IHP Magazine - November/December 2012 by IHP Magazine

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Salvestrols

Hyperthermia in Oncology

Female Fertility

By William R Ware, PhD

By Chris Habib, ND and Gurdev Parmar, ND, FABNO

By Gillian Flower, ND

Dr Joseph Gabriele, PhD Delivering the future of pain relief

001.IHP_Cover.indd 2

Continuing Education

What not to do; Vitamin A and beta carotene By Philip Rouchotas, MSc, ND and Heidi Fritz, MA, ND

12-11-15 9:16 AM

The evolution of pain management

Radical new science revolutionizes trans-dermal healing

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The pharMAX™ Topical PRO Series contains natural oils and extracts, and is powered by Delivra™, a revolutionized trans-dermal topical delivery system that penetrates deep into the skin, providing relief directly to affected areas.* • Alternative to oral medication • Potential to inhibit 5 pain pathways* • Contains natural oils and extracts • Non-greasy, non-sticky for variable glide and workability • No strong odours • Airless pump minimizes oxidation

“Deliver medication right through the skin with a cream – deeper than ever before” Joseph Gabriele PhD Molecular Pharmacologist Specialty: Signal transduction pathways of disease states Creator of Delivra™ trans-dermal delivery system

* These statements have not been evaluated by Health Canada. These products are not intended to diagnose, treat, cure, prevent any disease. This information is for healthcare practitioners only.

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from the publisher

Connect With Us

Unsung Heroes

fter speaking with many of our readers and advertisers we are glad to see many of you like the redesign of IHP, notably the separation of peer reviewed articles from stories, news, and profiles. Thank you for your support as we continually strive to elevate the quality of our publication. The NHL lockout has brought a lot of attention to the junior ranks of hockey. Talent and excitement is bursting at the seams in this area! I relate this situation to many of the physicians and scientists we highlight in IHP; mainstream medical news that makes the most noise catches the worldâ&#x20AC;&#x2122;s attention. We instead value those who work in the realm of creativity and ingenuity, flying under the radar yet truly achieving change. We acknowledge the loss of one such hero who has fallen. Glen Chiasson, the Event Director for the annual Primary Care Today convention held annually in Toronto, has recently passed. Glen was a bubbly and friendly guy who went out of his way to make sure everyone was accommodated. It was Glen who recognized the need for the presence of natural medicine at the Primary Care event, and helped ensure the success of IHP and Natureâ&#x20AC;&#x2122;s Source for the past several years within the venue. He will be dearly missed by his friends and family, especially his three young daughters and wife Sonya.

Sanjiv Jagota Publisher

4 www.ihpmagazine.com l November/December 2012

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12-11-16 2:30 PM

Mineral Matrix

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Infant supplement

The ideal dietary supplement, our Mineral Matrix® pure dehydrated goat whey is an all-natural, highly concentrated whole-food source of more than 25 naturally occurring macro and trace minerals in a bio-organic form that our bodies recognize and utilize with ease. Including goat milk whey as regular part of a balanced diet carries an astonishing range of health benefits: • alleviates osteoporosis • relieves the pain associated with joint disorders, including rheumatism and arthritis • treats stomach acidity, as well as sensitive digestion • alleviates constipation • an excellent source of the minerals and trace elements vital to a child’s nutrition

• a good supplement (in diluted form) to the diet of infants, one that is especially helpful in treating colic • a great means of supplying the much needed minerals and trace elements that are depleted through pregnancy or breast feeding in expectant or new mothers • strengthens a deficient immune system • helps in overcoming lethargy and fatigue

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Products Professionals Prefer® Health Canada Site License 300242

12-11-15 2:29 PM

Acid-Base Balance: ® The Secret to Health and Longevity

Mineral Matrix

The Role of Mineral Matrix in Helping to Maintain this Delicate Equilibrium

Product Monograph for IHP, November 2012 By Terry Vanderheyden, ND

Acid-Base Equilibrium

Nature’s Unique Whole Food Revitalizer

Despite having the highest per capita calcium and milk consumption, Western nations have the highest rates of hip fractures. It has been well documented by many authors for many years that hip fracture rate is related to metabolic acidosis caused by a diet rich in certain animal proteins, especially cow’s milk.i

Pain Reliever

Alleviates Constipation

Certain animal foods, refined sugar and flour products, have an acid-promoting effect in the body. Maintaining a proper acid-base balance is essential to maintaining healthy bones, as well as preserving general good health.

Infant supplement

It is simple to calculate the relative renal acid load of any food or product by using the following formula:ii 0.49 X protein (in grams) +0.037 X phosphorus (in mg)

Terry Vanderheyden, ND Research Consultant

-0.021 X potassium (mg) -0.026 X magnesium (mg) -0.013 X calcium (mg) Thus, for Mineral Matrix®, we can calculate the renal acid load to be -17.7. In other words, it has a significant net alkalizing effect. Compare this with similar sized (by weight) servings of a number of foods: Food

Net renal acid load (- is alkaline, + is acidic)

Cucumber

-0.6

Beet greens

-4.7

Brown rice

+0.3

It should be noted that net renal acid effect is closely related to the potassium content of a food. Note that regular measurings of urine and salivary pH can help one to maintain optimal pH. Measurements carried out over a 5-day period should show urine pH in the ideal range of 5.5 to 5.8, whereas optimal pH for saliva is 6.2 to 7.0.iii

References:

Frassetto LA, et al. ,“Worldwide Incidence of Hip Fracture in Elderly Women: Relation to Shiitake mushroom -0.4 Consumption of Animal and Vegetable Foods”, J Gerontology 2000; 55: M585–M592. Almonds +0.8 ii Thomas Remer, Triantafillia Dimitriou, and Cola +0.08 Friedrich Manz, “Dietary potential renal acid Consider daily use of Mineral Matrix® as load and renal net acid excretion in healthy, Watermelon -0.5 an easy way to maintain proper acid-base free-living children and adolescents”, Yam -1.7 balance in the body, which is especially Am J Clin Nutr 2003; 77: 1255–60. important, given the preponderance of Lemon juice -0.7 iii Donald Feeney, DC, Saliva & Urine pH acid-forming foods eaten in the typical Evaluation, Accessed online October 12, 2012 Mineral Matrix® -17.7 Standard American Diet. from http://councilonnutrition.com/ iv Julia Williams, “Alkalising Your Diet: The Essential Potassium Principles of the Naturopathic Diet”, Accessed Potassium should be present in the diet at roughly a 5:1 ratio with respect to sodium.iv Indeed, a recent online March 2012 from www.juliawilliams.co.uk v epidemiologic study of 12,267 adults has concluded that a®high level of sodium relative to potassium Quanhe Yang, Tiebin Liu, Elena V. Kuklina, The ideal dietary Mineral pure mortality dehydrated goatratio whey in one’s diet issupplement, associated with anour increased risk ofMatrix death: all-cause has a hazard of is an all-natural, et al,highly “Sodiumconcentrated and Potassium Intake and 1.46 comparing withnaturally the lowest quartile. The strongest was observed whole-food source the of highest more quartile than 25 occurring macroassociation and trace minerals in a bio-organic our bodies Mortalityform Amongthat US Adults”, Arch Intern Med for ischemic heart disease mortality, with a hazard ratio of 2.15. Higher potassium intake was associated July 11, 2011;171 (13): 1183–1191. recognize and utilize with ease. i

with lower mortality risk (hazard ratio 0.8).v

Enter goat’smilk milk whey whey. It as contains a whopping 1,000 potassium diet (typical assay) per Mineral range of health benefits: Including goat regular part of a mg balanced carries anserving. astonishing Matrix® is thus a great way to meet the daily potassium needs for optimal health and specifically for cardiovascular maintenance.

