and gamma-tocopherol levels in men with combined hyperlipidaemia. Eur J Clin Invest 1998;28(3):235-42. 41. Kishi T, Makino K, Okamoto T, Kishi H, Folkers K. Inhibition of myocardial respiration by psychotherapeutic drugs and prevention by coenzyme Q10. In: Biomedical and clinical aspects of coenzyme Q10. Yamamura Y, Folkers K, Ito Y, editors. Vol 2. Amsterdam: Elsevier/North-Holland Biomedical Press; 1980. p. 139-54.

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10 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 42. Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, et al. Evidence of plasma Co10- lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol 1993;33(3):226-9.

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11 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Creatine General Features It is now widely accepted that Creatine supplementation can increase muscle strength and mass. 1,2,3,4 Creatine is an amino acid that is stored in muscle in the form of Creatine phosphate. During explosive or intensive exercise, Creatine phosphate is broken down by a specific enzyme to yield Creatine, plus phosphate, plus free energy. The free energy released from the breakdown of Creatine phosphate is used to regenerate ATP, which is the fuel that powers muscle contraction.2 The normal daily requirement for Creatine is about 2 grams for a person weighing 70 kg. Animal protein (especially meats) normally provides at least half that amount, with approximately one gram per day synthesized by the liver. A half-pound of raw meat contains about 1 gram of Creatine, but fish is also a good source. A number of recent studies have demonstrated that short-term Creatine supplementation increases Creatine phosphate stores in skeletal muscle by 10% to 40%.3 This in turn leads to an increase in muscle mass, which is thought to occur from increased protein synthesis, as the muscle lays down an increased number of contractile myofilaments (protein bands that contract and generate force). Increased muscular fluid retention may also participate in muscle volume gains with Creatine use.5,6,7 Creatine has also been shown to provide antioxidant properties. This may be of some significance as free radicals generated from exercise can affect muscle fatigue and protein turnover.24 It also appears that Creatine supplementation may allow athletes to train harder (due to increased available energy for muscle concentration), which promotes strength gains, and increases muscle size due to hypertrophy (larger muscle fiber size).2,3 The established protocol for Creatine supplementation used by athletes involves a loading dosage of 20 to 25 grams per day for the first 5 to 7 days. Typically an athlete will mix a heaping teaspoon of Creatine monohydrate crystals into a glass of juice to obtain about 5 grams of Creatine. During the loading phase the athlete does this on 4 or 5 occasions throughout the day to attain an intake of 20-25 grams. After the loading phase is completed, the maintenance daily dosage is usually 5 to 10 grams per day. Recent reports suggest that taking Creatine with glucose (a simple carbohydrate) may increase the amount of Creatine absorbed by the muscles. As such, some manufacturers combine Creatine with carbohydrates in a premix product to help improve Creatine delivery to muscles.25

Clinical Application and Mechanism of Action 1. Increased Strength and Performance In Athletes Several studies have shown that Creatine supplementation improves performance in repeated bouts of high intensity strength work and repeated sprints, which are requirements for many sports. 8,9,10,11,12,13,14,16,17,18 In short, substantial evidence suggests that Creatine supplementation increases lean body mass, muscular strength, and sprint power.24 Significant gains in strength and lean mass often occur in the first 6 weeks of Creatine supplementation, when combined with proper training and diet. In one study, college football players who took Creatine supplements for 28 days during resistance and agility training had significant gains in lean mass when compared to players who took the placebo.15 Individuals may vary in their response to Creatine supplementation, but it is not uncommon to see a 5 to 10 lb. increase in weight within the first six weeks.

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12 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils Approximately 80% of Creatine studies have reported a performance-enhancing effect. This is quite impressive when you consider the fact that Creatine is not structurally or functionally related to anabolic steroids, and that Creatine supplements are not banned by the International Olympic Committee or the National Collegiate Athletic Association. Creatine use is based on the same principle as carbohydrate loading in that an athlete is manipulating their dietary intake to optimize muscle Creatine phosphate stores for more explosive power and enhanced performance. Athletes requiring repeated bouts of explosive power may also benefit from Creatine supplementation as demonstrated by M. Izquierdo et al. Among other positive benefits revealed in their study of nineteen trained athletes, they showed that short-term Creatine supplementation (20 gms per day for 5 days) enhanced repeated sprint performance and attenuated decline in jumping ability after repetitive high-power-output exercise bouts (MRPB).22 Similar results have been documented by G. Cottrell et al, in subjects performing repeated sprint cycling.23 These studies have important implications for many sports such as hockey, basketball, soccer, volleyball, lacrosse, football, tennis and any sport requiring repeated bouts of all-out lower extremity explosive power and/or jumps. 2. Neuromuscular Diseases Creatine supplementation in humans has been reported to enhance power and strength both in normal subjects and in patients with various neuromuscular diseases.14 Clinical studies in patients with ALS (amyotrophic lateral sclerosis).14 Huntingtonâ&#x20AC;&#x2122;s disease, Parkinsonâ&#x20AC;&#x2122;s disease, Duchenne muscular dystrophy, McArdles disease 15 and Myasthenia Gravis 16 have shown that Creatine supplementation can produce an increase in strength and thus, provide symptomatic treatment and improved quality of life for many of these patients.14,15,16 3. Heart Failure Creatine supplementation has been shown to improve exercise capacity in patients with heart failure in some studies. Along with Coenzyme Q10, hawthorn extract and L-carnitine, Creatine is one of few natural health products that is shown to reverse certain parameters of heart failure. As reported by K. Witte et al, there is evidence for a possible role for micronutrient deficiency in heart failure, of which Creatine may be one of the principle factors.10,11,17 4. Musculoskeletal Rehabilitation Creatine was shown to speed recovery of muscular power in a double blind, placebo-controlled study involving 20 male and female students whose right legs were immobilized in casts for a period of two weeks. Those given Creatine supplementation during and after leg immobilization displayed more muscular power and greater muscle size after three to ten weeks of physical rehabilitation than did subjects who took the placebo.18 5. Anti-Aging in Older Subjects Creatine supplementation provided to active subjects over 70 years of age, and subjects 59-72 years of age, have resulted in significant gains in several indices of muscle performance including increased maximal dynamic and isometric strength, lower body mean power, lower extremity functional capacity, increased fat-free mass, increased lean mass and endurance power. These studies suggest that Creatine supplementation may help to forestall or reverse muscular atrophy and progressive weakness that occurs during aging, and that Creatine may be useful as an intervention to improve the ability of certain elderly individuals to perform functional living tasks, decreasing dependency and, enhancing their quality of life.19,20 Other studies have noted that younger individuals respond to Creatine supplementation more efficiently than do older subjects in that muscular phosphocreatine stores were shown to increase on average by 35% in young subjects (~24 years of age) and 7% in older subjects (~70 years of age) after five days of Creatine supplementation

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13 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils (20 gms per day). As such, it may take a longer period to maximize Creatine stores in older subjects with Creatine supplentation.21

Absorption and Utilization Creatine absorption from the intestinal tract is very efficient. Studies show that a 6-8 gm oral load of Creatine results in approximately 50% of the ingested Creatine being excreted in the urine. Thus, researchers are still working to identify the ideal single, daily and cumulative doses of Creatine for various applications. 26 Other studies demonstrate that a 5 gm oral load of Creatine, followed by 93 gm oral load of simple carbohydrate in solution ( water ) at 30 minutes postCreatine intake (4-times per day), resulted in a 60% increase in total muscle Creatine compared to subjects ingesting the same amount of Creatine in the absence of a simple carbohydrate drink. Subjects ingesting Creatine and the simple carbohydrate drink had higher insulin levels and significantly less Creatine lost in their urine, indicating that higher insulin levels are likely a key to greater muscle uptake and utilization of Creatine, and a reduction in urinary loss. Thus, it is accepted that Creatine utilization is enhanced by concurrent ingestion of a simple carbohydrate drink (e.g. fruit juice).25 Additionally, concurrent administration of Creatine and glycogen reveal that Creatine supplementation enhances muscle levels of glycogen (glycogen supercompensation) beyond that attainable from glycogen loading alone. As supercompensation of muscle glycogen is also an ergogenic factor in exercise performance, the combination of Creatine and carbohydrate loading appear to improve performance by increasing muscle Creatine and muscle glycogen.27

Dosage and Standardized Grade (2:1 powdered extract) 1. Athletic Performance (strength, sprint and repeated sprint power, lean mass etc.) - The usual protocol is 5 gm, 4-5times per day for five consecutive days during the loading phase, followed by 5 gm, twice daily as the maintenance dose. Many athletes cycle one month on, one month off to prevent any possibility of toxicity and to prevent the body from compensating by reducing its own endogenous synthesis of Creatine in the liver.28,22,23,26,27 2. Neuromuscular Diseases / Amyotrophic Lateral sclerosis - One study used 20 gm per day in 5 gm divided doses for 7 days, followed by 3 gm per day for 3-6 months.14 This dose may be appropriate for all neuromuscular diseases mentioned above in regards to adult supplementation, 34 although one patient with myasthenia gravis demonstrated significant improvement with 5 gm of Creatine per day combined with resistance training, 3 times per week. 16 In McArdles disease, a daily dose of Creatine of approximately 10 gm per day, followed by a maintenance dose of approximately 4 gm per day has been used successfully to increase muscular strength. 35 Other researchers have shown that a daily adult dose of 10 gm of Creatine per day, and a daily dose of 5 gm of Creatine for children, have been beneficial for individuals with various muscular dystrophies.39,40 3. Heart Failure - A daily dose of 20 gm of Creatine per day, in 5 gm divided doses, has shown good results over the 5-10 day test period. Participants showed improvement in strength, endurance and improved skeletal function upon exertion.17,36,37 4. Musculoskeletal Rehabilitation During and After Immobilization - Same dose as for athletic performance.18 5. Anti-aging in Older Patients - Same dose as for athletic performance.19,20

Adverse Side Effects, Toxicity and Contraindications As for the safety of Creatine supplementation, a 1997 study showed that short-term Creatine use (20 grams per day for 5 days) did not increase markers of kidney stress in five healthy men.13 A study comparing Creatine users, for up to five years duration, to control subjects has shown that Creatine users have no remarkable differences in their Creatine,

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14 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils urea, and plasma albumin clearances compared to controls. The researchers conclude that neither short-term, medium-term, nor long-term oral Creatine supplements induce detrimental effects in the kidney of healthy individuals.29,30,31 To date no liver abnormalities have been evident in short-term Creatine challenge studies.30 However, individuals with pre-existing kidney disease should be cautious as evidenced by the development of kidney dysfunction in a 25 year old soccer player taking Creatine who previously had been treated for focal segmental glomerulosclerosis of the kidney. His kidney function returned to normal after discontinuing Creatine supplementation.28 Some experts suggest that compulsory regular kidney and liver monitoring should accompany the use of Creatine due to the increased burden placed upon the liver and kidneys.30 As pointed out by other experts, Creatine is normally found in cardiac muscle, brain, and testes, as well as skeletal muscle, and these former tissues have been largely unstudied with respect to the effects of Creatine supplementation.32 The Food and Drug Administration (FDA) has advised athletes to consult a physician or a health care professional before embarking on any scheme of Creatine loading or supplementaion.28 Nevertheless, few reported adverse side effects from Creatine use have been reported despite its widespread use among young athletes, with Creatine sales reaching $200 million in the U.S. in 1998. 1 Other infrequently reported side effects include gastrointestinal disturbances and muscle cramps. 30 In regards to children and younger athletes, the safety of Creatine supplementation has not yet been investigated in these individuals. Until all safety issues have been evaluated, experts strongly recommend against use of Creatine among children and adolescent athletes.33 Overall, Creatine supplementation appears to be safe for healthy adults. It's a low molecular weight compound that is excreted in the kidneys by simple diffusion. In the maintenance phase, athletes consume only slightly more Creatine (3-5 gm per day) than is generally found in the diet, which is usually about 2 gm per day.10,11

Drug-Nutrient Interactions There are no well-known drug-nutrient interactions for Creatine at this time.38

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15 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

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.

43. Kreider RB. Creatine, the next ergogenic supplement? Sportscience Trainng and Technology. Internet Society for Sports Science. Available at: http://www.sportsci.org/traintech/cretine/rbk.html. Accessed May 5, 1998 44. Kreider RB. Creatine supplement: analysis of ergogenic value, medical safety, and concerns. Journal of Exercise Physiology Online 1998; 1(1). Available at: httyp://www.css.edu/users/tboone2/asep/jan3.html. Accessed May 5, 1998 45. Bramberger M. The magic potion. Sports Illus 1998;88(16):58-65 46. Bessman SP, Savabi F. The role of the phosphocreatine energy shuttle in exercise and muscle hypertrophy, in: Taylor AW, Gollnick PD, Green HJ (eds.), International Series on Sport Sciences: Biochemistry of Exercise VII. Champaign, IL Human Kinetics 1988;19:167-78 47. Ingwall JS. Creatine and the control of muscle-specific protein synthesis in cardiac and skeletal muscle. Circ. Res 1976;38(5 suppl 1):1115-23 48. Sipila I, Rapola J, Simell O et al. Supplementary creatine as a treatment for gyrate atrophy of the choroids and retina. N Engl J Med 1981;304(5):867-70 49. Almada a, Kreider R, Ferreira M et al. Effects of calcium-HMB supplementation with or without creatine during training on strength and sprint capacity, abstract. FASEB J 1997;11:A374 50. Earnest CP, Snell PG, Rodriguez R et al. The effect of creatine monohydrate ingestion on anaerobic power indices, muscular strength and body composition. Acta Physiol Scand 1995;153(2):207-9 51. Burke LM, Pyne DB, Telford RD. Effect of oral creatine supplementation on single-effort sprint performance in elite swimmers. Int J Sports Nutr 1996;6(3):222-3 52. Dawson B, Cutler M, Moody A et al. Effects of oral creatine loading on single and repeated maximal short sprints. Aust J Sci Med Sports 1995;27(3):56-61 53. Redondo DR, Dowling EA, Graham BL et al. The effect of oral creatine monohydrate supplementaiton on running velocity. Int J Sports Nutr 1996;6(3):213-21 54. Kreider RB, Ferreira M, Wilson M et al. Effects of creatine supplementation on body composition, strength, and sprint performance. Med Sci Sports Exerc 1998;30(1):73-82 55. Poortmans JR, Auquier H, Renaut V et al. Effect of short-term creatine supplementation on renal responses in men. Eur J appl Phsiol 1997;76(6):566-7 56. Mazzini L, Balzarini C, Colombo R, Mora G, Pastore I, De Ambrogio R et al. Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. J Neurol Sci 2001 Oct 15;191(1-2):139-44 57. Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev 2001 Jun;53(2):161-76

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16 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 58. Stout JR, Eckerson JM, May E, Coulter C, Bradley-Popovich GE. Effects of resistance exercise and creatine supplementation on myasthenia gravis: a case study. Med Sci Sports Exerc 2001 Jun;33(6):869-72 59. Witte KK, Clark AL, Cleland JG. Chronic heart failure and micronutrients. J Am Coll Cardiol 2001 Jun1;37(7):1765-74 60. A leg to stand on. Better Nutrition May 2002;64(5):p20 61. Chrusch MJ, Chilibeck PD, Chad KE, Davison KS, Burke DG. Creatine supplementation combined with resistance training in older men. Med Sci Sports Exerc 2001 Dec;33(12):2111-7 62. Gotshalk LA, Volek JS, Staron RS, Denegar CR, Hagerman FC, Kraemer WJ. Creatine supplmentation improves muscular performance in older men. Med Sci Sports Exerc 2002 Mar;34(3):537-43 63. Rawson ES, Clarkson PM, Price TB, Miles MP Differential response of muscle phosphocreatine to creatine supplementation in young and old subjects. Acta Physiol Scand, 2002 Jan;174(1):57-65 64. Ezquierdo M, Ibañez J, González-Badillo JJ, Gorostiaga EM Effects of creatine supplementation on muscle power, endurance, and sprint performance. Med Sci Sports Exerc, 2002 Feb;34(2):332-43 65. Cottrell G.T, Coast JR, Herb RA Effect of recovery interval on multiple-bout sprint cycling performance after acute creatine supplementation. J Strength Cond Res, 2002 Feb;16(1):109-16 66. Lawler JM, Barnes, WS, Wu G, Song W, Demaree S. Direct antioxidant properties of creatine. Biochem Biophys Res Commun, 2002 Jan 11;290(1):47-52 67. Green AL, Hultman, E, Macdonald IA, Sewell DA, Greenhaff PL. Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am J Physiol, 1996 Nov;271(5 Pt 1):821-6 68. Burke DG, Smith-Palmer T Holt LE, Head B, Chilibeck PD The effect of 7 days of creatine suppelmentation on 24-hour urinary creatine excretion. J Strength Cond Res, 2001 Feb;15(1):59-62 69. Nelson AG, Arnall DA, Kokkonen J, Day R, Evans J. Muscle glycogen supercompensation in enhanced by prior creatine supplementation. Med Sci Sports Exerc, 2001 Jul;33(7):1096-100 70. Culpepper R Michael. Creatine supplementation: Safe as steak? Southern Medical Journal, Sep98;91(9):890-3 71. Poortmans, JR, Francaux, M. Long-term oral creatine supplementation does not impair renal function in healthy athletes. Med Sci Sports Exerc, 1999 Aug;31(8):1108-10 72. Poortmans, JR, Francaux, M. Adverse effects of creatine supplementation: fact or fiction? Sports Med, 2000 Sep;30(3):155-70 73. Schilling, B.K., Stone M.H., Utter, A., Kearney, J.T., Johnson, M., Coglianese, R., Smith, L., O’Bryant, H.S., Fry, A.C., Starks, M., Keith, R., Stone, M.E. Creatine supplementation and health variables: a retrospective study. Med Sci Sports Exerc, 2001 Feb;33(2):183-8 74. Juhn MS, Tarnopolsky M. Potential side effects of oral creatine supplementation: a critical review. Clin J Sport Med, 1998 Oct;8(4):298-304 75. Dietary Supplement Information Bureau.www.intramedicine.com 76. Tarnopolsky M, Martin J. Creatine monohydrate increases strength in patients with neuromuscular disease. Neurology. Mar 1999;52(4):854-7 77. Vorgerd, M., Grehl, T., Jager, M., et al. Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial. Arch Neurol. Jul 2000;57(7):956-63 78. Gordon A, Hultman E, Kaijeser L et al. Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance. Crdiovasc Res. Sep1995;30(3):413-8 79. Andrews R, Greenhaff P, Curtis S et al. The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure. Eur Heart J. Apr1998;19(4):617-22 80. Healthnotes, Inc 2001. www.healthnotes.com 81. Walter MC, Lochmuller H, Reilich P et al. Creatine monohydrate in muscular dystrophies: A double-blind.placebo-controlled clinical study. Neurology 2000;54:1848-50 82. Felber S, Skladal D, Wyss M et al. Oral creatine supplementation in Duchenne muscular dystrophy: a clinical and 31P magnetic resonance spectroscopy study. Neurol Res 2000;22:145-50

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17 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Dehydroepiandrosterone (DHEA) General Features DHEA is an intermediate steroid hormone produced mostly by the adrenal glands. All steroid hormones are derived from cholesterol. In the synthesis of adrenal androgen hormones cholesterol is converted to pregnenolone and then to DHEA. From DHEA the adrenal glands can synthesize androstenedione, which is further converted to testosterone. In fat tissue androstenedione can be converted to estrone hormone by the aromatase enzyme, which is also known as estrogen synthase enzyme. Thus, DHEA supplementation can affect the increased production of androstenedione as well as testosterone and estrogen. DHEA is the most abundant hormone made by the adrenal glands. Some DHEA is secreted by the adrenal glands and circulates in the bloodstream, where it is picked up by other tissues (i.e. adipose, testis, ovaries) and further converted into other androgens or estrogens. The serum concentration of DHEA (really DHEA - sulfate), is used as a measure of adrenal androgen production, when monitoring various conditions.1 DHEA supplements can be made in the laboratory from diosgenin a steroid compound found in wild yams. However, the body is unable to convert diosgenin into DHEA or any other hormone. Thus, supplementing with wild yam as a means to affect hormone levels is unsubstantiated.2 In humans, DHEA blood levels peak in early adulthood and then starts a lifelong descent. By the age of 70 DHEA levels have declined by up to 75 percent compared with young adult levels. By age 90, we make 90 percent less DHEA than a young adult.3,4 These findings have led some researchers to investigate whether returning DHEA levels to those of a young adult (through supplementation) can serve as an anti-aging, and degenerative disease prevention strategy. Preliminary reports in this regard are conflicting. Some evidence suggests that DHEA supplementation (25-200 mg per day) can reverse some parameters of aging and improve wellbeing. Other reports correlate higher blood DHEA levels (and supplementation in some cases) with increased risk of prostate cancer, postmenopausal breast cancer, and ovarian cancer.5-13 As a result many health authorities are cautious about recommending DHEA supplementation as an anti-aging intervention. Individuals with a history or family history of breast, ovarian or prostate cancer should not supplement with DHEA indiscriminately until further studies are completed.14 The average male produces 31 mg of DHEA per day, while women make about 19 mg.15

Supplementation Studies and Clinical Applications 1. Systemic Lupus Erythematesus (SLE) In a Stanford Medical Center study, DHEA supplementation (200 mg per day) decreased the SLE Disease Activity Index by nearly two points, while the placebo group increased by almost a full point. DHEA patients had significantly fewer flare ups and their required dosage of corticosteroid drug used to control symptoms decreased by 35 percent, whereas the placebo group increased their dose of corticosteroids by forty percent. This was a three-month study only. Long-term benefits are yet unknown and the major side effects in this study was mild to severe acne in women in the DHEA group.16,17

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18 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 2. Dementia (Age-Related) DHEA is found in high concentrations in the brain and declining levels with aging may affect memory and cognitive functions. DHEA supplementation shows promise in enhancing memory and improving cognitive function (men 2550 mg per day; women 15-25 mg per day).18,19 3. Erectile Dysfunction A double-blind research study provided evidence that 50 mg of DHEA per day (six months) improved erectile function in men presenting with erectile dysfunction problems.20 Be aware that other phytonutrients can correct erectile dysfunction and are known to have fewer potential side effects than DHEA (ie. Tribuls terrestris, ginkgo biloba, muira puama). 4. Diabetes A couple of short-term (3 week duration) studies have shown that DHEA supplementation increases insulin sensitivity at a daily dosage of 25-50 mg. There are no long-term human studies to indicate whether DHEA is appropriate for diabetics at this time.21,22

Dosage Ranges 1. 2. 3. 4.

Systemic Lupus Erythematosus: 100-200 mg per day for three months, maintenance dose unknown Dementia: men â&#x20AC;&#x201C; 25-50 mg per day women â&#x20AC;&#x201C; 15-25 mg per day Erectile Dysfunction: 50 mg per day Diabetes: 25-50 mg per day, but requires substantiation

Adverse Side Effects and Toxicity At doses of 50-200 mg patients often experience acne, increased facial hair and increased perspiration. Less frequently reported are breast tenderness, weight gain, mood alteration, headache, oily skin and menstrual irregularity.23

Contraindications Any history or family history of breast, ovarian or prostate cancer (extreme caution should be used in these cases) 14 precludes indiscriminate use of DHEA supplementation. Males taking DHEA should have their PSA (prostate-specific antigen) levels monitored to screen for prostate cancer development. Females taking DHEA should be monitored for breast, ovarian and endometrial cancer development.26-33

Drug-Nutrient Interactions Methyltestosterone DHEA supplementation has been shown to increase blood levels of testosterone, as does methyltestosterone. Thus, the addition of DHEA supplementation to methytestosterone treatment may result in an excessive increase of blood testosterone and increase risk of related side effects.24,25

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19 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

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.

Marks M, Marks A, Smith C. Basic medical biochemistry: A clinical approach. Balitmore, MD: Williams & Wilkins;1996. p. 675-88. Araghiniknam M, Chung S, Nelson-White T, Eskelson C, Watson RR. Antioxidant activity of dioscorea and dehydroepiandrosterone (DHEA) in older humans. Life Sce 1996;59:147-57. Migeon C, et al. DHEA and androsterone levels in human placenta. Effect of age and sex: day-to-day and diurnal variations. J Clin End Met 1957;17:1051-62. Ravaglia G, et al. The relationship of DHEAS to endocrin-metabolic parameters and functional status in the oldest old. J Clin Endocrinol Metab 1996;81:1173-7. Diamond P, Cusan L, Gomez J-L, Belanger A, Fabrie F. Metabolic effects of 12-month percutaneous DHEA replacement therapy in post menopausal women. J Emdocrinol 1996;150(Suppl):43S-50S. Villareal DT, Holloszy JO, Kohrt WM. Replacement of DHEA in aging men and women. Ann NY Acad Sci 1995;774:128-42. McNeil C. Potential drug DHEA hits snags on way to clinic. J Natl Cancer Inst 1997;89:681-3. Jones JA, Nguyen A, Straub M, Leidich R, Veech RL, Wolf S. Use of DHEA in a patient with advanced prostate cancer; a case report and review. Urology 1997;50:784-8. Zumoff B, Levin J, Rosenfeld RS, Marksham M, Strain GW, Fukushima DK. Abnormal 24-hr mean plasma concentration of DHEA and DHEAS in women with primary operable breast cancer. Cancer Res 1981;41:3360-3. Dorgan JF, Longcope C, Stephenson HE Jr, Falk RT, Miller R, Franz C, et al. Relationship of prediagnostic serum estrogen and androgen levels to breast cancer risk. Cancer Epidemiol Biomarkeres Prev 1996;5:533-9. Gordon GB, Bush TL, Helzlsouer KJ, et al. Relationship of serum levels of DHEA and DHEAS to the risk of developing postmenopausal breast cancer. Cancer Res 1990;50:3859-62. Morales AJ, et al. The effect of six months treatment with a 100mg daily dose of DHEA on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol (oxf) 1998;49:421-32. Skolnick AA. Scientific verdict still out on DHEA. JAMA 1996;276:1365-7. Balch J. The super antioxidants. New York, NY: M. Evans and Company, Inc.; 1998. p. 143-9. Aksoy IA, et al. Human lives DHEA â&#x20AC;&#x201C; sulfotransferase: Nature and extent of individual variation. Clin Parmacol Therapeutics 1993;54:498-506. van Vollenhoven RF, Engleman EG, McGuire JL. An open study of DHEA in system lupus erythermatosus. Arthritis Rheum 1994;37;9:1305-10. van Vollenhoven RF, Engleman EG, McGuire JL. DHEA in systemic lupus erythematosus: Results of a double-blind, placebo-controlled, randomized clinical trial. Arthritis Rheum 1995;38:1826-31. Yen SS, Morales AJ, Khorram O. Replacement of DHEA in aging men and women: Potential remedial effects. Ann NY Acad Sci 1995;774:128-42. Morales AJ, Nolan JJ, Nelson JC, Yen SSC. Effect of replacement dose of DHEA in men and women of advancing age. J Clin Endocrinol Metab 1994;78,6:1360-7. Reiter WJ, Pycha A, Schatzl G, et al. DHEA in the treatment of erectile dysfunction: a prospective double-blind reandomised, placebocontrolled study. Urology 1999;53:590-5. Bates CW, Bates CW, Egerman RS, Umstot ES, Buster JE, Casson PR. DHEA attenuates study-induced declines in insulin sensitivity in postmenopausal women. Ann NY Acad Sci 1995;291-3. Casson PR, Faquin LC, Stentz FB, Straughn AB, Anderson RN, Abraham GF, Buster JE. Replacement of DHEA enhancer T-lymphocyte insulin binding in postmenopausal women. Fertil Steril 1995;63:1027-31. Regelson W, et al. DHEA-a pleiotropic steroid: How can one steroid do so much? In: Klatz RM: Advances in anti-aging medicine. Larchment, NY: Mary Ann Liebert Publ; 1996. Vol 1. Wolf OT, Neumann O, Hellhammer DH, Geiben AC, Strasburger CJ, Dressendorfer RA, et al. Effects of a two-week physiological DHEA substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997;82:2263-7. Labrie F, BĂŠlanger A, Simard J, Luu-The V, Lebrie C. DHEA and peripheral androgen and estrogen formation: intracinology. Ann NY Acad Sci 1995;774:16-28. McNeil C. Potential drug DHEA hits snags on way to clinic. J Natl Cancer Inst 1997;89:681-3. Jones JA, Nguyen A, Straub M, Leidich RB, Veech RL, Wolf S. Use of DHEA in a patient with advanced prostate cancer: a case report and review. Urology 1997;50:784-8. Zumoff B, Levin J, Rosenfeld RS, Markham M, Strain GW, Fukushima DK. Abnormal 24-hr mean plasma concentrations of DHEA and DHEA-sulfate in women with primary operable breast cancer. Cancer Res 1981;41:3360-3. Helzlsouer KJ, Gordon GB, Alberg AJ, Bush TL, Comstock GW. Relationship of prediagnostic serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing premenopausal breast cancer. Cancer Res 1992;52:1-4.

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Comment [c1]: Could not find other authors. Comment [c2]: Could not find other authors

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20 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 30. Berrino F, Muti P, Micheli A, Bolelli G, Krogh V, Sciajno R, et al. Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst 1996;88:291-6. 31. Barrett-Connor E, Friedlander NJ, Khaw KT. Dehydroepiandrosterone sulfate and breast cancer risk. Cancer Res 1990;50:6571-4. 32. Bernstein L, Ross RK, Pike MC, Brown JB, Henderson BE. Hormone levels in older women: a study of post-menopausal breast cancer patients and health population controlds. Br J Cancer 1990;61:298-302. 33. Heinonen PK, Koivula T, Pystynen P. Decreased serum level of dehydroepiandrosterone sulfate in postmenopausal women with ovarian cancer. Gynecol Obstet Invest 1987;23:271-4.

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21 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Digestive Enzymes General Features The vast majority of Digestive Enzymes in the body are secreted by the pancreas and the epithelial cells of the upper intestinal tract. Saliva and stomach juices contain small quantities of Digestive Enzymes, such as amylase, lipase and pepsin, but these sources do not factor significantly into the overall digestion of a meal or snack.1 In certain conditions, such as cystic fibrosis and pancreatitis, there is a corresponding pancreatic enzyme deficiency, and supplementation of Digestive Enzymes has been shown to be a legitimate aspect of treatment.2 In health conditions, where there has been damage to the intestinal tract epithelial cells, (e.g., giardiasis, damage from non steroidal anti-inflammatory drugs, excess alcohol consumption, celiac disease and Crohn’s disease) or an in-born defect resulting in insufficient lactase enzyme synthesis (lactose intolerance), the use of Digestive Enzymes is also of proven value.3,4,5,6 There is also evidence that many people show a trend towards reduced digestive enzyme concentrations as they age. Some authorities link this decline to an increased risk of degenerative diseases and provide some evidence that digestive enzyme supplementation may be beneficial to counter these outcomes as we age. 7 Other studies reveal that digestive enzyme supplementation may be helpful in the management of various arthritic and allergic conditions as well as being a potentially important adjunctive treatment for certain cancers.2,8,9

Clinical Application and Mechanism of Action 1. Post-Meal Bloating and Abdominal Discomfort (Indigestion or Dyspepsia) Evidence has shown that digestive enzyme supplementation can improve digestion of a large, high fat, very rich meal, in individuals with normal digestive processes. The subjects given the Digestive Enzymes reported less bloating, perception of gas and fullness after consuming the same large, high fat, very rich meal as those given the placebo. One clinical observation of significance suggests that individuals who chronically experience post-meal (postprandial) bloating, belching or gas tend to have low gastric acidity if the symptoms arise shortly after consuming a meal, whereas in patients where these symptoms develop an hour or more after eating, the problem is more likely to be a result of digestive enzyme deficiency.10 Some reports indicate that 58% of the population suffer from some type of digestive disorder and may thus, benefit from the use of digestive enzyme supplementation.7 2. Cystic Fibrosis, Pancreatitis, Crohn’s Disease, Celiac Disease These conditions have been shown to benefit from the use of digestive enzyme supplementation as insufficient digestive enzyme synthesis and secretion are hallmark features of each of these conditions.2,3,4,5,6 3. Arthritic Conditions Although not well acknowledged, some health practitioners indicate good results with various arthritic patients when Digestive Enzymes are added to the treatment program. Dr. A. Renshaw from Manchester in England, reported in the Annals of Rheumatic Diseases that he obtained good results with enzyme treatment in over 700 patients with rheumatoid arthritis, osteoarthritis, or fibrositis. Some cases of ankylosing spondylitis and Still’s disease (Juvenile Rheumatoid Arthritis) have also responded well to this intervention. 7 Other reports include favorable outcomes in patients with multiple sclerosis and lupus (systemic lupus erthymatosus). The mechanism of action in these cases appears to involve interaction with the body’s immune system. Animal and human studies demonstrated that, in certain instances, a person can develop a leaky gut, which implies that the normal gut lining has been damaged or is somehow defective, allowing certain partially digested food matter to be absorbed from the gut into the bloodstream. Once in the bloodstream these substances trigger a response from the immune system, producing

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22 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils immune complexes (a type of antigen-antibody reaction), with accompanying inflammatory reaction and a worsening of the above-noted conditions. German researchers have shown that the use of digestive enzyme supplements in these cases can dissolve and clear these immune complexes, helping to improve the patientâ&#x20AC;&#x2122;s overall condition.2,11,12 4. Cancer Treatment Support Studies on humans and animals suggest that Digestive Enzymes may also be of value in the prevention and treatment of certain cancers. The Scottish embryologist, Dr. John Beard, proposed in 1906 that pancreatic enzymes represent the bodyâ&#x20AC;&#x2122;s main defense against cancer and would be useful in cancer treatment. Acting on his hypothesis, a number of researchers pursued this line of investigation and the medical literature in the first two decades of the 20th century provided documentation of several case reports of tumor regression and even remission in terminal cancer patients treated with pancreatic enzymes.9 Dr. Beard (an embryologist) discovered that in all animals the pancreas is secreting enzymes well before birth. Beard also noted that the placenta of all mammals invades the uterus and then on a certain day, its invasive growth is shut off, which in humans is 56 days after conception. Beard realized that the day the placenta stopped growing was the same day the pancreas started producing enzymes. From this he theorized that pancreatic Digestive Enzymes were a signaling agent that stopped the cancer-like invasion of the placenta into the uterus. Despite the ridiculing he received for this theory, Beard and others went on to shown that Digestive Enzymes can, in fact, stop the growth of invasive cells, including many different human cancer cell lines.13 After Beardâ&#x20AC;&#x2122;s death in 1923, the enzyme theory was largely forgotten until 1963, when Dr. Gonzalez, a doctor involved in the use of Digestive Enzymes, was diagnosed with pancreatic cancer and treated himself with high dose oral pancreatic enzymes. The treatment was successful and in 1993, Dr. Gonzalez was asked by the National Cancer Institute (NCI) to present some of his cancer cases. He presented 25 cases involving a variety of different cancers. Based on his presentation, Dr. Gonzalez was a awarded a research grant from the NCI to perform a study on 12 patients with diagnosed pancreatic cancer.9,13 The overall survival rate for pancreatic cancer is normally less than one percent at five years, after diagnosis. It is one of the most highly malignant cancers of humankind, is considered to be incurable at this time, and is the fifth leading cause of cancer death in the United States, claiming 27,800 lives in 1996. In the two-year study by Gonzalez, he was able to significantly improve survival in the majority of patients who followed his protocol, which included diet, nutritional supplements, detoxification procedures and large doses of proteolytic enzymes (25-40 gms of porcine lyophilized pancreas product daily, taken in capsule form, away from meals, and spread evenly throughout the day). Gonzalez has now gone on to receive full funding to do multi-institute studies using Digestive Enzymes, based on these encouraging preliminary results.9 5. HIV and AIDS Nutrient malabsorption is a negative prognostic factor in acquired immunodeficiency syndrome (AIDS). Recent studies have shown that pancreatic insufficiency is a co-determining factor of malabsorption in these cases. As such, a study was performed to test the efficacy of pancreatic enzyme supplementation in AIDS patients with known fat malabsorption problems. The study showed that the use of the digestive enzyme product Creon, at a dose of 1000 units of lipase enzyme per gram of ingested dietary fat, was highly effective in reducing fecal fat loss. The researchers indicate that if other double-blind studies reveal similar findings, then pancreatic enzyme supplementation can be added to the weapons in the fight against HIV/AIDS-associated malabsorption.14

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23 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Dosage and Standardized Grade Digestive Enzymes are available in two forms, those derived from the glands of animals (usually hog pancreas), and those derived from non-animal sources (e.g., the fermentation of wheat bran by Asperigillus oryzae to yield carbohydrases such as alpha and beta amylase, cellulase, lactase, sucrase and maltase, as well as protease I and protease II Digestive Enzymes). Bromelain and papain enzymes are also available from the pineapple stem and the papaya, respectively. Potency of Digestive Enzymes is often listed as U/gm, where U equals activity units, and 1 unit (U) is defined as the amount, which catalyzes the transformation of one micromole of substrate per minute under defined conditions (e.g., 25 degrees C and optimal pH conditions). Each commercial digestive enzyme product has a different composition and U/g potency, making it very difficult to decide which of these is effective for certain applications. For improvement of digestion and general health support, the following minimum requirements would define a respectable digestive enzyme product on a per dosage basis: Amylase - 24,000 U/g Proteases - 6,000 U/g Cellulase - 200 U/g Lactase - 4,000 U/g Lipase - 1,000 U/g 15,16 1. General Health Support and Improved Digestion (see above minimum requirements) 2. Celiac Disease - a proven intervention has used a pancreatic enzyme source yielding 5,000 IU of lipase, 2,900 IU of amylase, and 330 IU of protease. Patients took six to ten capsules per day17 3. Multiple Sclerosis and Cystic Fibrosis - a product known as Pancreatin (10X) has been used in these cases, at 350700 mg, three times per day between meals, where IX potency indicates that the preparation of hog pancreatic enzymes has in each milligram not less that 25 USP units of amylase activity, not less than 2 USP units of lipase activity, and not less than 25 USP units of protease activity (USP represents United States Pharmacopoeia). A full strength product usually provides 10 times the 1X dosage or is listed as 10X potency.18 4. Cancer Treatment - the study by Gonzalez used 25-40 gms per day of porcine lyophilized pancreas product in the treatment of pancreatic cancer.9 5. HIV/AIDS - researchers used a product known as Creon at 1,000 units of lipase enzyme per gram of ingested fat. 14 6. Severe Pancreatic Insufficiency - doses as high as 1,000,000 USP units of Pancreatin were successful in managing severe pancreatic insufficiency in a clinical trial.19

Adverse Side Effects, Toxicity and Contraindications At supplemental doses used to improve digestion and health optimization, Digestive Enzymes are not associated with any adverse side effects or toxicity. Studies using significantly higher doses for the treatment of cancer, allergies and pancreatic insufficiency etc., have also reported very few side effects and/or cases of intolerance.2,3,4,5,6,7,8,9,10,11,12,13,14,17,19

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24 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Drug-Nutrient Interactions There are no well-known drug-nutrient interactions for Digestive Enzymes, although the inclusion of high dose bromelain may potentially enhance the anti-clotting effects of warfarin. It is best not to take betaine hydrochloride at the same time as Digestive Enzymes to improve digestion, as the acidity from betaine hydrochloride will denature the Digestive Enzymes, rendering them inactive. Experts suggest taking betaine hydrochloride at the beginning of a meal and Digestive Enzymes at the end of a meal, when these supplements are being used to improve digestion and absorption.20

2. 3. 4. 5. 6. 7. 8. 9.