• alleviates osteoporosis

• a good supplement (in diluted form) to the diet of infants, one that is especially helpful in treating colic

Electrolyte Replacement • relieves the pain associated with joint disorders, including The issue and with modern electrolyte sports drinks is their saturation with sugar, usually in the form of • a great means of supplying the much needed minerals and rheumatism arthritis high-fructose corn syrup, combined with too-high sodium content relative to other electrolytes like trace elements that are depleted through pregnancy or potassium and magnesium. A serving of Mineral Matrix® contains far more potassium than typical • treats stomach acidity, as well as sensitive digestion Products breast electrolyte replacement products, while including sufficient magnesium, sodium, and a rangefeeding of trace in expectant or new mothers • alleviates constipation minerals as well. • strengthens a deficient immune system Professionals Note that diarrhea also causes electrolyte depletion; Mineral Matrix® represents an ideal mineral ratio Prefer® • an excellent source of the minerals and trace elements • helps in overcoming lethargy and fatigue for repletion in individuals suffering from this problem. vital to a child’s nutrition Hippocrates is reputed to have said that, “if you want to be healthy, buy a goat and live on the south side of a mountain.” Modern science has certainly attested to the vital truth behind this maxim!

For more® INGREDIENTS: information, visit the website at www.stfrancisherbfarm.com MINERAL MATRIX Pure Dehydrated Goat Whey

Phone: 866.562.9131 | Fax: 866.353.0427 IHPAPR2012_XXXX_ADVERTISER_Product_FP.indd 2

Contact us today to place an order. 1.866.562.9131 | Fax: 866-353-0427 info@stfrancisherbfarm.com www.stfrancisherbfarm.com

Products Professionals Prefer® 12-11-15 2:29 PM

Provides support for Publisher | Sanjiv Jagota (416) 203-7900 ext 6125 Editor-in-Chief | Philip Rouchotas, MSc, ND (416) 203-7900 ext. 6109 Associate Editor | Angela MacNeil, MSc, ND

healthy glucose metabolism

Art Director | Scott Jordan Design | Sarah Vincett Production | Erin Booth (416) 203-7900 ext. 6110 Contributors Angela MacNeil, MSc, ND, Christopher Habib, ND Philip Rouchotas, MSc, ND, Heidi Fritz, MA, ND William R. Ware, PhD, Maria Shapoval, ND Gurdev Parmar, ND, FABNO, Gillian Flower, ND

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Advertising Information Sanjiv Jagota | Tel: (416) 203-7900 ext 6125 Email: sanjiv@ihpmagazine.com Paul Airut | Tel: (416) 203-7900 ext 6103 Email: paul@gorgmgo.com Jeff Yamaguchi | Tel: (416) 203-7900 ext 6122 Email: jeff@gorgmgo.com Erin Poredos | Tel: (416) 203-7900 ext 6128 Email: erin@gorgmgo.com

The botanical extracts found in DB-Matrix have been clinically shown to reduce blood sugar levels in diabetic patients. This unique combination has additional benefits derived from Quercetin, R-Alpha Lipoic Acid, Zinc and Lutein related to diabetic associated symptoms such as glaucoma, cataracts and polyneuropathy. TM

Circulation Garth Atkinson | Publication Partners 345 Kingston Rd., Suite 101 Pickering, Ontario, L1V 1A1 Telephone: 1-877-547-2246 Fax: 905-509-0735 Email: ihp@publicationpartners.com

Subscription Rates Canada $80 (gst included) for six issues | $120 International

Published by Canada Post Canadian Publication Mail Agreement Number 4067800 The publisher does not assume any responsibility for the contents of any advertisement and any and all representations or warranties made in such advertising are those of the advertiser and not of the publisher. The publisher is not liable to any advertiser for any misprints in advertising not the fault of the publisher and in such an event the limit of the publisher’s liability shall not exceed the amount of the publisher’s charge for such advertising. No portion of this publication may be reproduced, in all or part, without the express written permission of the publisher. ihp magazine is pleased to review unsolicited submissions for editorial consideration under the following conditions: all material submitted for editorial consideration (photographs, illustrations, written text in electronic or hard copy format) may be used by ihr Media Inc. and their affiliates for editorial purposes in any media (whether printed, electronic, internet, disc, etc.) without the consent of, or the payment of compensation to, the party providing such material. Please direct submissions to the Editor, ihp magazine.

Improving health and wellness…naturally 1 866 783-7504 www.cyto-matrix.com November/December 2012 l www.ihpmagazine.com 7

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contents

This Issue: November/December 2012 • Vol. 5 • No. 6

30 Dr Joseph Gabriele, MD Cover Story

Delivers the future of pain management

38 Simmonds McMurrer Clinic Profile

Integrating naturopathic medicine into “the island way of life”

42 The Journal of IHP

Peer-reviewed articles on clinically revelant topics

Coming Next Issue ➜ Bioidentical Hormone Replacement Therapy ➜ Cortisol and CVD ➜ DHEA-Clinical applications

Departments

4 Publisher’s Letter 11 Research News 19 Industry News 24 Calendar 25 Product Profiles 43 Editor’s Letter 45 Peer Review Board 47 Editorial Board 73 Continuing Education: What not to do:

Vitamin A and Beta Carotene

8 www.ihpmagazine.com l November/December 2012

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PRODUCT MONOGRAPH Bio-Fen Bio-Fen Plus is an oral natural health product used in the treatment of hereditary androgenic alopecia (AGA) for male or female pattern baldness. Without treatment, AGA is progressive, and causes social distress for in many men and women (Sinclair 1998). Bio-Fen Plus contains extracts BIO-FEN Men and Women M ETAGENICS Paffected HYTO M ULTI of fenugreek seeds, saw palmetto berries and flax lignans, as well as specific vitamins. Each ingredient is known to possess inhibitors of the enzyme 5α-reductase. These inhibitors are responsible for relieving symptoms associated with hereditary AGA. Bio-Fen represents a line of products approved by Health Canada for hair growth and restoration. Bio-Fen Plus for and Bio-Fen Plus forand Women are both natural health PhytoMulti by Metagenics is a robust multivitamin fortified with over 20 phytonutrient extracts, includingMen lutein, greet tea extract, resveratrol. Asoral such, One of the primary causes of hair loss is a high level of the male hormone dihydrotestosterone (DHT) within hair follicle (Vierhapper, 2001). products (NHPs) which support hair growth in men and women with hereditary androgenic alopecia (AGA), or female/male pattern baldness. Bio-Fen contains a combination of PhytoMulti is an ideal product for use in adults in order to optimize vitamin and mineral status, in lieu of poor dietary intake or the increased physiological herb extracts andwith vitamins minerals thata are known inhibit the enzyme -reductase (5AR), pathway implicated in the progression of AGA. For people AGA, their follicles have atogreater number of5inandrogen receptors to whicheffects DHT 5-α-reductase catalyzes requirements, but&also provides broad spectrum of plant nutrients order to mimic thea key many health of aattaches. plant-based diet. The USDA MyPlate the enzymatic recommendations includeto between 9-10 servings of fruits and vegetables but lessfive-fold than 10% more of adults achieve thisthe target (Murphy 2011). conversion of testosterone dihydrotestosterone, which binds to per theday, receptor avidly than parent compound (Sinclair 1998). AGA Pathophysiology One of theThe primary causes of dietary hair losspattern is a high level of theof male hormone, dihydrotestosterone the hair follicle (Hoffmann 2002). is produced from Mediterranean is an example a well-researched diet that is very (DHT) high in within phytonutrients. The Mediterranean diet isDHT associated with markedly Saw palmetto (Serenoa repens) testosterone in the testes (males), the adrenal glands, and the follicle. Afterdisease a period time, anVitamins over abundance of DHTConsortium causes the hair follicle to degrade and shortens the active lower risk of several chronic diseases, including cardiovascular andofdiabetes (Eustruch 2006, Interact 2011, Nordmann 2011), and a high fruit phase of the eventually leading thinning hairbeen and loss. There isina large familial tendency forstudy stepwise miniaturization of had the hair follicle and an increase in the calcium ratio a Polish of of 46combined women who symptoms of diffuse alopecia, Standardized (lipophillic) Serenoa extract found tohair be(Block a potent inhibitor andhair, vegetable diet has beentoshown to has reduce riskeventual of cancer 1992), partIn due to high amounts phytonutrients. Phytonutrients have been of of telogen (resting to anagen (growth phase)through hairs, which is promoted by systemic and modulation local effectsofofsignal androgens. Althoupathways, gh everyone produces DHT, those with pantothenate was orally administered twice a day inproperties, dosesonly of 100 mg fora four to 5α-reductase, resulting in decreased tissue DHT. An open-label, dose response shown to phase) confer beneficial health effects numerous mechanisms, including transduction antioxidant and through higher of androgen receptors in contains their follicles, sitessubstances, fora DHT, and greaterlutein, androgen sensitivity experience hair loss (Prager 2002). 5AR istoresponsible forrepeated the hormonal effects. 20 of binding these including: zeaxanthin, nilotica, and extracts of artichoke leaf, grape seedand five months, and acacia vitamin B6 was injected every day for 20 30 days studynumber was conducted onPhytoMulti 42 healthy maleshair toover determine the plant effect of combination conversion of testosterone to dihydrotestosterone, which binds to the sameon androgen but rosemary, with five-fold greater(Brzezińska-Wcisło affinity. (Hoffmann 2002, Trueb extract, green coffee, green tea, citrus bioflavonoids, resveratrol, prune skin,receptor, watercress, lycopene, cinnamon, bitter and blueberry. after sixpomegranate, months 2001). It melon, was2002) determined that vitamin again of carotenoid astaxanthin and saw palmetto berry lipid extract DHT and

testosterone levels (Angwafor 2008). The men were divided into two groups:

B6 administered parenterally for a few weeks induces improvement in the hair

Flax Multivitamin supplementation been shown to benefit a varietyand of physical and cognitive parameters particularly in children, pregnant women or women who condition in subset women and Flax reduces hair are loss. onelignans group received 800 mg/day ofhas the combination supplement the other Flax thepregnant, enzyme 5AR, thus balancing formation of the male hormones thatabsorption, are responsible fora elderly. hair lossof 1995). lignans converted the body to mayinhibit become individuals under increased stress, individuals with poor and the In(Evans pregnancy, supplementation with a folicby acid group received 2000 mg/daywith of the supplement for 14 days. ANOVA-RM showed enterolactones, which compete estrogen and testosterone for receptor binding, and increase sex hormone binding globulin (SHBG), resulting in levels of free (ie active) containing multivitamin has been shown to reduce risk of complications such as placental abruption, preeclampsia, in addition to decreasinglower risk of congenital significant within-group increases in serum total testeosterone significant estrogen and testosterone. hasdefects, been shown to reduce serum levelsand of 17-beta-estradiol and facial estronecleft, sulfate (Hutchins andlimb results in a shift in estrogen metabolism to defects includingFlaxseed neural tube anencephaly, myelomeningocele, meningocele, oral structural heart2001), defects, defects, urinary Ingredients Dosetract Peranomaly, Capsule decreases serum DHT from both (P=0.05). There(WilsonMedicinal favor the less biologically active estrogens (Brooks 2004).dose andin hydrocephalus when usedbaseline prior to in conception and groups during the first trimester 2007).

was no significant difference between dose groups with regard to the increase of

Fenugreek (Trigonella foenum graecum)