Standard Textbooks of Nutritional Science: A. Shils M, Shike M, Olson J and Ross C. Modern nutrition in health and disease. 9th ed. Lippincott Williams & Wilkins 1993. B. Escott-Stump S and Mahan LK, editors. Food, nutrition and diet therapy. 10th ed. W.B. Saunders Company 2000. C. Bowman B and Russell RM, editors. Present knowledge in nutrition, 8 th ed. ILSI Press 2001. D. Kreutler PA and Czajka-Narins DM, editors. Nutrition in perspective, 2nd ed. Prentice Hall Inc. 1987. Hendler S. The Doctorâ&#x20AC;&#x2122;s Vitamin and Mineral Encyclopedia. Simon and Schuster 1990:347-8 Ramirez FC, Lee K, Graham DY. All lactase preparations are not the same: results of a prospective, randomized, placebo-controlled trial. Am J Gastroenterol. Apr1994;89(4):566-70 Layer P, Keller J. Pancreatic enzymes: secretion and luminal nutrient digestion in health and disease. J Clin Gastroenterol Jan1999;28(1):3-10 Patel RS, Johlin FC Jr., Murray JA. Celiac disease and recurrent pancreatitis. Gastrointest Endosc 1999;50:823-7 Gullo L. Indication for pancreatic enzyme treatment in non-pancreatic digestive diseases. Digestion 1993;54(suppl 2):43-7 Bitonsky, Marilyn. Digestive Enzymes: The Missing Link. Life Extension, Feb2000;6(2):p16 Oelgoetz AW, Oelgoetz PA, Wittenkind J. The treatment of food allergy and indigestion of pancreatic origin with pancreatic enzymes. Am J Dig Dis Nutr 1935;2:422-6 Gonzalez NJ, Issacs, LL. Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, withâ&#x20AC;Ś Nutrition & Cancer 1999;33(2):p117

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25 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 10. Gaby, AR. Literature review & commentary: Pancreatic enzymes improve digestion. Townsend letter for Doctors & Patients, Apr 2000(210):p40 11. Cichoke AJ. The effect of systemic enzyme therapy on cancer cells and the immune system. Townsend Letter for Doctors and Patients. 1995;Nov:30-2 12. Wolf M, Ransberger K. Enzyme Therapy. New york: Vantage Press 1972:135-220 13. Gonzalez, N. Preliminary results of Pancreatic Cancer Study. Innovation: The health Letter of FAIM, Sep97(3):p13 14. Carroccio A, Guarino A, Zuin G, Verghi F, Berni Canani R, et al. Efficacy of oral pancreatic enzyme therapy for the treatment of fat malabsorption in HIV-infected patients. Aliment Pharmacol Ther 2001 Oct;15(10):1619-25 15. Specialty Enzymes and Biochemicals Co. (Product Brochure) www.4enzymes.com 16. Sabinsa Corporation Product Manual; Digesyme. www.sabinsa.com 17. Murray M, Pizzorno J. Encyclopedia of Natural Medicine 2nd ed. Prima publishing 1997:327-8 18. Murray M, Pizzorno J. Encyclopedia of Natural Medicine 2nd ed. Prima publishing 1997:138-9 19. Nakamura T, Tandoh Y, Terada A et al. Effects of high-lipase pancreatin on fecal fat, neutral sterol, bile acid, and short-chain fatty acid excretion in patients with pancreatic insufficiency resulting from chronic pancreatitis. Int j Pancreatol 1998;23:63-70 20. Healthnotes, Inc. 2001; Healthnotes Online. www.puritan.com/healthnotes

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26 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Dimethylaminoethanol (DMAE) (Deanol) General Features Dimethylaminoethanol (DMAE), also known as Deanol, is a naturally occurring substance that is structurally similar to choline, a nutrient used by the brain to make the memory chemical acetylcholine. Studies on DMAE date back to the 1950’s and indicate that DMAE may be of value in the treatment of autism and for children with hyperkinetic behavior and learning disorders. Initially, it was claimed that DMAE could increase brain levels of acetylcholine based upon animal experimentation, but concrete evidence is lacking to support this effect in humans.1,2,3,7

Principle Active Constituents 2-Dimethylaminoethanol (DMAE) is the active ingredient and was marketed as a prescription drug in the 1960’s and 1970’s under the name Deanol.4,5 DMAE is now a natural health product and is no longer categorized as an over-thecounter or prescription drug.9

Clinical Application and Mechanism of Action 1. Attention Deficit Disorder, Childhood Hyperactivity and Autism Some studies have shown that DMAE can improve attention span and decrease irritability in children affected by attention deficit problems and hyperactivity disorders.4, In one study involving 74 children referred for treatment for childhood hyperactivity, 500 mg of Deanol per day was shown to be as effective or better than the drug methylphenidate with respect to improved learning capability and correction of behavior disorders.4 A 1988 survey by the Institute for Child Behavior in San Diego revealed that DMAE was the second most popular supplement used by parents to help their children with autism, after vitamin B6 and magnesium, with two parents indicating improvement for every one parent reporting a worsening of the condition from DMAE supplement use. 1 2. Dementia and Alzheimer’s disease Several studies have tested the use of DMAE in Alzheimer’s and dementia patients. Overall, results do not show an improvement in memory or cognitive function, but do suggest that it may reduce depression, irritability and anxiety, and increase motivation-initiative.3,1,8

Dosage and Standardized Grade 1. Childhood Attention Deficit Disorder, Hyperactivity And Autism - 500 mg per day has been used in various studies, but 100 mg once or twice per day can be used. DMAE’s effects generally develop slowly over a period of two to four weeks.4,9 2. Alzheimer’s disease and Dementia - Doses up to 600 mg, three times per day, have been used without untoward side effects.3 However, some patients have reported increased confusion and drowsiness in trials with Alzheimer’s patients.10,11,12 3. General Wellness - Doses as low as 10 to 20 mg per day have been used to produce a pleasant degree of central nervous system stimulation within 7-10 days. One study on medical students demonstrated greater daytime energy, attentiveness, sounder sleep and better ability to concentrate than the placebo group, when given a daily

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27 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils dosage of 10 mg for the first week and two, 10 mg tablets per day for the second week, after which the subjects could modify their own dosage for a total of six consecutive weeks.13

Adverse Side Effects, Toxicity and Contraindications DMAE can cause drowsiness and confusion in some Alzheimerâ&#x20AC;&#x2122;s patients. Other reported side effects include lucid dreaming, depression and hypomania (moderate mania). 10,11,12 As well, dull headache can occur when used in large initial doses and continued over-dosage can produce insomnia and tenseness of the neck, jaw, legs, and other sites. Thus, it is better to build up the dosage slowly over time.13 Studies on humans and animals do not reveal any significant toxicity of DMAE.13 Epilepsy - DMAE may exacerbate epileptic seizure frequency.13

Drug-Nutrient Interactions Anticholinergic Medications - DMAE has the potential to alter the action of drugs intended to increase acetylcholine levels, such as atropine, benztropine, hyposcyamine, ipratropium, scopolamine, trihexyphenidyl and scopolamine. 9

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

Sahelian R. DMAE for brain health. Better Nutrition, Apr99;61(4):p32 Jope RS, Jenden DJ. Dimethylaminoethanol (deanol) metabolism in rat brain and its effect on acetylcholine synthesis. J Pharmacol Exp Ther, Dec1979;211(3):472-9 Ferris SH, Sathananthan G, Gershon S, Clark C. Senile dementia: treatment with deanol. J Am Geriatr Soc, Jun1977;25(6):241-4 Lewis JA, Young R. Deanol and methylphenidate in minimal brain dysfunction. Clin Pharmacol Ther, May1975;17(5):534-40 Zahniser NR, Chou D, Hanin I. Is 2-dimethylaminoethanol (deanol) indeed a precursor of brain acetylcholine? A gas chromatographic evaluation. J Pharmacol Exp Ther 1977;200:545-59 Pfeiffer CC. Parasympathetic neurohumors. Possible precursors and effect on behavior. International Review of Neurobiology, 1959;1:195-244

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28 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 7. 8. 9. 10. 11. 12. 13.

Levin ED, Rose JE, Abood L. Effects of nicotinic demithylaminoethyl esters on working memory performance of rats in the radial-arm maze. Pharmacol Biochem Behav, Jun-Jul1995;51(2-3):369-73 Fisman M, Mersky H, Helmes E. Double-blind trial of 2-dimethylaminoethanol in Alzheimerâ&#x20AC;&#x2122;s disease. Am J Psychiatry, Jul1981;138(7):970-2 Dietary Supplement Information Bureau. www.intramedicine.com/DMAE Fisman M, Mersky H, Helmes E. Double-blind trial of 2-dimethylaminoethanol in Alzheimerâ&#x20AC;&#x2122;s disease. Am J Psychiatry, 1981;138:970-2 Sergio W. Use of DMAE (2-dimethylaminoethanol) in the induction of lucid dreams. Med Hypotheses, 1988;26:255-7 Casey DE. Mood alterations during deanol therapy. Psychopharmacology, 1979;62:187-91 Walker, Morton. Meical journalist report of innovative biologics: Forestalling the effects of aging with Dimethylaminoethanol. Townsend Letters for Doctors & Patients; 11/01/1990;8:752-6

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29 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Docosahexaenoic Acid (DHA) (Fish Oil) (See also EPA) General Features DHA is an omega-3 fatty acid that is found in fish oil along with EPA (Eicosapentaenoic Acid). Unlike EPA, DHA does not directly participate in the formation of prostaglandins or eicosanoids (hormone-like substances produced by local tissue). However, DHA can be converted to EPA, which is the immediate precursor of prostaglandin series-3. It also appears that unlike EPA, DHA may not reduce platelet clotting behaviour.1,2,3 DHA is one of the most abundant fatty acids in the brain, where it is required for normal growth and development of the brain, nervous system and retina. DHA is essential for normal visual and neurological development in infants.4,5 Double-blind evidence links DHA supplementation in premature infants to better brain functioning.6 DHA has been shown to reduce levels of blood triglycerides.1

Supplementation Studies and Clinical Applications 1. Eczema Supplementation with various essential fatty acids has been shown to be beneficial in the treatment of eczema. Although good results have been reported with gamma-linolenic acid, flaxseed oil or fish oil supplementation, studies seem to show that the degree of improvement correlates with the increased concentration of DHA in serum phospholipids. Thus fish oil supplementation may be the preferred essential oil supplement for these patients. 7 2. Asthma Increasing DHA and EPA intake (through supplementation) can improve asthma in children by reducing the concentrations of arachidonic acid. Arachidonic acid is the precursor of inflammatory 4-series leukotrienes. The ingestion of fish oil supplements shifts leukotrienes synthesis from series 4 to series 5, which are less inflammatory, helping to relieve asthma symptoms and improving respiratory function.8,9,10 3. Attention Deficit Hyperactivity Disorder (ADHD) Some evidence suggests that children with ADHD may have significantly lower proportions of plasma Docosahexaenoic Acid, which may reflect an impairment in the ability to convert EPA into DHA, or enhance metabolism of EPA and DHA. Burgess et al, are conducting a large intervention trial with ADHD children to see if essential fatty acid supplementation yields an improvement over placebo.11 4. Nerve Conduction Individuals with a genetic disorder known as Zellweger Syndrome are known to have low levels of DHA. DHA supplementation in these individuals has demonstrated improvement in nerve myelination and nerve impulse conduction, helping to improve muscle and vision function.15

Dosage Ranges Therapeutic use of DHA is usually in the range of 1-3 gms of DHA from fish oil, most commonly 250 â&#x20AC;&#x201C; 1,000 mg per day.16

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30 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Adverse Side Effects and Toxicity See EPA (Eicosapentaenoic Acid)

Contraindications and Drug-Nutrient Interactions Fish oil supplementation may increase blood cholesterol and at high doses may increase insulin resistance in diabetics, who should not exceed 2.5 gm of fish oil per day (taken as a supplement). Unlike EPA, DHA does not potentiate the effects of anti-coagulant drugs and therefore, is not contraindicated with their use. There are no well-known drug-nutrient interactions for DHA.12,13,14

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

Davidson MH, Maki KC, Kalkowski J, Schaefer EJ, Torri SA, Drennan KB. Effects of docosahexaenoic acid on serum lipoproteins in patients with combined hyperlipidemia: A randomized, double-blind, placeb-controlled trial. J Am coll Nutr 1997:16,3:236-43. Conquer JA, Holub BJ. Supplementation with an algae source of DHA increases (n-3) fatty acid status and alters selected risk factors for heart disease in vegetarian subjects. J Nutr 1996;126:3032-9. Nelson GJ, et al. The effect of dietary DHA on platelet function, platelet fatty acid composition, and blood coagulation in humans. Lipids 1997;32:1129-36. Gibson RA, Neumann MA, Makrides M. Effect of dietary DHA on brain composition and neural function in term infants. Lipids 1996;31(Suppl):1775S-81S. Makrides M, Neumann MA, Gibson RA. Is dietary DHA essential for term infants? Lipids 1996;31:115-9. Werkman SH, Carlson SE. A randomized trial of visual attention of preterm infants fed DHA until nine months. Lipids 1996:31:91-7. Soyland E, et al. Dietary supplementation with very long-chain n-3 fatty acids in patients with atopic dermatitis: a double-blind, multicentre study. Br J Dermatol 1994;130:757-64. Arm JP, et al. The effects of dietary supplementation with fish oil lipids on the airway response to inhaled allergen in bronchial asthma. Am Rev Respiratory Dis 1989;139:1395-400. Dry J, et al. Effect of a fish oil diet on asthma: Results of a 1-year double-blind study. Int Arch Allergy Apply Immunol 1991;95:156-7. Broughton KS, Johnson CS, Pace BK, Liebman M, Kleppinger KM. Reduced asthma symptoms with n-3 fatty acid ingestion are related to 5-series leukotriene production. Am J Clin Nutr 1997;65:1011â&#x20AC;&#x201C;7. Burgess JR, Stevens L, Zhang W, Peck L. Long-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorder. Am J Clin Nutr 2000;71,7(Suppl):327S-30S. Schectman G, Kaul S, Kassebah AH. Effect of fish oil concentrate on lipoprotein composition in NIDDM. Diabetes 1988;37:1567-73. Axelrod L. Effects of a small quantity of omega-3 fatty acids on cardiovascular risk factor in non-insulin dependent diabetics(NIDD). Diabetes Care 1994;17:37-45. Healthnotes Online. Healthnotes Inc 2000:DHA. Martinez M. Resortin the DHA levels in the brains of Zellweger patients. J Mol Neurosci 2001;85(6):966-74. Dietary Supplementation Information Bureau. www.content.intramedicine.com:DHA.

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31 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Eicosapentaenoic Acid (EPA) (Fish Oil) (see also DHA) General Features Fish oil contains Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA). These omega-3 fatty acids occur in fish oil typically as 18 percent EPA, 12 percent DHA, for a total of 30 percent omega-3 composition. These unique omega-3 fatty acids provide a number of health benefits such as lowering triglycerides, reducing platelet stickiness and providing immediate precursors that provide anti-inflammatory activity.1,2 Supplementation with fish oil has been shown to increase the synthesis of prostaglandins (hormone-like substances) and other eicosanoids that reduce inflammation and decrease platelet coaguability and thrombotic tendencies, while facilitating vasodilation.3,4,5 Various polyunsaturated fats of the omega-6 and omega-3 series provide the precursors for prostaglandin and eicosanoids synthesis. Omega-3 fats from fish oil have been studied extensively and a number of clinical trials reveal the benefit of omega-3 fatty acid supplementation in the prevention and management of various health conditions.3,4,5,6

Supplementation Studies and Clinical Applications 1. Lower Triglycerides Fish oil supplementation has consistently been shown to help reduce hypertriglyceridemia by 30-64 percent5 (i.e. salmon oil 30 gms per day). More typically 15 gm of fish oil per day is used to lower triglyceride levels.5 2. Decrease Platelet Stickiness Studies demonstrate that fish oil supplementation reduces platelet coaguability and thrombotic tendencies, via the conversion of EPA to prostaglandin-series 3 end products.5,7 3. Blood Pressure Many studies have revealed that supplementation with either fish oil or flaxseed oil can lower blood pressure in hypertensive subjects.8,9,10 4. Rheumatoid Arthritis Studies using fish oil supplementation in patients with rheumatoid arthritis demonstrate that it can profoundly reduce morning stiffness, joint tenderness and the synthesis of pro-inflammatory eicosanoids. Over a dozen studies of this nature suggest its superiority in this regard to oils that feature gamma-linolenic acid (i.e. evening primrose oil).6 5. Multiple Sclerosis Dr. Roy Swank, a professor of Neurology, provided evidence that manipulating dietary fats can slow the progression of M.S. In short the Swank Diet encourages less saturated and hydrogenated fats, one teaspoon per day of cod liver oil (containing EPA and DHA), 40-50 gms (3-4 tablespoons) of polyunsaturated vegetable oils, with fish consumption three or more times per week (plus low fat protein foods, vegetables and some nuts).6,11,12 6. Crohnâ&#x20AC;&#x2122;s Disease Fish oil supplementation has been shown to benefit patients with Crohnâ&#x20AC;&#x2122;s Disease via its effects on promoting the formation of anti-inflammatory eicosanoids.2

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32 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 7. Ulcerative Colitis Treatment with EPA (3-4 gms per day) was shown to decrease the synthesis of pro-inflammatory leukotrienes and platelet responsiveness in patients with ulcerative colitis in a small study.13 8. Raynaud’s Phenomenon Due to its effects on prostaglandin metabolism, fish oil has helped some people with Raynaud’s Phenomenon in double-blind research.14 N.B.: for eczema and asthma, see DHA (fish oil)

Dosage Ranges For the above conditions mentioned in this section the usual dosage of fish oil is 10-15 gms of EPA plus DHA A lesser, ideal amount for healthy people has not been determined.

Side Effects and Toxicity Some individuals report gastrointestinal upset and fish-tasting regurgitation.6 DHA and EPA are very non-toxic, but fish oil is easily damaged by oxygen forming undesirable peroxides and other free radicals. It should be consumed with adequate vitamin E to guard against oxidation (100-400 I.U. per day).15 Some patients experience nose bleeds due to the anti-clogging effect of EPA.16

Contraindications and Drug-Nutrient Interactions Patients on anti-coagulant therapy must consult with their physicians before supplementing with fish oil. Fish oil can further enhance the anti-clotting behaviour of platelets and potentially increase risk of bleeding disorders.17 Fish oil supplementation may also increase blood cholesterol, thus, certain heart disease patients must exercise caution with use of fish oil supplementation.18 High doses of fish oil can increase insulin resistance in diabetics. The maximum dosage for diabetics should not exceed 2.5 gm fish oils or 900 mg of purified EPA supplementation. This level appears to be safe and may decrease platelet stickiness, which may help diabetics reduce risk of cardiovascular complications.19

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

von Schacky C, Angerer P, Kothny W, Theisen K, Mudra H. The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized,

double-blind, placebo-controlled trial. Ann Intern Med 1999;130:554-62. Mate J, Castanos R, Garcia-Samaniego J, Pajares JM. Does dietary fish oil maintain the remission of Crohn’s disease: a case study. Gastroenterology 1991;100:A228[abstract]. Lee TH, Hoover RL, Williams JD. Effect of dietary enrichment with eicosapentaenoic and docosahexanoic acids on in vitro neutraphil and monocyte leukotriene generation and neutrophil generation. New Eng J Med 1985,312:1217-24. Strasser T, Fischer S, Weber P. Leukotriene B5 is formed in human neutrophils after dietary supplementation with EPA. Proc Nat Acad Sci 1985;82:1540-3. Kinsella JE, Lokesh B, Stone RA. Dietary n-3 polyunsaturated fatty acids and amelioration of cardiovascular disease: possible mechanisms. Am J Clin Nutr 1990;52:1-28. Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 249-78. Cobiac L, Clifton PM, Abbey M, et al. Lipid, lipoprotein, and hemostatic effects of fish vs fish oil w-3 fatty acids in mildly hyperlipidemic males. Am J Clin Nutr 1991;53:1210-6. Schmidt EB, Dyerberg J. Omega-3 fatty acids: Current status in cardiovascular medicine. Drugs 1994;47:405-24.

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33 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Appel LJ, Miller ER, Seidler AJ, Whelton PK. Dose supplementation of diet with “fish oil” reduce blood pressure? A meta-analysis of controlled clinical trials. Arch Intern Med 1993;153:1429-38. Singer P. Alpha-linolenic acid vs long-chain fatty acids in hypertension and hyperlipidemia. Nutrition 1992;8:133-5. Swank RL. Multiple sclerosis: fat-oil relationship. Nutrition 1991;7:368–76. Swank RL, et al. The Multiple Sclerosis Diet Book. Garden City, NY: Doubleday; 1977. Belluzzi, A, Boschi, S, Brignola, C, Munarini, A, Cariani, G, Miglio F. Polyunsaturated fatty acids and inflammatory bowel disease. Am J Clin Nutr 2000;71(Suppl):339S-42S. DiGiacoma RA, Kremer JM, Shah DM. Fish-oil dietary supplementation in patients with Raynaud’s phenomenon: A double-blind, controlled prospective study. Am J Med 1989;86:158-64. Piche LA, Draper HH, Cole PD. Malondialdehyde excretion by subjects consuming cod liver oil vs a concentrate of n-3 fatty acids. Lipids 1988;23:370-1. Clarke JTR, Cullen-Dean G, Reglink E, et al. Increased incidence of epistaxis in adolescents with familial hypercholesterolemia treated with fish oil. J Pediats 1990;116:139-41. Pederson HS, et al. n-3 fatty acids as a risk factor for hemorrhagic stroke. Lancet 1999;353:812-3. Schectman G, Kaul S, Kassebah AH. Effect of fish oil concentrate on lipoprotein composition in NIDDM. Diabetes 1988;37:1567-73. Axelrod L, Camuso J, Williams E, Kleinman K, Briones E, Schoenfeld D. Effects of a small quantity of omega-3 fatty acids on cardiovascular risk factors in NIDDM: a randomized, prospective, double-blind, controlled study. Diabetes Care 1994;17:37-44.

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34 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Flaxseed Oil and Alpha-Linolenic Acid General Features Flaxseed Oil is a very rich source of alpha-linolenic acid, an omega-3 fat that the body can slowly convert to eicosapentaenoic acid (EPA). EPA is the prominent omega-3 fat found within fish and fish oil that is linked to the prevention of heart disease, cancer and demonstrates anti-inflammatory properties.1-4 Flaxseed Oil supplementation can help the body achieve a more optimal ratio of omega-6 fatty acids to omega-3 fatty acids, which is considered to be 4:1.5 The North American diet provides a 20:1 ratio of omega-6 fatty acids to omega3 fatty acids, which is thought to contribute to the development of many chronic degenerative diseases. 6 Various polyunsaturated fats of the omega-6 and omega-3 series give rise to the formation of eicosanoids, including prostaglandins (hormone-like substances that regulate local tissue inflammation, proliferation and other factors). Studies reveal that supplementing with omega-3 fatty acids and lowering the omega-6 to omega-3 ratio results in increase of synthesis of anti-inflammatory and more health-promoting prostaglandins.7,8 Studies reveal that Flaxseed Oil has a favourable effect on the immune system and that its alpha-linolenic acid is converted to eicosapentaenoic acid (EPA), the immediate precursor of prostaglandin series-3 derivatives.9,10

Supplementation Studies and Clinical Applications 1. Anti-inflammatory and Autoimmune Reaction Some evidence suggests that Flaxseed Oil inhibits autoimmune reactions as well as fish oil (EPA). It may take a little longer, but it is less expensive and Flaxseed Oil does not produce the fish smelling regurgitation associated with fish oil supplementation.11 2. Cancer Dr. Joanna Budwig of Germany is a leading expert on essential fatty acid nutrition and has built an international reputation for treating cancer and other degenerative diseases with Flaxseed Oil.12 A major study demonstrated that the combination of high dose antioxidants with essential fatty acids (including alpha-linolenic acid) was able to halt the further progression of breast cancer in a group of 32 affected women, with spread of their condition to the axillary lymph nodes. Supplementation was initiated as an adjustment to standard breast cancer treatment. 13 3. Heart Disease Alpha-linolenic acid has been reported to lower cholesterol and blood pressure, in preliminary trials.14,15

Dosage Range Flaxseed Oil supplementation for most applications is in the range of 1,000-4,000 mg per day.

Contraindications and Toxicity Flaxseed Oil toxicity has not been reported at the above levels of intake and there are no known contraindications.

Drug-Nutrient Interactions There are no well-known drug interactions with Flaxseed Oil.16

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35 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

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

Nordstrom DCE, Honkanen VEA, Nasu Y, Antila E, Friman C, Konttinen YT. Alpha-linolenic acid in the treatment of rheumatoid arthritis. A double-blind placebo-controlled and randomized study: flaxseed vs safflower oil. Rheumatol Int 1995;14:231-4. von Schacky C, Angerer P, Kothny W, Theisen K, Mudra H. The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1999;130:554-62. Mate J, Castanos R, Garcia-Samaniego J, Pajares JM. Does dietary fish oil maintain the remission of Crohnâ&#x20AC;&#x2122;s disease: a case control study. Gastroenterology 1991;100:A228[abstract] Gonzalez MJ. Fish oil, lipid peroxidation and mammary tumor growth. J Am Coll Nutr 1995;14:325. Schlomo Y, et al. Modulating the learning pain thresholds, and thermoregulation in the rat by preparations of free purified alpha-linolenic and linolenic acids: Determination of the optimal w3-to w6 ratio. Proc Nat Acad Sci 1993;90:10345-7. Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 249-78 Lee TH, Hoover RL, Williams JD, Sperling RI, Ravalese J, Spur BW, et al. Effect of dietary enrichment with eicosapentaenoic and docosahexanoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil generation. New Eng J Med 1985;312:1217-24. Strasser T, Fischer S, Weber P. Leukotrien B5 is formed in human neutrophils after dietary supplementation with eicosapentaenoic acid. Proc Natl Acad Sci 1985;82:1540-3. Bjerve KS, et al. Clinical studies with alpha-linolenic acid and long n-3 fatty acids. Nutrition 1992;8:130-2. Mantzioris E, James MJ, Gibson RA, Cleland LG. Dietary substitution with alpha-linolenic acid-rich vegetable oil increases EPA concentrations in tissues. Am J Clin Nutr 1994;59:1304-9. Kelly DS. Alpha-linolenic acid and immune response. Nutrition 1992;8:215-7. Erasmus U. Fats and oils. Vancouver, BC: Alive Books; 1986. p. 273. Lockwood K, Moesgaard S, Folkers K. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10. Biochem Biophys Res Comm 1994;199:1504-8. Chan JK, Bruce VM, McDonald BE. Dietary alpha-linolenic acid is as effective as oleic acid and linoleic acid in lowering blood cholesterol in normolipidemic men. Am J Clin Nutr 1991;53:1230-4. Singer P, Jaeger W, Berger I, et al. Effects of dietary oleic, linoleic and alpha-linolenic acids on blood pressure, serum lipids, lipoproteins and the formation of eicosanoid precursors in patients with mild essential hypertension. J Human Hypertansion 1990;4:227-233. Healthnotes online. 2000 Healthnotes Inc: Flaxseed Oil.

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36 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Gamma-Linolenic Acid (GLA) General Features Evening primrose oil, black currant oil and borage oil contain Gamma-Linolenic Acid, which is an omega-6 fatty acid. Gamma-Linolenic Acid is a precursor in the synthesis of prostaglandin E1 (PGE1), which is known to have antiinflammatory properties.1 Thus, Gamma-Linolenic supplementation has been used in the treatment of rheumatoid arthritis and other inflammatory conditions.2 The body can synthesize Gamma-Linolenic Acid from linolenic acid (found in many vegetable oils), however people with certain conditions appear to have a defect in the delta-6 desaturase enzyme that converts linolenic acid (LA) to Gamma-Linolenic Acid (GLA). Patients with premenstrual syndrome, diabetes, scleroderma, Sjogrenâ&#x20AC;&#x2122;s Syndrome, Tardive Dyskinesia, eczema, and other skin conditions tend to have this metabolic block and research demonstrates that supplementation with a medicinal oil, rich in GLA, has helped people with these conditions. Furthermore, the delta-6 desaturase enzyme requires vitamin B 6, magnesium and zinc as cofactors to convert LA to GLA. Suboptimal status of these micronutrients also impairs the conversion of LA to GLA, as does the presence of transfatty acids and alcohol in the diet.3-15 There is also evidence that an excess intake of LA stimulates conversion of GLA to arachidonic acid via the delta-5 desaturase enzyme. Arachidonic acid is proinflammatory and contributes to cardiovascular risk and other health problems.16 Nevertheless, supplementation with oils that contain Gamma-Linolenic Acid have shown them to be of benefit for certain conditions.11-15 As a general reference, evening primrose oil contains 9 percent Gamma-Linolenic Acid, borage seed oil is 22 percent GLA and black currant seed oil is 22 percent GLA and also contains 13 percent omega-3 fatty acids as alpha-linolenic acid.1

Supplementation Studies and Clinical Application 1. Diabetic Neuropathy Supplementation with Gamma-Linolenic acid-containing oil has been shown to help repair diabetic neuropathy and prevent nerve damage in diabetics as evidenced by placebo-controlled studies. Objective parameters, including nerve conduction studies, sensation and reflex testing were used to verify the neurological improvement. Diabetics have a decreased ability to convert LA to GLA, which is important for nerve cell membrane structure and impulse conduction. Supplementation of oils yielding as little as 240 to 480 mg of GLA have shown proven benefit in the prevention and treatment of diabetic neuropathy. 17 2. Arthritis and Joint Inflammatory Diseases Some studies have demonstrated that supplementation with evening primrose oil or black currant oil can significantly reduce symptoms and signs of rheumatoid arthritis in double-blind, placebo-controlled, randomized trials. Other studies have failed to show improvement and researchers attribute this failure to the ability of GLA to raise tissue levels of arachidonic acid, while reducing cell membrane concentrations of omega-3 fatty acids. In these

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37 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils cases fish, fish oil or flaxseed oil may be more beneficial. The dosage of GLA used in the successful studies reported here used an oil yielding 2.8gm per day of GLA.18,19,20 3. Skin Inflammatory Conditions (Eczema, Psoriasis) Supplementation with oils that yield GLA have demonstrated improvement in patients suffering from eczema (atopic dermatitis) and psoriasis (GLA content of 274 mg, twice a day). - Studies using increased fish consumption or fish oil supplementation have also shown benefit in patients with psoriasis.21-24

Dosage Ranges For most conditions mentioned in this review supplementation of 270-540 mg GLA per day is typically used. This implies that 3,000-6,000 mg of evening primrose oil would be required to yield this amount of pure GLA, as evening primrose oil is 9 percent GLA content.

Side Effects and Toxicity GLA is very non-toxic. Evening primrose oil has been reported to exacerbate symptoms of temporal lobe epilepsy, which can sometimes be mistaken for schizophrenia.25,26 Drug-Nutrient Interactions GLA-containing oils may increase seizure activity in patients taking anti-seizure medications.27 N.B. Concurrent supplementation of GLA, EPA, or LNA with a B-50 complex, vitamin E, vitamin C, zinc and magnesium helps to encourage the synthesis of anti-inflammatory prostaglandins (series 1 and 3). These vitamins and minerals act as cofactors to help catalyze enzymatic conversion of essential fatty acids to the more desirable prostaglandins of the one and three series.1

1. 2. 3.

Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 252-68. Joe LA, Hart LL. Evening primrose oil in rheumatoid arthritis. Ann Pharmacother 1993;27:1475-7[review]. Horrobin DF. The importance of gamma-linolenic acid and prostaglandin E1 in human nutrition and medicine. J Holistic Med 1981;3:118-39. 4. Horrobin DF, Manku M, Brush M, et al. Abnormalities in plasma essential fatty acid levels in women with pre-menstrual syndrome and with non-malignant breast disease. J Nutr Med 1991;2:259-64. 5. Keen H, Payan J, Allawi J, et al. Treatment of diabetic neuropathy with gamma-linolenic acid. Diabetes Care 1993;16:815[reviews]. 6. Horrobin DF. Essential fatty acid metabolism in diseases of connective tissue with special reference to scleroderma and to Sjogren’s syndrome. Med Hypoth 1984;14:233-47. 7. Horrobin DF, Campbell A. Sjogren’s syndrome and the sicca syndrome: the role of prostaglandin E1 deficiency. Treatment with essential fatty acids and vitamin C. Med Hypoth 1980;6:225-32. 8. Vaddadi KS, Gilleard CJ. Essential fatty acids, tardive dyskinesia, and schizophrenia. In: Horrobin DF, editor. Omega-6 Essential Fatty Acids: Pathophysiology and Roles in Clinical Medicine. New York, NY: Alan R Liss; 1990. p. 333–43. 9. Manku MS, Horrobin, DF, Morse NL, et al. Essential fatty acids in the plasma phospholipids of patients with atopic eczema. Br J Derm 1984;110:643. 10. Horrobin DF. Essential fatty acids in clinical dermatology. J Am Acad Dermatol 1989;20:1045-53. 11. Mansel RE, Pye JK, Hughes LE. Effects of essential fatty acids on cyclical mastalgia and noncyclical breast disorders. In: Omega6 Essential Fatty Acids: Pathophysiology and Roles in Clinical Medicine. Horrobin DF, editor. New York, NY: Alan R Liss, 1990. p. 557-66. 12. Keen H, Payan J, Allawi J, Walker J, Jamal GA, Weir AI, et al. Treatment of diabetic neuropathy with gamma-linolenic acid. Diabetes Care 1993;16:8-15.

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Comment [c10]: Could not find the other authors Comment [c11]: Could not find the other authors

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38 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 13. Horribin DF. Essential fatty acid metabolism in diseases of connective tissue with special reference to scleroderma and to Sjogrenâ&#x20AC;&#x2122;s syndrome. Med Hypoth 1984;14:233-47. 14. Vaddadi KS, Gilleard CJ. Essential fatty acids, tardive dyskinesia, and schizophrenia. In: Horrobin DF, editor. Omega-6 Essential Fatty Acids: Pathophysiology and Roles in Clinical Medicine. New York, NY: Alan R Liss; 1990. p. 333-43. 15. Schalin-Karrila M, Mattila L, Jansen CT, Uotila P. Evening primrose oil in the treatment of atopic eczema: effect on clinical status, plasma phospholipid fatty acids and circulating blood prostaglandins. Brit J Dermatol 1987;117:11-9. 16. Janti J. Evening primrose oil in rheumatoid arthritis: changes in serum lipids and fatty acids. Annals Rheumatol Dis 1989;48:124-7. 17. Keen H, Payan J, Allawi J, Walker J, Jamal GA, Weir AI, et al. Treatment of diabetic neuropathy with gamma-linolenic acid. The Gamma-Linolenic Acid Multicenter Trial Group. Diabetic Care 1993;16:8-15. 18. Zurier RB, Rossetti RG, Jacobson EW, et al. Gamma-linolenic acid treatment of rheumatoid arthritis. A randomized, placebocontrolled trial. Arthritis Rheum 1996;11:1808-17. 19. Leventhal LJ, Boyce EG, Zurier Rb. Treatment of rheumatoid arthritis with black currant seed oil. Br J Rheumatol 1994;9:847-52. 20. Jantti J, Nikkari T, Solakivi T, Vapaatalo H, et al. Evening primrose oil in rheumatoid arthritis. Changes in serum lipids and fatty acids. Annals Rheum Dis 1989;48:124-7. 21. Andreassi M, Forleo P, Di Lorio Z, Masci S, Abate G, Amerio P. Efficacy of gamma-linolenic acid in the treatment of patients with atopic dermatitis. J Int Med Res 1997;5:266-74. 22. Borrek S, Hildebrandt A, Forster J. Gamma-linolenic acid-rich borage seed oil capsules in children with atopic dermatitis. A placebocontrolled double-blind study. Klin Padiatr 1997;3:100-4. 23. Hederos C, Berg, A. Epogam evening primrose oil treatment on atopic dermatitis and asthma. Arch Dis Child 1996;6:494-7. 24. Collier PM, Ursell A, Zaremba K, Payne CM, Staughton RC, Sanders T. Effect of regular consumption of oily fish compared with white fish on chronic plaque psoriasis. Ew J Clin Nutr 1993;4:251-4. 25. Vaddadl KS. The use of gamma-linolenic acid and linolenic acid to differentiate between temporal lobe epilepsy and schizophrenia. Prostaglandins Med 1981;6:375-9. 26. Holman CP, Bell AFJ. A trial of evening primrose oil in the treatment of chronic schizophrenia. J Orthomol Psychiatr 1983;12:302-4. 27. Miller LG. Selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:220011.

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39 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Gamma-Oryzanol General Features Gamma-Oryzanol (esters of ferulic acid) is a growth-promoting substance in grains and is isolated from rice bran oil for use as a supplement. In 1970 Gamma-Oryzanol was approved as a medicinal treatment to lower cholesterol and triglycerides (Japan).1 As far back as the 1960â&#x20AC;&#x2122;s, Gamma-Oryzanol was shown to be effective in the treatment of menopausal symptoms, including hot flashes, and subsequent studies have supported these findings. 1 Orally administered Gamma-Oryzanol is converted in the body to free ferulic acid.2

Supplementation Studies and Clinical Applications 1. Menopausal Symptoms Supplementation with Gamma-Oryzanol (150 mg, twice per day) has been shown to reduce the secretion of leutinizing hormone (LH) by the pituitary and promote endorphin release by the hypothalamus. 3 Hot flashes and other menopausal symptoms (profuse sweating, mood changes) result indirectly from the over-secretion of leutinizing hormone, which is attempting to initiate the start of another ovulatory cycle. The lack of response by the immature egg cells in the ovaries in menopause results in an over-secretion of FSH (follicle stimulating hormone) and LH by the pituitary, contributing to the onset of hot flashes and related symptoms. 4 Clinical trials involving menopausal women and women who had their ovaries surgically removed, have revealed that 67-85 percent of women treated with Gamma-Oryzanol have experienced a significant reduction in menopausal symptoms.5,6 2. Cholesterol and Triglyceride Lowering (Hypo-Lipidemic Effects) A number of clinical traits reveal that 300 mg per day of Gamma-Oryzanol supplementation can lower cholesterol by 8-12 percent and triglycerides by approximately 15 percent in subjects with elevated lipid levels.7,8,9 Gamma-Oryzanol supplementation increases the conversion of cholesterol to bile acids, increases bile acid excretion, and inhibits the absorption of cholesterol from the intestinal tract to the bloodstream.10,11 These are important considerations for post menopausal women as heart disease is the most common cause of death in women over 50 years of age in North America. The decline in circulating estrogen levels with menopause predisposes postmenopausal women to a rise in blood cholesterol and the development of atherosclerosis. This is, in part, due to the fact that estrogen increases the number of LDL- cholesterol receptors on body cells, enabling the body to remove LDL-cholesterol from the bloodstream very effectively.12,13

Dosage Menopausal Symptoms: 300 mg per day, taken in divided doses (ie. 150 mg, twice per day) Hypolipidemic Effects: 300 mg per day, taken in divided doses (i.e. 150 mg, twice per day)

Adverse Side Effects and Toxicity Toxicity studies on animals demonstrate that it is a very safe compound. No significant side effects have been reported in human trials or experimental studies.14,15

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40 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Drug Nutrient Interactions There are no reported drug-nutrient interactions for gamma-olyzanol.

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

Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 332-5. Fujiwara S, et al. Mass fragmentographic determination of ferulic acid in plasma after oral administration of gamma-oryzanol. Chem Parm Bull 1982;30:973-979. Yamauchi J, et al. Inhibition of LH secretion by gamma-oryzanol in rat. Horm Metabol Res 1981;13:185. The Merk Manual. 16th edition. Merck & Co. 1992. p. 1767-8. Murase Y, Iishima H. Clinical studies of oral administration of gamma-oryzanol on climacteric complaints and its syndrome. Obtet Gynecol Prac 1963;12:147-9. Ishihara M. Effect of gamma-oryzanol on serum lipid peroxide levels and climacteric disturbances. Asia Oceania J Obstet Gynecol 1984;10:317. Yoshino G, Kazumi T, Amano M, et al. Effects of gamma-oryzanol on hyperlipidemic subjects. Curr Ther Res 1989;45:543-52. Yoshino G, et al. Effects of gamma-oryzanol and probucol on hyperlipidemia. Durr Ther Res 1989;45,975-82. Sasaki J, et al. Effect of gamma-oryzanol on serum lipids and apolipoproteins in dyslipidemic schizophrenics receiving major tranquilizers. Clin Ther 1990;12:263-8. Seetharamaiah GS, Chandrasekhara N. Effect of oryzanol on cholesterol absorption and biliary & fecal bile acids in rats. Ind J Med Res 1990;92:471-5. Sakamoto K, et al. Effects of gamma-oryzanol and cycloartenol ferulic acid ester on cholesterol diet induced hyperlipidemia in rats. Jap J Pharmacol 1987;45:559-65. Gura T. Estrogen: key player in heart disease among women. Science 1995;269:771-3. Colditz G, Willett W, Stampfer M, Rosner B, Hennekens C. Menopause and the risk of coronary heart disease in women. New Engl J Med 1987;316:1105-10. Tamagawa M, Otaki Y, Takahashi T, Otaka T, Kimura S, Miwa T. Carcinogenicity study of gamma-oryzanol in B6C3F1 mice. Food Chem Toxicol 1992;30:49-56. Tamagawa M, Shimizu Y, Takahashi T, Otaka T, Kimura S, Kadowaki H, et al. Carcinogenicity study of gamma-oryzanol in F344 rats. Food Chem Toxicol 1992;30:41-8.

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41 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Glucosamine Sulfate General Considerations Glucosamine-6-phosphate is the precursor from which all proteoglycans are synthesized. Proteoglycans are found in the synovial fluid of joints, the vitreous humor of the eye, arterial walls, as well as bone and cartilage. They are major components of the extracellular matrix or ground substance, a gelatinous material that forms a meshwork between cells. Proteoglycans are proteins that contain many chains of glycosaminoglycans (formerly called mucopolysaccharides). Glycosaminoglycans are long, unbranched polysaccharides composed of repeating disaccharide units. The repeating disaccharides usually contain an uronic acid or a glucuronic acid, and a hexosamine, and are frequently sulfated. All hexosamines are derived from glucosamine-6-phosphate. Hence the synthesis of glucosamine-6-phosphate is essential to the production of ground substance throughout our lives. This extracellular matrix is more than glue that holds cells together. It also serves as a barrier to microorganisms from reaching cells. Because they are long and negatively charged, glycosaminoglycans chains repel each other. As well, the proteoglycans occupy a very large space and act as â&#x20AC;&#x153;molecular sievesâ&#x20AC;?, determining which substances approach and leave cells. Their properties also give resilience to substances such as cartilage, permitting compression and reexpansion (shock absorbing function) There are at least seven types of glycosaminoglycans, which differ from each other based upon the monosaccharides present in their repeating disaccharide units: 1. Chondroitin sulfate 2. Dermatan sulfate 3. Heparin 4. Heparin sulfate 5. Hyaluronic acid 6. Keratan sulfate I 7. Keratan sulfate II Except for hyaluronic acid, the glycosaminoglycans are linked to proteins, usually attached covalently to serine or threonine residues, and are hence also referred to as proteoglycans. Keratan sulfate I is attached to asparagine. The synthesis of all glycosaminoglycans is dependent upon the presence of glucosamine-6-phosphate. Glucosamine-6-phosphate The body normally synthesizes glucosamine-6-phosphate by the transfer of an amino group from the amide of glutamine to fructose 6-phosphate. Glucosamine can then be N-acetylated by an acetyltransferase enzyme to yield Nacetyl glucosamine-6-phosphate and N-acetyl galactosamine, which are then linked to UDP. Both N-acetyl glucosamine and N-acetyl galactosamine are used as monosaccharides to form various glycosaminoglycans. The glycosaminoglycans in joint cartilage are comprised of repeating units of glucuronic acid and N-acetyl galactosamine. It appears that as some people age, they lose the ability to manufacture sufficient levels of glucosamine-6-phosphate, and thus, there is a reduction in the synthesis of N-acetyl galactosamine and N-acetyl glucosamine. The result is that cartilage loses its ability to act as a shock absorber and erosion of cartilage and ground substance can lead to osteoarthritis. Radioisotope studies using C14 glucosamine indicate that glucosamine supplementation is a good substrate for a kinase enzyme which yields glucosamine-6-phosphate, which can then be used to form glycosaminoglycans.

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42 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils The best form of glucosamine has been shown to be Glucosamine Sulfate. N-acetylglucosamine is a poor substrate for a kinase activity and glucosamine hydrochloride has poor supportive evidence for its use. It appears that the sulfur component of Glucosamine Sulfate may be critical to its beneficial effects on arthritis and other problems. Glucosamine ingestion also has a concurrent effect on increasing collagen production by chondrocytes, helping to reverse the osteoarthritic process.1-9

Clinical Conditions and Mechanisms 1. Osteoarthritis Oral Glucosamine Sulfate has been shown to decrease pain and improve mobility in osteoarthritic patients without side effects, in a large number of double-blind, placebo controlled studies. Mechanism: promoting the synthesis of glycosaminoglycans and collagen by chondrocytes. This may also have application in Rheumatoid Arthritis as well.10-16 2. Wound healing Oral glucosamine may speed the healing of surgical wounds and may diminish scarring, keloids, adhesions, strictures. Mechanism: Promoting the synthesis of hyaluronic acid by fibroblasts in the early stages of healing. 3. GI ulcers and inflammatory bowel disorders In animal studies, glucosamine supplementation has been shown to be clinically useful for these conditions. Mechanism: oral glucosamine increases production of heparan sulfate proteoglycans by the vascular endothelium, thereby improving the endothelium’s barrier function. Extravasation of leukocytes and metastatic cancer cells requires degradation of heparan sulfate. Heparan can inhibit neutrophil activation, adhesion, and chemotaxis and like glucosamine has been reported to be effective for managing inflammatory bowel syndromes. Interestingly, the metastatic capacity of cancer cells tends to correlate with their ability to produce heparanase. It is concluded that heparan sulfate proteoglycans play an important role in stabilizing the subendothelial extracellular matrix, cross-linking proteins and reducing their susceptibility to proteolytic degradation. Heparan therapy has been successful in animals and humans with ulcerative colitis. In both ulcerative colitis and Crohn’s disease there’s a marked deficiency in extracellular sulfated glycosaminoglycans in the mucosa (ulcerative colitis) and submucosa (Crohn’s disease), as well as along the vascular endothelium and subepithelial basal lamina.17-28

Dosage and Standardized Grade For arthritic conditions and wound healing an oral dose of 500 mg taken three times per day is typical. In heavier patients and those on diuretics, the total daily dosage should be 20 mg/kg body weight. For arthritic patients improvement is usually noted within 8-12 weeks. The best form of glucosamine is Glucosamine Sulfate.

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43 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Toxicity and Contraindications At the above recommended levels glucosamine sulfate is highly non toxic. Rare side effects have included stomach upset, heartburn, diarrhea, nausea and indigestion. Patients with sulfa drug or sulfite allergies can still take Glucosamine Sulfate. It is impossible to be allergic to sulfur because it is an essential mineral for life. Individuals taking diuretics may need higher dosages (20 mg/kg body weight).29 There is some suggestion that glucosamine supplementation may increase insulin resistance in diabetics. The clinical importance of this remains to be determined.30,31

Drug-Nutrient Interaction There are no well-known drug-nutrient interactions for Glucosamine Sulfate.

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

Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 336-42. Marks DB, Marks AD, Smith CM, editors. Basic Medical Biochemistry: A clinical Approach. Baltimore, Maryland: Williams and Wilkins; 1996. p. 452-64. McCarthy M. Neglect of glucosamine as a treatment for osteoarthritis-a personal perspective. Medical Hypotheses 1994;42:323-7. McCarthy M. Glucosamine for wound healing. Medical Hypothesis 1996;47:273-5. Palmoski MJ, Brankt KD. Effects of some nonsteroidal anti-inflammatory drugs on proteoglycan metabolism and organization in canine articular cartilage. Arthritis Rheum 1980;23:1010-20. Roden L. Effect of hexosamines on the synthesis of chondroitin sulphuric acid in vitro. Arc Kemi 1956;10:345-52. Karzel K, Domenjoz R. Effects of hexosamine derivatives and uronic acid derivatives on glycosaminoglycan metabolism of fibroblast cultures. Pharmacology 1971;5:337. Kim JJ, Conrad HE. Effect of D-glucosamine concentration on the kinetics of mucopolysaccharides biosynthesis in cultured chick embryo vertebral cartilage. J Biol Chem 1974;249:3091-7. Matalon R, Dorfman A. The structure of acid mucolpolysaccharides produced by Hurler fibroblasts in tissue culture. Proc Nat Acad Sci USA 1968;60:179-85. Vidal RR, et al. Articular Cartilage Pharmacology: Parmacol Res Comm 10 1978;557-569. D'Ambrosia E, Casa B, Bompani R et al. Glucosamine sulphate. A controlled clinical investigation in arthrosis. Pharmacotherapeutica 1982;2:504-8. Vas AL. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulfate in the management of osteoarthroses of the knee in out-patients. Current Med Res Opinion 1982;8:145-9. Refinster JY, et al. Glucosamine sulfate significantly reduces progression of knee osteoarthritis (KOA). Arthritis Rheum 1999;42:292. Delafuente JC. Glucosamine in the treatment of osteoarthritis. Rheum. Dis Clin North Am 2000;26(1):1-11. Gottleib MS. Conservative management of spinal osteoarthritis with glucosamine sulfate and chiropractic treatment. J Manipulative Physiol Ther 1997;20(6):400-14. Glucosamine Sulfate [monograph]. Altern Med Rev 1999;4(3):193-5. Moriga M, Aono M, Murakami M, Uchino H. The activity of N-acetylglucosamine kinase in rat gastric mucosa. Gastroenterol Japonica 1980;15:7-13. Vlodavsky I, Fuks Z, Bar-Ner M, et al. Lymphoma-cell-mediated degradation of sulfated proteoglycans in the subendothelial extracellular matrix: Relationship to tumor cell metastasis. Cancer Res 1983;43:2704-11. Nakajima M, Irimura T, Di ferrante D, et al. Heparam sufate degradation: Relation to tumor invasion and metastsitc properties of mouse B16 melanoma sublines. Science 1983;220:611-2. Ricovery W, Cappelletti R. Heparan sulfate endoglycosidase and metastatic potential in murine fibrosarcoma and melanoma. Cancer Res 1986;45:3855-61. Nakajima M, Irimura T, Nicolson GL. Heparanase and tumor metastasis. J Cell Biochem 1988;36:157-67. Vlodavsky I, Eldor A, Bar-Ner M, et al. Heparan sufate degradation in tumor cell invasion and angiogenesis. Adv Exp Med Biol 1988;233:201-10.

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44 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 23. Clodavsky I, Korner G, Ishai-Michaeli R, et al. Extracellular matrix resident growth factors and enzymes: Possible involvement in tumor metastasis and angiogenesis. Cancer Metastasis Rev 9 1990;203-26. 24. Dwarakanath AD, Yu LG, Brookes C, et al. ‘Sticky’ neutropolis pathergic arthritis and response to heparin in pyoderma gangrenosum complicationg ulcerative colitis. Gut 1995;37:585-8. 25. Gaffney PR, O’Leary JJ, Doyle CT, et al. Response to heparin in patients with ulcerative colitis. Lancet 1991;337:238-9. 26. Gaffney PR, Doyle CT, Hogan J, Gaffney A. Paradoxical response to heparin in 10 patients with ulcerative colitis. Gastroenterology 1993;104:A703. 27. Murch SH, MacDonald TT, Walder-Smith JA, et al. Disruption of sulfated glycosaminoglycans in intestinal inflammation. Lancet 1993;341:711-4. 28. Lee JCL, Spittel JA Jr., Sauer WG, et al. Hypercoagulability associated with chronic ulcerative colitis: Changes in blood coagulation factors. Gastroenterology 1968;54:76-85. 29. Murray MT. The Healing Power of Herbs. 2nd Ed. Rocklin, CA: Prima Publishing; 1995. 30. Monauni T, Zenti MG, Cretti A, Daniels MC, Targher G, Caruso B, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes. 2000;49(6):926-35. 31. Shankar RR, Zhu JS, Baron AD. Glucosamine Infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus. Metabolism 1998; 47(5):573-7.

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45 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Glutamine General Features L-Glutamine is the most abundant amino acid in the bloodstream and in the body. It is involved in more metabolic processes than any other amino acid, fulfilling a number of biochemical needs. It operates as a nitrogen shuttle, taking up excess ammonia and forming urea. Ammonia, a by-product of certain normal biochemical reactions in the body (including the brain) is toxic to the human body and thus glutamine serves an important function in helping to convert ammonia into urea, a non toxic end product, which the body can easily eliminate. L-Glutamine can contribute to the production of other amino acids, glucose, nucleotides, protein and glutathione. It is the principal metabolic fuel for the epithelial cells that line the small intestine (enterocytes), and for certain immune cells, namely lymphocytes, macrophages, and fibroblasts.1 Glutamine intake has been shown to enhance glutathione stores in conjunction with N-acetylcysteine, which may forestall the progression of HIV infection to AIDS in afflicted patients. 2 Glutamine supplementation has been shown to help protect the gastrointestinal tract from damage by certain chemotherapy drugs (i.e. fluorouracil) and also prevents diarrhea that these drugs are known to produce.1,3 Glutamine supplementation has been shown to enhance immune system function and result in a lower level of infection and a shorter stay in hospital following surgery, radiation treatment, bone marrow transplantation, and in patients suffering from injury, compared with patients receiving Glutamine-free parenteral nutrition.4,5,6 Glutamine is a non-essential amino acid in that the body can synthesize it from the amino acid glutamic acid via the Glutamine synthase enzyme.7 However, during periods of fasting, starvation, critical illness, cancer, AIDS and following trauma, radiation treatment, surgery, bone marrow transplantation or in patients with a weakened immune system or catabolic stress, extra Glutamine replenishment has been shown to be beneficial to re-establish homeostatis.7 Glutamine is also a main anti-catabolic agent in muscle, which when supplemented, may help preserve muscle tissue (preventing its breakdown), during and after exercise. The heavier one trains, the greater the stress on the muscle and the greater is the use of Glutamine.8 During and following exercise or trauma, large amounts of alanine and Glutamine are released from muscle. They then travel through the blood stream to the liver where they can be used to form glucose and glycogen. The total loss of alanine and Glutamine induced by exercise is above the amount available in muscle and represents more than 50 percent of the total loss of muscle amino acids and nitrogen loss from muscle tissue during exercise. Studies show that during exercise other muscle amino acids (branched-chain amino acids) are used to donate their carbon skeletons to make alanine and certain alpha ketoacids and amino acids, such as alpha ketogluturate and glutamic acid are converted within the muscle to glutamine. Most notably, the branched-chain amino acid, leucine, isoleucine and valine serve as a substrate for alanine synthesis, but higher levels of intramuscular glutamine (via supplementation) may help to stop the catabolism of branched chain-amino acids, as glutamine can diffuse from the muscle and become a source of glucose in the liver to help maintain blood glucose and liver glycogen levels during periods of stress (i.e. exercise)8,9,10 This is also the role played by alanine, and thus, higher glutamine concentrations may reduce the requirement for alanine synthesis in the muscle, and thereby spare the breakdown of muscle tissue (branched-chain amino acid catabolism) during exercise and under other periods of catabolic stress (burn victims, infection, post surgery etc). 8,9,10

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46 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Supplementation Studies and Clinical Applications 1. HIV-Infection Glutamine supplementation plus N-acetylcysteine supplementation enhances glutathione levels in HIV patients. Higher glutathione status correlates with a slowing of the progression of HIV to AIDS. Glutathione depletion is common in these patients due to increased free radical production. Glutathione is a first line antioxidant in the quenching of free radicals and participates in Phase I and Phase II liver detoxification functions. 2 2. Post-Trauma, Radiation Therapy, Post Bone Marrow Transplant, Certain Chemotherapy Agents These patients have been shown to benefit from additional Glutamine, although it may be required as part of parenteral nutrition requiring medical prescription and supervision.4 3. Anti-Catabolic Effect with Exercise Oral Glutamine has been shown to maintain muscle mass in catabolic patients. 11 However, Glutamine supplementation may increase ammonia levels and add to the ammonia burden of certain patients and athletes, jeopardizing recovery and performance respectively.8 To overcome this burden the use of alpha-ketogluturate has been shown to act as a Glutamine precursor, without contributing to ammonia build up. However, L-glutamine at a dose of up to 2,000-5,000 mg per day appears to be safe. Oral ornithine alpha-ketogluturate reduces muscle catabolism in burn and surgery patients and is known to increase muscle Glutamine levels. Ornithine alpha-ketogluturate also stimulates the release of growth hormone and may thereby further provide an anti-catabolic and indirect anabolic effect on muscle tissue and lean mass, in general. A daily dosage of 2-4 mg per day of ornithine alpha-ketogluturate is required to increase growth hormone levels. 12,13,14 4. Prevention of Infections in Athletes Glutamine supplementation in endurance athletes has been shown to reduce the incidence of infections in this population, who are known to have their immune system suppressed by excess training of this nature. A doubleblind, placebo-controlled study showed that Glutamine supplementation at a dose of 5 gm, taken after the end of exercise, in 151 endurance athletes resulted in a significantly lower incidence of infections (19%) compared to the placebo group (51%), during the study period.24 It has been suggested that the immune system suppression associated with endurance exercise, may be in part, due to reduction in Glutamine that results from intensive training.25 Another study, using the same protocol, demonstrated that 81% of athletes taking Glutamine had no subsequent infection during the study period compared to 49% in the placebo group.24

Dosage Ranges N.B. As oral Glutamine supplementation can potentially produce undesirable levels of ammonia in the body, it is unclear as to what levels of intake are safe (as a supplement). As an alternative oral ornithine alpha-ketogluturate has been used to elevate Glutamine status without ammonia build up when taken orally. 1. HIV-infection: 7 gm, twice daily with 7 gm of L-Arginine twice daily.22 2. Recovering from illness (elderly), surgery, burn or wound healing: 10-30 gms per day of ornithine alphaketogluturate, in divided doses.15,16 3. Muscle anti-catabolic-anabolic effect with exercise training: 2-4 gms, three times daily with meals (ornithine alphaketogluturate) or 2,000 mg per day of L-Glutamine.17 4. Prevention of Infections in Athletes: 5,000 mg per day of L-Glutamine post exercise session.24,25

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47 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Side Effects and Toxicity L-Glutamine supplementation may increase the ammonia load on the body. Thus, medical supervision should accompany high dose supplementation of L-Glutamine (above 2,000-5,000 mg per day).8 Ornithine alpha-ketogluturate supplementation is not associated with any side effects to date. 18,19 Glutamine may trigger epileptic seizures in epileptic patients, two case reports exist to support this side effect.26 Mania symptoms may develop at doses above 2,000 mg per day. These symptoms may develop in the absence of prior bipolar disease.26

Drug-Nutrient Interactions L-Glutamine: Supplementation with L-Glutamine has been shown to reduce side effects associated with the use of methotrexate, paclitaxel and chemotherapy drugs. It may also improve the efficacy of some chemotherapy drugs. Use of Glutamine in these applications should be implemented in collaboration with the attending medical physician.20,21 Ornithine Alpha-ketogluturate: There are no well-known drug interactions with ornithine alpha-ketogluturate.22 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Miller AL. Therapeutic considerations of L-glutamine: a review of the literature. Altern Med Rev 1999;4:239-48. Patrick L. Nutrients and HIV: part three N-acetylcysteine, alpha-lipoic acid, L-Lglutamine, and L-carnitine. Altern Med Rev 2000;4:290-305. Daniele B, Perrone F, Gallo C, Pignata S, De Martino S, De Vivo R, et al. Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial. Gut 2001;48:28-33. Griffiths RP. Outcome of critically ill patients after supplementation with glutamine. Nutrition 1997;13:752-4. Chang WK, Yang KD, Shaio MF. Effect of glutamine on TH1 and TH2 cytokine responses of human peripheral blood mononuclear cells. Clin Imunol 1999;3:294-301. Calder PC, Yaqoob P. Glutamine and the immune system. Amino Acids 1999;17;3:227-41. Buchman AL. Glutamine for the gut: mystical properties or an ordinary amino acid? Curr Gastroenterol Rep 1999;417-23. Roth E, et al. Glutamine: An anabolic effector. J Parent Ent Nutr 1990;14:1305-65. Felig P, Wahren J. Amino acid metabolism in exercising man. J Clin Invert 1971;50:2703-8. Felig P. The glucose-alanine cycle. Metabolism 1973;22:179-86. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr Rev 1990;48:297-309. Cynobar L, et al. Action of ornithine alpha-ketoglutarate, ornithine hydrochloride and calcium alpha-ketoglutarate on plasma amino acid and hormonal patterns in healthy subjects. J Amer Coll Nutr 1990;9:2-12. Cynobar L, et al. Action of ornithine alpha-ketoglutarate on protein metabolism in burn patients. Nutrition 1987;3:187-91. Leander U, et al. Nitrogen sparing effects Ornicetil in the immediate post operative state. Clin Nutr 1985;4:43-51. Cynobar L. Amino Acid Metabolism in thermal burns. JPEN 1989;13:196. De Bandt JP, Coudray-Lucas C, Lioret N, Soo-Kyung-Lim, Saizy R, Giboudeau J, et al. A randomized controlled trial of the influence of the mode of enteral ornithine alpha-ketoglutarate administration in burn patients. J Nutr 1998;128:563-9. Colgan M. Optimum Sports Nutrition, Your Competitive Edge. A Complete Nutritional Guide for Optimising Athletic Performance. New York, NY: Advanced Research Press: 1993. p. 379. Le Boucher J, Cynober LA. Ornithine alpha-ketoglutarate: the puzzle. Nutrition 1998;14:870-73 [review]. Brocker P, Vellas B, Albarede JL, Poynard T. A two-centre, randomized, double-blind trial of ornithine oxoglutarate in 194 elderly, ambulatory, convalescent subjects. Age Aging 1994;23:303-6.

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Comment [c25]: Could not find other authors.

Comment [c26]: Could not find other authors. Comment [c27]: Could not find other authors. Comment [c28]: Could not find other authors.

48 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 20. Klimberg VS, Nwokedi E, Hutchins LF, Pappas AA, Lang NP, Broadwater JR, et al. Glutamine facilitates chemotherapy while reducing toxicity. J Parent Ent Nutr 1992;16(6Suppl):83S-7S. 21. Klimberg VS, Nwokedi E, Hutchins LF, et al. Glutamine facilitates chemotherapy while reducing toxicity. JPEN J Parenter Enteral Nutr 1992;16(6Suppl):83S-7S. 22. Healthnotes online. Healthnotes, Inc 2000. 23. Klatz R. Grow Young with HGH. New York: Harper Perrenial Pub 1977. p. 206-7. 24. Castell LM, Poortmans JR, Newsholme EA. Does glutamine have a role in reducing infections in athletes? Eur J Appl Physiol Occup Physiol 1996;23:488-90. 25. Rowbottom DG, Keast D, Morton AR. The emerging role of glutamine as an indicator of exercise stress and overtraining. Sport Med 1996;21:80-90[review]. 26. Mebane AH. L-glutamine and mania. Am J Psychiatry 1984;141:1303[letter].

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Comment [c29]: Could not find other authors.

49 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Grape Seed Extract and Related Procyanodolic Oligomers (Pycnogenol) General Features Grape Seed Extract and pine bark extract belong to a group of compounds known as procyanidolic oligomers (PCO). These extracts contain flavonoids called proanthocyanidins, which are bound to other proanthocyanidins forming proanthocyanidin dimers, trimers, tetramers and larger molecules. These unique flavonoid compounds are powerful antioxidants and have been shown to inhibit the destruction of collagen, preserving the integrity of blood vessels and capillaries throughout the body. These features make them useful agents in the prevention and treatment of capillary fragility, venous insufficiency, varicose veins, diabetic retinopathy and macular degeneration. They also inhibit the inflammatory process to a certain degree. 1,2 Grape Seed Extract and pine bark extract (Pycnogenol) products should contain 92-95 percent and 80-85 percent PCO, respectively, to ensure sufficient amounts these bioactive agents.2

Supplementation Studies and Clinical Applications 1. Blood Vessel Support PCO support collagen and ground substance, decreasing capillary permeability and fragility. PCO extracts have been used to treat venous and capillary disorders, including venous insufficiency, varicose veins, capillary fragility, diabetic retinopathy and macular degeneration of the eye.3-9 2. Connective Tissue Support PCO support the collagen and ground substance of tendons, ligaments and cartilage. They also help to prevent cartilage destruction associated with inflammation and arthritis. PCO also inhibit the release of pro-inflammatory mediators such as histamine, proteases, prostaglandins and leukotrienes. PCO also demonstrate powerful antioxidant function. No clinical trials with arthritis patients have been published, however, anecdotal evidence and biological plausibility suggest that PCO extract supplementation may be useful in chronic arthritic and connective tissue disorders.10,11,12 3. Vision PCO extract has been used to help reverse or stabilize diabetic retinopathy and macular degeneration. It has also been used to improve visual performance in the dark and after exposure to glare (200 mg per day). 8,9

Daily Dosage (standardized to 92-95% PCO content) 1. Therapeutic Purposes (Venous insufficiency, varicose veins, capillary fragility, diabetic retinopathy, macular degeneration): 150-300 mg per day, in divided doses 2. General Health Support: 50-75 mg per day2

Toxicity and Contraindications Procyanidolic oligomer extracts have been shown to be very non-toxic. They are water-soluble and any excess is excreted in the urine. No side effects have been reported to date.

Drug-Nutrient Interactions There are no known drug interactions for procyanidolic oligomer extracts.13 www.meschinohealth.com

50 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

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

Schwitters B, Masquelier J. OPC in Practice: Biflavanols and their Applications. Rome, Italy: Alfa, Omega; 1993. Murray M. The Healing Power of Herbs. 2nd edition. Rocklin, CA: Prima Publishing; 1995. p. 184-91. Henriet JP. Veno-lymphatic insufficiency. Phlebologie 1993;46:313-25. Lagrue G, Oliver-Martin F, Grillot A. A study of the effects of procyanidolic oligomers on capillary resistance in hypertension and in certain nephropathies. Sem Hosp Paris 1981;57:1399-401. Gomez Trillo JT. Varicose veins of the lower extremities:symptomatic treatment with a new vasculotrophic agent. Prensa Med Mex, 1973;38:293-6. Soyeux A, et al. Endotelon: Diabetic retinopathy and hemorrheology (preliminary study). Bull Soc Ophthalmol Fr 1987;87:14441-4 Proto F, et al. Electrophysical study of vitis vinifera procyanoside oligomers effects on retinal function in myopic subjects. Ann OH Clin Ocul 1988;114:85-93. Corbe C, Boissin JP, Siou A. Light vision and chorioretinal circulation: study of the effect of procyanidolic oligomers (Endotelon). J Fr Ophthalmol 1988;11:453-60. Boissin JP, Corbe C, Siou A. Chorioretinal circulation and dazzling: use of procyanidol oligomers. Bull Soc Ophthalmol Fr 1988;88:1734,177-9. Masquelier J, Dumon MC, Dumas J. Stabilization of collagen by procyanidolic oligomers. Acta Therap 1981;7:101-5. Tixier JM, Godeau G, Robert AM, Hornebeck W. Evidence by in vivo and in vitro studies that binding to pycnogenols to elastin affects its rate of degradation by elastases. Biochem Pharmocol 1984;33(24):3933-9. Maffei F, Facino R, Carinin M, et al. Free radicals scavenging action and anti-enzyme activities of procyanidines from Vitis vinefera. Arzniem Forsch 1994;44:592-601. Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 320-31.