Fenugreek 260 by mgup to 46% testeosterone or the decrease of DHT;use therefore both doses were shown effective Periconceptional multivitamin in lean women has been to (Angwafor decrease the risk of small-for-gestational-age under the 5th percentile seed extract 4:1 such(SGA) Fenugreek has been to used traditionally as an oral treatment for hair loss. contained in fenugreek as -sitosterol have beenwomen, shown to block DHT non-users (OR=0.54, 95%and CI),topical and has been associated with aPlant 71%sterols reduction in preeclampsia risk (OR=0.29, 95% CI) in lean users versus 2008). compared receptor sites (Prager 2002,2007; see below). non-users (Catov Bodnar 2006). Periconceptional multivitamin use has also been associated with berry reducedextract risk of several pediatric cancers, Saw palmetto containing 160 including mg leukemia (OR=0.61) (39% reduced risk); tumors (OR=0.73) (27% reduced risk); and neuroblastoma (OR=0.53) (47% reduced risk) in a recent metaAnother study tested liposterolic extract of pediatric Serenoa brain repens (LSESr) and beta45% free fatty acids Saw Palmetto (men’s product) analysis 2007). sitosterol inextract the(Goh treatment of males (23-64 of age)resulting with mild to moderate AGA. Saw palmetto is a potent inhibitor of 5 years -reductase, in decreased tissue DHT (Prager 2002). In a pilot study of 26 men with mild to moderate AGA, treatment with Flax lignans, standardized toblinded 20% Six of 10 (60%) subjects were rated improved atstress, the beta-sitosterol final visit, thus50mg establishing a combination of lipophilic saw palmetto extract 200mg and improved by up to 60%, as levels scoredofby (Prager 2002). In a meta 100parameters. mg In patients under high levels of as psychological use of a multivitamin has beensymptoms shown improve perceived stress andassessors psychometric secoisolariciresinol diglucoside (SDG) the effectiveness of inhibitors AGA (Prager 2002).resulted Chronic analysis by the Cochrane palmetto also been found to be effective as a treatment for overall symptoms of BPH (Wilt 2002). Gruenwald et 5α-reductase al group, (2002)saw found that usehas ofagainst a multivitamin for 6 months in a 40.7% improvement in self rated stress levels using a psychologicalinflammation of thequestionnaire hair follicle istoconsidered to be a contributing factor for AGA. A neurological assess “psycho-organic, central vegetative, and somatic discomforts.” Other outcomes included 29% decrease10.40 in frequency D-calcium pantothenate (Vitamina B5) mg of Silica (women’s product) study by Chittur et al91% sought to determine whether blockade of inflammation using infections and decrease in gastrointestinal discomfort. Schlebusch et al (2000) found similar benefit on various psychometric parameters in a 30 day trial Silica is a trace mineral that has been found to increase hydroxyproline concentration in connective tissue (Barel 2005). In a randomized, double blind, placebo controlled study, 50 Harris found that multivitamin supplementation canacid) improve stress, and(Vitamin alertness B3) in older men (2011). Importantly, LSESr (1997), and twoand anti-inflammatory agents (carnitine and thioctic couldmeasures alter of mood, Niacinamide 10.25supplementation mg women with skinofwere treated orally with 10mg silica as orthosilicic (OSA) for(Stough 20 weeks. The treatment group reported a significant decrease in visual analog withdamaged a spectrum B vitamins has also been shown to reduce ratings of workplace stress 2011). the expression of molecular markers of inflammation (Chittur 2009). It acid was found daily scale ratings of hair brittleness (Barel 2005). A second randomized, double blind, placebo controlled trial conducted in 50 women with brittle hair found that 10mg silica as OSA Pyridoxine HCl (Vitamin B6) 2 mg that the combination suppressedhair lipopolysaccharide-activated gene (thickness) expression(Wickett of for 9 months significantly improved elasticity, breakage, and diameter 2007).supplement. Benton et al (1988) found a significant increase in nonSeveral trials have shown increased cognitive performance inand children taking a multivitamin chemokines associated with pathways involved in inflammation apoptosis. verbal intelligence in children taking a multi versus those taking placebo after 8 months’ intervention. In a 14B2) month study of 608 children, Vazir al (2006) found Riboflavin (Vitamin 1.58etmg study thatincell 5-alpha inhibitors inscores combination withmetabolism. B The vitamins are concluded supportincrease healthy growthreductase and division, and facilitate optimal hormone a significant attention-concentration increment in those supplemented with a micronutrient-fortified beverage versus those receiving placebo. blockade of inflammatory processes could represent a new two-pronged approach Additional benefits demonstrated in children include a reduced mean duration (5.0 versus 7.5acid days, supplement versus placebo) of several common Folic 0.095childhood mg Medicinal ingredients per capsule bothcough the men’s anddiarrhea, women’s: in the treatment of AGA. illnesses including such as in fever, and cold, and ear infections (Sarma 2006). Fenugreek (Trigonella foenum graecum) seed extract 4:1 ....................................................260 mg Biotin 400 mcg equivmultivitamin 1040mg) supplementation has been shown to significantly improve status of such nutrients as vitamin D, vitamin B6, vitamin B12, folate, Fenugreek Seeds In the(dry elderly, Flax lignans, standardized to E, 50% SDG Non-Medicinal Ingredients vitamin C, contain vitamin zinc, and...............................................................................100 selenium Girodon 1997). In addition,mg supplementation has also been found to significantly reduce rates of infection Fenugreek seeds 5% to 30% protein,(McKay steroid 2000; saponins, sterols, flavonoids d-calciuminpantothenate (Vitamin mg the elderly, as found aB5) trial..................................................................................10.4 in 81 subjects givenSteroid various supplemental combinations of micronutrients and followed over a 2 year period (Girodon 1997). and alkaloids (notably trigonelline and choline). saponins bind and Niacinamide (Vitamin B3) ...................................................................................................10.3 mg Inert microcrystalline cellulose and vegetable-based magnesium eliminateHCl extra cholesterol and hormones in the body; DHT is made from mg Pyridoxine (Vitamin B6) ...............................................................................................2.0 stearate in a veggie-based capsule testosterone, which is in turn is made from cholesterol. Therefore, when excess Riboflavin (Vitamin B2) .......................................................................................................1.6 mg is eliminated, less DHT can be made (Stark 1993). In a study of 20 cholesterol References Folic acid ..............................................................................................................................95 mcg PhytoMulti: Active Ingredients* (per 1 tablet) D, Roberts Lancet. 1988 Jan 23;1(8578):140-3. adult dose: One capsule per day adults....................................................................................................................................250 who consumed 12.5g and 18.0g of germinated fenugreek seedBenton powder for G.Recommended Biotin mcg Ingredient Dose Unit Block G, et al. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutrition

one month, higher levels of consumption resulted in a significant reduction in total

and cancer 1992;18(1):1-29. Vitamin A as retinyl acetate 2500 IU Men’s also has: cholesterol and low-density lipoprotein (LDL)2500 levels (Sowmya 1999).Bodnar LM, Tang G, Ness RB, Harger G, Roberts JM. Am J Epidemiol. 2006 Sep 1;164(5):470-7. Epub Vitamin A as carotenoids IU Saw palmetto berry extract 4:1 .............................................................................................125 2006 Jun 13.mg Vitamin E d-alpha tocopherol 50 IU Catov JM, Bodnar LM, Ness RB, Markovic N, Roberts JM. Am J Epidemiol. 2007 Aug 1;166(3):296-303. (dry equiv. 500 mg) Flax lignans Epub 2007 May 11. Vitamin C ascorbic acid 60 mg Flax reduces the amount of DHT produced by levels inJE,the Rich-Edwards JW, Rosner BA, Willett WC. Fertil Steril. 2008 Mar;89(3):668-76. Epub 2007 Vitamin 500reducing IU cholesterolChavarro Women’s also has: D3 cholecalciferol Jul 10. body.(silicon A meta-analysis of 28 studies between 1990 2008 showed that flaxseed Silicon dioxide) ........................................................................................................40 mg Vitamin K phytonadione 60 and mcg Eustruch R, Martínez-González MA, Corella D, et al. Ann Intern Med. 2006 Jul 4;145(1):1-11 significantly reduces circulating total and LDL-cholesterol concentrations (Pan Iron (ferric Thiamine citrate) ................................................................................................................20 mononitrate 12.50 mg Girodon F, Lombardmg M, Galan P, Brunet-Lecomte P, Monget AL, Arnaud J, Preziosi P, Hercberg S. Ann

2009). Flaxseed interventions reduced total and LDL cholesterol by 0.10 mmol/L

Nutr Metab. 1997;41(2):98-107. Riboflavin 7.50 mg Gohmmol/L), YI,Plus Bollano E, Einarson TR, Koren G. Clin Pharmacol Ther. 2007 May;81(5):685-91. Epub 2007 Feb Recommended use:0.00 one mmol/L) capsule twice capsules perCI: bottle). Bio-Fen® capsules are usually effective (95% CI: -0.20, and daily 0.08 (60 mmol/L (95% -0.16, 0.00 Niacin 6.25 mg 21. at respectively. stopping hair Significant loss within the first two were months. Anyonewith experiencing new growth reductions observed whole flaxseed (-0.21should and see it within four months. Grieger JA, Nowson CA, Jarman HF, Malon R, Ackland LM. Eur J Clin Nutr. 2007 Nov 28. Niacinamide 18.75 mg Once Bio-Fen is stopped, the hairand growth pattern will and slowly return to its original point, however some people may -0.16 mmol/L, respectively) lignan (-0.28 -0.16 mmol/L, respectively) Gruenwald J, Graubaum HJ, Harde A. Adv Ther. 2002 May-Jun;19(3):141-50. Pantothenic acid mg besupplements able to continue with a lower maintenance dose. 37.5 (Pan 2009). Harris E, Kirk J, Rowsell R, Vitetta L, Sali A, Scholey AB, Pipingas A. Hum Psychopharmacol. 2011 Vitamin B6 pyridoxine HCl 12.50 mg Dec;26(8):560-7. L-Mefolinate 400received mcg Bio-Fen hasCalcium been approved by Health Canada and has a unique NPN number. In addition to being InterAct Consortium. Diabetes Care. approved 2011 Sep;34(9):1913-8. McKay DL,.Perrone G, Rasmussen H, Dallal G, Hartman W, Cao G, Prior RL, Roubenoff R, Blumberg JB. for hair growth applications, Bio-Fen has been approved health benefits Vitamin B12 cyanocobalamin 120 for additional mcg J Am Coll Nutr. 2000 Oct;19(5):613-21. Biotin 250 mg MM, Journal of the American Dietetic Association testosterone 2011:in press.and estradiol levels in healthy males. J Angwafor F III, Anderson ML. An open label, dose response study to determineMurphy the effect ofeta al. dietary supplement on dihydrotestosterone, Magnesium citrate 20 mg Int Soc Sports Nutr 2008;5:12. Nilsen RM, Vollset SE, Rasmussen SA, Ueland PM, Daltveit AK. Am J Epidemiol. 2008 Apr Contraindications: ingredient combination in100 Bio-Fen mcg Plus for Men/Women 1;167(7):867-74. is generally safe for most adults. ChromiumThe polynicotinate Epub 2008 Jan 10. Bio-Fen should not citrate be used by patients withB6 diabetes, hypersensitivity to any ingredients. Brzezińska-Wcisło L. Evaluation of vitamin and calcium pantothenate effectiveness onAJ, hair growth from clinical and trichographic for treatment of diffuse alopecia in women. Wiad Copper 500or known mcg Nordmann Suter-Zimmermann K, Bucher HC, et al. Amaspects J Med. 2011 Sep;124(9):841-51.e2. Lek 2001;54:11-8.

Ribeiro ML, Arçari DP, Squassoni AC, Pedrazzoli J Jr. Mech Ageing Dev. 2007 Oct;128(10):577-80. Epub Iodine potassium iodide 75 mcg 2007 Aug 15. References citrateG. Inhibition of inflammatory 250 genemcg Chittur S,Manganese Parr B, Marcovici expression in keratinocytes using a composition containing carnitine, thioctic acid and saw palmetto extract. Evid Based Sarma KV, Udaykumar P, Balakrishna N, Vijayaraghavan K, Sivakumar B. Nutrition. 2006 Jan;22(1 Brooks JD, et al. Am J Clin Nutr. Complement Alternat Med 2009. 2004 Feb;79(2):318-25. Molybdenum aspartate 25 mcg Suppl):S8-14. Evans BA, et al. 1995 Nov;147(2):295-302. Selenium aspartate 50X. Meta-analysis mcg L, Boschinterventions BA, Polglase on G, blood Kleinschmidt Pillay BJ,Nutr Cassimjee MH. S Afr Med J. 2000 Pan A, YuR. D,Clin Demark-Wahnefried W, Franco OH, Lin of the Schlebusch effects of flaxseed lipids. I, Am J Clin 2009;90:288-97. Hoffmann Exp Dermatol. 2002 Jul;27(5):373-82. Dec;90(12):1216-23. Zinc citrate 7.50 mg 2001;39(1):58-65. Hutchins AM,et al.K, Nutr Cancer. Stough C, Scholey A, to Lloyd J, Spongthe J, effectiveness Myers S, Downey LA. Hum Psychopharmacol. 2011 Prager N, Bickett French N, Marcovici G. A randomized, double-blind, placebo-controlled trial determine of botanically derived inhibitors of 5-alpha-reductase in the Inandrogenetic addition to alopecia. extracts of over 20 phytonutrients. Prager N, et*of al. 2002 Apr;8(2):143-52. treatment J Altern Complement Med 2002;8:143-52. Oct;26(7):470-6. Tanvetyanon T, Bepler G. Cancer. 2008 Jul 1;113(1):150-7. Trüeb RM. Exp Gerontol. 2002 Aug-Sep;37(8-9):981-90. Serenoa repens monograph. Alternative Medicine Review 1998;3:227-9. Vazir S, Nagalla B, Thangiah V, Kamasamudram V, Bhattiprolu S. Nutrition. 2006 Jan;22(1 Suppl):S26Wickett RR, et al Arch Dermatol Res. 2007 Dec;299(10):499-505. 32. Wilt T et al. Database Syst Rev. 2002;(3):CD001423. Sinclair R. Cochrane Male pattern androgenetic alopecia. BMJ 1998;317:865-9. Wilson RD, et al. J Obstet Gynaecol Can. 2007 Dec;29(12):1003.