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51 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

5-Hydroxytryptophan (5-HTP) General Features 5-HTP is a naturally occurring agent that is extracted from the seed of an African plant, known as the â&#x20AC;&#x153;Griffonia Simplicifoliaâ&#x20AC;?. 5-HTP, unlike the amino acid tryptophan, easily crosses the blood-brain barrier. As a result, while only three percent of an oral dose of tryptophan is converted to serotonin in the brain, studies indicate that over seventy percent of an oral dose of 5-HTP is converted to serotonin. As serotonin is a neurotransmitter that elevates mood and improves sleep quality, 5-HTP has been used in clinical trials to treat depression, insomnia and other conditions where a rise in serotonin levels may be desirable. Some evidence suggests that 5-HTP also increases endorphin and other neurotransmitter levels as well.1

Supplementation Studies and Clinical Applications 1. Depression In several clinical trials 5-Hydroxtryptophan has been tested on its own or against other antidepressant drugs, including selective serotonin re-uptake inhibitor drugs (SSRI) such as fluvoxamine (Luvox). Fluvoxamine exerts anti-depressant activity comparable to Prozac, Zoloft, and Paxil. In general, 5-Hydroxytryptophan has been shown to be as effective as other traditional antidepressants and tends to be associated with fewer and less severe side effects. The usual dosage for this application is 100 mg, three times daily.1-5 However, patients with depression should be under the care of a qualified health professional and combining 5-Hydroxytryptophan supplementation with other anti-depressant drugs or supplements is contraindicated and may result in life-threatening side effects (i.e. serotonin syndrome).6 2. Insomnia 5-HTP has been shown to improve insomnia and quality of sleep in affected subjects. For insomnia, a single 100 mg dose of 5-HTP, one hour before bedtime has been shown to improve duration and depth of sleep in one placebo-controlled study.7 3. Fibromyalgia Some evidence suggests that 100 mg (5-HTP) taken three times per day may reduce symptoms of fibromyalgia, including pain and insomnia.8 4. Migraine Migraine Headache Studies have provided evidence that patients who suffer from migraine headaches may experience a reduction in frequency and severity of attacks with a dosage range of 400-600 mg per day, in divided doses.9-13

Dosage Ranges 1. 2. 3. 4. 5.

Depression: 100 mg, three times daily2 Insomnia: a single dose of 25-100 mg, one hour before bedtime.4 Fibromyalgia: 100 mg, three times daily8 Migraine headaches: 150 mg, three times per day9 Anxiety: 100 mg, three times daily8

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52 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils Adverse Side Effects In clinical studies using the above dosages, some patients experience gastrointestinal upset (i.e. nausea) or, less often, headache, sleepiness, muscle pain, or anxiety.1-13 Drug-Nutrient Interactions and Contraindications 5-HTP should not be taken with other antidepressants, weight control drugs, other serotonin-modifying substances, or agents known to cause liver damage. Individuals with liver disease or scleroderma should also avoid 5-HTP.2,6,14 Herb-Nutrient Interactions St. Johnâ&#x20AC;&#x2122;s Wort 5-HTP may potentiate the effect of St. Johnâ&#x20AC;&#x2122;s Wort on brain neurotransmitters and vice versa. These supplements should not be taken concurrently.17 Toxicity Animal studies have shown that high doses of 5-HTP can cause muscle jerks in guinea pigs, and when injected has caused kidney damage in rats. To date, these problems and serotonin syndrome have not been reported in humans, but the potential for serotonin syndrome to develop under certain circumstances (i.e. in combination with antidepressant drugs) is very plausible.6,15,16

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

Van Hiele JJ. L-5 hydroxytryptophan in depression: the first substitution therapy in psychiatry? Neuropsychobiology 1980;6:230-40. Byerley WF, Judd LL, Reimherr FW, Grosser BI. 5-hydroxytryptophan: A review of its antidepressant efficacy and adverse effects. J Clin Psychopharmacol 1987;7:127-37 [review]. Van Praaf HM. Management of depression with serotonin precursors. Biol Psychiatry 1981;16:291-310. Poldinger W, Calanchini B, Schwarz W. A functional-dimensional approach to depression: serotonin deficiency as a target syndrome in a comparison of 5-hydroxytryptophan and fluvoxamine. Psychopathology 1991;24:53-81. Praag HM, Lemus C. Monoamine precursors in the treatment of psychiatric disorders. In: Wurtman RJ, Wurtman JJ editors. Nutrition and the Brain. New York: Raven Press: 1986. Vol 7. p. 89-139 Martin TG. Serotonin syndrome. Ann Everg Med 1996;28:520-6. Soulairac A, Lambinet H. Etudes cliniques de liaction du precurseurs de la serotinine le L-5-hydroxy-tryptophane, sur les troubles du sommell. Schweiz Bundaschau Med (Praxis). 1998;77(34a):19-23. Caruso I, Sarzi Puttini P, Cazzola M, Azzolini V. Double-blind study of 5-hydroxytyptophan versus placebo in the treatment of primary fibromyalgia syndrome. J Int Med Res 1990;18:201-9. De Benedittis G, Massei R. 5-HT precursors in migraine prophylaxis: a double-blind cross-over study with L-5 hydroxytryptophan versus placebo. Clin J Pain 1986;3:123-9. Titus F, Davalos A, Alom J, Codina A. 5-hydroxytryptophan versus methysergide in the prophylaxis of magraine. Eur Neurol 1986;25:327-9. Maissen CP, Ludin HP. Comparison of the effect of 5-hydroxytryptophan and propranoiol in the interval treatment of migraine. Schweiz. Med Wochen 1991;121:1585-90. Matlew WT. 5-hydroxytryptophan in the prophylaxis of magraine. Headache 1978;18:111-3. De Giorgis G, Miletto R, Iannuccelli M, Camuffo M, Scerni S. Headache in association with sleep disorders in children. A Psychodiagnostic evalutation and controlled clinical study with L-5HTP versus placebo. Drugs Exptl Clin Res 1987;13:425-33. Sternberg EM, Van Woert MH, Young SN, Magnussen I, Baker H, Gauthier S et al. Development of a soleroderma-like illness during therapy with L-5-hydroxytryptophan and carbidoba. New Engl J Med 1980;303:782-7.

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53 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 15. Hagan JJ, Hatcher JP, Slade PD. The role of 5-HTID and 5-HTIA receptors in mediating 5-hydroxytryptophan induced myoclonic jerks in guinea pigs. Eur J Pharmacol 1995;294:743-51. 16. Hirai M, Nakajima T. Biochemical studies on the mechanism of difference in the renal toxicity of 5-hydroxy-L-Tryptophan between Sprague Dawley and Wistar rats. J Biochem (Tokyo) 1979;86:907-13. 17. Kahn RS, Westenberg HG. L-5-hydroxytryptophan in the treatment of anxiety disorders. J Affect Disord 1985;8(2):197-200.

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54 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Indole-3-Carbinol General Features Indole-3-Carbinol has been shown to be one of the major anti-cancer substances found in cruciferous vegetables. Frequent consumption of these vegetables (broccoli, cauliflower, cabbage, Brussels sprouts, kale and bok choy) is associated with reduced risk of cancer in many human and animal studies. 1-8 Indole -3-Carbinol is a member of the class of sulfur-containing chemicals called glucosinolates (previously called thioglucosides).9 It is formed by the action of myrosinase enzyme acting on the parent compound glucosinolates, whenever cruciferous vegetables are crushed (e.g., chewing) or cooked.10,11 Indole-3-Carbinol and other glucosinolates (e.g., other indoles and isothiocyanates such as sulforphane) are antioxidants and potent stimulators of Phase I and Phase II detoxification enzymes in the liver and intestinal epithelial cells.12,13,14 In this capacity it helps the body more easily eliminate toxic compounds, including many carcinogens.15,16,17 Indole-3-Carbinol also acts as a phytoestrogen (plant-based estrogens) and, in this capacity, can bind to estrogen receptors in the body, reducing the ability of stronger estrogens from over stimulating reproductive tissues such as the breast, cervix, uterus, and in males, the prostate gland. In this regard, the ingestion of Indole-3-Carbinol is highly associated with the prevention of reproductive organ cancers in women and men. 3,4,8 It also promotes the metabolism of certain endogenous estrogens (estrone) into a safer, less cancer-promoting form (2OH-estrone), further helping to reduce risk of reproductive organ cancers, according to modern wisdom. 18,19,20 Thus far, human studies have used a dose of 300-400 mg per day to demonstrate this outcome.33

Clinical Application and Mechanism of Action 1. Prevention of Female Reproductive Cancers In experimental animal testing with mice and rats, Indole-3-Carbinol and brussels sprouts, respectively, have demonstrated an ability to reduce mammary cancer incidence in animals exposed to carcinogens that are known to promote mammary cancer in these species.21,22 In human studies, the ingestion of Indole-3-Carbinol has been shown to increase the metabolism of estrone hormone to 2-hydroxyestrone rather than the16-alpha-hydroxyestrone metabolite. Studies indicate that 16-alpha-hydroxyestrone is associated with an increased risk of breast cancer in women and, conversely, 2-hydroxyestrone is associated with a reduction in breast cancer risk. Thus, Indole-3Carbinol influences the bodyâ&#x20AC;&#x2122;s enzyme systems in a fashion that favorably influences the 2-hydroxyestrone to 16alpha-hydroxyestrone ratio, helping to reduce risk of breast cancer.20,21,23,24 A large prospective study involving 5,000 Italian women and a second study of patients with either benign or malignant breast lesions highlighted the ability of a higher 2/16 hydroxyestrone ratio to predict which women were less prone to breast cancer development. a. Breast Cancer: Epidemiological studies and experimental evidence strongly suggests that Indole-3-Carbinol may reduce breast cancer risk through the above-cited mechanisms.25,26,27,28 To date there are no human intervention trials that have tested Indole-3-Carbinol as a preventive or therapeutic agent against breast cancer. b. Cervical Cancer: In a 12-week double-blind study, 8 of 17 patients with early-stage cervical cancer given 200 or 400 mg of Indole-3-Carbinol per day experienced a complete reversal of their condition. 29 Animal studies have also shown that indole-3-carbinol can help prevent cervical cancer in the presence of various carcinogens.30,31 2. Respiratory Tract Papillomas Indole-3-Carbinol supplementation reduced or halted the formation of papillomas (precancerous lesions) in 12 out of 18 patients with recurrent respiratory tract papillomas in a small trial.32

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55 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 3. Prostate Cancer In animal studies, the ingestion of Indole-3-Carbinol has been shown to inhibit the growth of PC-3-type human prostate cancer cells by arresting their cell division cycle and by promoting apoptosis (programmed cell death).8 A Seattle study of men living in that city indicated that men consuming three or more servings per week of cruciferous vegetables had a risk of prostate cancer that was 50% lower than men consuming fewer servings of these vegetables, after controlling for other confounding variables.33 To date there no human intervention trials have tested Indole-3-Carbinol as a preventive or therapeutic agent against prostate cancer.

Dosage and Standardized Grade 1. General Health Maintenance: 25-100 mg per day34 2. Therapeutic Applications: 300-400 mg per day23

Adverse Side Effects, Toxicity and Contraindications At doses of 800 mg per day, Indole-3-Carbinol has caused dizziness and unsteady gait (signs of nervous system toxicity) in humans and in animal studies. As well, Indole-3-Carbinol is a powerful stimulator of phase I detoxification enzymes, and as such, it may speed up the detoxification of certain medications, changing their required dosage. However, one challenge study of this kind revealed that Indole-3-Carbinol intake did not interfere with oral contraceptive medications.33 Nevertheless, health practitioners and patients should monitor their response to Indole-3Carbinol supplementation, if taken at therapeutic doses concurrently with other drugs. According to animal studies, this appears to be especially true in regards to the following medications:  testosterone replacement therapy  oral contraceptives  hormone replacement therapy  anti-seizure medications  immune-suppressant and anti-viral drugs  digoxin33

Drug-Nutrient Interactions 1. Antacids and Heartburn medications (H-2 antagonist drugs ): By reducing stomach acidity these drugs reduce the absorption of indole-3-carbinol. Therefore, they should not be taken at the same time of day or at the same meal.33 2. More Rapid Detoxification Of Other Drugs: As stated above, Indole-3-Carbinol may speed up the detoxification of any number of drugs due to its stimulation affect on phase I detoxification centers. Thus, patient monitoring is required with Indole-3-Carbinol supplementation at the therapeutic doses mentioned previously (300-400 mg per day).33

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56 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

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

Hecht SS. Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism. J Nutr, 1999;129:7688-94S Verhoeven DT, Goldbohm RA, van Poppel G, et al. A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chem Biol Interact, 1997;103:79-129 [review] Verhoeven DT, Goldbohm RA, van Poppel, G., et al. Epidemiological studies on brassica vegetables and cancer risk. Cancer Epidemiol Biomarkers Prev, 1996;5:733-48 [review] Talaley P, Zhang Y. Chemoprotection against cancer by isothiocyanates and glucosinolates. Biochem Soc Trans, 1996;24:806-10 Maheo L, Morel F, Langouet S, et al. Inhibition of cytochromes P-450 and induction of glutathione S-transferases by sulforaphane in primary human and rat hepatocytes. Cancer Res, 1997;57:3649-52 Barcelo S, Gardiner JM, Gescher A. Chipman JK. CYP2E1-mediated mechanism of anti-genotoxicity of the broccoli constituent sulforaphane. Carcinogenesis, 1996;17:277-82 Plumb GW, Lambert N, Chambers SJ, et al. Are whole extracts and purified glucosinolates from cruciferous vegetables antioxidants? Free Radic Res, 1996;25:75-86 Dhinmi SR, Li Y, Upadhyay S, Koppolu PK, Sarkar FH. Indole-3-carbinol (I3C) â&#x20AC;&#x201C; induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene, 24May2001;20(23):2927-36 Stoewsand GS. Bioactive organosulfur phytochemicals in Brassica oleracea vegetables â&#x20AC;&#x201C; a review. Food Chem Toxicol, 1995;33:537-43 Broadbent TA, Broadbent HS. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl) Indole. [Part I]. Curr Med Chem, 1998;5:337-52 Broadbent TA, Broadbent HS. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl) Indole. [Part II]. Curr Med Chem, 1998;5:469-91 Broadbent TA, Broadbent HS. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl) Indole. [Part I]. Curr Med Chem, 1998;5:337-52 Broadbent TA, Broadbent HS. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl) Indole. [Part II]. Curr Med Chem, 1998;5:469-91 Beecher CW. Cancer preventive properties of varieties of Brassica oleracea: a review. Am J Clin Nutr, May1994;59(5suppl):1166S-70S Loub WD, et al. Aryl hydrocarbon hydroxylase induction in rat tissues by naturally occurring indoles of cruciferous plants. JNCI, 1975;54:985-8 McDanell R, et al. Differential induction of mixed-function oxidase (MFO) activity in rat liver and intestine by diets containing processed cabbage. Food chem. Toxicol, 1987;25:363-8

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57 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 17. Hendrich S. Bjeldanes, LF. Effects of dietary cabbage, Brussels sprouts, Ilicium verum, Schizandra chinensis and alfa alfa on the benzopyrene metabolic enzyme system in mouse liver. Food Chem Toxicol, 1983;21:479-86 18. Osborne MP, et al. Increase in the extent of estradiol 16 alpha-hydroxylation in human breast tissue: A potential biomarker of breast cancer risk. JNCI, 1993;85:1917-20 19. Michnovicz JJ. Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. Int J Obes Relat Metab Disord, 1998;22:227-9 20. Bradlow HL, Michnovicz JJ, Halper M., et al. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev, 1994;3:591-5 21. Tiwari RK., et al. Selective responsiveness of human breast cancer cells to indole-3-carbinol, a chemopreventive agent. JNCI, 1994;86(2):126-31 22. Stoewsand GS, et al. Protective effects of dietary Brussels sprouts against mammary carcinogenesis in Sprague-Dawley rats. Cancer Lett, 1988;39:199-207 23. Michnovicz JJ, Bradlow, H.L. (1990) Induction of estradiol metabolism by dietary indole-3-carbinol in humans. JNCI, 1990;82:947-9 24. Bradfield CA, Bjeldanes LF. Effect of dietary indole-3 carbinol on intestinal and hepatic monooxygenase, gluatathione-S-Transferase and epoxide hydrolase activities in rat. Food Chem Toxicol, 1984;22:977-82 25. Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Indole-3-carbinol. A novel approach to breast cancer prevention. Ann NY Acad Sci, 1999;889:204-13 26. Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Indole-3-carbinol. A novel approach to breast cancer prevention. Ann NY Acad Sci, 1995;768:180-200 27. Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent. Ann NY Acad Sci, 1999;889:204-13 28. Meng Q, Qi M, Chen D.X. et al. Suppression of breast cancer invasion and migration by indole-3-carbinol: associated with up-regulation of BRCA1 and E-cadherin/catenin complexes. J Mol Med, 2000;78:155-65 29. Bell MC, Crowley-Nowick P, Bradlow HL, et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol, 2000:78;123-9 30. Yuan F, Chen DZ, Liu K, et al. Anti-estrogenic activities of indole-3-carbinol in cervical cells. Implication for prevention of cervical cancer. Anticancer Res, 1999;19(3A):1673-80 31. Jin L, Qi M, Chen DZ, et al. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res, 1999;59:3991-7 32. Rosen CA, Woodson GE, Thompson JW, et al. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg, 1998;118:810-5 33. Zeligs M. The Cruciferous Choice. Townsend Letter for Doctors & Patients. Aug/Sept 2001, (217/218):p47-48 34. Sabinsa Corporation. Indole-3-Carbinol Product Manual (www.sabinsa.com)

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58 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Lipoic Acid (Thioctic Acid) General Features Lipoic Acid is a sulfur-containing, vitamin like substance. Although the body manufactures Lipoic Acid, under certain circumstances, supplementation has been shown to be beneficial. Lipoic Acid functions as a co-enzyme (with vitamin B1 and niacin) in the conversion of pyruvate to acetyl co-enzyme A, thus it is essential for aerobic energy metabolism.1 Lipoic Acid is also a water soluble and fat soluble antioxidant.2 With coenzyme Q10 and vitamin E, it appears to protect mitochondrial DNA from the damaging effects of oxygen-free radicals; providing a potential anti-aging effect in preserving mitochondrial DNA structure and function.3

Supplementation Studies 1. Diabetic Neuropathy In Germany Lipoic Acid is approved as a drug for the treatment of diabetic neuropathy. Its therapeutic effects appear to be mediated through its antioxidant effects. However, it has also been shown to improve blood glucose metabolism, reduce glycosylation of amino acids (i.e. hemoglobin glycosylation), improve blood flow to peripheral nerves and stimulate regeneration of nerve fibers in diabetic subjects. Lipoic Acid enhances insulin sensitivity in diabetics, which explains its beneficial effects on blood glucose regulation and reduced blood amino acid glycosylation. For diabetic neuropathy studies reveal that combining 600 mg of Lipoic Acid daily, with 100 mcg of selenium, or 1,200 I.U. of vitamin E, produced significant results over the placebo.4-9 2. AIDS Lipoic Acid supplementation in AIDS patients has been shown to increase plasma ascorbic acid, glutathione, and T-helper lymphocytes and T-helper/suppressor cell ratio in a significant number of patients. All of these factors are important biomarkers in AIDS progression, suggesting that Lipoic Acid supplementation may help slow the progression of HIV and AIDS. The daily dosage was 1,500 mg, three times daily. Studies indicate that Lipoic Acid inhibits HIV replication by reducing the activity of reverse transcriptase (the enzyme responsible for manufacturing the virus from the DNA of lymphocytes) and inhibits the activation in HIV that leads to viral replication.10,11,12 3. Other Applications Lipoic Acid supplementation may be considered in liver cirrhosis and other liver damage, heart disease, cataracts, heavy metal toxicity and support for detoxification and antioxidant functions.

Dosage 1. Diabetic Neuropathy: 300-600 mg daily1,3 2. AIDS (HIV): 1,500 mg three times daily 3. General Support: 20 â&#x20AC;&#x201C; 50 mg daily

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59 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Toxicity and Contraindications Lipoic Acid is a very safe supplement with no significant adverse effects reported in over three decades of use in diabetics. Animal studies demonstrate low toxicity.

Drug-Nutrient Interactions As Lipoic Acid supplementation increases insulin sensitivity, insulin-dependent diabetics will need to adjust their insulin dosage with Lipoic Acid supplementation. Therefore, these patients should not use Lipoic Acid supplementation without consulting their physician or diabetic specialist. In non-insulin dependent diabetics, the dosage of oral hypoglycemic drugs may also need to be adjusted with Lipoic Acid supplementation.1

1. 2.

Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 343-6. Kagan VE, Shvedova A, Serbinova E, Khan S, Swanson C, Powell R, et al. Dihydrolipoic acid-A universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals. Biochem Pharmacol 1992;44:1637-49. 3. Barbiroli B, Medori R, Tritschler HJ, Klopstock T, Seibel P, Reichmann H, et al. Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo 31P-MRS in a patient with mitochondrial cytopathy. J Neurol. 1995;242:472-7. 4. Packer L. Antioxidant properties of lipoic acid and its therapeutic effects in prevention of diabetes complications and cataracts. Annals NY Acad Sci 1994;738:257-64. 5. Kahler W, Kuklinski B, Ruhlmann C, Plotz C. Diabetes mellitus: a free radical-associated disease. Results of adjuvant antioxidant supplementation. Z Gesamte Inn Med 1993;48(5):223-32. 6. Nagamatsu M, Nickander KK, Schmelzer JD. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetic Care 1995;18:1160-7. 7. Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, et al. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneim Forsch 1995;45(8):872-4. 8. Kawabata T, Packer L. Alpha-lipoate can protect against glycation of serum albumin, but not low density lipoprotein. Biochem Biophys Res Comm 1994;203,99-104. 9. Suzuki YJ, Tsuchiya M, Packer L. Lipoate prevents glucose-induced protein modifications. Free Rad Res Comms 1992;17:211-7. 10. Fuchs J, Schofer H, Milbradt R, et al. Studies on lipoate effect on blood redox state in human immunodeficiency virus infected patients. Arzneim Forsch 1993;43:1359-1362. 11. Baur A, Harrer T, Peukert M. Alpha-lipoic acid is an effective inhibitor of human immuno-deficiency virus (HIV-1) replication Klin Wochenschr 1991;69:722-4. 12. Suzuki YJ, Aggarwal BB, Packer L. Alpha-lipoic acid is a potent inhibitor of NF-kB activation in human T cells. Biochem Biophys Res Comm 1992;189:1709-15.

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Comment [c30]: Could not find other authors.

60 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

L-Lysine General Features Lysine is an essential amino acid, which implies that it cannot be synthesized by the body. All essential amino acids must be supplied by the diet or supplements in order to avoid a deficiency state. 1 Lysine deficiency is rare in developed countries. At supplemental levels of intake lysine interferes with replication of herpes viruses. A review of the research trials investigating the benefits of lysine supplementation for people with cold sores (herpes type I) or genital herpes (herpes type II) generally supports its use for these conditions.1,2 Herpes viruses tend to extract the amino acid arginine from the bloodstream in order to synthesize proteins they require. L-Lysine appears to block the uptake of arginine or substitutes for it, inhibiting the herpes virus from accessing the arginine it requires to thrive.2,3 Foods high in arginine content include chocolate, peanuts, seeds, almonds and other nuts. It is though that these foods should be restricted in patients with herpes viruses to help minimize or contain outbreaks. Foods high in lysine include most vegetables, peas, beans, fish, turkey and chicken.4

Supplementation Studies and Clinical Applications 1. Herpes I and II At the first sign of an outbreak, 1,000 mg L-Lysine, three times daily has been shown to help contain the episode. Taking 1,000-3,000 mg per day may also help to reduce the number of outbreaks as a prophylactic measure.5 2. Growth Hormones L-lysine supplementation has been shown to increase the release of growth hormones and thus may be used to support lean mass and an anti-aging intervention by some individuals.7 Dosage Ranges 1. Herpes Simplex: 1,000-3,000 mg per day is the usual daily dosage in the treatment or prevention of herpes I and II. 2. Growth Hormone Release: 1,000 â&#x20AC;&#x201C; 2,000 mg taken just prior to bedtime, usually in conjunction with 1,000 â&#x20AC;&#x201C; 2,000 mg of arginine pyroglutamate.7

Adverse Side Effects and Toxicity At supplemental amounts (1,000-3,000 mg per day) no consistent adverse effects have been reported in humans. Abdominal cramps and transient diarrhea have been reported at doses of 15-40 gms per day.1 Note that during a herpes outbreak some patients my take more than 10 gm per day to block the replication of the virus.

Drug-Nutrient Interactions There are no well known drug interactions with L-Lysine.6

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61 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

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

Flodin NW. The metabolic roles, pharmacology and toxicology of lysine. J Am Coll Nutr 1997;16:7-21. Griffith R, DeLong D, Nelson J. Relation of arginine-lysine antagonism to herpes simplex growth in tissue culture. Chemotherapy 1981;27:209-13. DiGiovanna JJ, Blank H. Failure of lysine in frequently recurrent herpes simplex infection. Arch Dermatology 1984;120:48-51. Murray M, Pizzorno J. Encyclopedia of Natural Medicine. Revised 2nd Edition. Rocklin, CA: Prima Publishing, 1998. p. 521-2. Griffith RS, Walsh DE, Myrmel KH. Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis. Dermatoliga 1987;175:183-90. Healthnotes online. Healthnotes 2000, Inc: Lysine. Klatz R. Grow young with HGH. New York: Harper Perrenial Publishers; 1997. p. 204-5.

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62 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Malic Acid General Features Malic Acid is synthesized in humans as one of the steps in the Krebâ&#x20AC;&#x2122;s cycle during the production of ATP, which is the bodyâ&#x20AC;&#x2122;s primary source of energy. 1 It occurs in high concentrations in apples and is often referred to as apple acid. In food processing it is used to acidify wines, acid drinks, fruit juices, soda water and various soft drinks. Malic Acid is also used in cosmetic products to adjust the pH of the product and to act as a moisturizing agent, often in the form of sodium malate. 2

Clinical Application and Mechanism of Action 1. Fibromyalgia - Malic Acid supplementation in combination with magnesium supplementation has been shown to improve fibromyalgia in a six-month, double-blind, cross-over trial, involving 24 fibromyalgia patients. In this study, the treatment group demonstrated a significant reduction in the severity of pain and tenderness and in some psychological symptoms associated with their condition, during the period they ingested 1200-2400 mg of Malic Acid and 300-600 mg of magnesium per day. During the cross-over period, when placed on the placebo, their muscle pain scores rose from 6.8 to 21.5 within two days, in the six patients comprising this sub-group. However, in a shorter trial of only four weeks, the combination of Malic Acid (1200 mg) and magnesium (300 mg) was not effective in reducing pain in a double-blind, cross-over trial of patients with fibromyalgia. This may indicate that a longer period of treatment is required to realize improvement in these cases. 3,4 2. Chronic Fatigue Syndrome - It is speculated that Malic Acid supplementation in combination with magnesium supplementation may be helpful in the treatment of chronic fatigue syndrome. There is one published report to support this contention, but better controlled studies are required to substantiate this application. However, chronic fatigue syndrome is similar in nature to fibromyalgia, thus practitioners may wish to utilize this intervention on a therapeutic trial basis. 5

Dosage and Standardized Grade Fibromyalgia (and Chronic Fatigue Syndrome) - Malic Acid, 600 mg, twice per day and magnesium, 150 mg, twice per day (up to 2400 mg of Malic Acid and 600 mg of magnesium have been used safely). 3,4

Adverse Side Effects, Toxicity and Contraindications Current research does not indicate any adverse side effects from the use of Malic Acid at the above-cited levels of intake. 6 Drug-Nutrient Interactions At present there are no known drug-nutrient interactions with Malic Acid. 6

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63 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

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

Baynes J, dominiczak M. Medical Biochemistry. New York: Mosby, 1999:182-3 Fiume Z. Final report on the safety assessment of Malic Acid and Sodium Malate. Int J Toxicol 2001;20(Suppl1):47-55 Russell IJ, Michalek JE, Flechas JD, Abraham GE. Treatment of fibromyalgia syndrome with Super Malic: a randomized, double blind, placebo controlled, crossover pilot study. J Rheyumatol, May1995;22(5):953-8 Abraham GE, Flechas JD. Hypothesis: Management of fibromyalgia rationale for the use of magnesium and malic acid. J Nutr Med 1992;3:49,59 Anonymous. A follow-up on malic acid: CFIDS Buyers Bluc Health Wathc. Spring, 1993 Healthnotes, Inc. 2001. Malic acid:www.puritan.com

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64 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Melatonin General Feature Melatonin is a molecule that has been found in every animal and plant studied to date, from human beings to the most primitive one-celled algae that evolved more than three billion years ago. In each organism, Melatonin’s molecular structure is identical. This sameness is a rare occurrence in biology. In all the life forms studied, Melatonin has been produced in the same circadian (daily secretion pattern) rhythm, with higher levels produced at night than during the daytime. In humans, Melatonin is produced and secreted by the pineal gland in the brain. It is synthesized from serotonin, which itself is synthesized from 5-hydroxytryptophan and tryptophan. In the human body Melatonin acts as a hormone, neurotransmitter, antioxidant and immune system modulator. It is best known for its ability to induce sleep and elevate mood. Humans produce five to ten times more Melatonin at night than during the day, a circadian rhythm found in animals as well. Peak amounts occur around two or three o’clock in the morning. After puberty the body’s production of Melatonin declines. By age 40 humans produce approximately 60 percent less Melatonin than a 10 year old and by age 70 or 80 Melatonin levels may be undectable. 1 With respect to its antioxidant properties, Melatonin is unique in that it is both a water-soluble antioxidant and a fatsoluble antioxidant. Some studies suggest that as an antioxidant it is twice as effective as Vitamin E, five times as efficient as glutathione, and five hundred times more effective than the synthetic DMSO. However, Melatonin is produced in picograms (a trillionth of a gram – the smallest amount of any hormone), whereas Vitamin E, and other antioxidants, are present in much higher concentrations.2

Supplementation Studies and Clinical Applications 1. Insomnia Low Melatonin secretion at night which commonly accompanies aging, can be a cause of insomnia. Several double-blind trails show that Melatonin supplementation can be useful in the treatment of insomnia. Taken within one hour of bedtime, Melatonin has been shown to shorten the time needed to fall asleep, reduce the number of night awakenings, and improve sleep quality. Low Melatonin levels are an extremely common cause of insomnia in the elderly, who manufacture 90-99 percent less Melatonin than a ten-year old.3-10 2. Jet Lag Several double-blind studies demonstrate that Melatonin is very effective in relieving jet lag. The best approach appears to be taking Melatonin in the first evening after arriving at the new destination (where there is a time zone change). Shift workers may also take advantage of this strategy to reset the body internal wake-sleep cycle.11-16 3. Other Considerations As Melatonin is also an antioxidant, an immune system modulator and a core temperature regulator it is being tested for various other health applications:

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Comment [c31]: Melatonin is capitalized as per instructions of Arlene.

65 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils a. Tension and cluster headaches - Some preliminary, double-blind studies suggest that Melatonin supplementation may help in certain cases (1-3 mg at night).17,18 This affect has been attributed to Melatoninâ&#x20AC;&#x2122;s ability to prevent a rise in core temperature, which is linked to cluster headaches.35,36 b. Sarcoidosis - Preliminary evidence has shown improvement in patients with sarcoidosis (20 mg at night).19 c. Adjunctive Cancer Treatment - Early trials indicate that Melatonin supplementation, as an adjunct to cancer treatment may help inhibit the progression of breast cancer, reduce the PSA levels in prostate cancer patients and improve disease-free survival in melanoma patients, as well as patients with brain and lung cancer (20 mg at night). Of course, more research is required before any conclusive statements can be made about this application.20-27 In a study of cancer patients with solid tumors in various organs the intake of Melatonin (40 mg per day) enhanced the effectiveness of interleukin-2 therapy by enhancing its anti-tumor immune effect or by increasing susceptibility of cancer cells to the cytolysis by cytotoxic lymphocytes.37 d. Immune System and AIDS - Maestroni and Conti demonstrated in 1995 that T-helper-2 lymphocytes possess Melatonin receptors. When Melatonin docks with its receptor on the T-helper cell, a cascade of events is set in motion releasing important signalling agents (cytokines) that strengthen immune function in various ways. For example, natural killer cell production rose by 240 percent in healthy young men taking 20 mg of Melatonin each night for a period of two months. Melatonin may also inhibit viral replication and has been shown to increase T-helper cell numbers and natural killer cell numbers in HIV-infected individuals. Further research is underway to substantiate these findings (20 mg at night).28,29 e. Birth Control/Contraceptive - Very high doses of Melatonin inhibits ovulation in animals and women. A new birth control is now being tested known as B-Oval. It contains no estrogen, but rather high dose Melatonin (75 mg) and 0.3 mg of progestin.30

Dosage Ranges Insomnia and Jet Lag (Shift Workers) - 0.1 mg to 3.0 mg (note 0.1 mg equals 100 mcg), one to two hours before bedtime. It is best to start with a small dose and work up, based upon improved sleep with no awakening and morning drowsiness. N.B. Taking a high dosage of Melatonin (5 â&#x20AC;&#x201C; 75 mg) should only be undertaken with knowledge of a physician, who is able to monitor blood work and other parameters, as these dosages are still experimental and long-term safety is unknown at this time.38

Adverse Side Effects and Toxicity Taking doses that are too high can result in morning grogginess, headaches and/or abdominal cramps. 31,32 Melatonin testing in humans and animals indicate that it is very non-toxic.1,33

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Contraindications and Drug-Nutrient Interactions Some cases of depression can be aggravated by Melatonin supplementation. 34 Some antidepressant drugs stimulate the production of Melatonin and others, such as fluoxetine (Prozac), may lower Melatonin levels. It is probably best at this time not to combine Melatonin with any other drug that targets brain chemistry or neurotransmitter levels. 35,36 A number of drugs have been shown to deplete Melatonin levels. Some of these include aspirin, ibuprofen, betablockers, calcium channel blockers, sleeping pills, tranquillizers, fluoxetine (Prozac), caffeine, steroids and tobacco.1 The clinical significance of this is yet to be determined, in regards to whether or not patients on these substances require Melatonin supplementation to compensate for the depletion of Melatonin (author’s note).