Sowmya P, Rajyalakshmi P. Hypocholesterolemic effect of germinated fenugreek seeds in human subjects. Plant Foods Hum Nutr 1999;53:359-65. Stark A, Madar Z. The effect of an ethanol extract derived from fenugreek (Trigonella foenum-graecum) on bile acid absorption and cholesterol levels in rats, Br J Nutr 1993;69:277-87. Vierpper H, Nowotny P, Maier H, Waldhausl W. Production rates of dihydrotestosterone in healthy men and women and in men with male pattern baldness: determination by stable isotope/ dilution and mass spectrometry. J Clin Endocrinol Metab 2001;86:5762-4.

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research news Red wine influences gut microbiota ecology and biochemical biomarkers

Ginger decreases pain in primary dysmenorrhea This randomized, controlled trial was conducted to evaluate the effects of ginger on pain relief in moderate or severe primary dysmenorrhea (N = 120). The ginger and placebo groups in two different treatment protocols received 1500 mg of ginger root powder daily or placebo. In the first protocol, ginger and placebo were given two days before the onset of the menstrual period and continued through the first three days of the menstrual period. In the second protocol, ginger and placebo were given for the first three days of the menstrual

period. Severity of pain was determined by a verbal multidimensional scoring system and a visual analogue scale. No differences were reported for baseline characteristics between the two groups. Significant differences were reported in the severity of pain between the ginger and placebo groups for protocol one (P = 0.015) and protocol two (P = 0.029). Protocol one (but not protocol two) also resulted in a significant difference in duration of pain (P = 0.017). Therefore, five days of treatment with ginger relieves the intensity and duration of pain in primary dysmenorrhea. BMC Complement Altern Med. 2012 Jul 10;12(1):92. PMID: 22781186

Soy isoflavone supplementation reduces body weight and improves glucose metabolism: meta-analysis This meta-analysis was conducted to confirm the effects of soy isoflavone supplementation on body weight, fasting glucose, and insulin level in non-Asian postmenopausal women. PubMed, EMBASE, and Cochrane databases up to October 2010 were searched for randomized controlled trials; 9 studies with 528 participants for body weight, 11 studies with 1182 participants for fasting glucose, and 11 studies with 1142 participants for fasting insulin were included. Significant reductions were found in body weight (95% CI -0.895 to -0.134), glucose level (95% CI -0.344 to -0.033), and fasting insulin level (95% CI -1.721 to -0.159) with soy isoflavone supplementation compared to placebo. Furthermore, shorter duration of isoflavone supplementation (<6 mo) reduced body weight (P = 0.009) and longer duration of supplementation (â&#x2030;Ľ6 mo) reduced blood glucose (P = 0.001). Greater weight loss reduction was observed in the lower dose subgroup (< 100 mg). Moreover, supplementation was more effective to reduce body weight and fasting insulin level in normal weight (BMI < 30) than obese (BMI â&#x2030;Ľ 30) women. Therefore, soy isoflavone supplementation could be beneficial for body weight reduction, glucose, and insulin control in post-menopausal women. Nutrition. 2012 Aug 1. PMID: 22858192

This randomized, crossover, controlled intervention study was conducted to evaluate the effect of a moderate intake of red wine polyphenols on select gut microbial groups implicated in host health benefits. After a washout period, 10 healthy male subjects received red wine, the equivalent amount of de-alcoholized red wine, or gin for 20 days each. Total

fecal DNA was submitted to polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis and realtime quantitative PCR to monitor and quantify changes in fecal microbiota. Several biochemical markers were also measured. Compared with baseline, the daily consumption of red wine polyphenols significantly increased the number of Enterococcus, Prevotella, Bacteroides, Bifidobacterium, Bacteroides uniformis, Eggerthella lenta, and Blautia coccoides-Eubacterium rectale groups (P < 0.05). In parallel, systolic and diastolic blood pressures and triglyceride, total cholesterol, HDL cholesterol, and C-reactive protein concentrations decreased significantly (P < 0.05). Interestingly, changes in cholesterol and C-reactive protein concentrations were linked to changes in the bifidobacteria number. The authors concluded that red wine consumption can significantly modulate the growth of select gut microbiota in humans, suggesting a possible prebiotic benefit associated with the inclusion of red wine polyphenols in the diet. Am J Clin Nutr. 2012 May 2. PMID: 22552027

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research news Ubiquinol improves semen parameters in men with idiopathic infertility This 26-week randomized, placebo-controlled trial investigated the effects of 200 mg ubiquinol (a reduced form of coenzyme Q10) daily on semen parameters in infertile men with idiopathic oligoasthenoteratozoospermia (N=228). After completion of the 26week treatment phase, participants were followed for another 12-week off-drug period. Upon completion of the treatment period, sperm density in the ubiquinol and placebo groups was 28.7 × 10(6)/ml and 16.8 × 10(6)/ml (P = 0.005), sperm motility was 35.8% and 25.4% (P = 0.008), and sperm strict morphology was 17.6% and 14.8% (P = 0.01) of normal sperm, respectively. Serum follicle-stimulating hormone levels decreased (P = 0.02) and serum inhibin B concentrations increased (P = 0.01) during the treatment period. Although semen parameters gradually returned to baseline values during the offdrug period, differences remained significant for sperm density (P = 0.03) and sperm motility (P = 0.03). A positive association was found between the duration of treatment with ubiquinol and sperm density (r = 0.74, P = 0.017), sperm motility (r = 0.66, P = 0.024), and sperm morphology (r = 0.57, P = 0.027). Therefore, ubiquinol was effective for improving sperm parameters in men with unexplained oligoasthenoteratozoospermia. J Urol. 2012 Aug;188(2):526-31. PMID: 22704112

Infant origins of childhood asthma associated with specific molds This birth cohort study was conducted to examine whether specific mold exposures during infancy are associated with childhood asthma development. Infants were identified from birth certificates and when they reached eight months of age, dust samples were collected from 289 homes. The dust samples were analyzed for concentrations of 36 molds that comprise the Environmental Relative Moldiness Index (ERMI) and included the endotoxin, house dust mite, cat, dog, and cockroach allergens. Asthma was diagnosed in 24% of the children at age seven years based

on reported symptoms and objective measures of lung function. A statistically significant increase in asthma risk was associated with high ERMI values in the child’s home in infancy (the adjusted relative risk for a 10-unit increase in ERMI value was 1.8; 95% CI 1.5-2.2). The summation of levels of the three mold species, Aspergillus ochraceus, Aspergillus unguis, and Penicillium variabile, was significantly associated with asthma (the adjusted relative risk was 2.2; 95% CI 1.8-2.7). The authors concluded that exposure to three mold species common to water-damaged buildings during infancy was associated with childhood asthma at age seven years. J Allergy Clin Immunol. 2012 Jul 10. PMID: 22789397