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

Reitar RJ, Robinson J. Melatonin. New York, NY: Bantam Books; 1995. p. 3-30. Shida CS, Castrucci AML, Lamy-Freund MT. High melatonin solubility in aqueous medium. J Pineall Res 1994;16:198-201. Waldhauser F, Saletu B, Trinchard-Lugan I. Sleep laboratory investigations on hypnotic properties of melatonin. Psychopharmacol 1990;100:222-6. Zhdanova IV, Wurtman RJ, Morabito C, Piotrovska VR, Lynch HJ. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther 1995;57:552-8. Dahlitz M, Alverez B, Vignau J, English J, Arendt J, Parkes JD. Delayed sleep phase syndrome response to melatonin. Lancet 1991;337:1121-4. MacFarlane JG, Cleghorn JM, Brown GM, Streiner DL. The effects of exogenous melatonin on the total sleep time and day-time alertness of chronic insomniacs: A preliminary study. Biol Psychiatry 1991;30:371-6. James SP, et al. Melatonin administration in insomnia. Neuropsychopharmacology 1990;3:19-23. Nave R, Peled R, Lavie P. Melatonin improves evening napping. Eur J Pharmacol 1995;275:213-6. Haimov I, Laudon M, Zisapel N, Souroujon M, Nof D, Shlitner A, et al. Sleep disorders and melatonin rhythms elderly people. BMJ 1994;309:167. Hughes RJ, Sack RL, Lewy AJ. The role of melatonin and circadian phase in age-related sleep maintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep 1998;21:52-68. Arendt J, Aldhous M, English J, Marks V, Arendt JH, Marks M, et al. Some effects of jet-lag and their alleviation by melatonin. Ergonomics 1987;30:1379-98. Claustrat B, Brun J, David M, Sassolas G, Chazot G. Melatonin and jet lag: Confirmatory result using a simplified protocol. Biol Psychiatry 1992;32:705-11. Petrie K, Conaglen JV, Thompson L, Chamberlain K. Effect of melatonin on jet lag after long haul flights. Br Med J 1989;298:705-7. Lino A, Silvy S, Condorelli L, Rusconi AC. Melatonin and jet lag: Treatment schedule. Biol Psychiatry 1993;34:587. Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biol Psychiatry 1993;33:526-30. Folkard S, Arendt J, Clark M. Can melatonin improve shift workers’ tolerance of the night shift: Some preliminary findings. Chronobio Intern 1993;10,5:315-20. Nagtegaal JE, Smits MG, Swart AC, Kerkhof GA, van der Meer YG. Melatonin-responsive headache in delayed sleep phase syndrome: Preliminary observations. Headache 1998;38:303-7. Leone M, D’Amico D, Moschiano F, et al. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalagia 1996;16:494-6. Cagnoni ML, Lombardi A, Cerinic MC, Dedola GL, Pignone A. Melatonin for treatment of chronic refractory sarcoidosis [letter]. Lancet 1995;346(4):1229-30. Lissoni P, et al. A randomized study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma. Br J Cancer 1994;69:196-9. Lissoni P, Barni S, Fossati V, Ardizzoia A, Cazzaniga M, Tancini G, et al. A randomized study of neuroimmunotherapy with low-dose subcutaneous interleukin-2 plus melatonin compared to supportive care alone in patients with untreatable matastatic solid tumor. Support Care Cancer 1995;3(3):194-7.

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Comment [c32]: Could not find other authors

Comment [c33]: Could not find the other authors

67 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 22. Neri B, Fiorelli C, Moroni F, Nicita G, Paoletti MC, Ponchieatti R, et al. Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma: A phase II study. Cancer 1994;73(12):3014-9. 23. Lissoni P, Barni S, Meregalli S, Fossati V, Cazzaniga M, Esposti D, et al. Modulation of cancer endocrine therapy by melatonin: A phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer 1995;71(4):8546. 24. Lissoni P, Barni S, Ardizzoia A, Paolorossi F, Crispino S, Tancini G, et al. Randomized study with the pineal hormone melatonin versus supportive care alone in advanced non-small cell lung cancer resistant to a first-line chemotherapy containing cisplatin. Oncology 1992;49:336-9. 25. Lissoni P, Barni S, Cattaneo G, Tancini G, Esposti G, Esposti D, et al. Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 1991;48:448-50. 26. Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni G. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 1994;73:699-701. 27. Lissoni P, Cazzaniga M, Tancini GE, et al. Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone. Eur Urol 1997;31:17881. 28. Maestroni, GJ. T-Helper-2 lympocytes as peripheral target of melatonin signalling. J Pineal Res 1995;18:84-9. 29. Reiter RJ, et al. The role of melatonin in the pathophysiology of oxygen radical damage. In: Advances in Pineal Research. Vol. 8. Moller M, Pevet P, editors. London: John Libbey and Co.; 1994. p. 278. 30. Reitar RJ, Robinson J. Melatonin. New York, NY: Bantam Books; 1995. p. 166-7. 31. Shannon M. Alternative medicines toxicology: A review of selected agents. Clin Toxicol 1999;37:709-3. 32. Guardiola-Lemaitre B. Toxicology of melatonin. J Biol Rythms 1997;12:697-706. 33. Barchas J, et al. Acute Pharmacology of Melatonin. Nature 1967;214:919-220. 34. Rubin RL, et al. Neuroendocrine aspects of primary indogenous depression, XI, Xerum melatonin measures in patients and matched control subjects. Arch Gen Psychiat 1992;49:558-567. 35. Peres MF, Seabra ML, Zukerman E, Tufik S. Cluster headache and melatonin. Lancet 2000;355:147[letter]. 36. Blau JN, Engel HO. A new cluster headache precipitant: increased body heat. Lancet 1999;354:1001-2. 37. Lissoni P, Barni S, Cazzaniga M, Ardizzoia A, Rovelli F, Brivio F, et al. Efficacy of the concomitant administration of the pineal hormone melatonin in cancer immunotherapy with low-dose IL-2 in patients with advanced solid tumors who had progressed on IL-2 alone. Oncology 1994;51(4):344-7. 38. Natural Products Encyclopedia. www.consumerslab.com: Melatonin.

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Comment [c34]: Could not find the other authors

Comment [c35]: Could not find the other authors

Comment [c36]: Could not find the other authors. Comment [c37]: Could not find the other authors.

68 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Modified Citrus Pectin General Features Modified Citrus Pectin is a dietary supplement that has demonstrated an ability to prevent the spread of cancer (metastasis), with strong evidence to support its use in the prevention and/or management of prostate cancer metastasis. Modified Citrus Pectin is a special form of pectin that has been altered in the laboratory by a proprietary process that shortens the length of pectin’s polysaccharide chain. This results in a lower molecular weight, enabling the molecule to be absorbed through the intestinal wall into the bloodstream. By contrast, pectin itself cannot be absorbed from the intestinal tract into the bloodstream and thus, is primarily categorized as a type of water-soluble fiber with a proven ability to lower cholesterol and provide other health benefits via its actions in the intestinal tract. Pectin is found in the peel and pulp of citrus fruits such as lemons, grapefruits, oranges and tangerines. Its long chain of monosaccharides has numerous branches with important binding capabilities, which play a key role in pectin’s unique anti-metastatic attributes. Therefore, researchers were interested in manipulating pectin’s structure is such a way as to allow it to be absorbed into the bloodstream, while maintaining its ability to bind to carbohydrate-binding proteins (glycoproteins) on the surface of metastatic cancer cells, blocking their ability to invade adjacent tissue, and inhibiting their proliferation and colonization into new tumor masses. As explained below, Modified Citrus Pectin does not prevent the development of cancer (cancer initiation), but rather appears to play an important role in preventing the spread of cancer to other tissues (metastasis), which usually is the manner in which cancer death occurs.

Principle Active Constituents The laboratory modification of citrus pectin to Modified Citrus Pectin yields a galactose-rich pectin product with a lower molecular weight than citrus pectin in its native (original) form. This structural modification allows Modified Citrus Pectin to be absorbed from the intestinal tract into the bloodstream, and exert an anti-metastatic effect on cancer cells, which contain certain carbohydrate-binding proteins (galectins) on their cell surface.

Clinical Application and Mechanism of Action 1. Preventing the Spread of Cancer (Anti-metastatic) One of the dominant carbohydrates contained within Modified Citrus Pectin is galactose. Galactose has a strong affinity for binding to the surface of metastatic cancer cells, which express a particular cell surface receptor known as galectin-3 (a galactoside-binding lectin). In turn, the binding of Modified Citrus Pectin to the galectin-3 receptor on metastatic cancer cells creates a type of galectin-3 blockade. With the galectin-3 receptor blocked in this fashion, cancer cells are less able to adhere to other healthy tissues and cells, essentially inhibiting cancer cells from invading and spreading to new areas and tissues in the body (anti-metastatic effect). As well, the blockade of the galectin-3 receptor prevents cancer cells from adhering to each other, discouraging their ability to form colonies (tumor mass). If cancer cells are deprived of their own adhesive ability, they fail to thrive and can be more easily destroyed by the body’s immune system. Thus, Modified Citrus Pectin has been shown to attach to galectin-3 receptors on metastatic cancer cells, preventing their clustering and colonization into a larger tumor mass and blocking their ability to spread to other tissues. Interestingly, non-metastatic cancer cells do not have high levels of galectins on their cell surface. Thus, it appears that these galectins are essential for the spread of cancer (metastasis) to a very significant degree. Research into this area, in fact, confirms that galectin-3 receptors play a very pivotal role in the metastasis of cancer in the body. Galectins on the surface of cancer cells are known for their carbohydrate-binding abilities,

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69 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils playing an important role in cellular interactions during the metastatic process. In short, galectin-3 receptors bind to the galactose molecules on neighboring cancer cells, as well as to the other sugars and monosaccharides on the surface of healthy cells. Upon binding to other cancer cells they encourage the development of a larger tumor mass (colonization) and upon binding to healthy cells they are able to invade these tissues and propagate further spread of the cancer. In essence, Modified Citrus Pectin denies metastatic cancer cells of the opportunity of attaching to other cancer cells and healthy cells, by binding to and fully saturating all of their galectin-3 cell surface receptors. The importance of this mechanism of action is highlighted by the fact that many human cancer cells express galectins on their cell surface, including carcinoma of the prostate, breast, colon, and larynx, as well as lymphoma, melanoma and glioblastoma. Human studies of the colon, stomach and thyroid cancers have also shown that the amount of galectin produced increases proportionally as the cancer progresses from its early to advanced stages. Higher galectin levels encourage greater adhesion of cancer cells to each other, and also facilitates the process of binding to non-cancerous cells at distant sites within the body.1,2,3,4,5,6 There is also evidence to show that Modified Citrus Pectin may augment the immune response in cancer by enhancing cytotoxicity of CD3+ T-cells and natural killer cells, while also mediating increased monocyte cytotoxicity. These effects have been shown to be due to the presence of rhamnogalacturonan, another constituent of Modified Citrus Pectin.1 A significant number of animal trials have revealed that Modified Citrus Pectin inhibits metastasis of melanoma cancer in mice, prostate cancer in rats 1,2,3 with other in vitro studies showing similar effects for cancer of the breast and larynx.1 Human Cancer Studies - A pilot study involving prostate cancer patients who failed first-line androgen-deprivation therapy, were in relapse after radical prostatectomy, external beam radiation therapy or cryosurgery, and were either untreated or off intermittent hormone blockade, demonstrated that supplementation with 15 gms per day of Modified Citrus Pectin (5 gms, three times per day) increased the length of the PSA doubling time by 30% in 4 of 7 patients, one patient had a partial response, one patient had stable disease and one patient did not respond. The researchers conclude that Modified Citrus Pectin appears to slow the PSA doubling time in prostate cancer patients with low levels of PSA, and that all patients were still alive three years after the official end of the study. This research abstract of this study was presented at the International Conference on Diet and Prevention of Cancer; May 28-June 2, 1999, Tampere, Finland.1 As reported by PM Kidd, Ph.D., Modified Citrus Pectinâ&#x20AC;&#x2122;s apparent safety and proven anti-metastatic action, and the lack of proven therapies against metastasis would justify its inclusion into comprehensive orthomolecular anticancer regimes.2,6 2. Reversal of Atherosclerosis and Heavy Metal Chelation In its native form citrus pectin is a water-soluble fiber that is known to bind to cholesterol and bile acids in the intestinal tract and block their absorption into the bloodstream. Bile acids are a building block of cholesterol in the body, thus pectin fiber is known to help reduce high blood cholesterol by inhibiting the absorption of both dietary cholesterol and bile acids. Pectin fiber also binds to certain heavy metals (lead, aluminum, cadmium) in the intestinal tract and helps to block their absorption into the bloodstream. As Modified Citrus Pectin still retains much of the properties of pectin fiber (with the exception that it can be absorbed into the bloodstream and pectin fiber cannot), Modified Citrus Pectin appears to be able to pull cholesterol out of the artery wall in places where it was previously deposited. This effect helps to open up the artery, allowing improved blood flow and reducing risk of heart disease and stroke. Modified Citrus Pectin has also been shown to act as chelating agent in the bloodstream by pulling out heavy metals that were previously deposited due to environmental exposures and heavy metals entering the body from contaminated food and water. Modified Citrus Pectin is currently under investigation to see how effectively it can perform these functions.1,7

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Comment [U38]: Spelling? Prostatectomy? Yes , prostatectomy is correct

70 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Dosage and Standardized Grade 1. To Help Prevent Cancer Metastasis - Typically 5 gms, three times per day. Dilute Modified Citrus Pectin powder in favorite beverage. Up to 30 gms per day may be taken safely. It is also available in capsules and tablets.1,8 2. Cholesterol Lowering - 5 gms, three times per day 1,7

Adverse Side Effects, Toxicity and Contraindications Modified Citrus Pectin is well tolerated, with no reported side effects except for occasional mild gastrointestinal complaints. No toxic effects have been seen in animal or human intervention studies.1Drug-Nutrient Interactions

Drug-Nutrient Interactions There are no well-known drug-nutrient interactions for Modified Citrus Pectin.1

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

Eliaz I. The role of modified citrus pectin in the prevention of cancer metastasis. Townsend Letter for Doctors & Patients, Jul99(192):p64 Kidd PM. A new approach to metastatic cancer prevention: modified citrus pectin (MCP), a unique pectin that blocks cell surface lectins. Alternative medicine Review Jan 1, 1997;1(1):4-10 Inohara H, Raz, A. Effects of natural complex carbohydrate 9citrus pectin) on murine melanoma cell properties related to galextin-3 functions. Glycoconj J 1994 Dec;11(6):527-32 Modified Citris Pectin-Monograph. Altern med Rev Dec2000;5(6):573-5 Pienta KJ, Naik H, Akhtar A, Yamazaki K, Replogle TS, Lehr J, et al. Inhibition of spontaneious metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst 1995 Mar 1;87(5):348-53 Klotter J. Scientific Journal for Natural Therapies: Alternative Medicine Review. Townsend Letter for Doctors & Patients, Jul97(168):p145 Vargo D, Doyle R, Floch MH. Colonic bacterial flora and serum cholesterol: Alterations induced by dietary citrus pectin. Am J Gastroenterol, May1985;80(5):361-4

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71 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 8.

Strum S, Scholz M, McDermed J. Modified citrus pectin slows PSA doubling time: A pilot clinical trial. Presentation: International Conference On Diet and Prevention of Cancer. Tampere, Finland. May 1999

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Methylsulfonyl Methane (MSM) General Features MSM is a naturally occurring sulfur compound, which first arose from a complex series of reactions in the surface waters of the ocean, according our present scientific understanding. 1 One of the products of oceanic phytoplankton production is the compound DMS (dimethylsulfide). DMS is a volatile liquid that easily finds its way into the upper layers of the atmosphere, where it becomes oxidized (photochemically) to form a variety of sulfur compounds, including MSM and DMSO (dimethylsulfoxide). 2 Rain of marine origin is the dominant carrier of atmospheric MSM, which provides much of the sulfur used to make biologically important sulfur –containing nutrients that we derive from plant and animal foods. MSM’s hexavalent sulfur atom is abstracted by living organisms and is primarily used for the biochemical synthesis of many divalent sulfur-containing products. When MSM is broken apart by plants and animals, a portion of the sulfur is used to synthesize sulfur-containing amino acids (methionine and cystine) and another portion is used directly to produce many other biologically important organo-sulfur molecules (e.g., isothiocyanates, allicin, allyl propyl disulfide, diallyl disulfide). 3 Yet, many foods contain unadulterated MSM in its native form that has been absorbed from the soil by plants and passed up the food chain. As such, MSM in its native form is a common nutrient found in small amounts in grains, green vegetables, fish, meat and cow’s milk. 4,5 In this native form MSM is well absorbed and shows up in human urine with an excretion rate ranging from 4–11mg per day. 6 Maintenance levels of MSM in humans has been shown to be as low as 0.5–1.0 mg/kg of body weight per day. 7 Thus, a person weighing 70 kg would require 35–70 mg per day of MSM, which primarily acts as a sulfur donor to repair and restore damaged covalent disulfide bonds and the sulfhydral groups of many enzymes. 8 In this capacity, MSM is considered to be an integral part of maintaining the structural integrity of connective tissues, cartilage, nails, skin, hair, and certain enzymes, hormones, and immunoglobulins. 3 From a therapeutic standpoint, MSM supplementation, at levels that exceed those attainable from food alone, is emerging as a significant intervention in the treatment and prevention of a number of common conditions. Thus, many holistically minded practitioners are showing a high level of interest in MSM supplementation for use as a preventive and therapeutic agent. In regards to stability, MSM is very volatile and considerable amounts are destroyed during modern day food processing. From a historical perspective it has been argued that MSM is a chemical that has been present on earth for a very long time. During the development of higher life forms on this planet three nutrients were always present: water, sodium chloride and MSM. As such, MSM has been shown to be a factor in the diets of our ancestors, which serves to strengthen the notion that MSM may be an overlooked and vital nutrient that is required for health maintenance. 3

Clinical Application and Mechanism of Action 1. Arthritis and Inflammatory Conditions Of The Musculoskeletal System For many years the compound DMSO (dimethylsulfoxide) has been used as a topical agent in veterinary medicine due to its well established anti-inflammatory and analgesic properties. 9 DMSO has also been used by athletes for topical treatment of sports-related injuries involving inflammation of muscles, tendons, ligaments and bursitis problems. 10 Unfortunately, toxicity studies using DMSO revealed that it causes damage to the lens of the eye in animal studies, which was shown to be reversible upon DMSO with drawl. Although this effect has not been demonstrated in humans, The Food and Drug Administration (FDA) was reluctant to approve its use as a

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73 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils therapeutic compound for humans. However, in 1978, DMSO was approved by the FDA for its use as an effective treatment for interstitial cystitis. 11, 12 An additional drawback to the use of DMSO is the strong garlic-breath one is left with after its application. This occurs due to the fact that the body metabolizes much of DMSO to DMS. 10 Approximately 15% of DMSO is metabolized by the body into MSM, which does not produce the garlic-breath effect generated by DMS. 13 Unlike DMSO, MSM can be taken orally for therapeutic purposes. It is very soluble in water and is readily absorbed from the GI tract. 1,14,15,16 Animal studies have demonstrated that MSM has potent anti-inflammatory properties and can help to halt the further destruction of joint cartilage in osteoarthritis. These studies also revealed an improvement in joint mobility. 17,18,27

More recently, a number of human trials have been undertaken to establish the efficacy of MSM in musculoskeletal disorders. Drs. Jacob and Lawrence have conducted controlled studies using MSM in cases of arthritis. Dr. Jacob compared MSM to the over-the-counter, nonsteroidal anti-inflammatory drug, Motrin. Subjects in both groups reported the same degree of pain relief after one month of follow up. 19 Dr. Lawrence compared MSM to a placebo in a double-blind study. Results demonstrated that pain relief was significantly greater in patients given the MSM. Eighty-two percent of the patients given the MSM reported significant pain reduction versus 18% in the placebo group. 20 Both Drs. Jacob and Lawrence indicate that efficacy of MSM is further enhanced by combining it with glucosamine sulfate. 19 Both of these clinicians also use MSM supplementation in the treatment of back pain. For the treatment of a broad spectrum of pain and inflammatory conditions (non-migraine headache, fibromyalgia, tendonitis, carpal-tunnel syndrome) the authors cite figures of up to 70% of patients reporting marked relief of symptoms when MSM was added to the treatment regime. Other conditions that may benefit from MSM supplementation include rheumatoid arthritis, lupus, scleroderma and interstitial cystitis. 19 Dr. Jacobs has used MSM in the treatment of more than 18,000 patients suffering from osteoarthritis and a variety of autoimmune diseases, including rheumatoid arthritis. It is generally accepted that MSM acts to support the structural integrity of joint cartilage, provides an anti-inflammatory effect to some degree and may have mild analgesic properties as well. The combination of these effects is thought to account for the results seen in clinical studies involving arthritic patients and patients presenting with other musculoskeletal and inflammatory conditions. 19 2. Scleroderma When applied topically, MSM may also reduce scarring and provide benefit for people with sclerodermaâ&#x20AC;&#x201D;a disorder that involves hardening of the skin as one clinical aspect.19 3. Interstitial Cystitis Based on the proven benefit of DMSO in the cases, preliminary research has been undertaken with MSM. It appears that MSM may also be of useful in the treatment of interstitial cystitis, but further investigation is necessary to substantiate this application.19

Dosage and Standardized Grade When administered as a single treatment agent a dose as low as 250 mg per day has been shown to be effective. Other studies have used doses as high as 2,000-6,000 mg per day. As indicated by Drs Jacob and Lawrence, it is likely best to use MSM in conjunction with glucosamine sulfate, and possibly other natural anti-inflammatory agents, to assist in the management of arthritis and other musculoskeletal disorders. 19, 20, 21

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74 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Adverse Side Effects, Toxicity and Contraindications There are naturally occurring concentrations of MSM in the human system of approximately 0.2–0.25 ppm, presumably originating from food. 22 The LD-50 in rats has been determined in excess of 20g/kg BM/d, indicating that MSM is an extremely non-toxic compound. 23 Other animal studies of toxicity have provided similar evidence, reporting no or very low toxicity at extremely high doses. 23 In humans, MSM has been established as a safe supplement. At high doses (28 gms per day), some gastric upset or diarrhea may occur. 24,25

Drug-Nutrient Interactions There are no well-known drug-nutrient interactions at this time in regards to MSM supplementation. 26

Other Frontiers Of MSM Research Include Cancer Prevention In animal studies MSM supplementation has been shown to prevent and delay the development of colon and breast cancer in rats treated with known chemical carcinogens. 13, 28 This effect may be due to its ability to support methionine levels (helping to prevent hypomethylation of DNA, which results in fragile chromosomal linkages leading to mutations) or related more to its anti-proliferative action. 29,30 How this applies to humans at this time is not known.

1. 2. 3. 4. 5.

Lovelock, J.E. Atmospheric dimethyl sulphide and the natural sulphur cycle. Nature1972;237:453-453 Hucker, H.B., et al. Studies on the absorption, excretion and metabolism of dimethyl sulfoxide (DMSO) in man. J Pharmacol Exp Ther 1967;155(2):309-317 Herschler, R.J. MSM: The Scientific Rationale For Nutritional Sulfur – A summary of writings and conversations with R.J. Herschler Williams, K.I.H., et al. Dimethyl sulfone: isolation from cows’ milk. Proc Soc Exp Biol Med 1966;122:865 Pearson, T.W. Natural occurring levels of dimethyl sulfoxide in selected fruits, vegetables, grains, and beverages. J Agr Food Chem 1981;29:1089

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75 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 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.

Williams, K.I.H. Dimethyl sulfone: Isolation from human urine. Arch Biochem Biophys 1966;113:251-252 Herschler, R.J. 1986. MSM: A nutrient for the horse. Equ Vet Data;7:268-269 Herschler, R. Use of Methylsulfonylmethane to enhance the diet of an animal. 1991, United States Patent 5,071,878 Metcalf, J. MSM – A dietary derivative of DMSO. Equine Vet Data 1983;3(5):174-175 Cronin, J.R. Methylsulfonylmethane. Nutraceutical of the Century. Rubin, L.F. Barnett, K.C. Ocular effects of oral and dermal application of dimethyl sulfoxide in animals. Ann NY Acad Sci 1967;141:333345 National Academy of Sciences Research Council. Dimethyl sulfoxide as a therapeutic agent: Report of the ad hoc committee on dimethyl sulfoxide. New York: National Academy of Sciences 1973 Challem, J. Sulfur Power, Natural Way Publications, 1998Feb28 Richmond, V.L. Incorporation of methylsulfonylmethane sulfur into guinea pig serum proteins. Life Sci 1986;39:263-8 Richmond, V.A. Incorporation of methylsulfonylmethane sulfur into methionine and cysteine of guinea pig serum protein. Am J Clin Nutrition;43(6):Abs 42 Richmond, V.A. Incorporation of methylsulfonylmethane sulfur into guinea pig serum proteins. Life Sciences 1986;39:263-8 Hanson, R.R. DVM, DACVS. Will medicine keep your horse sound? 1996, The Horse, April issue:38-40 Repine, J.E., Fox, R.B., Berger, E.M. Effect of dimethyl sulfoxide on the bactericidal function of polymorphonuclear leukocytes. Ann NY Acad Sci 1983;411:11-13 Jacob, S.W., Lawrence, R.M., Zucker, M. The Miracle of MDM: The Natural Solution for Pain. New York. G.P. Putman’s Sons 1999 Lawrence, R.M. Methylsulfonylmethane (MSM): A double-blind study of its use in Degenerative Arthritis. Int J Anti-Aging Medicine 1998;1(1):50 MSM Herbal Advisor, www.herbaladvisor.com 2001 Jacob, S.W., Herschler, R. Introductory Remarks: Dimethyl sulfoxide after twenty years. Ann NY Acad Sci 1983;411:13-17 Metcalf, J.W. MSM status report. Eq Vet Data 1986;7:332-4 Deichman, W.B. Gerards, H.W. (eds.) Toxicology of Drugs and Chemicals. (ed.) New York:Academic Press 1969 Challem, Jack. The Power of MSM: Let’s Live (magazine) 2001January 2000 Healthnotes, Inc;Sulfur. www.healthnotes.com Moore, R.D., Morton, J.I. Diminished inflammatory joint disease in MRL/1pr mice ingesting dimethyl sulfoxide (DMSO) or dimethylsulfone (MSM). Federation of American Societies for Experimental Biology, 69th Annual Meeting 1985 April:p.692 Layman, D. Growth inhibitory effects of dimethyl sulfoxide and dimethyl sulfone on vascular smooth muscle and endothelial cells in vitro. In Vitro Cell Develop Biol 1987;23(6):422-8 Richmond, V.I. Incorporation of methylsulfonylmethane sulfur into guinea pig serum proteins. Life Sci 1986;39:263-8 Morton, J.I., Siegel, B.V. Effects of oral dimethyl sulfoxide and dimethyl sulfone on marine autoimmune lymphoproliferative disease. Proc Soc Exp Biol Med 1986;183:227-30

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N-Acetylcysteine (NAC) General Features N-Acetylcysteine is a modified form of the amino acid cysteine, which when taken as a supplement can help the body increase its glutathione stores – an important antioxidant and detoxification agent. In conditions of heightened oxidative stress, HIV infection and certain chemical toxicities that damage the liver, the supplementation of NAcetylcysteine can be used to elevate or re-establish more optimal levels of liver and blood glutathione. In liver detoxification the most important antioxidant for neutralizing the free radicals produced as Phase I by products is glutathione. Glutathione is a tripeptide composed of three amino acids, namely cysteine, glutamic acid and glycine. Glutathione also provides a detoxification role in Phase II detoxification by acting as a conjugating agent. Conjugation reactions either neutralize toxins produced by Phase I detoxification enzymes and/or make the toxin more easily excreted through the urine or bile. When high levels of toxin exposure results in extensive free radical intermediate build up from Phase I detoxification processes, glutathione is rapidly used up and a glutathione deficiency state may occur. Glutathione conjugation is extremely useful to convert fat-soluble toxins into a water-soluble form, allowing more effective excretion via the kidneys. Certain conditions that increase oxidative stress also more rapidly use up glutathione in its antioxidant function. In turn this can lead to glutathione deficiency and a worsening of the patient’s condition. Conditions that are linked to glutathione deficiency include HIV infection, idiopathic pulmonary fibrosis and adult respiratory distress syndrome. Glutathione supplements are not well absorbed, however supplementation with vitamin C (500-3,000 mg per day) and Vitamin E (400 – 800 i.u. per day) have been shown to raise blood and liver glutathione levels in various studies. In patients with AIDS or HIV infection, supplementation with N-Acetylcysteine has been shown to be a very effective way to boost glutathione levels.1

Clinical Application and Mechanism of Action 1. HIV Infection and AIDS Studies reveal that individuals infected with HIV have compromised antioxidant status.2,3 Certain antioxidants, such as glutathione, prevent viral replication while reactive oxidants tend to stimulate the virus.3 Moreover, a decline in glutathione status may be a biomarker signalling a more rapid progression of HIV to full blown AIDS.4 There is evidence that supplementing HIV patients with N-Acetylcysteine can significantly increase the synthesis of glutathione and slow the progression of the disease.5, 16 Studies have shown that intracellular concentrations of glutathione are correlated with the absolute CD 4 (T-helper cells) lymphocyte counts. A single dose of N-Acetylcysteine has been shown to increase the concentration of cysteine in the plasma and mononuclear cells of HIV-infected patients.6 N-Acetylcysteine supplementation in these patients has been shown to cause approximately a 2-fold inhibition of HIV reverse transcriptase activity and had a synergistic effect when tested simultaneously with vitamin C.7 As glutathione is the main intracellular defence against oxidative stress, and is decreased in the plasma, lung fluid, and T-lymphocytes in individuals with AIDS, N-acetylcysteine, vitamin C, vitamin E and selenium are important

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77 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils considerations for these patients because they help to replenish glutathione, when taken as supplements.2 NAC supplementation has been shown to significantly increase glutathione in HIV patients and improve survival in a 2 to 3 year follow-up trial.9 2. Liver Damage Glutathione plays a key role in the detoxification of acetaminophen, nicotine from cigarette smoke, organophosphates (i.e. insecticides) and epoxides (carcinogens). 1 Under circumstances of acute or chronic exposure to the drug acetaminophen (Tylenol), liver glutathione is used up in the detoxification process, resulting in a glutathione deficiency state. In turn, this reduces the antioxidant capacity of the liver, allowing free radical intermediates to accumulate from Phase I detoxification enzyme activity. These reactive free radical species are left unchecked to damage liver cells and can lead to acute liver failure and death. Early treatment with N-Acetylcysteine (given intravenously) is the medical antidote for acetaminophen induced liver toxicity because it is known to reconstitute liver glutathione levels. In chronic acetaminophen toxicity states a hepatitis-like clinical picture develops involving liver scarring, at doses as low as 3 gms of acetaminophen per day.10

Dosage Ranges 1. HIV and AIDS: 1,000-3000 mg per day 2. Acetaminophen Poisoning (Acute Overdose): Doses of 10-15 gms of acetaminophen require treatment with NAcetylcysteine at 140mg/kg followed by 70 mg/kg q 4h for 3 days, or 300 mg/kg infused over 20 hours, with half the dose given in the first 15 minutes. Therapy must begin within 10-12 hours of poisoning; delay beyond 16 to 20 hours renders the treatment ineffective, and life threatening consequences may ensue. This circumstance requires appropriate medical attention and monitoring.10 3. Liver Support: N-Acetylcysteine helps the liver defend itself against various toxins (acetaminophen, carbon tetrachloride, also methylmercury and arsenic-induced oxidative stress). Patients with unusually high chronic exposures may benefit from 1,000-2,000 mg NAC per day, in these cases.1,11,12

Adverse Side Effects, Toxicity and Contraindications N-Acetylcysteine is non-toxic, even when given at high doses (i.e. treatment of acute acetaminophen poisoning). 10 Some gastrointestinal effects may occur at high oral doses. While supplementing the diet with high doses of NAC may be beneficial in cases of extreme oxidative stress (i.e. AIDS, carbon tetrachloride or acetaminophen exposure), it may lead to increased free radical formation in otherwise healthy individuals. In these individuals, it may act as a pro-oxidant rather than as an antioxidant. Thus, it is not recommended for general prevention and anti-aging practices at this time.13

Drug-Nutrient Interactions N-Acetylcysteine may reduce the effectiveness certain drugs such as acetaminophen, some chemotherapy drugs and may produce adverse reactions with metoclopramide, nitroglycerine and nitroglyn.14

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N To raise liver glutathione levels, N-Acetylcysteine is best taken in conjunction with vitamin . E (400 I.U. – 800 I.U.) selenium (100 – 200 mcg),1 and Vitamin C (500 - 3,000 mg). B N-Acetylcysteine supplementation may increase the urinary loss of zinc. Therefore, supplemental zinc and copper should be added when supplementing with NAC for extended periods.15

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

Murray M, Pizzoino J. Encyclopedia of Natural Medicine. 2nd edition. Rocklin, CA: Prima Publishing; 1998. p. 104-25;199-210. Staal FJ, Ela SW, Roederer M, Anderson MT, Herzenberg LA, Herzenberg LA. Glutathiore deficiency and human immunodeficiency virus infection. Lancet 1992;339:909-12. Favier A, Sappey C, Leclerc P, Faure P, Micoud M. Antioxidant status and lipid peroxidation in patients infected with HIV. Chem Biol Interact 1994;91:165-80. Marmor M, Alcabes P, Titus S, Frenkel K, Krasinski K, Penn A, et al. Low serum thiol levels predict shorter times-to-death among HIVinfected injecting drug users. AIDS 1997;11:1389-93. Roberts RL, Aroda VR, Ank BJ. N-acetylcysteine enhances antibody-dependent cellular cytotoxicity in neutrophils and mononuclear cells from healthy adults and human immunodeficiency virus-infected patients. J Infect Dis 1995;172(6):1492-502. Breitkreutz R, Pittack N, Thomas Nebe C, Schuster D, Brust J, Beichert M, et al. Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials. J Mol Med 2000;78(1):55-62. Roederer M, Staal FJ, Raju PA, Ela SW, Herzenberg LA. Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine. Proc Natl Acad Sci 1990;87:4884-8. Robinson MK, Hong RW, Wilmore DW. Glutathione deficiency and HIV infection. Lancet 1992;339:1603–4. De Rossa SC, Zaretsky MD, Dubs JG, et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest 2000;30,10:91529. The Merck Manual. 16th edition. San Diego, CA: Merck Research Laboratories; 1992. p. 906-9. Ballatori N, Lieberman MW, Wang W. N-acetylcysteine as an antidote in methylmercury poisoning. Environ Health Perspect 1998;106(5):267-71. Flora SJ. Arsenic-induced oxidative stress and its reversibility following combined administration of N-acetylcysteine and meso 2,3dimercaptosuccinic acid in rats. Clin Exp Pharmacol Physiol 1999;26(11):865-9. Kleinveld HA, Demacker PNM, Stalenhoef AFH. Failure of N-acetylcysteine to reduce low-density lipoprotein oxidizability in healthy subjects. Eur J Clin Pharmacol 1992;43:639-42. Healthnotes 2000. Healthnotes Inc. (www.healthnotes.com): Drug Interactions Summary for N-Acetylcysteine. Brumas V, Hacht B, Filella M, Berthon G. Can N-acetylcysteine affect zinc metabolism when used as a paracetamol antidote? Agents Action 1992;36:278-8. Herzenberg LA, De Rosa SC, Dubs JG, Roederer M, Anderson MT, Ela SW, et al. Glutathione deficiency is associated with impaired survival in HIV disease. Proc Natl Acad Sci 1997;94:1967-72.

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79 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Phosphatidylserine General Features Phosphatidylserine is the major phospholipid in the brain and plays a role in determining the integrity and fluidity of nerve cell membranes (the outer skin of brain cells). The brain can manufacture Phosphatidylserine, but requires folic acid, vitamin B12 and S-adenosylmethionine as cofactors (methyl donors) for its synthesis. Low levels of Phosphatidylserine in the brain are associated with impaired cognitive function and depression in the elderly.1,11,12 In Italy, Scandinavia and other parts of Europe Phosphatidylserine is widely used to help restore declining mental function and depression in the elderly. As noted, the body makes its own Phosphatidylserine, but when required to treat mental decline and memory loss, a therapeutic dosage is required from external sources. 11,12 The serine portion of Phosphatidylserine can also be converted into choline and significantly improve acetylcholine synthesis in the brain, aiding memory and reversing some age-related brain changes. Acetylcholine is the neurotransmitter (brain chemical) required for memory.2,3,4 Thus, Phosphatidylserine may aid memory and cognitive function via its participation as a vital phospholipid component of the nerve cell membrane and as a bioactive agent that can increase brain levels of the memory chemical acetylcholine.1-4

Clinical Application and Mechanism of Action Treatment of Depression and/or Impaired Mental Function in the Elderly Numerous studies in elderly patients (65-93 yrs) with moderate to severe senility and depressed elderly patients have demonstrated significant improvement in memory, behaviour, mood states and cognitive function with Phosphatidylserine supplementation of 100 mg, three times daily. 5-10 A number of double-blind studies, involving more than 1,000 patients suggest that Phosphatidylserine supplementation improves behaviour and mental function in patients with moderate to severe mental decline, including Alzheimerâ&#x20AC;&#x2122;s disease patients. 12 This is largely attributable to the role that Phosphatidylserine plays within the nerve cell membrane, aiding the conduction of nerve impulses and improving the movement of nutrients in and out of nerve cells. The serine fraction of Phosphatidylserine can also be converted into choline within the brain and is used as substrate from which brain cells can synthesize acetylcholine, the neurotransmitter required for memory function.1-4,11,12

Dosage Range Age-Related Cognitive Decline (Age-Associated Memory Impairment), and Depression in the Elderly: 100 mg, three times per day in the treatment of age-related cognitive impairment, senility and depression of the elderly has been used successfully in a number of well designed clinical trials. Once improvement is noted (usually within 3-6 months), the dosage can be reduced to 100 mg per day as a maintenance regime. Note that the above cited studies used bovine (cow-brain)-derived Phosphatidylserine, a product that is no longer available (due to the possible risk of â&#x20AC;&#x153;mad cowâ&#x20AC;? disease, or more correctly Creutzfeld-Jacob disease). Most of the Phosphatidylserine available in the marketplace today is derived from soy, but there have been only a limited number of studies using this source of Phosphatidylserine in studies evaluating cognitive function. The use of Phosphatidylserine in the treatment of agerelated memory loss and depression is primarily based upon the positive results demonstrated by bovine-derived Phosphatidylserine. Soy-derived Phosphatidylserine is a relatively new product by comparison. Soy and bovinederived Phosphatidylserine are not chemically identical; however, preliminary animal studies show that soy-derived Phosphatidylserine does have effects on brain function similar to that of bovine-derived Phosphatidylserine.

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80 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils Nevertheless, human trials are necessary to confirm the clinical efficacy of soy-derived Phosphatidylserine for the above-cited purposes.1-4,11,12

Adverse Side Effects and Toxicity Phosphatidylserine is generally regarded as safe when used at recommended dosages. No significant side effects or adverse reactions have been noted, other than mild gastrointestinal distress on rare occasions.1,11,12 Drug-Nutrient Interactions There are no well known drug-nutrient interactions for Phosphatidylserine.1

1. 2.

Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 356-358. Vannucchi MG, Casamenti F, Pepeu G. Decrease of acetylcholine release from cortical slices in aged rats: Investigations into its reversal by phosphatidylserine. J Neurochem 1990;55:819-25. 3. Valzelli L, Kozak W, Zanotti A, Toffano G. Activity of phosphatidylserine on memory retrieval and on exploration in mice. Meth Find Extl Clin Pharmacol 1987;9:657-60. 4. Nunzi MG, Milan F, Guidolin D, et al. Effects of phosphatidylserine administration on age-related structural changes in the rat hippocampus and septal complex. Pharmacopsychiat 1989;22:125-8. 5. Cenacchi T, Bertoldin T, Farina C, et al. Cognitive decline in the elderly: A double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration. Aging 1993;5:123-33. 6. Engel, RR, Satzger W, Gunther W, Kathmann N, Bove D, Gerke S, et al. Double-blind cross-over study of phosphatidylserine vs. placebo in subjects with early cognitive deterioration of the Alzheimer type. Eur. Neuropsychopharmacol, 1992;2:149-55. 7. Crook T, Petrie W, Wells C, Massari DC. Effects of phosphatidylserine in Alzheimer’s disease. Psychopharmacol Bull 1992;28:61-6. 8. Crook TH, Tinklenberg J, Yesavage J, Petrie W, Nunzi MG, Massari DC. Effect of phosphatidylserine in age-associated memory impairment. Neurology 1991;41:644-9. 9. Funfgeld EW, Baggen M, Nedwidek P, Richstein B, Mistlberger G. Double-blind study with phosphatidylserine (PS) in parkinsonian patients with senile dementia of Alzheimer’s type (SKAT). Prog Clin Biol Res 1989;317:1235-46. 10. Maggioni M, Picotti GB, Bondiolotti GP, Panerai A, Cenacchi T, Nobil P, et al. Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand 1990;81:265-70. 11. Healthnotes Online. Healthnotes Inc, 2000. 12. Natural Products Encyclopedia. www.consumerslab.com: Phosphatidylserine.

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Comment [c40]: Couldn’t find the other authors Comment [c41]: Couldn’t find the other authors.

81 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Policosanol (Saccharum officinarum) General Features Policosanol is a natural compound derived from sugar cane wax, which has been shown to significantly reduce high cholesterol in human and animal studies. It also has been shown to reduce platelet stickiness, improving blood flow and aiding patients with intermittent claudication and non-insulin dependent diabetes mellitus. 1,2,3 The efficacy, safety and lack of toxicity of this natural health product makes it a very desirable supplement in the management of high cholesterol as it has been shown to reduce cholesterol levels equally as well as many prescription medications, without producing significant side effects. 4,5

Principle Active Constituents Policosanol is a mixture of higher primary aliphatic alcohols isolated from sugar cane wax, whose main component is octacosanol. Octacosanol is a long chain fatty alcohol (similar in structure to cholesterol, which is also an alcohol ). Policosanol is a combination of octacosanol and several other long chain alcohols â&#x20AC;&#x201D; hence the name poli-cosanol. Keeping octacosanol together with other naturally occurring fatty alcohols makes it more stable and seems to enhance the efficacy of this supplement. 1,4 Clinical Application and Mechanism of Action 1. Cholesterol Lowering - Policosanol has been shown to reduce high levels of blood cholesterol to a significant degree (LDL-cholesterol reduction ~ 20%) in human and animal studies. Its mechanism of action is not completely understood, but it is known to suppress cholesterol synthesis in the liver. This effect appears to be related to its modulation of the HMG-CoA reductase enzyme, a rate-limiting enzyme in cholesterol synthesis. However, it is not officially considered to be an HMG-CoA reductase inhibitor, as are statin drugs. Nor does it produce the side effects associated with the use of statin drugs, which include potential liver damage, muscle pain, fatigue, dizziness, skin rash, diarrhea, heartburn, skin rash and male impotence. 4,6,30 Large trials over long periods have demonstrated that Policosanol supplementation can lower and maintain blood cholesterol levels as well as most conventional drugs, without producing untoward side effects. 1,4,7,8,9 Human Trials A review of the clinical trials using Policosanol to lower cholesterol levels in humans appeared in the American Heart Journal in 2002. A review of the available peer-reviewed journal publications revealed that Policosanol, at doses of 10 to 20 mg per day lowers total cholesterol by 17% to 21% and low-density lipoprotein (LDL) cholesterol by 21% to 29%, and raises high-density lipoprotein (HDL, the good cholesterol) cholesterol by 8% to 15%. The researchers state that because higher doses have not been tested up to now, it can not be excluded that effectiveness may be even greater. Daily doses of 10 mg of Policosanol have been shown to be equally effective in lowering total and LDL cholesterol as the same dose of simvastatin or pravastatin (two widely prescribed cholesterol-lowering statin drugs). Triglyceride levels are not influenced by Policosanol supplementation. At doses of up to 20 mg per day, Policosanol is safe and well tolerated, as studies of greater than three years of therapy indicate. 1 Postmenopausal Women - Policosanol has been shown to reduce elevated total and LDL-cholesterol levels in postmenopausal women by 17.3% and 26.7%, respectively, in 56 women who showed no cholesterol lowering to a 6-week standard lipid-lowering diet that has been followed prior to the administration of Policosanol. This is of great clinical significance as heart disease is the number one cause of death in postmenopausal women. After

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82 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils menopause the decline in estrogen levels is associated with a decrease in LDL-cholesterol receptors on the cell surface. In turn, this reduces clearance of cholesterol from the bloodstream permitting blood levels of LDLcholesterol to rise, predisposing women to heart attack and ischemic stroke. 9 Type II Hypercholerterolemia - Patients with type II hypercholesterolemia are known to have a genetically based defect that encourages lifelong elevation of blood cholesterol- a condition that is difficult to manage through diet and exercise alone. Studies have shown in a convincing manner that Policosanol supplementation significantly lowers cholesterol levels even in these more challenging patients. Total and LDL-cholesterol can be expected to drop by up to 17.4% and 25.6%, respectively. HDL-cholesterol levels have been shown to rise by 15.5% to 28.4% in these patients, which is a remarkable finding due to the fact that it is difficult to raise HDL levels and that higher HDL levels are known to significantly reduce risk of heart attack. HDL-cholesterol collects the cholesterol that has been deposited in the artery wall and transports it back to the liver where it can be cleared from the blood stream and eliminated from the body via its conversion to bile acids. 10 Even in older patients with type II hypercholesterolemia presenting with more than one concomitant atherosclerotic risk factor, the administration of Policosanol at 5 mg or 10 mg per day was shown to significantly reduce total and LDL-cholesterol levels and raise HDL- levels by up to 29.1%. The 10 mg dose produced better results in all cholesterol parameters compared to the 5 mg dose. 11 Head-To-Head Trials Against Statin Drugs - A study involving older patients with type II hypercholesterolemia tested the efficacy of the statin drug Pravastain against Policosanol, in a randomized, double-blind study. The results showed that Policosanol was more effective than Pravastatin in reducing total and LDL-cholesterol and was able to raise HDL-cholesterol by 18.4%, whereas Pravastatin showed no effect on HDL-cholesterol levels. Policosanol also more effectively reduced platelet aggregation than did Pravastatin, another important risk factor in cardiovascular disease. Patients receiving Pravastatin over the 6-week trial period experienced a rise in their serum levels of alanine amine transferase enzyme, which indicates potential damage to liver cells. This did not occur in the Policosanol group. Two patients dropped out of the Pravastatin group due to adverse side effects (myocardial infarction and jaundice, likely due to liver damage). The researchers conclude â&#x20AC;&#x153;the effects of Policosanol (10 mg per day) on lipid profile, platelet aggregation and endothelemia in older patients with type II hypercholesterolemia and high coronary risk are more favorable than those induced by the same doses of Pravastatin.â&#x20AC;? 12 A second study tested the efficacy of Policosanol against Lovastatin and Simvastatin (two popular statin drugs). The results showed that Policosanol reduced LDL-cholesterol by 24% on average compared to a 22% and 15% reduction with Lovastatin and Simvastatin, respectively. HDL levels rose significantly in the Policosanol group and no change was seen in the patients receiving Lovastain or Simvastatin. This was a 6- week trial involving patients with an LDL-cholesterol level of over 160 mg/dl. 13 Used In Conjunction With Fibrate Drugs - A study combining the use of Bezafibrate and Policaosanol demonstrated that these cholesterol and triglyceride-lowering agents can be used together to produce a positive outcome on blood lipids with no untoward side effects. Fibrate drugs are often used to help lower triglyceride levels, an effect that is not produced to a substantial degree by Policosanol. Thus, in patients with high cholesterol and high triglycerides, the combination of both agents has been shown to be effective and safe. 14 Intermittent Claudication - Sixty-two patients with intermittent claudication were given either 10 mg of Policosanol, twice per day or a placebo for 6 weeks. The Policaosanol group realized a significant improvement on treadmill walking distance during the course of the study. No change was seen in the placebo group. 15 Improved Exercise ECG Results in Coronary Patients - Policosanol supplementation was tested in patients with myocardial ischemia (severe blood flow restriction to the heart muscle) versus placebo. The results showed that www.meschinohealth.com

83 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils after 20 months the Policosanol group experienced an incremental improvement in ECG exercise testing (aerobic functional capacity percent) and a decline in blood cholesterol levels. The researchers state that Policosanol treated patients with coronary heart disease showed improved clinical evolution, and exercise-ECG responses, owing to the amelioration of myocardial ischemia. These results were even better when Policosanol was combined with 125 mg of aspirin per day, indicating that the use of aspirin in conjunction with Policosanol may be of greater benefit to certain heart patients than is aspirin alone. 16 Coronary Heart Disease Patients - A randomized single-blinded, placebo-controlled trial was conducted on 23 middle-aged outpatients with established coronary heart disease. The 12 patients given the Policosanol demonstrated a significant reduction in blood cholesterol levels and exhibited a clinical tendency to improvement of their coronary heart disease, in comparison to no improvement in these parameters in the placebo group. “ These findings show the effectiveness of low dose of Policosanol lowering total cholesterol and LDL-cholesterol and suggest a coronary heart disease improvement in middle-aged patients with primary or marginal hyperlipidemia.” 17 Diabetic Patients With High Cholesterol - In a study of non-insulin dependent diabetic patients with high cholesterol levels, Policosanol supplementation at 10 mg per day was shown to reduce total cholesterol by 17.5% and LDLcholesterol by 21.8% compared with baseline and placebo. HDL-cholesterol levels rose by 11.3% and triglyceride levels fell by 6.6% in the Policosanol group. None of these changes occurred in the placebo group. Moreover, Policosanol did not adversely affect glucose levels or glycemic control. The researchers conclude “ Policosanol is effective and safe in patients with non-insulin dependent diabetes mellitus and hypercholesterolemia.” 18 2. Anti-Coagulant Effects Policosanol has been shown to exert anti-coagulant effects on platelet function. However, this does not seem to be the case when administered at 5 or 10 mg per day. Anti-coagulant effects appear to start at a dose of 20 mg per day, with increasing anti-coagulant effects at 40 mg per day. Thus, patients taking other anti-coagulants (warfarin, coumadin, aspirin ) appear to be able to safely take up to 10 mg per day of Policosanol to lower cholesterol without risk of potentiating the action of anti-coagulant drugs. 19 A dose of 20 mg per day of Policosanol has been shown to provide the same degree of anti-coagulant activity as 100 mg of aspirin per day in human subjects. 20 This implies that if an anti-coagulant effect is desired along with a cholesterol lowering effect, then Policosanol can be used alone at a dose of 20 or 40 mg per day. If the patient is already on anti-coagulant therapy, then it is wise to limit the dose of Policosanol to 10 mg per day, where a cholesterol lowering effect is desirable.

Dosage and Standardized Grade Cholesterol Lowering - To lower cholesterol in patients not taking anti-coagulant therapy (including aspirin) doses of Policosanol from 5 mg per day to 40 mg per day have been used. Most typically, 10 mg, twice per day is the most common daily dosage of Policosanol used to treat hypercholesterolemia. In patients using anti-coagulant drugs, it is best to limit the dose of Policosanol to 5 mg, twice per day. 1,4,7,8,9,19,20,21

Adverse Side Effects, Toxicity and Contraindications Long term studies with Policosanol in humans has not shown any significant side effects and appears to have a safer profile than statin drugs (HMG-CoA reductase inhibitor drugs) that are commonly prescribed to lower cholesterol. 1,4,7,8,9 A case of erthyma was reported in one trial with diabetics. 18 Animal studies reveal that Policosanol is extremely safe even when administered to beagle dogs at 180 mg/kg for 52 weeks, which is 620 times higher than the therapeutic dose of 20 mg per day. 22 Studies in mice showed no adverse effects or carcinogenicity at doses of 50500 mg/kg administered orally for 18 months. 23 Overall Policosanol is considered to be an extremely safe therapeutic agent for cholesterol lowering. 4,5,24

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84 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Drug-Nutrient Interactions 1. Anti-coagulant Drugs - Policosanol has been shown to inhibit platelet aggregation and therefore, may potentiate the effects of anti-coagulant drugs such as warfarin, coumadin and aspirin. Studies on humans and animals have not shown a significant enhancement of anti-platelet activity when Policoasanol has been combined with warfarin or aspirin. Nevertheless, in the interest of patient safety, it is best not to recommend a daily dosage of more than 5 mg, twice per day in patients on concomitant anti-coagulant therapy, and even then, their prothrombin time should be properly monitored. 25,26,27,28 2. Beta-Blocker, Anti-Hypertensive Drugs - Human and animal studies reveal that Policosanol can potentiate the effects of beta-blockers used to lower high blood pressure. Thus, blood pressure should be monitored in order to see if a dose reduction in beta-blocker medication is required once Policosanol supplementation has been implemented.29

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

Gouni-Berthold I, Berthold HK. Policosanol: Clinical pharmacology and therapeutic significance of a new lipid-lowering agent. Am Heart J 2002Feb;143(2):356-65 Torres O, Agramonte AJ, Illnait J, Más Ferreiro R, Fernández L, Fernández JC. Treatment of hypercholesterolemia in NIDDM with policosanol. Diabetes Care 1995Mar;18(3):393-7 Castaño G, Más R, Roca J, Fernández L, Illnait J, Fernández JC, Selman E. A double-blind, placebo-controlled studyof the effects of policosanol in patients with intermittent claudication. Angiology 1999Feb;50(2):123-30 A Natural Anti-Cholesterol Dietary Supplement: Policosanol. Life Extension Jun2001;7(6):24 Prat H, et al. Comparative effects of policosanol and two HMG-CoA Reductase inhibitors on type II hypercholesterolemia. Rev Med Chil Mar1999;127(3):286-94 Menéndez R, Amor AM, Rodeiro I, González RM, González PC, Alfonso JL, et al. Policosanol modulates HMG-CoA Reductase activity in cultured fibroblasts. Arch med Res 2001Jan-Feb;32(1):8-12 Canetti M, Moreira M, Más R, Illnait J, Fernández L, Fernández, JC, et al. A two-year study on the efficacy and tolerability of policosanol in patients with type II hyperlipoproteinaemia. Int J Clin Pharmacol Res 1995;15(4):159-65

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85 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

Stusser R, et al. Long-term therapy with policosnol improves treadmill exercise-ECG testing performance of coronary heart disease patients. Int J Clin Pharmacol Ther 1998;36:469-73 Mirkin A, Más R, Martinto M, Boccanera R, Robertis A, Poudes R, et al. Efficacy and tolerability of policosanol in hypercholesterolemic postmenopausal women. Int J Clin Pharmacol Res 2001;21(1):31-41 Más R, Castaño G, Illnait J, Fernández L, Fernández J, Alemán C, et al. Effects of policosanol in patients with type II hypercholesterolemia and additional coronary risk factors. Clin Pharmacol Ther 1999Apr;65(4):439-47 Castaño G, Más R, Fernández JC, Illnait J, Fernández L, Alvarez E. Effects of policosanol in older patients with type II hypercholesterolemia and high coronary risk. J Gerontol A Biol Sci med Sci 2001Mar;56(3):186-92 Castaño G, Más R, Arruzazabala ML, Noa M, Illnait J, Fernández JC, et al. Effects of policosanol and pravastatin on lipid profile, platelet aggregation and endothelemia in older hypercholesterolemic patients. Int J Clin Pharmacol Res 1999;19(4):105-16 Prat H, Román O, Pino E. Comparative effects of policosanol and two HMG-CoA Reductase inhibitors on type II hypercholesterolemia. Rev Med Chil 1999Mar;127(3):286-94 Marcello S, Gladstein J, Tesone P, Más R. Current Therapeutic Research 2000Jun;61(6):346-57 Castaño G, et al. A double-blind placebo-controlled study of the effects of policosanol in patients with intermittent claudication. Angiology. Feb1999;50(2):123-30 Stüsser R, Batista J, Padrón R, Sosa F, Pereztol O. Long-term therapy with policosanol imporves treadmill exercise-ECG testing performance of coronary heart disease patients. Int J Clin Pharmacol Ther 1998Sep;36(9):469-73 Batista J, Stüsser R, Saéz F, Peréz B. Effect of policosanol on hyperlipidemia dn coronary heart diseases in middle-aged patients. A 14-month pilot study. Int J Clin Pharmacol Ther Mar1996;34(3):134-7 Torres O, et al. Treatment of hypercholesterolemia in NIDDM with policosanol. Diabetes Care. Mar1995;18(3):393-7 Arruzazabala ML, et al. Effect of policosanol successive dose increases on platelet aggregation in healthy volunteers. Pharmacol Res Nov1996;34(5-6):181-5 Arruzazabala ML, et al. Comparative study of policosanol, aspirin and the combination therapy policosanol-aspirin on platelet aggreagation in healthy volunteers. Pharmacol Res Oct1997;36(4):293-7 Carbajal D, et al. Effect of policosanol on platelet aggregation and serum levels of arachidonic acid metabolites in healthy volunteers. Prostaglandins Leukot Essent Fatty Acids Jan1998;58(1):61-4 Mesa AR, Mas R, Noa M et al. Toxicity of policosanol in beagle dogs: one-year study. Toxicol Lett 1994;73:81-90 Aleman CL, Mas R, Hernandez C et al. A 12-month study of policosanol oral toxicity in Sprague Dawley rats. Toxicol Lett 1994;70:77-87 Mas R, et al. Effects of policosanol in patients with type II hypercholesterolemia dn additional coronary risk factors. Clin Pharmacol Ther Apr1999;65(4):439-47 Carbajal D, Arruzazabala ML, Valdes S, Mas R. Effect of policosanol on platelet aggreagation and serum levels of arachidonic acid metabolites in healthy volunteers. Prostaglandins Leukot Essent Fatty Acids Jan1998;58(1):61-4 Arruzazabala ML, et al. Comparative study of policosanol, aspirin and the combination therapy policosanol-aspirin on platelet aggregation in healthy volunteers. Pharmacol Res Oct1997;36(4):293-7 Stusser R, Batista J, Padron R, et al. Long-term therapy with policosanol improves treadmill exercise-ECG testing performance of coronary heart disease patients. Int J Clin Pharmacol Ther Sep1998;36(9):469-73 Carbajal D, et al. Interaction policosanol-warfarin on bleeding time and thrombosis in rats. Pharmacol Res Aug1998;38(2):89-91 Molina Cuevas V, et al. Effect of policosanol on arterial blood pressure in rats. Study of the pharmacological interaction with nifedipine and propranolol. Arch Med Res Mar1998;29(1):21-4 Griffith W, MD. Complete Guide to Prescription and Nonprescription Drugs. The Body Press 1999;MHG-CoA Reductase inhibitors:418-419

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Prebiotics (FOS and other Oligosaccharides) General Features Prebiotics is a term used to refer to short-chain polysaccharides (carbohydrates) that are not completely digested by the human intestinal tract, but rather serve as a food supply for the friendly bacteria of the large bowel (bifodobacteria and lactobacilli), enhancing their growth and cell division rate.1,2,3 The official definition of Prebiotics is stated as â&#x20AC;&#x153;nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth and activity of one species or a limited number of species of bacteria in the colonâ&#x20AC;?. 4 Human studies show that supplementation with FOS (fructo-oligosaccharides) increases bifodobacteria and lactobacilli populations in the flora of the large intestine while simultaneously reducing the colonies of detrimental bacteria. The same has been shown for supplementation with two other Prebiotics; namely inulin and galacto-oligosaccharides (GOS).5-9 Fructo-oligosaccharides (FOS) and inulin consist of short chains of fructose molecules. Galacto-oligosaccharides consist of short chains of galactose molecules.1,2,3 The estimated average daily intake of FOS from food sources (mostly vegetables) is 800 mg.10 Supplementation studies demonstrate that 2,000-3,000 mg a day of additional FOS can favourably alter the bacteria populations of the large bowel.5-9 Higher doses may help to lower cholesterol, triglycerides and help better regulate blood glucose in type II diabetics.11,12 From a standpoint of general wellness, supplementation with Prebiotics or probiotics have been shown to improve digestion and absorption of some nutrients, enhance detoxification by intestinal mucosal cells, reduce the concentrations of large bowel mutagens and carcinogens, aid elimination processes and favorably affect the immune system of the gut and the systemic immune system. These effects are related to favorable changes in the concentrations of friendly gut bacteria resulting from pre- and probiotic supplementation. In regards to immune modulation, these positive effects extend to include reduced hypersensitivity reactions secondary to food sensitivities, improved control of autoimmune conditions and a lessening of skin reactions secondary to food-induced hypersensitivity reactions.4,13,14 An important feature of prebiotic supplementation is its potential impact on reducing risk of colorectal cancer, which is the second leading cause of cancer death in North America (combining statistics for men and women), after lung cancer. Human studies demonstrate that supplementation with Prebiotics (and probiotics) encourages the growth of lactic acid bacteria (LAB). Experimental data and some epidemiological evidence indicate that increased LAB protects against colon cancer development. Experimental data demonstrates that Prebiotics increase the proliferation of LAB which also, through fermentation of Prebiotics and other fiber sources, gives rise to the production of short-chain fatty acids and lowers the pH of the colon; making it a more acidic environment. Lower pH in the colon is associated with a reduced risk of colon cancer in various studies. This appears related to an inhibition of certain enzymes that are known to produce bowel carcinogens. Human studies have shown that prebiotic supplementation reduce concentrations of components that are genotoxic in human colon cells. Butyrate has been shown to increase the proliferation of normal cells, while inhibiting the proliferation of cancerous cells. This short-chain fatty acid also induces apoptosis (programmed cell death) of colon cancer cells, under experimental conditions. It is an important fuel for colon cells and evidence exists to show that colon cells exposed to various carcinogens are less inclined to be transformed into malignant cells in the presence of adequate butyrate supply. Butyrate has also been shown to increase the concentrations of glutathione transferase enzyme in colon cells. â&#x20AC;&#x153;Thus, enzyme induction by butyrate, or

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87 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils by the microflora and increased activity by Prebiotics, may be an important mechanism or protection against carcinogen-enhanced colon cancer.â&#x20AC;?15

Clinical Application and Mechanism of Action 1. Digestive Disorders, Food Sensitivity and Intolerances, Autoimmune Conditions, Rheumatoid Arthritis, Skin Conditions Prebiotics may be used to increase friendly gut bacteria (Bifidobacterium, bifidum and longum, and Lacto bacillus acidophilus). In these conditions a therapeutic dosage of â&#x20AC;&#x201C; 2,000-3,000 mg of FOS per day and/or other Prebiotics (inulin, GOS) is commonly utilized.5-9 2. Lipid Lowering Prebiotics are metabolized by large bowel bacteria, yielding short chain fatty acids like butyrate. Butyrate is known to inhibit liver cholesterol synthesis and provide a source of energy for human colon epithelial cells. Some studies, but not all, demonstrate that supplementing with 8-15 gms of Prebiotics can significantly lower blood cholesterol and triglycerides. This is not a consistent finding at this time.11,12,16 3. Type II Diabetes Some evidence suggests that prebiotic supplementation at 8-15 gm per day can help better regulate blood glucose in type II diabetics. Other studies have not shown this beneficial effect. Thus, more research is required before any conclusive statements can be made in this regard.12,16 4. General Wellness For health promotion purposes (e.g. to reduce concentrations of carcinogens in the large bowel, improve digestion, elimination and immune function) a daily dosage of 500-1,000 mg is often recommended.

Adverse Side Effects and Toxicity Generally, oligosaccharides are well tolerated. Some individuals report increased flatulence initially. At very high levels, (40 gm), FOS and other oligosaccharides may induce diarrhea.1

Drug-Nutrient Interactions There are no well-known drug interactions with FOS or other Prebiotics.17

1. 2. 3. 4. 5.

Tomomatsu H. Health effects of oligosaccharides. Prog Food Nutr Sci 1983;7:29-37. Molis C, Flourie B, Ourne F, Gailing MF, Lartique S, Guibert A, et al. Digestion, excretion, and energy value of fructooligosaccharides in healthy humans. Am J Clin Nutr 1996;64:324-8. Alles MS, Hautvast JG, Nagengast FM, Hartemink R, Van Laere KM. Fate of fructo-oligosaccharides in the human intestine. Br J Nutr 1996;76:211-21. Duggan C, Gannon J, Walker WA. Protective nutrients and functional foods for the gastrointestinal tract. Am J Clin Nutr 2002:75(5):789-808. Gibson GR, Beatty EH, Wang X, Cummings JH. Selective stimulation of bifidobacteria in the human colon by oligofructose and mutin. Gastroenterology 1995;106:975-82.

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88 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Bouhnik Y, FluoriĂŠ B, Dagay-Abensour L, Pochart P, Gramet G, Durand M, et al. Administration of transgalacto-oligosaccharides increases faecal Bifidobacteria and modifies colonic fermentation metabolism in healthy humans. J Nutr 1997; 127: 444-8. Bouhmik Y, et al. Short-chain fructo-oligosaccharide administration dose-dependently increases fecal bifodobacteria in healthy humans. J Nutr 1999;129:113-6. Roberfroid M. Dietary fibre, inulin and oligosaccharides. Crit Rev Good Sci Nutr 1993;33:103-48 [review]. Tomomatsu H. Health effects of oligosaccharides. Food Technology 1994;48(10):61-5. Gibson GR, Beatty ER, Wang X, Cummings JH. Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology 1995;108:975-82. Jackson KG, Taylor GRJ, Clohessy AM, Wlliams CM. The effect of the daily intake of inulin on fasting lipid, insulin and glucose concentrations in middle-aged men and women. Br J Nutr 1999;82:23-30. Yamashita, K, Kawai, K, and Itakura, M. Effects of fructo-oligosoccharides on blood glucose and serum lipids in diabetic subjects. Nutr Res 1984;4:961-6. Roberfroid M. Prebiotics: preferential substrates for specific germs. Am J Clin Nutr.2001;73(Suppl 2):406S-9S. Isolauri E, Sutas Y, Kankaanpaa P, Arvilommi H, Salminen S. Probiotics; effects on immunity. Am J Clin Nutr 2001:73(Suppl 2):444S-50S. Wollowski I, Rechkemmer G, Pool-Zobel BL. Protective role of probiotics and prebiotics in colon cancer. Am J Clin Nutr 2001;73(Suppl 2):451S-5S. Roberfroid M. Dietary fibre, inulin and oligofructose. A review comparing their physiological effects. Crit Rev Food Sci Nutr 1993;33:103-48. Healthnotes online. 2000 Healthnotes, Inc. (www.healthnotes.com):FOS.