Low maternal folate status is associated with childhood emotional problems This population-based cohort study (N = 3,209) assessed the association of maternal folate status during pregnancy with child emotional and behavioral problems at age three years. It also examined whether any association between folate status and child problems

is a consequence of maternal folic acid supplement use or a variation in maternal MTHFR genotype (mothers of European descent were genotyped for the MTHFR 677 C→T polymorphism). Children of mothers with prenatal folate deficiency were at higher risk of emotional problems (OR 1.57; 95% CI 1.03-2.38) but not behavioral problems (OR 1.00; 95% CI 0.64-1.56) after adjustment for confounders. A higher risk of emotional problems was also found in children whose mothers started using folic acid supplements late or did not use supplements at all (OR 1.45; 95% CI 1.14-1.84) compared to children whose mothers started periconceptionally. However, low plasma folate concentrations only partly explained this association (OR 1.38; 95% CI 1.08-1.78). Although related to plasma folate concentrations, maternal MTHFR genotype did not explain the association of folate status with offspring emotional problems. Therefore, low maternal folate status during early pregnancy is associated with a higher risk of childhood emotional problems. Am J Clin Nutr. 2012 May 9. PMID: 22572645

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COLD & FLU RESCUE with ESTER-C

Your patients can feel better faster this winter

NEW

• Supports the immune system and inhibits viruses without the risks of over-the-counter drugs

• Fast relief without side effects

• Great-tasting chewable tablets contain echinacea, zinc, Ester-C®, vitamin A, and beta-carotene

• Powerful combination of Ester-C® vitamin C for 24-hour immune support and potent antioxidant protection, plus echinacea, andrographis, and NAC

• Naturally flavoured and naturally sweetened

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• Reduces the severity of symptoms, shortens the duration of colds and flu

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SISU Cold & Flu Rescue Monograph

COLD & FLU RESCUE with ESTER-C

SISU Cold & Flu Rescue

Active constituents: Each vegetarian capsule contains: 300 mg Ester C® brand vitamin C, 200 mg N-acetyl-L-cysteine (NAC), 200 mg Andrographis (extract, standardized to 10% andrographolides), 45 mg Echinacea angustifolia (5:1 extract standardized to 4% echinacosides), 60 mg Echinacea purpurea (4:1 extract).

General information:

Andrographis: In a systematic review of 4 clinical trials, Poolsup et al (2004) concluded that the evidence is substantial for the ability of Andrographis to reduce symptoms of upper respiratory tract infection (URTI). Significant symptomatic improvement when using Andrographis products has been reported in particular for the following: headache, throat and nasal symptoms (including sinusitis) ( Gabrielian, et al), myalgia, fever and cough (Melchior, et al).

Your patients can feel better faster this winter

N-acetyl-L-cysteine: In a randomized, double-blind, placebo-controlled, multicentre clinical trial, 262 patients received either NAC or placebo during “cold and flu” season. Although rates of exposure and infection with influenza virus (as demonstrated by seroconversion) did not vary significantly between active and placebo groups, the incidence of clinical illness did. The NAC group had a significantly lower incidence of clinical signs and symptoms of illness when compared to placebo (29% vs. 51%). The beneficial and protective effects of NAC are likely due to its role as a glutathione (GSH) precursor. Nencioni, et al (2003) have demonstrated that GSH content of a cell contributes to its ability to down-regulate the replication of influenza virus. Vitamin C: This nutrient is highly concentrated in white blood cells and supports proper function of these cells. The evidence suggests vitamin C helps reduce the duration and severity of symptoms and that those under stress (particularly significant physical stresses such as those associated with competitive sports) may reduce their risk of common cold by as much as 50% when vitamin C is used preventatively. In a randomized, placebo-controlled clinical trial, Ester-C® at a dose of 1,000 mg per day for 60 days was found to significantly reduce the incidence and duration of common cold symptoms vs. placebo. Echinacea : This herbal medicine has a long history of traditional use in the treatment of URTI.

Doses and directions: 2 capsules, 3 times per day, begin taking within 72 hours of symptom onset or as directed by a health care practitioner.

Therapeutic effects: Helps to shorten the severity and duration of cold and flu symptoms.

Quality Assurance

Purity

USP<2021>/MFHPB<18>

<5,000

Escherichia coli

USP<2022>/MFHPB<19>

Negative

Salmonella

USP<2022>/MFLP<75>

Negative

Staphylococcus aureus

USP<2022>/MFHPB<21>

Negative

Total Mold & Yeast

USP<2021>/MFHPB<22>

<1,000

cfu/g

Arsenic

ICP / AA

<0.14

μg/kg b.w./day

Cadmium

ICP / AA

<0.09

μg/kg b.w./day

Lead

ICP / AA

<0.29

μg/kg b.w./day

Total Mercury

ICP / AA

<0.29

μg/kg b.w./day

Solvent Residues NEW

GC/GC-MS

Conforms to USP/ICH tolerance limits

Pesticides

USP<561>

N-acetyl-L-cysteine (NAC)

Identity

HPLC

Conforms to reference material

Quantity

HPLC

200mg

Identity

TLC / HPLC

Conforms to reference material

Echinacosides

HPLC

1.8mg

(80 – 120%)

Quantity

Input

45mg

(95 – 105%)

Purple coneflower 4:1 extract (Echinacea purpurea)

Identity

TLC / HPLC

Conforms to reference material

Quantity

Input

60mg

Andrographis extract (Andrographis paniculata)

Identity

HPLC

Conforms to reference material

• Supports the immune system Andrographolides and inhibits Quantity viruses without the risks of over-the-counter drugs Vitamin C (Calcium ascorbate) Identity

References

Tolerances

SPC

Narrow-leaf echinaecea 5:1 extract (Echinacea angustifolia)

Identity & Potency (per capsule)

Method

Test

Test Parameters

Quantity • Great-tasting chewable tablets contain echinacea, zinc, Ester-C®, vitamin A, and beta-carotene

Flora, et al., “Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment.” Eur J Resp.1997;10:1535-1541.

• Naturally flavoured and naturally sweetened

Gabrielian, et al., “A double-blind, placebo-controlled study of Andrographis paniculata fixed combination Kan Jang in the treatment of acute upper respiratory tract infections including sinusitis.” Phytomedicine, 2002;9:589-597. Kelly, Greg S., “Clinical applications of N-acetylcysteine.” Alt Med Rev.1998;3(2):114-127. Lindenmuth and Lindenmuth, “The efficacy of echinacea compound herbal tea preparation on the severity and duration of upper respiratory and flu symptoms: a randomized, double-blind placebo-controlled study.” J Alt Compl Med.2000;6(4):327-334. Melchior, et al.,”Double-blind, placebo-controlled pilot and Phase III study of activity of standardized Andrographis paniculata,Herba Nees extract fixed combination (Kan jang) in the treatment of uncomplicated upper-respiratory tract infection.” Phytomedicine,2000;7(5):341-350.