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Probiotics General Features Probiotics is a term used to describe supplementation with the friendly bacteria of the large intestine; the most important of which are lactobacillus acidophilus and bifidobacteria. The official definition of the term probiotic (as defined by Havenaar and Huis In’t Veld) is described as “microorganisms in sufficient numbers, which alter the microflora (by implantation or colonization) in a compartment of the host and by that exert beneficial health effects in this host.” The health effects attributed to the use of Probiotics are numerous. Well documented effects include lower frequency and duration of diarrhea associated with antibiotics, rotavirus infection, chemotherapy, and to a lesser degree traveler’s diarrhea; stimulation of humoral and cellular immunity; and decrease in unfavourable metabolites in the bowel that are linked to colon cancer development (ammonium and procarcinogenic enzymes). Other health benefits are also related to the use of Probiotics as reviewed below.1,2 It has been shown that lactobacilli inhibit the growth of less desirable organisms in the large intestine through competition for nutrients, alteration of pH and oxygen tension to levels less favourable to pathogens (disease-causing organisms), prevention of attachment of pathogens by physically covering attachment sites, and production of limiting factors such as antimicrobial factors.1,3,4 The gut microflora (normal bacterial population) is an important constituent in the intestine’s defense barrier, as demonstrated by increased antigen transport across the gut mucosa in the absence of an intestinal microflora. The gut microflora also elicits specific immune responses at a local and systemic level. A healthy composition of microflora has also been shown to tone-down hypersensitivity reactions involving food allergies, infant atopic dermatitis, autoimmune conditions (rheumatoid arthritis, juvenile arthritis), and inflammatory bowel conditions. In general, evidence exists to show that probiotic supplementation reduces the entry of pathogens and antigens from reaching the bloodstream. Supplementation with probiotics tends to stimulate and enhance systemic immune function in healthy individuals, while toning-down (down-regulating) the exaggerated immune reactions that contribute to food allergies and inteolerance, atopic dermatitis (eczema), certain autoimmune diseases and inflammatory bowel conditions such as Chrohn’s disease and ulcerative colitis, as noted above. In one placebo-controlled trial, patients with pouchitis (inflammation of the ileal pouch-anal anastamosis after colectomy) had fewer episodes of clinical relapse when treated with Probiotics, and had clinical outcomes as good as those treated with the anti-inflammatory agent mesalamine. Probiotic supplementation has also been shown to reduce the secretion of pro-inflammatory cytokines (particularly, tumor necrosis factor alpha) from white blood cells that promote inflammatory responses in conditions such as atopic dermatitis. At the same time, Probiotics stimulate the release of interferon gamma which has positive effects on the gut, preventing inflammation, and providing systemic benefits as well.5,6 One researcher states “these data point to the conclusion that Probiotics can be used as innovative tools for treating dysfunction of the gut mucosal barrier, including acute gastroenteritis, food allergy, and inflammatory bowel disease. Many of the probiotic effects are mediated via immune regulation, in particular by control of the balance of proinflammatory and anti-inflammatory cytokines.5

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Clinical Application and Mechanism of Action 1. Post Antibiotic Therapy During and after antibiotic therapy supplementation with a mixture of bifidobacterium bifidum and L. acidophilus can prevent the candida overgrowth, diarrhea and urinary tract infections that can result from antibiotic therapy. Probiotic supplementation can maintain or re-establish the bacterial flora equilibrium during or after treatment with ampicillin. Research exists to support the use of probiotic supplementation during antibiotic administration. 1,3,7,8,9 2. Fibrocystic Breast Disease (FBD) and Premenstrual Syndrome (PMS) To improve the excretion of estrogen conjugated with glucuronic acid some practitioners recommend the ingestion of 10-20 billion L. acidophilus living organisms per day. L. acidophilus inhibits the overpopulation of the bacteria that secrete beta-glucorinadase enzyme, which in turn deconjugates estrogen from glucuronic acid. In this instance, estrogen can be re-absorbed back into the bloodstream (entero-hepatic pathway) and over stimulate metabolic processes that exacerbate FBD and PMS. Research supports the view that FBD and PMS are aggravated and possibly caused by a high estrogen to progesterone ratio. Improving estrogen detoxification and intestinal excretion of estrogen has been shown to improve symptoms of FBD and PMS.10 3. Gastroenteritis Gastroenteritis is the main cause of acute diarrhea. It is usually due to viral or bacterial pathogens or to parasites, but the most frequent cause in children is rotavirus. A number of clinical trials have shown that supplementation with Probiotics (especially with Lactobacillus rhamnosus), is effective in shortening the duration of this condition, particularly in infantile gastroenteritis. Other studies have shown that probiotic supplementation can reduce risk of diarrhea in children admitted to hospital.11 4. Travelerâ&#x20AC;&#x2122;s Diarrhea Acute diarrhea occurs in half of travelers who visit high-risk areas. Although most cases are mild and self-limiting, there is considerable morbidity. Some, but not all, studies indicate that the use of probiotic supplementation can reduce the incidence of travelerâ&#x20AC;&#x2122;s diarrhea (from 71% to 43% in one study).11 5. Irritable Bowel Syndrome and Inflammatory Bowel Disease Limited evidence exists to support the use of Probiotics for the treatment of irritable bowel syndrome, other than to control symptoms of diarrhea in some cases. Evidence is stronger to support the use of probiotic supplementation for ulcerative colitis and Crohnâ&#x20AC;&#x2122;s disease. In a study of 120 ulcerative colitis patients, comparable results were seen in relapse of the disease in patients receiving probiotic supplementation as compared to those taking the antiinflammatory drug, mesalamine. A second study involving 116 ulcerative colitis patients revealed similar findings. As noted above, patients with pouchitis have also experienced benefit from the use of Probiotics, with respect to a reduction in inflammation and pain. In general, the positive effects upon immune function and the suppression of the inflammatory process are likely the ways in which Probiotics reduce relapse of inflammatory bowel disease and help to effectively manage pouchitis and related inflammatory conditions of intestinal tract.5,6,11

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Dosage Range 1. Concurrent or Post Antibiotic Therapy: 15-20 billion living organisms per day8,9 2. Fibrocystic Breast Disease and Premenstrual Syndrome: 5-10 billion living organisms per day7 3. Gastroenteritis, (Prevention of Traveler’s Diarrhea), Ulcerative Colitis, Crohn’s Disease: 10 billion living organism per day.12

Adverse Side Effects and Toxicity Amounts exceeding 10 billion living organisms per day may lead to mild gastrointestinal disturbances. Probiotics are extremely safe with no toxicity reported at the above recommended doses. Some probiotic preparations contain the yeast organism Saccharomyces boulardii. In patients with compromised immune status, this organism has produced severe, invasive fungal infections. In otherwise healthy individuals this yeast has been shown to work synergistically with other Probiotics, producing positive health outcomes.6,13

Drug-Nutrient Interactions L. acidophilus and B. bifidum are negatively affected by alcohol and antibiotics.14 They may also interfere with the metabolism of sulfasalazine, chloramphenicol palmitate, and phthalylsulfathiazole, especially L. acidophilus.15

Author’s Note on Quality Assurance Unlike other types of supplements that can have their potencies confirmed by third party analytic methods, when purchasing a probiotic supplement it is impossible to know the true potency of the product. This is due to the fact that many variables can affect the number of live bacteria that exist within the capsules at any given time. As a rule, Probiotic supplements should be refrigerated from the time they are encapsulated until the time they are purchased by the end user in order to slow down the division rate (germination rate) of the bacteria, as bacteria can only multiply a fixed number of times before death of the bacteria occurs. Unfortunately, most probiotic supplements are not refrigerated during shipping and transportation to distribution centers and on route to retail outlets, or during direct shipment to consumers (e.g. Internet sales, catalog sales, shipped directly to the consumer’s home by mail or courier). Thus, it is thought that a large number of probiotic products sold in the market place contain no live bacterial cultures or a minimal concentration, by the time consumers begin using them. Bacterial germination is also much faster during the summer time and in warmer climates, as heat is a factor that increases the cell division rate of these bacteria. As such, the expiry date should be shortened in the summer and in warm weather areas. As a rule of thumb, it is probably best to use a probiotic within the first three months of its encapsulation, and to purchase only refrigerated products, and then to refrigerate the product within one’s home as soon after the purchase as possible. Keep in mind that the use of prebiotics may be considered as a substitute for Probiotics. Prebiotic supplements can have their potency verified through third party analysis, and do not lose their potency over time in the fashion as do Probiotics (see Prebiotics in this document). Finally, the first method of delivery, and likely the most effective delivery of Probiotics is through the intake of foods that contain live bacterial cultures, such as yogurt and other soured dairy products. (see the Am J Clin Nutr 2001, volume 73, supplement 2 edition, for more details on probiotic quality). N.B. A 1990 study showed that most Probiotic supplements purchased in retail outlets contained no living bacteria at the time of purchase. Thus Prebiotic supplementation and soured dairy products may be a preferred method by which to modify the gut micro-flora.1 www.meschinohealth.com

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

AUTHOR. Human Intestinal Microflora. In: Health and Disease. Hentges DJ editor. New York, NY: Academic Press; 1983. Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics-approaching a definition. Am J Clin Nutr 2001;73(Suppl 2):361S-4S. Shahani KM, Ayebo AD. Role of dietary lactobacilli in gastrointestinal microecology. Am J Clin Nutr 1980;33:2448-57. Shahani KM, Friend BA. Nutritional and therapeutic aspects of lactobacilli. J Appl Nutr 1984;36:125-52. Isolauri E, et al. Probiotics : effects on immunity. Am J Clin Nutr 2001;73(Suppl 2):444S-50S. Duggan C, Gannon J, Walker WA. Protective nutrients and functional foods for the gastrointestinal tract. Am J Clin Nutr 2001;75:789808. Zoppi G, Deganello A, Benoni G, Saccomani F. Oral bacteriotherapy in clinical practice, I. The use of different preparations in infants treated with antibiotics. Eur J Ped 1982;139:18-21. Gotz VP, Romankiewics JA, Moss J, Murray HW. Prophylaxis against ampicillin-induced diarrhea with lactobacillus preparation. Am J Hosp Pharm 1979;36:754-7. Zoppi G, Deganello A, Benoni G, Saccomani F. Oral bacteriotherapy in clinical practice, I. The use of different preparations in the treatment of acute diarrhea. Eu J Ped 1982;139:22-4. Murray M, Pizzorno J. Encyclopedia of Natural Medicine. 2nd edition. Rocklin, CA: Prima Publishing; 1998. Marteau PR, de Vrese M, Cellier CJ, Schrezenmeir J. Protection from gastrointestinal disease with use of probiotics. Am J Clin Nutr 2001;73(Suppl 2):430S-6S. Dietary Supplement Information Bureau. www.content.intermedicine.com: Lactobacillus acidophilus. Healthnotes Inc. 2001 www.healthnotes.com: Lactobacillus acidophilus. Daikas GK, et al. Intestinal flora ecology after oral use of antibiotics. Chemotherapy 1968;13:146-60. Pradhan A, Majumdar MK. Metabolism of some drugs by intestinal lactobacilli and their toxicological considerations. Acta Pharmacol Toxicol 1986;58:11-5. Hughes VL. Microbiologic characteristics of Lactobacillus products used for colonization of the vagina. Obstet Gynecol 1990;75:244-8.

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Psyllium (Psyllium husk fiber or Psyllium seed) General Features Psyllium is native to Iran and India. It is currently cultivated all over the world and the seed husks are used medicinally. The seed husks are unique in that they contain a high level of mucilage content and soluble fiber, which provide a health-promoting effect on the function of the large bowel, reduce high cholesterol levels, and help regulate blood sugar levels in diabetics. Psyllium seeds have been used for many years in traditional herbal medicine. 1,2

Principle Active Constituents Mucilage and Soluble Fiber - Psyllium seed husks are high in both mucilage (10 â&#x20AC;&#x201C; 30% by weight) and soluble fiber. The laxative effect is due to swelling of the husk when it comes into contact with water, creating a gelatinous fecal mass that stimulates peristalsis (movement of fecal content through the intestinal tract) and voiding of the bowel (bowel movements). 3 The soluble fiber is responsible for its ability to lower cholesterol and regulate blood sugar. 4,5

Clinical Application and Mechanism of Action 1. Laxative The laxative properties of Psyllium are due to the ability of the mucilage portion of the seed husk to absorb water, in a similar fashion as a sponge. This swelling creates a large gelatinous mass that applies pressure to the bowel wall and thereby, stimulates more frequent contractions of the muscles that rhythmically contract to propel fecal matter through the large intestine. Due to the high water content of this gelatinous fecal mass, the developing fecal matter is softened, and hydrated, provided sufficient water is ingested to allow this to occur. Thus, as a bulkforming laxative, Psyllium supplementation encourages more rapid movement of fecal contents through the large bowel, softens the stool for easier elimination, and by absorbing water it may help to dilute the effects of bowel carcinogens; a means proposed to reduce risk of colon and rectal cancers. 3,6 Studies show that Psyllium is highly effective in relieving lifestyle-related and functional constipation, but not in cases caused by diseases of the intestinal tract. 7 In functional cases, Psyllium has been shown to be better than, or at least as effective as, standard laxative medications (e.g., docusate sodium). Psyllium also has fewer side effects than most other laxative medications and offers better stool consistency. 6 2. Diarrhea Psyllium has been used successfully to control diarrhea due to its ability to increase the thickness of stools. 8,9 This also has important application for HIV patients, taking Protease Inhibitor drugs, which commonly produce diarrhea and thereby further contribute to malnutrition, weight loss, and immunosuppression, often seen in these patients. Psyllium is one of the interventions that is shown to reduce diarrhea in these patients. 10 3. High Cholesterol Based upon substantial clinical and scientific evidence, the United States Food and Drug Administration (FDA) has approved a health claim for Psyllium in regards to its ability to reduce cardiovascular disease risk. 4 This is primarily attributable to the ability of the soluble fiber fraction of Psyllium seed husk to drag cholesterol and bile acids (bile acids may otherwise be re-absorbed and converted into cholesterol within the liver) through the intestinal

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94 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils tract and eliminate them from the body in the stool. 4,11 It may also stimulate the liver to convert cholesterol to bile acids, lowering the total cholesterol load on the body. 11,13 Through these mechanisms, Psyllium supplementation has been shown to reduce blood cholesterol levels to a modest degree in patients with high cholesterol and in patients whose cholesterol levels fall within the normal range. Numerous double-blind studies have shown that Psyllium supplementation can lower total cholesterol and LDL-cholesterol (bad cholesterol), with no significant effect on HDL-cholesterol levels (good cholesterol). 12,14 Studies involving children have also shown a significant cholesterol lowering effect in subjects with elevated cholesterol levels. 15 In the Lipid Assessment Treatment Project (L-TAP), the success rates for lipid-regulating therapies and treatments according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel II (ATP II) were reported to be a 43% reduction in LDL-cholesterol for bile acid sequestrant drugs, 39% for high-dose niacin, 32% for gemfibrozil, 28% for Psyllium fiber, 40% for statin drugs (e.g., lovastatin), and 40% for combination therapies. 25 A meta-analysis conducted to evaluate the hypolipidemic effects of Psyllium fiber (which pooled eight controlled studies, involving 384 and 272 subjects with mild to moderate hypercholesterolemia receiving Psyllium or cellulose placebo, respectively), revealed that Psyllium supplementation (10.2 gm per day), as an adjunct to a low fat diet, lowered total cholesterol by 4%, LDL-cholesterol by 7% and the ratio of apolipoprotein (apo) B to apo A-1 by 6%, relative to the placebo. The researchers concluded that Psyllium is well tolerated and safe when used as an adjunct to a low-fat diet in individuals with mild-to-moderate hypercholesterolemia. 26 A study involving 34 hypercholesterolemic men with type II diabetes showed that men receiving 5.1 gm of Psyllium 20-30 minutes prior to breakfast and evening meals for eight weeks, reduced their total cholesterol levels on average by 8.9% and LDL-cholesterol levels by 13%, compared to the placebo group. As well, their post-lunch glucose levels dropped by 4.2%, compared with a 12.7% increase in the placebo group. 27 4. Diabetics and Blood Sugar The soluble portion of Psyllium has been shown to improve blood glucose regulation in both insulin-dependent and non-insulin dependent diabetic patients. 16,17,18 Soluble fiber is known to slow the absorption of simple sugars (monosaccharides) from the intestinal tract, helping to prevent a hyperglycemic response following a meal containing carbohydrate foods. Challenge studies have shown that Psyllium supplementation can significantly lower the glycemic response to a carbohydrate test meal in these patients, producing lower, more controlled blood glucose levels, postprandially. 12 5. Ulcerative Colitis A double-blind trial involving patients with ulcerative colitis showed that Psyllium supplementation significantly reduced symptoms such as bleeding, and helped patients remain in remission longer (upon ingesting 20 gm of ground Psyllium seeds, twice daily with water), compared to the use of the medication mesalamine alone. However, the combined effects of mesalamine and Psyllium produced the best overall outcomes in this study. 19 6. Irritable Bowel Syndrome (IBS) Some studies suggest that Psyllium supplementation may be helpful in the management of IBS. An illuminating study by J. Holtz, et al, showed that both Psyllium and wheat bran supplementation improved stool frequency and consistency in a 6-week trial of thirty IBS patients. However, the Psyllium group demonstrated superior outcomes with respect to stool frequency and degree of abdominal distension, making it the preferred intervention, according to the researchers involved in this trial. 20 As there are few effective interventions in the treatment of IBS, it is worth noting that well-designed trials support the use of Psyllium supplementation in these cases, although outcomes may vary greatly from patient to patient. 1,21

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95 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 7. Blood Pressure There is some evidence to suggest that Psyllium supplementation can help reduce high blood pressure by enhancing the fecal excretion of sodium absorbed in the intestinal tract. Although this evidence comes mostly from animal studies, a trial involving sixty-eight hypercholesterolemic patients demonstrated a small reduction in blood pressure in patients receiving 8 gm of Psyllium supplementation each day for four weeks. Their cholesterol levels were also reduced, providing a desirable synergistic effect in reducing cardiovascular disease risk. 4,22

Dosage and Standardized Grade 1. Constipation (from non organic disease), Diarrhea, IBS and Non-insulin Dependent Diabetes and InsulinDependent Diabetes: 5 gm (one teaspoon), three times per day, or 10 to 30 gm of whole seeds per day, taken in three evenly divided doses. This should be stirred into a large glass of water or fruit juice and ingested as a beverage (before it thickens in the glass). 1,5,6,20 2. Cholesterol-lowering: 5 gm (one teaspoon), two or three times per day. Follow instructions above. 1,2,11,25,26,27 3. Ulcerative Colitis: 5 gm (one teaspoon), twice per day; or 10 gm whole seed, twice per day. Follow instructions above. 19

Adverse Side Effects, Toxicity and Contraindications Psyllium supplementation has been shown to be safe when taken at recommended doses. 1 Some patients with IBS may see a worsening of their condition upon supplementation with Psyllium as has been reported in some cases. 1,21 Patients with bowel obstruction and diabetics with extreme blood sugar sensitivities should not use Psyllium. 21 Allergic skin reactions from Psyllium are primarily limited to people working in factories manufacturing Psyllium products. 1

Drug-Nutrient Interactions Psyllium supplementation may potentiate the action of the following medications and thereby lower the required dosages of these medications: 1. Hypoglycemic Medications (e.g., glyburide, glipizide, metformin, rosiglitazone, glimepiride, tolbutamide, acarbose, chlorpropamide etc.) 18 2. Insulin 18 3. Cholesterol-lowering drugs. 23,24

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

Healthnotes, Inc. 2001. www.healthnotes.com: Psyllium Dietary Supplement Information Bureau. www.content.intramedicine.com: Psyllium Seed Leung AY, Foster S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics, 2nd ed. New York:John Wiley & sons 1996:427-9 Jenkins, DJ, Kendall CW, Vuksan V, Vidgen E, Parker T, Faulkner D, et al. Soluble fiber intake at a dose approved by the US Food and Drug Administration for a claim of health benefits: serum lipid risk factors for cardiovascular disease assessed in a randomized controlled crossover trial. Am J Clin Nutr May 2002;75(5):834-9 Frati Muari AC, et al. Lowering glycemic index of food by acarbose and Plantago psyllium mucilage. Arc Med Res Jun1998;29(2):137-41 McRorie JW et al. Psyllium is superior to docusate sodium for treatment of chronic constipation. Aliment Pharmacol Ther May1998;12(5):491-7 Voderholzer WA, Schatke W, M端hldorfer BE, et al. Clinical response to dietary fiber treatment of chronic constipation. Am J Gastroenterol 1997;92:95-8 Washington N et al. Moderation of lactulose-induced diarrhea by psyllium: effects on motility and fermentation. Am J Clin Nutr Feb1998:;67(2):317-21 Leib MS. Treatment of chronic idiopathic large-bowel diarrhea in dogs with a highly digestible diet and soluble fiber: a retrospective review of 37 cases. J Vet Intern Med Jan2000;14(1):27-32 Sherman DS, Fish DN. Management of Protease Inhibitor-associated Diarrhea. Clin Infect Dis Jun2000;30(6):908-14 Davidson MH, et al. Long-term effects of consuming foods containing psyllium seed husk on serum lipids in subjects with hypercholesterolemia. Am j Clin Nutr Mar1998;67(3):367-76 Anderson JW, Aligood LD, Turner J, et al. Effects of psyllium on glucose and serum lipid response in men with type 2 diabetes and hypercholesterolemia. Am J Clin Nutr 1999;70:466-73 Schwesinger WH, et al. Soluble dietary fiber protects against cholesterol gallstone formation. Am J Surg Apr1999;177(4):307-10 Oson BH, Anderson SM, Becker MP et al. Psyllium-enriched cereals lower blood total cholesterol and LDL cholesterol, but not HDL cholesterol, in hypercholesterolemic adults:Results of a meta-analysis. J nutr 1997 1997;127:1973-80 Davidson MH, Dugan LD, Burns JH, et al. A psyllium-enriched cereal for the treatment of hypercholesterolemia in children: A controlled, double-blind, crossover study. Am J Clin Nutr 1996;63:96-102 Florholmen J, Arvidsson-Lenner R, Jorde R, Burhol PG. The effect of Metamucil on postprandial blood glucose and plasma gastric inhibitory peptide in insulin-dependent diabetics. Acta Med Scand 1982;212:237-9

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97 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 17. Rodriguez-Moran M, Guerrero-Romero F, Lazcano-Burciaga G. Lipid- and glucose-lowering efficacy of plantago psyllium in type II diabetes. J Diabetes Complicaitons 1998;12:273-8 18. Anderson JW, Allgood LD, Turner J et al. Effects of psyllium on glucose and serum lipid response in men with type 2 diabetes and hypercholesterolemia. Am J Clin Nutr 1999;70:466-73 19. Fernandez-Banares F, Hinojosa J, Sanchez-Lombrana JL, et al., Randomized clinical trial of Plantago ovata seeds (dietary fiber as compared with mesalamine in maintaining remission in ulcerative colitis. Am J Gastroenterol 1999;94:427-33 20. Hotz J et al. Effectiveness of plantago seed husks in comparison with wheat brain on stool frequency and manifestations of irritable colon syndrome with constipation. Med Klin Dec1994;89(12):645-51 21. Blumenthal M, Busse WR, Goldberg A, et al. (eds). The Complete Commission E Monographs: Therapeutic Guide to herbal medicines, Boston, MA: Integrative Medicine Communication 1998:190-2 22. Obata K et al. Dietary fiber, psyllium, attenuates salt-accelerted hypertension in stroke-prone spontaneously hypertensive rats. J Hypertens Dec1998;16(12 Pt 2):1959-64 23. Brown L et al. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr Jan1999;69(1):30-42 24. Anderson JW et al. Long-term cholesterol-lowering effects of psyllium as an adjunct to diet therapy in the treatment of hypercholesterolemia. Am J Clin Nutr Jun2000;71(6):1433-8 25. Gaw A. A new reality: achieving cholesterol-lowering goals in clinical practice. Atheroscler Suppl 2002Apr;2(4):5-11 26. Anderson JW, Allgood LD, Lawrence A, Altringer LA, Jerdack GR, Hengehold DA et al. Cholesterol-lowering effects of psyllium intake adjunctive to diet therapy in men and women with hypercholesterolemia: meta-analysis of 8 controlled trials. 27. Larsen HR. Psyllium decreases cholesterol. Alive: Canadian journal of Health & Nutrition 0228586X Feb2000;208

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Quercetin General Features Quercetin is a flavonoid that serves as the backbone for many other flavonoids in nature, including the citrus flavonoids rutin, quercitin, and hesperidin. These derivates differ from Quercetin in that they have sugar molecules attached to their Quercetin backbone. Experimental studies reveal that many medicinal plants owe much of their biological activity to their high Quercetin content.1 This water-soluble pigment has been shown to inhibit histamine release at therapeutic doses, making it an attractive agent in the management of some allergic conditions, such as hay fever. It also demonstrates impressive antiinflammatory and antioxidant properties, and like some other flavonoids (e.g. genistein, diadzein), appears to possess phytoestrogen effects. Under experimental conditions, its phytoestrogen effects have been shown to inhibit the proliferation of human breast cancer cells in test tube experiments. In one human trial, Quercetin supplementation demonstrated improvement in prostatitis, with 67% of patients experiencing significant improvement in the Quercetin group compared to only 20% of patients reporting improvement in the placebo group. This benefit may be due to its phytoestrogen activity and/or its anti-inflammatory properties. Experimental studies also reveal that Quercetin may help to prevent cataracts in diabetics, by inhibiting the enzyme that forms sorbitol (aldose reductase) in the lens of the eye.2,3

Clinical Applications and Mechanism of Action 1. Anti-Inflammatory Quercetin inhibits the manufacture and release of histamine and other allergic/inflammatory mediators, which gives Quercetin supplementation application in a variety of inflammatory and allergic reactions (arthritis, joint inflammation, asthma, hay fever, lupus).4-12 2. Diabetic Cataracts Quercetin inhibits the aldose reductase enzyme, which converts glucose into sorbitol. Sorbitol build up in the lens of the eye (secondary to diabetes and hyperglycemia) is involved in the development of cataracts. Elevated sorbitol may also contribute to the development of diabetic neuropathy and retinopathy. Thus, Quercetin may be beneficial in diabetes management for a number of reasons. 13,14 Animal studies reveal that Quercetin effectively delays the onset of cataracts in diabetic animals.14 3. Anti-Tumor Many flavonoids inhibit tumor formation, but Quercetin has demonstrated a very consistent effect in this regard. Under experimental conditions, Quercetin demonstrates a significant antiproliferative effect in regards to squamous cell carcinoma, leukemia, and cancers of the breast, ovaries, colon, rectum and brain.15-18 It is thought that Quercetin down-regulates enzymes that control the rate of cellular division (i.e. protein kinase, DNA-topoisomerase, ornithine decarboxylase), in addition to its mild phytoestrogen effects.2,3,19,20

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Dosage 1. Anti-Inflammatory/Anti-Allergy: as a single agent; 200-400 mg, three times per day. Combinations of bromelain and Quercetin have been shown to potentiate or enhance each others anti-inflammatory activity.21 The amount of bromelain should be equal to the amount of Quercetin.1 Bromelain also enhances the absorption of Quercetin.1 2. Diabetes (neuropathy or cataract protection): consider 200-400 mg (three times per day).2,3

Adverse Side Effects and Toxicity Animal studies demonstrate that Quercetin is extremely non-toxic and non-carcinogenic.22,23,24 In rare cases, allergic reactions to Quercetin can occur in humans.1

Drug-Nutrient Interactions 1. Estradiol (found in oral contraceptives and hormone replacement therapy) Quercetin may slow down the detoxification of estradiol by liver enzymes. There are no human reports of Quercetin potentiating the effects of estradiol through this mechanism at this time. 2. Felodipine Felodipine is a calcium channel blocker used in the treatment of congestive heart failure, hypertension and Raynaudâ&#x20AC;&#x2122;s Syndrome. Test tube studies indicate that Quercetin inhibits the enzyme in the liver that is responsible for the breakdown of felodipine. This may result in higher, more potentially dangerous levels of felodipine in the bloodstream, although no human reports of adverse effects have been reported to date.25

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

Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 320-31. Beyer-Meyers A, et al. Diminished sugar cataractogenesis by quercetin. Exp Eye Res 1979; 28(6): 709-16 Chaudry PS, et al. Inhibition of human lens aldose reductase by flavonoids, sulindac, and indomethacin. Biochem Pharmacol. 1983; 32: 1995-98 Havsteen B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharmacol 1983;32:1141-8. Middleton E. The flavonoids. Trends Pharmaceut Sci 1984;5:334-8. Ferrandiz ML, Alcaraz MJ. Anti-inflammatory activity and inhibition of arachidonic acid metabolism by flavonoids. Agents Action 1991;32:283-7. Middleton E, Drzewiedi G. Flavonoid inhibition of human basophil histamine release stimulated by various agents. Biochem Pharmacol 1984;33:3333-8. Middleton E, Drzewieki G. Naturally occurring flavonoids and human basophil histamine release. Int Arch Allergy Appl Immunol 1985;77:155-7. Amella M, Bronner C, Briancon F, Haag M, Anton R, Landry Y. Inhibition of mast cell histamine release by flavonoids and bioflavonoids. Planta Medica 1985;51:16-20. Pearce F, Befus AD, Bienenstock J. Mucoal mast cells, III. Effect of quercetin and other flavonoids on antigen-induced histamine secretion from rat intestinal mast cells. J Allergy Clin Immunol 1984;73:819-23. Busse WW, Kopp DE, Middleton E. Flavonoid modulation of human neutrophil function. J Allergy Clin Immunol 1984;73:801-9. Yoshimoto T, Furukawa M, Yamamoto S, Horie T, WatanabeKohno S. Flavonoids: Potent inhibitors of arachidonate 5-lipoxygenase. Biochem Biophys Res Common 1983;116:612-8. Chaundry PS, Cambera J, Juliana HR, Varma SD. Inhibition of human lens aldose reductase by flavonoids, sulindac and indomethacin. Biochem Pharmacol 1983;32:1995-8. Varma SD, Muzuno A, Kinoshita JH. Diabetic cataracts and flavonoids. Science 1977;195:87-9. Elangovan V, et al. Studies on the chemopreventative potential of some naturally-occurring biovlavonoids in 7,12dimethylbenz(a)anthracene-induced carcinogens in mouse skin. J Clin Biochem Nutr 1994;17:153-60.

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100 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 16. Verma AK, Johnson JA, Gould MN, Tanner MA. Inhibition of 7,12-dimenthylbenz(a)anthracene and N-nitrosomethyl urea induced rat mammary cancer by dietary flavonol quercetin. Cancer res 1988;48:5754-5758. 17. Stavric B. Quercetin in our diet: from potent mutagen to probable anticarcinogen. Clin Biochem 1994;27:245-8. 18. Larocca LM, Giustacchini M, Maggiano N, Ranelletti FO, Piantelli M, Alcini E et al. Growth-inhibitory effect of quercetin and presence of type II estrogen binding sites in primary human transitional cell carcinomas. J Urol 1994;152:1029-33. 19. Castillo MH, Perkins E, Campbell JH, et al. The effects of the bioflavonoid quercetin on squamous cell carcinoma of head and neck origin. Am J Surg 1989: 351-5 20. Kuo SM. Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Letter 1996;110:41-8. 21. Tarayre JP, Lauressergues H. Advantages of a combination of proteolytic enzymes, flavonoids and ascorbic acid in comparison with non-steroid anti-inflammatory agents. Arzneim Forsch 1077;27:1144-9. 22. Hirono I, Ueno I, Hosaka S, Takanashi H, Matsushima T, Sugimura T et al. Carcinogenicity examination of quercetin and rutin in ACI rats. Cancer Lett 1981;13:15â&#x20AC;&#x201C;21. 23. Kato K, et al. Lack of promotive effect of quercetin on methlazoxy acetate carcinogenesis in rats. J Toxicol Sci 1984;9:319-25. 24. Kato K, et al. Absence of initiating activity by quercitin in the rate liver. Ecotoxicol Environ Safety 1985;10:63-9. 25. Healthnotes online. Healthnotes Inc, 2000.

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S-Adenosylmethionine (SAM) General Features S-Adenosylmethionine (SAM) is an important methyl donor (CH3) in the transmethylation reactions required for the synthesis of DNA bases, creatine, glutathione, neurotransmitters (i.e. melatonin), phosphatidylcholine, and for liver detoxification reactions. In the body, SAM is synthesized from methionine and ATP. Methionine, required for the synthesis of SAM, is obtained from diet, or produced from homocysteine, which accepts a methyl group (CH 3) from vitamin B12; that was transferred to vitamin B12 from folic acid originally. Thus the synthesis of methionine and SAM are primarily dependant upon an adequate nutritional status of folic acid and vitamin B12.1,2,3 Curiously, high doses of methionine do not increase levels of SAM, but rather are associated with some degree of toxicity.4 The most natural way to optimize endogenous synthesis of S-Adenosylmethionine is to ensure adequate intake of folic acid, vitamin B12 and protein.3 Of clinical significance is the fact that SAM supplementation on its own has been shown to provide significant results in depression, osteoarthritis, fibromyalgia and liver disorders.5

Clinical Applications and Mechanism of Action 1. Depression, Anxiety and Dementia As a principle donor of methyl groups (CH3) to various reactions, SAM is necessary for the synthesis of phospholipids (phosphatidylcholine, phosphatidylserine) and neurotransmitters. SAM supplementation in depressed or anxious patients has resulted in increased levels of serotonin, dopamine and phosphatidylserine. It improves binding of neurotransmitters to receptor sites, and affects brain cell membrane fluidity, resulting in significant clinical improvement in depression and anxiety.2,3,6,7,8 A number of excellent clinical trials have demonstrated the value of SAM as a natural biochemical intervention in depression. The typical dosage is 400 mg, three to four times per day (studies include general depression and post-partum depression).9-13 Alzheimerâ&#x20AC;&#x2122;s disease patients have been shown to have low levels of SAM and may therefore, benefit from its administration.2,3 2. Osteoarthritis SAM has demonstrated impressive results in the treatment of osteoarthritis. SAM is required for the synthesis of cartilage components and appears to exert pain-relieving and anti-inflammatory properties.14,15 At least 21,524 patients with osteoarthritis have participated in clinical trials using SAM supplementation. Even when tested against commonly used anti-inflammatory drugs (i.e. Advil, Motrin, Nuprin, Naproxen) SAM supplementation has provided significant relief of osteoarthritic symptoms and improved joint function and quality of life. An MRI (magnetic resonance imaging) study demonstrated increased cartilage formation in 14 patients with osteoarthritis of the hands, given SAM vs. the placebo. Unlike non-steroidal anti-inflammatory drugs SAM is not harmful to the intestinal tract, kidney or liver. In fact, it is used to support liver detoxification functions in anti-aging and certain diseases.16-24 In the above studies, the typical dosage of SAM was 400 mg, three times per day.

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102 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 3. Fibromyalgia Several clinical studies show that SAM can help improve various aspects of fibromyalgia, including a reduction in the number of trigger points, painful areas and improvements in mood. Other symptoms that may respond to SAM supplementation include morning stiffness and fatigue. Treatment doses were in the range of 800 mg of SAM per day.25,26,27 4. Liver Disorders SAM is beneficial for a variety of liver disorders because of its ability to promote bile flow and relieve cholestasis. It has been used successfully in cirrhosis, Gilbertâ&#x20AC;&#x2122;s Syndrome, and oral contraceptive induced liver damage. Its benefits are directly attributable to its role as a major methyl donor in the liver (detoxification process) and its lipotropic activity (transporting fat out of the liver). In Gilbertâ&#x20AC;&#x2122;s Syndrome SAM at a dosage of 400 mg, three times daily has resulted in a significant decrease in serum bilirubin. In liver cirrhosis it has been shown to improve cell membrane function, improve bile flow and increase levels of glutathione; possibly the most important liver antioxidant and detoxification agent. Animal studies provide evidence of protection against liver cancers from SAM supplementation in animals exposed to liver carcinogens. 2838

In alcoholic cirrhosis, damage to the liver prevents the natural formation of SAM from the amino acid methionine. In a double-blind study, individuals with alcoholic cirrhosis of the liver who took SAM supplementation for two years had a 47% lower rate of death or need for liver transplantation, compared with those receiving the placebo. In patients with less severe cirrhosis, the results were even more impressive.39 5. Migraine Headaches A long-term study revealed that SAM supplementation may be helpful in reducing the incidence of migraines in sensitive individuals.40

Dosage Range For most conditions the therapeutic dosage range is typically 400 mg, two or three times daily. SAM can cause nausea and gastrointestinal disturbances in some people, thus, some patients may benefit from starting with 200 mg doses and working their way up to 400 mg per individual dose.5 1. Depression and Anxiety: 400 mg, three times per day 2. Osteoarthritis: 400 mg, two or three times per day 3. Fibromyalgia: 400 mg, two times per day 4. Liver Disorders: 400 mg, three times per day 5. Migraine Headache: 400 mg, two times per day (as a preventative intervention).2

Adverse Side Effects, Toxicity and Contraindications SAM should not be taken by individuals with bipolar (manic) depression, which may trigger a manic phase in these individuals. No other significant side effects have been reported with oral SAM supplementation other than occasional nausea and gastrointestinal disturbances.5

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Drug-Nutrient Interactions No known drug-nutrient interactions have been reported. However, as with folic acid, vitamin B 12 and choline, SAM is a methyl donor, which may speed up the detoxification of various drugs in the liver. 41 As well, SAM can affect neurotransmitter levels, caution should be exercised when using SAM in conjunction with anti-depressant and antianxiety medications. Excess serotonin production, for example, can lead to serotonin syndrome, characterized by myoclonus, rigidity, hyperreflexia, shivering, confusion, agitation, restlessness, coma, autonomic instability, low-grade fever, nausea, diarrhea, diaphoresis, flushing and rarely, rhabdomyloysis and death. This is true for all natural health products that can either increase the synthesis of serotonin or inhibit its degradation.42.43

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

Marks D, Marks A, Smith C, editors. Basic Medical Biochemistry: a Clinical Approach. Balitmore, MD: Williams & Wilkins. 1996. p. 61421. Healthnotes, Inc. 2001. www.healthnotes.com: SAMe. Dietary Supplement Information Bureau. www.content.intramedicine.com: SAMe Strementinoli G. Parmacological aspects of S-adenosylmethionine: pharmacokinetics and parmacodynamics. Am J Med 1987;83:35-42. Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 365-73. Baldessarini RJ. Neuropharmacology of S-adenosyl-L-methionine. Am J Med 1987;83:95-103. Reynolds E, Carney M, Toone B. Methylation and mood. Lancet 1983;ii:196-9. Bottiglieri T, Laundry M, Martin R, et al. S-adenosylmethionine influences monoamine metabolism. Lancet 1984;ii:224. Kagan BL, Sultzer DL, Rosenlicht N, Gerner RH. Oral S-adenosylmethionine in depression: a randomized, double-blind placebocontrolled trial. Am J Psychiatry 1990;147:591-5. Rosenbaum JF, Maurizio F, William E, et al. An open-label pilot study of oral S-adenosylmethionine in major depression. Psychopharmacol Bull 1988;24:189-94. De Vanna M, Rigamonti R. Oral S-adenosyl-L-methionine in depression. Curr Ther Res 1992;52:478-85. Salmaggi P, Bressa GM, Nicchia G, Coniglio M, La Greca P, Le Grazie C. Double-blind, placebo-controlled study of S-adenosyl-Lmethionine in depressed postmenopausal women. Psychother Psychosom 1993;59:34-40. Cerutti R, Sichel MP, Perin M, et al. Psychological distress during puerperium: A novel therapeutic approach using Sadenosylmethionine. Curr Ther Res 1993;53:707â&#x20AC;&#x201C;16. Harmand M-F, Vilamitjana J, Maloche E, et al. Effects of S-adenosylmethionine on human articular chondrocyte differentiation. Am J Med 1987;83:48-54. Strementinoli G. Pharmacological aspects of S-adenosylmethionine: Pharmacokinetics and pharamcodynamics. Am J Med 1987;83:3542. Muller-Fassbender H. Double-blind clinical trial of S-adenosylmethionine versus ibuprofen in the treatment of osteoarthritis. Am J Med 1987;83:81-3. Glorioso S, Todesco S, Mazzi A, Marcolongo R, Giordano M, Colombo B, et al. Double-blind multicentre study of the activity of Sadenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharmacol Res 1985;5:39-49. Marcolongo R, Giordano N, Colombo B, et al. Double-blind multicentre study of the activity of S-adenosylmethionine in hip and knee osteoarthritis. Curr Ther Res 1985;37:82-94. Domljan Z, Vrhovac B, Durrigl T, Pucar I. A double-blind trial of ademetionine vs Naproxen in activated gonarthrosis. Int J Clin Pharmacol Ther Toxicol 1989;27:329-33. Caruso I, Peitrogrand V. Italian double-blind multicentre study comparing S-adenosylmethionine, Naproxen, and placebo in the treatment of degenerative joint disease. Am J Med 1987;83:66-71. Vetter G. Double-blind comparative clinical trial with S-adenosylmethionine and indomethacin in the treatment of osteoarthritis. Am J Med 1987;83:78-80. Maccagno A. Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med 1987;83:89-94. Konig B. A long-term (two years) clinical trial with S-adenosylmethionine for the treatment of osteoarthritis. Am J Med 1987;83:89-94.

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104 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 24. Berger R, Nowak H. A new medical approach to the treatment of osteoarthritis: report of an open phase IV study with ademetionine (Gumaral). Am J Med 1987;83:84-8. 25. Tavoni A, Vitali C, Bombardieri S, Pasero G. Evaluation of S-adenosylmethionine in primary fibromyalgia: a double-blind crossover study. Am J Med 1987;83:107-10. 26. Jacobsen S, Danneskiold-Samsoe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia: double-blind clinical evaluation. Scand J Rheumatol 1991;20:294-302. 27. Di Benedetto P, Iona LG, Zidarich V. Clinical evaluation of S-adenosyl-L-methionine versus transcutaneous nerve stimulation in primary fibromyalgia. Curr Ther Res 1993;53:222-9. 28. Mazzanti R, et al. On the antisteatosic effects of S-adenosyl-L-methionine in various chronic liver diseases: a multicentre study. Curr Ther Res 1979;25:25-32. 29. Frezza M, Surrenti C, Manzillo G, Fiaccadori F, Bortolini M, Di Padova C. Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis: a double-blind, placebo-controlled study. Gastroenterology 1990;99:211-5. 30. Adachi Y, et al. The effects of S-adenosyl-L-methionine on intrahepatic cholestasis. Jap Arch Int Med 1986;33:185-92. 31. Padova C, Tritapepe R, Padova F, et al. S-adenosyl-L-methionine antagonizes oral contraceptive-induced bile cholesterol supersaturation in healthy women: preliminary report of a controlled randomized trial. Am J Gastroenterol 1984;79:941-4. 32. Frezza M, Pozzato G, Chiesa L, Stramentinoli G, di Padova C. Reversal of intrahepatic cholestasis of pregnancy in women after high dose s-adenosyl-L-methionine administration. Hepatol. 1984;4:274-278. 33. Frezza M, Pozzato G, Pison G, et al. S-adenosylmethionine counteracts oral contraceptive hepatotoxicity in women. Am J Med Sci 1987;293:234-8. 34. Bombardieri G, Milani A, Bernardi L, Rossi L. Effects of S-adenosyl-L-methionine (SAM) in the treatment of Gilbert’s syndrome. Curr Ther Res 1985;37:580-5. 35. Angelico M, Gandin C, Nistri A, Baiocchi L, Capocaccia L. Oral S-adenosyl-L-methionine (SAM) administration enhances bile salt conjunction with taurine in patient with liver cirrhosis. Scand J Clin Lab Invest 1994;54:459-64. 36. Kakimoto H, Kawata S, Imai Y, et al. Changes in lipid composition of erythrocyte membranes with administration of S-adenosyl-Lmethionine in chronic liver disease. Gastroenterolia Japonica 1992;27:508-13. 37. Loguercio C, Nardi G, Argenzio F, Aurilio C, Petrone E, Grella A, et al. Effect of S-adenosyl-L-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease. Alcohol Alcoholism 1994;54:597-604. 38. Pascale RM, Marras V, Simile MM, Daino L, Pinna G, Bennati S, et al. Chemoprevention of rat liver carcinogenesis by S-adenosyl-Lmethionine: a long-term study. Cancer Res 1992;52:4979-86. 39. Mato JM, Cámara J, Fernández de Paz, Caballería L, Coll S, Caballero AM, et al. S-adenosyl-L-methionine in alcoholic liver cirrhosis: a randomized placebo-controlled, double-blind, multicentre clinical trial. J Hepatol 1999;30:1081-9. 40. Gatto G, Caleri D, Michelacci S, Sicuteri F. Analgesizing effect of a methyl donor (S-adenosylmethionine) in migraine: an open clinical trial. Int J Clin Pharmacol Res 1986;6:15-7. 41. Reicks M, Hathcock JN. Effects of methionine and other sulfur compounds on drug conjugations. Pharmac Ther 1998;37:67-79. 42. Bodner RA, Lynch T, Lewiss L, Kahn D. Serotonin syndrome. Neurology 1995;45:219-23. 43. Bressa GM. S-adenosylmethionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl 1994;154:714.

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105 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Shark Cartilage General Features Contrary to the popular marketing campaign associated with the use of Shark Cartilage as a dietary supplement, shark’s do get cancer, and promoting the use of Shark Cartilage based upon the notion that shark’s do not get cancer is false and highly misleading. However, some experimental and animal studies show that a particular Shark Cartilage extract may play role in one aspect of cancer prevention and/or treatment, but how this translates into the prevention and/or treatment of human cancers is not well understood, although some preliminary studies have been encouraging. At present, Shark Cartilage is one of many natural health products that continue to be studied as potential chemopreventive and cancer treatment agents. 1, 2

Principle Active Constituents Shark Cartilage is a type of connective tissue comprised of proteoglycans (mucopolysaccharides), protein substances, calcium, sulfur, and collagen protein. Which of these constituents exerts anti-tumor effects is unknown at this time. 1

Clinical Application and Mechanism of Action 1. Cancer – Preliminary research in the 1980’s suggested that Shark Cartilage inhibits angiogenesis (the growth of new blood vessels). Since cancer cells must build new blood vessels to provide themselves with nourishment for growth and replication, this effect (anti-angiogenesis) is associated with potentially stopping the spread of cancer. 3,4,5,6,7,8,9 (see also soy isoflavones, genistein, in this document) Shark Cartilage also inhibits matrix metalloproteases (MMP’s), which break down the ground substance between cells, and more easily permit the spread of cancer to adjacent tissues. 4 A few preliminary studies suggest that individuals with certain cancers may benefit from Shark Cartilage supplementation, however, well-designed research trials yielded negative results. 1,2,16,17 Nevertheless, there is some evidence to support the use of Shark Cartilage as part of the complementary treatment for various cancers, including lung, prostate, and breast cancer. 10,11,12,13,14,15 Double-blind trials, which are currently underway in Canada and the United States, are required to provide conclusive evidence that Shark Cartilage is a useful adjunct in cancer treatment, but there are no significant risks attached to using Shark Cartilage supplementation in individual cases at this time. 1,2 2. Osteoarthritis – The use of glucosamine sulfate has been shown to be very effective in the treatment of osteoarthritis. As glucosamine provides the body with raw material from which if can synthesize certain components of joint cartilage, some individuals promote the idea that ingesting cartilage itself may act in a similar manner as glucosamine. Presently, there are no studies of any kind to support this contention, and as is the case with the use of chondroitin sulfate, bovine cartilage, sea cucumber, green-lippid mussel (all of which contain whole cartilage components). It is unlikely that Shark Cartilage provides as significant an effect on the repair, regeneration and preservation of joint cartilage, as does glucosamine sulfate. 2 (see glucosamine sulfate in this document)

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106 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Dosage and Standardized Grade Cancer Treatment: 60-100 gms per day, orally or by enema. This is a very high dose, which provides the body with 2 â&#x20AC;&#x201C; 2.5 gms (2500 mg of calcium) daily. This is considered the upper limit of safe intake for calcium, although no cases of calcium toxicity have been reported at this level of Shark Cartilage supplementation. Nevertheless, practitioners and patients should be on the look out for any signs or symptoms of calcium toxicity when doses in this range are being used (see calcium in this document, for signs and symptoms of toxicity). 1

Adverse Side Effects, Toxicity and Contraindications Shark Cartilage appears to be a safe supplement. 1,2 There is one reported case of a patient who developed liver inflammation after taking Shark Cartilage supplements, but later recovered fully after the Shark Cartilage supplement was discontinued. 18 Therapeutic doses of Shark Cartilage may increase the potential for calcium toxicity, although there are no reported cases of this occurring to date. 1

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

1,2

1. 2. 3. 4. 5.

Healthnotes, Inc. 2001. www.healthnotes.com: Cartilage (Bovine and Shark) Natural Product Encyclopedia. www.consumerslab.com: Shark Cartilage Lee A, Langer R. Shark cartilage contains inhibitors of tumor angiogenesis. Science 1983;221:1185-7 Dupont E, Savard PE, Jourdain C et al. Antiangiogenic properties of a novel shark cartilage extract: Potential role in the tratment of psoriasis. J Cutan med Surg 1998;2:146-52 Sheu JR, Fu CC, Tsai ML et al. Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-antiogenesis and and anti-tumor activities. Anticancer Res 1889;18:4435-41

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107 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Davis PF, he Y, Furneaux RH et al. Inhibition of angiogenesis by oral ingestion of powdered shark cartilage in a rat model. Microvasc Res 1997;54:178-82 Oikawa T, Ashino-Fuse H, Shimamura M et al. A novel angiogenic inhibitor derived from Japanes shark cartilage (I). Extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis. Cancer Lett 1990;51:181-6 McGuire TR, Kazakoff PW, Hoie EB et al. Antiproliferative activity of shark cartilage with and without tumor necrosis factor-alpha in human umbilical vein endothelium. Pharmacotherapy 1996;16:237-44 Lee A, Langer R. Shark cartilage contains inhibitors of tumor angiogenesis. Science 1983 1983;221:1185-7 Riviere M, Latreille J, Falardeau P et al. AE-941 (Neovastat), an inhibitor of angiogenesis: phase I/II cancer clinical trial results. Cancer invest 1999;17(suppl1):16-7 Jamali M-A, Riviere M, Falardeau P et al. Effect of AE-941 (neovastat), an angiogenesis inhibitor, in the Lewis lung carcinoma metastatic model, efficacy, toxicity prevention and survival. Clin Invest Med 1998;(suppl):S16 Riviere M, Falardeau P, Latreille J et al. Phase I/II lung cancer clinical trial results with AE-941 (neovastat), an inhibitor of angiogenesis. Clin Invest Med 1998;(suppl):S14 Riviere M, Alaoui-Jamali M, Falardeau P et al. Neovastat: an inhibitor of angiogenesis with anti-cancer activity. Presented at: American Association for Cancer Research Annual Meeting 39 March 28-April 1 1998;New Orleans, LA Blaseck J, Alaoui-Jamali M, Wang T et al. Oral administration of Neovastat inhibits tumor progression in animal models of progressive tumor growth and metastasis. Int J Oncol 1997;11(suppl):934 Dupont E, Alaoui-Jamali M, Wang T et al Angiostatic and antitumoral activity of AE-941 (Neovastat), a molecular fraction derived from shark cartilage. Presented at: American Association for Cancer Research Annual Meeting 38 April 12-16 1997;San Diego CA Horsman MR, Alsner J, Overgaard J. The effect of shark cartilage extractrs on the growth and metastatic spread of the SCCVII carcinoma. Acta Oncol 1998;37:441-5 Miller DR, Anderson GT, Stark JJ et al. Phase I/II trial the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 1998;16:3649-55 Ashar B, Vargo E. Shark cartilage-induced hepatitis. Ann Intern Med 1996;125:780-1

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108 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils

Soy and Soy Extract James Meschino DC, MS,ND General Features Soybeans contain a variety of biologically active components that are associated with the prevention of certain cancers, detoxification, bone density support, cholesterol lowering and cardiovascular health, prevention of prostate enlargement and antioxidant function.

Principle Active Constituents      

Some of their more potent bioactive constituents include: Isoflavonoids Saponins Phenolic acids Coumarins Protease inhibitors Phytic acid 1,2,3,4

Clinical Application and Mechanism of Action 1. Reproductive Cancers Of the above bioactive constituents, isoflavones and protease inhibitors have been studied most thoroughly for their anti-cancer effects. Soy isoflavones may reduce risk of breast, prostate and other hormone-dependent cancers. The low breast cancer mortality rates in Asian countries and the putative anti-estrogen effects of isoflavones support this contention. Strong evidence for the prevention of prostate cancer may explain, in part, the 80 percent lower incidence of prostate cancer in Asia compared to Canada, the United States and other western countries, that do not include Soy as a common dietary staple. Soy and Soy isoflavones have been shown to decrease reproductive organ cancers in animal-based studies. Human research also suggests a protective role of Soy against cancer, however, the data is currently insufficient to make formalized recommendations. There are literally hundreds of in vitro studies showing that genistein (a predominant Soy isoflavone) inhibits the growth of a wide range of both hormone-dependent and hormone-independent cancer cells, including breast, prostate, colon and skin cells. In vitro, genistein also inhibits the metastasic activity of both breast and prostate cancer cells independent of the effects on cell growth. Genistein is known to inhibit several enzymes involved in signal transduction, including tyrosine protein kinase, MAP kinase, rhibosomal S6 kinase, and DNA topoisomerase II. Genistein also increases the concentration of transforming growth factor B (TGF-B). Together these biological mechanisms account for the ability of genistein to arrest cancer cell growth. These findings may have important implications, as the breast cancer rate in Japan is only about one-quarter of that of the United States. Similar data exists for prostate and colon cancer incidence.

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109 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils In vitro, genistein inhibits the growth of both androgen-dependent and androgen-independent prostate cancer cells. Genistein has also been shown to inhibit the 5-alpha reductase enzyme that is strongly linked to prostate enlargement (benign prostatic hyperplasia) and prostate cancer metastasis. The 5-alpha reductase enzyme converts testosterone to dihydrotestosterone (DHT). DHT build up encourages more rapid prostate cell proliferation leading to prostate enlargement and fuels the proliferation and spread of existing prostate cancer. Increased Soy intake in men under clinical trial conditions demonstrates a reduction in DHT metabolites in the blood, indicating that Soy consumption reduces DHT production in men. Soy isoflavones concentrate in prostate fluid and increased isoflavone intake has been linked to significant apoptosis (programmed cell death) of prostate cancer cells (adenocarcinoma) in a patient taking 160 mg of isoflavone content per day, one week before prostate surgery.1 Genistein also inhibits angiogenesis, the growth of new blood vessels that contribute to the spread of cancer. 5 2. Menopausal Symptoms and Female Bone Health After menopause Soy isoflavones and other phytoestrogens can provide sufficient estrogenic activity as to reduce hot flashes and other menopausal symptoms, as well as help to support bone density. Soy intervention trials have shown a reduction in hot flashes by up to 40 percent in various studies.1,6,7,8 Soy constituents (especially diadzein and genistein) have been linked to favourable effects on bone density in postmenopausal women and in animal experimental studies, often using ovariectomized rats. Dailais et al found that early postmenopausal women had a 5 percent increase in bone mineral content compared with baseline values after only 3 months of consuming Soy flour. Ipriflavone, a semisynthetic compound similar to the Soy isoflavone, diadzein, has been shown to increase bone density in postmenopausal women, at a dosage of 200 mg, three times daily.1 It is approved in Japan, Hungary and Italy as a drug for the treatment and prevention of osteoporosis.1,9 3. Cholesterol-Lowering and Cardiovascular Health Soy isoflavones appear to have favourable effects on vascular function and lipid metabolism. Soy isoflavones, structurally similar to estrogens, interact with estrogen receptors and appear to increase LDL-receptor formation. In turn this helps the body clear LDL-cholesterol and VLDL-cholesterol from the bloodstream.2 The meta-analysis of 38 controlled studies demonstrated that an average intake of 47 gm per day of Soy protein was associated with a 9.3 percent lowering of cholesterol, 12.7 percent lowering of LDL-cholesterol, 10.5 percent lowering of triglycerides and a 2.4 percent elevation of HDL-cholesterol.10 Genistein also inhibits thrombin formation and platelet activation in vitro and Soy isoflavones act as antioxidants, which may help prevent LDL-cholesterol oxidation in the bloodstream. All of these factors help to support the positive influence that Soy has on cardiovascular health.2 4. Detoxification Soy and Soy Extract have been shown to induce phase II detoxification enzymes such as Quinone reductase, Glutathione-S transferase and uridine-S-diphosphate glucuronodyl transferase. These enzymes function to detoxify and destroy electrophilic (free radicals) metabolites, formed during phase I detoxification activity. This function may also explain some of Soyâ&#x20AC;&#x2122;s anti-cancer effects.3

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Supplementation Studies and Clinical Application Clinical studies are underway to help determine the ideal Soy or Soy Extract intake level that may help prevent cancer, cardiovascular disease, prostate enlargement, osteoporosis and to help manage menopausal symptoms. Societies demonstrating the best health effects and the early intervention trials from human studies suggest that a Soy intake yielding 50-100 mg per day of Soy isoflavones provides a level of intake associated with the above mentioned benefits according to recent reviews.1,11

Dosage and Standardized Grade Soy or Soy Extract intake yielding 50 - 100 mg of isoflavones per day support the following applications:  General health support  Menopausal symptom management  Bone density support  Cholesterol and triglyceride lowering and cardiovascular system support  Enhancement of phase II detoxification and liver support 1, 2, 6, 7, 8, 10

Adverse Side Effects, Toxicity and Contraindications Soy products and cooked soybeans are safe at a wide range of intakes. A small percentage of people have allergies to soybeans and thus should avoid Soy products.

Drug-Nutrient Interactions Simultaneous intake of Soy or Soy Extract with estrogen replacement, the birth control pill (oral contraceptives) or thyroid hormone may decrease the absorption of these drugs. It is best not to take these drugs at the same time as Soy foods or Soy Extract supplements. Due to the coumarin content of Soy it may potentiate the effects of warfarin, 12 however, no reports of bleeding disorders have been documented in patients using Soy products and anti-coagulants, concurrently. Estrogen–containing drugs and Tamoxifen: There is uncertainty at this time as to the interaction of soy phytoestrogens with oral contraceptives, hormone replacement therapy, and the use of the drug tamoxifen, which is used to help prevent a recurrence of cancer in women who previously had estrogen-receptor positive breast cancer. To date, no human studies have revealed a negative interaction in this regard. Although some researchers caution against combining these interventions, there is evidence to support the intake of soy and possibly other phytoestrogens in these cases. Isoflavones are a form of “selective estrogen receptor modulator (modifier), which preferentially activate the beta estrogen receptor on reproductive and other tissues, while having little affinity for alpha estrogen receptors on these tissues (this is similar to the effect of Tamoxifen, which is used to help prevent recurrence of estrogen receptorpositive breast cancer). Over-stimulation of alpha receptors from estradiol and estrone (two of the body’s natural estrogens that are found in estrogen-containing drugs) tends to result in more rapid cell division and increased risk of breast cancer. Due to their greater affinity for beta receptors, 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 a potential to prevent breast cancer and other reproductive cancers, and may also be useful in containing or controlling existing cancers in certain cases. Intensive investigation is underway at this time to determine if this latter application is valid. Until this is clearly established, women should not take soy isoflavone supplements of any kind to help treat existing reproductive cancer or to help block recurrence of a reproductive cancer, without the consent of her attending physician. 13,14,15

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

Messina M. Legumes and soybeans: an overview of their nutritional profiles and health effects. Am J Clin Nutr 1999;70(suppl):439-450. Anderson JW et al. Cardiovascular and renal benefits of dry bean and soybean intake. Am J Clin Nutr 1999;70(suppl):464-474. Appelt LC. Soy feeding induces Phase II enzymes in rat tissue. Nutr Cancer,1997;28,3:270-275 Wei H et al. Antioxidant and antipromotional effects of the soybean isoflavone genistein. Proc Soc Exp Med 1995;208:124-129. Fotsis T et al. Genistein a dietary-derived inhibitor of in vitro angoigenesis. Proc Natl Acad Sci USA 1993;90:2690-2694. Murkeis AL et al. Dietary flour supplementation decreases post-menopausal hot flashes: Effect of soy and wheat. Maturitas 1995;21,3:189-195. Albertazzi P et al. The effect of dietary soy supplementation on hot flashes. Obstet Gynecol 1998;91:6-11. Cassidy A et al. Biological effects of a diet of soy protein rich isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr 1994;60:333-340. Brandi M.L. New treatment strategies: Ipriflavone, strontium, Vitamin D metabolites and analogs. Am J Med 1993;95(suppl 5A):69-74. Anderson JW et al. Meta-analysis of effects of soy protein intake on serum lipids in humans. N Engl J Med 1995;333:276-282. Messina M. To recommend or not to recommend soy foods. J Am Diet Assoc. 1994;94,11:1253-1254. Healthnotes online. Healthnotes online, Inc.2000. Mills S and Bone K. Principles and Practice of Phytotherapy. Churchill Livingstone, Publisher (2000): 54-6;67-8. Medical Post, Oct 3,2000: Isoflavones and Menopause. Dornstauder E, Jisa E, Unterrieder I, Krenn L, Kubelka W, Jungbauer A. Estrogenic 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

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Taurine General Features Taurine is a non-essential, sulfur窶田ontaining amino acid. In the body it can be synthesized from the sulfur-containing amino acids methionine and cysteine. However, some dietary taurine appears to be important to ensure adequate taurine status as retarded growth and degeneration of the retina of the eye have been shown in animals fed a taurinedeficient diet.1 Very large quantities of taurine are found in the retina of many mammals (including humans), where it helps to protect the photoreceptors in the retina of the eye from ultra-violet light-induced free radical damage. Studies indicate that it may be important as a dietary supplement in cases of optic endemic neuritis and other conditions of the retina.2 Besides the retina, taurine is concentrated in other organs that have high electrical activity such as the heart and the brain. Premature infants, patients with cystic fibrosis and some otherwise normal individuals are unable to synthesize sufficient amounts of taurine, making it an essential nutrient in these cases.1,5 Taurine is only found in foods of animal origin and thus, a vegan vegetarian, with an inborn defect resulting in impaired taurine synthesis, may be at higher risk in developing a taurine deficiency state.1,5

Clinical Application and Mechanism of Action 1. Congestive Heart Failure Taurine helps to regulate the contraction and pumping action of the heart muscle. Studies indicate that taurine may support heart muscle function while helping to reverse symptoms of congestive heart failure. In a double-blind, randomized, crossover, placebo-controlled study, taurine supplementation in patients with congestive heart failure was shown to result in significant improvement in the New York Heart Association functional class, pulmonary crackles, and chest film abnormalities as compared to the placebo. Side effects did not occur in the taurine group and the researchers concluded that these results indicate that addition of taurine to conventional therapy is safe and effective for the treatment of patients with congestive heart failure.6 In a second study by J Azuma et al, 24 patients with congestive heart failure were given 2 gms of taurine supplementation per day for four to eight weeks. Taurine supplementation resulted in objective signs of improvement in 19 of the 24 patients and, thirteen of fifteen patients who were designated as New York Heart Association functional class III or IV before receiving taurine could be designated as class II after they completed the study, suggesting that taurine was capable of reversing congestive heart disease to a very significant degree in these patients.7 2. Insulin-dependent Diabetes Mellitus There is evidence to show that Insulin-dependent diabetics (IDDM) may have low taurine levels, which may be a factor in their increased susceptibility to excessive platelet clotting leading to cardiovascular disease. In a study by F Franconi et al, 39 IDDM patients and 34 control subjects were recruited for a taurine supplementation study using a dose of 1,500 mg of taurine per day. Initially, the IDDM patients were shown to have significantly lower plasma and platelet levels of taurine than the controls prior to taurine supplementation. After supplementation with taurine the IDDM group realized the same plasma and platelet levels of taurine as the control group and platelet aggregation in this group was reduced, as compared to pre-supplementation measures. This study showed that taurine appears to help reduce the activation of arachidonic acid in the biochemical pathway leading to the formation of pro-inflammatory eicosanoids such as thromboxane A2, which increases platelet aggregation.8

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113 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 3. Cystic Fibrosis Children with cystic fibrosis frequently have steatorrhea (high levels of fat in their stools due to impaired fat absorption), which has now been linked in part to a deficiency of taurine in their bile acids. Bile acids emulsify fats as part of the fat digestion process. Cystic Fibrosis patients secrete normal levels of pancreatic enzymes and thus, their inability to absorb fat stems from some other defect. Studies have shown that taurine supplementation can effectively reverse steatorrhea in cystic fibrosis patients.3,4 The study by LJ Smith et al, used a daily dosage of 30 mg/kg body weight per day, in thirteen children with cystic fibrosis. They showed a significant reduction in steatorrhea with a reduction of fecal fatty acid excretion dropping from 26.5g/24 hours to 15.4g/24 hours. Taurine appears to improve the micellar phase of fat digestion as an essential component of the bile complex.4 4. Liver Protective Effect (Hepatoprotection) and Detoxification Animal studies show that taurine supplementation can reduce the toxic effects of cadmium, acetaminophen and carbontetrachloride on the liver and other organs. Under these test conditions, taurine appears to help maintain normal levels of glutathione (in a similar fashion as N-acetyl cysteine, the anti-dote for acute acetaminophen poisoning), which is otherwise greatly depleted by these toxic compounds. Liver cell damage is also minimized to a significant degree and increased fecal elimination of cadmium has been noted with taurine supplementation in these experimental studies.9,10,11 In general, the dose of taurine commonly used in animal testing is approximately 200 mg/kg of body weight, which is the dose that prevented acetaminophen toxicity in rats injected with 800 mg/kg body weight of acetaminophen intraperitoneally â&#x2C6;&#x2019; a level that would otherwise severely damage liver cells. The above noted dose of taurine prevented liver damage in this study and the researchers conclude that taurine supplementation possesses prophylactic and therapeutic effects in acetaminophen-induced hepatic injury.10 This is an important finding, as chronic use of the pain killer acetaminophen is a frequent cause of severe liver and kidney damage in humans.12

Dosage and Standardized Grade 1. 2. 3. 4.

Congestive Heart Failure â&#x20AC;&#x201C; 1500 to 2000 mg per day in divided doses 7 Insulin-dependent Diabetes Mellitus - 1500 mg per day in divided doses 8 Cystic Fibrosis - 30 mg per kg body weight per day, in cases of steatorrhea 4 Liver Support and Protection - 500 to 5,000 mg per day, depending upon exposures to toxic compounds and degree of previous liver damage 5 (see also N-acetyl cysteine in compendium)

Adverse Side Effects, Toxicity and Contraindications Taurine has been shown to have a depressant effect on the central nervous system and may adversely affect shortterm memory. It is the nerve-depressant aspect of taurine that has attracted interest in those who are examining its potential as an agent to treat epilepsy, which involves a state of over excitation. Some preliminary studies indicate that it may have application for epileptics, but further investigation is necessary to establish its efficacy in these cases.5,13,14,15

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Drug-Nutrient Interactions There are no known instances where taurine supplementation interferes with or potentiates the effects of any drugs, although its biological action in reversing congestive heart failure may be similar to that of cardiac glycoside drugs, such as digitalis and digoxin. Thus, the attending physician should be made aware of the patientâ&#x20AC;&#x2122;s intent to use taurine supplementation in cases where digitalis is being administered. 5,6,7 It has been established that various chemotherapy drugs, such as cyclophosphamide, cisplatin, docetaxel, fluorouracil, methotrexate and paclitaxel, deplete body stores of taurine and, thus, supplementation with taurine may be advisable when taking these drugs. 16

1. 2.

Hendler S. The Doctorâ&#x20AC;&#x2122;s Vitamin and Mineral Encyclopedia. Simon and Schuster 1990;224-5 Gonzalez-Qevedo A, Obregon F, Santiesteban Freixas R, et al. Amino acids as biochemical markers in epidemic and endemic optic neuropathies. Rev Cubana med Trop 1998;50(Suppl):241-4 3. Thompson GN. Excessive fecal taurine loss predisposes to taurine deficiencyin cystic fibrosis. J Pediatr Gastroenterol Nutr Mar1988;7(2):214-9 4. Smith LJ, Lacaille F, Lepage G, et al. Taurine decreses fecal faty acid and sterol excretion in cystic fibrosis. A randomized double-blind trial. Am j Dis Child Dec1991;145(12):1401-4 5. Dietary Suplement Information Bureau, USA: Taurine (Dietary Supplementation Education Alliance, copyright 2001) 6. Azuma J, et al. Therapeutic Effect of taurine in congestive heart failure: a double-blind crossover trial. Clin Cardiol May 1985;8(5):276-82 7. Azuma J, et al. Therapy of congestive heart failure with orally administered taurine. Clin Ther 1983;5(4):398-408 8. Franconi F et al. Plasma and platelet taurine are reduced in subjects iwith insulin-dependent diabetes mellitus: effects of taurine supplementation. Am J Clin Nutr May1995;61(5):1115-9 9. Hwang DF, Wang LC. Effect of taurine on toxicity of cadmium in rats. Toxicology Oct2001;167(3):173-80 10. Waters E, Wang JH, Redmond HP, et al. Role of taurine in preventing acetaminophen-induced hepatic injury in the rat. Am J Physiol Gastrointest Liver Physiol Jun2001;280(6):G1274-9

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115 Meschino Health Comprehensive Guide to Accessory Nutrients and Essential Oils Accessory Nutrients and Essential Oils 11. Wu C, Kennedy DO, Yano Y, et al. Thiols and polyamines in the cytoprotective effect of taurine on carbon tetrachloride-induced heptotoxicity. J Biochem Mol Toxicol 1999;13(2):71-6 12. Drugs.com 13. Barbeau A. Zinc, taurine and epilepsy. Archives of Neurology 1974:30-52 14. Barbeau A, et al. The neuropharmacology of taurine. Life Sciences 1975;17:669-78 15. Takahashi R, Nakane Y. Clinical trial of taurine in epilepsy. In:Barbeau A and Huxtable RJ (eds.), Taurine and Neurological Disorders, New York. Raven Press 1978:p375 16. Desai TK, Maliakkal J, Kinzie JL, et al. Taurine deficiency after intensive chemotherapy and/or radiation. Am J Clin Nutr 1992;55:708-11

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Trimethylglycine (Betaine) General Features Trimethylglycine functions in the body as a methyl donor (as do folic acid, vitamin B 12, choline and S-adenosylmethionine).1,2 As a methyl donor Trimethylglycine is particularly involved in liver function, including detoxification reactions. As well, it plays a role in carnitine synthesis, which also occurs in the liver.3 Trimethylglycine is closely related to choline (tetramethylglycine) in that as choline donates one of its four methyl groups to another molecule, it becomes Trimethylglycine (Betaine). If Trimethylglycine donates one of its methyl groups, then it becomes dimethylglycine.2 In animals Trimethylglycine has been shown to protect against chemical damage to the liver.4-7 In alcohol-induced liver damage, the first stage is accumulation of fat in the liver (fatty liver degeneration). Trimethylglycine has been shown to be of benefit in these cases due to its lipotropic properties (donating a methyl group to aid in the transport of fat out of the liver) in both animal and human studies.8,9 Betaine as a treatment for alcohol-related liver damage is very popular in Germany, Italy and France, as is the use of milk thistle and S-adenosylmethionine.8-16 Betaine should not be confused with Betaine hydrochloride, which is primarily a supplement to provide hydrochloric acid to patients with low stomach acidity, aiding digestion. Betaine or Trimethylglycine supplementation is usually in the form of betaine citrate or betaine aspartate.13,14

Clinical Application and Mechanism of Action 1. Alcohol-Induced Fatty Liver Disease The first step in liver damage that results from drinking alcohol is the accumulation of fat in the liver. Due to its lipotropic effects, betaine has been shown to produce significant improvement in this condition in several human studies.10-16 2. Hyperhomocysteinemia Trimethylglycine may aid folic acid and vitamin B12 in helping to reduce elevated levels of homocysteine (1,000 mg, two or three times daily). Betaine has been reported to be helpful in some patients whose homocysteine levels did not improve with supplementation with folic acid, vitamin B6 and vitamin B12.17 High levels of homocysteine increases risk of heart disease, and therefore, betaine supplementation should be considered as an adjunctive treatment in patients whose elevated homocysteine levels do not respond adequately to supplementation with B-vitamins alone (see folic acid in this document for a detailed discussion regarding hyperhomocysteinemia).

Dosage Ranges 1. Liver Disease: 1,000 mg to 2,000 mg, three times per day.10,11,12,13,14,15,16 2. Hyperhomocysteinemia (unresponsive to folic acid, vitamin B 6 and vitamin B12): 1,000 mg, two to three times per day.17 3. General Wellness Support: 500-1,000 mg per day.10-16

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Adverse Side Effects and Toxicity No side effects have been reported at recommended levels of intake. Betaine is a very non-toxic compound.

Drug-Nutrient Interactions A Betaine-containing substance in the urine (glycine-betaine) has been shown to reduce the effectiveness of antibiotic therapy for urinary tract infections (UTI), and compounds similar to betaine are known to enhance the growth of bacteria that cause UTIs. Thus, betaine supplementation should not be used during active urinary tract infects or in concert with antibiotics intended to treat UTIs.18,19

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

Selhub J. Homocysteine metabolism. Ann Rev Nutr 1999;19:217-46. Barak AJ, Tuma DJ. Betaine, metabolic by-product or vital methylating agent? Life Sci 1983;32:771-4. Chambers ST. Betaines: their significance for bacteria and the renal tract. Clin Sci 1995;88(1):25-7. Junnila M, Barak AJ, Beckenhauer HC, Rahko T. Betaine reduces hepatic lipidosis induced by carbon tetracholoride in Sprague-Dawley rats. Vet Hum Toxicol 1998;40:263-6. Kim SK, Kim YC, Kim YC. Effects of singly administered betaine on hepatotoxicity of chloroform in mice. Food Chem Toxicol 1998;36:655-61. Barak AJ, Beckenhauer HC, Matti J, Tuma DJ. Dietary betaine promotes generation of hepatic S-adenosylmethione and protects the liver from ethanol-induced fatty infiltration. Alcohol Clin Exp Res 1993;17:552-5. Murakami T, Nagamura Y, Hirano K. The recovering effect of betaine on carbon tetrachloride-induced liver injury. J Nutr Sci Vitaminol 1998;44:249-55. Barak AJ, Beckenhauer HC, Tuma DJ. Betaine, ethanol, and the liver: a review. Alcohol 1996;13:395-8[review]. Barak AJ, Beckenhauer HC, Badakhsh S, Tuma DJ. The effect of betaine in reversing alcoholic steatosis. Alcohol Clin Exp Res 1997; 21:1100-2. Semmler F. Treatment of liver diseases, especially of fatty liver with betaine citrate. Ther Ggw 1977;116:2113-24 [in German]. Kandziora J. Therapeutic experience with the lipotropic hepatic drug Flacar in the internal medicine practice. AFA 1976;5f2:1561-3 [in German]. Babucke G, Sarre B. Clinical experience with betain citrate. Med Klin 1973;68:1109-13 [in German]. Hilt G, Tuzin P. Clinical results using betaine citrate (Flacar) in fatty livers. Med Monatsschr 1973;27(7):322-5 [in German]. Nicrosini F. Therapeutic activity of betaine aspartate. Clin Ter 1972;15;61:227-36 [in Italian]. Cairella M, Volpari B. Betaine aspartate in the therapy of liver diseases. Clin Ter 1972;60:513-34 [in Italian]. Cachin M, Pergola F. Betaine aspartate in the hepato-digestive domain. Sem Ther 1972;60:513-34 [in Italian]. Healthnotes, Inc. 2001. www.healthnotes.com : Betaine. Peddie BA, Chambers ST. Effects of betaines and urine on the antibacterial activity of aminoglycosides. J Antimicrob Chemother 1993;31:481-8. Chambers ST, Peddie BA, Randall K, Lever M. Inhibitors of bacterial growth in urine: what is the role of betaines? Int J Antimicrob Agents 1999;11:293-6 [review].

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