@sisuvitamins

cfu/g

Conforms to USP tolerance limits

HPLC Input

(80 – 120%)

(95 – 105%)

• Fast relief20mg without side effects

(80 – 120%)

200mg

(95 – 105%)

300mg

(90 – 150%)

• Reduces the severity of symptoms, shortens Conforms to reference material the duration of colds and flu

Titrimetry / HPLC

• Powerful combination of Ester-C® vitamin C for 24-hour immune support and potent Nencioni, et al.,”Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl-2.” FASEB (online), Feb 19 antioxidant protection, plus echinacea, 2003. andrographis, NACtreatment of uncomplicated upper respiratory tract infections: systematic review Poolsup, et al.,”Andrographis paniculata inand the symptomatic of randomized controlled trials.” J Clin Pharm Ther.,2004;29:37-45. Van Straten, et al.,”Preventing the common cold with a vitamin C supplement: a double blind, placebo controlled survey.” Advances in Therapy,2002 May;19(3):151-159. Saxena RC, Singh R, Kumar P, Yadav SC, Negi MP, Saxena VS, Joshua AJ, Vijayabalaji V, Goudar KS, Venkateshwarlu K, Amit A, “A randomized double blind placebo controlled clinical evaluation of extract of Andrographis paniculata (KalmCold) in patients with uncomplicated upper respiratory tract infection.” Phytomedicine, 2010 Mar;17(3-4):178-85. Epub 2010 Jan 25.

The Better Vitamin C.

release your inner strengthtM

Ester-C and Ester -C logo are reg. TMs of The Ester C Company

sisu.com • 1.800.663.4163

sisu.com

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RELEASE YOUR INNER STRENGTH TM

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12-11-15 2:17 PM

research news Persistent cannabis users show neuropsychological decline from childhood to midlife

The fiber and/or polyphenols present in lingonberries null the glycemic effect of the sugars present in the berries Two postprandial crossover studies with healthy normal-weight male subjects were conducted to study the influence of commercial lingonberry (Vaccinium vitis-idaea L.) powder on postprandial glycemia and lipemia. The test meals contained fat-free yogurt with either glucose (50 g) or triacylglycerols (35 g) with or without the lingonberry powder. The lingonberry powder, which is a rich source of polyphenols, provided the meals with a known amount of fiber and a known amount and composition of sugars. Postprandial glucose, insulin, and triacylglycerol responses were analyzed.

There were no significant differences in the postprandial glucose concentration between the meals in the glycemia trial despite the fact that the lingonberry meal contained more glucose and fructose. No glycemia or lipemia-lowering effects were detected when the meal contained added triacylglycerol without the added sugar. On the contrary, there were indications of higher glycemic and insulinemic effects after the lingonberry meal. The authors concluded that the fibers and/or polyphenols present in lingonberries null the glycemic effect of the sugars present in the berries when consumed together with added glucose. By contrast, the lingonberry powder did not affect the postprandial lipemic response. Nutr Res. 2012 Jul;32(7):4718. PMID: 22901554

Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus This three-month prospective, openlabel, randomized, controlled trial was conducted to investigate whether oral supplementation of resveratrol would improve glycemic control and the associated risk factors in patients with type 2 diabetes mellitus (T2DM). Sixty-two patients with T2DM were randomized into control and intervention groups whereby the control group received only oral hypoglycemic agents and the intervention group received resveratrol (250 mg/d) along with their oral hypoglycemic agents. Hemoglobin A(1c) (HBA1c), lipid profile, urea nitrogen, creatinine, and protein were measured at baseline and again at the end of three months. Results revealed that supplementation of resveratrol significantly improved mean HBA1c (9.99 ± 1.50 vs 9.65 ± 1.54; P < 0.05), mean systolic blood pressure (139.71 ± 16.10 vs 127.92 ± 15.37; P <0 .05), mean total cholesterol (4.70 ± 0.90 vs 4.33 ± 0.76; P <0 .05), and mean total protein (75.6 ± 4.6 vs 72.3 ± 6.2; P < 0.05) in T2DM. No significant changes in body weight, high-density lipoprotein, and low-density lipoprotein cholesterols were observed. These results suggest that resveratrol may possibly provide a potential adjuvant for the treatment and management of diabetes. Nutr Res. 2012 Jul;32(7):537-41. PMID: 22901562

The current study was conducted to test the association between persistent cannabis use and neuropsychological decline. In addition, the study sought to determine whether decline is concentrated among adolescent-onset cannabis users. Participants were members of the Dunedin Study, a prospective study of a birth cohort of 1,037 individuals

followed from birth (1972/1973) to age 38 years. Cannabis use was ascertained in interviews at ages 18, 21, 26, 32, and 38 years. Neuropsychological testing was conducted at age 13 years, before initiation of cannabis use, and again at age 38 years, after a pattern of persistent cannabis use had developed. Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning, even after controlling for years of education. More cognitive problems were also reported for persistent cannabis users. Impairment was concentrated among adolescentonset cannabis users with more persistent use being associated with greater decline. Furthermore, cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users. The authors concluded that cannabis might have neurotoxic effects on the adolescent brain and that these results highlight the importance of prevention and policy efforts targeting adolescents. Proc Natl Acad Sci U S A. 2012 Aug 27. PMID: 22927402

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research news Higher anthocyanin intake is associated with lower arterial stiffness and blood pressure This cross-sectional study of 1,898 women aged 18-75 years examined associations between habitual flavonoid intakes and direct measures of arterial stiffness, central blood pressure, and atherosclerosis. Total flavonoids and their subclasses were calculated from validated food-frequency questionnaires while arterial stiffness and atherosclerosis were measured via central systolic blood pressure (cSBP), central diastolic blood pressure, mean arterial pressure (MAP), augmentation index, pulse wave velocity (PWV), and intima-media thickness. A higher anthocyanin intake was associated with significantly lower mean cSBP (-3.0 ± 1.4 mm Hg for highest versus lowest quintiles; P-trend = 0.02), MAP (-2.3 ± 1.2 mm Hg for highest versus lowest quintiles; P-trend = 0.04), and PWV (-0.4 ± 0.2 m/s for highest versus lowest quintiles; P-trend = 0.04). A higher flavone intake was associated with a lower PWV (-0.4 ± 0.2 m/s for highest versus lowest quintiles; P-trend = 0.04). No associations were observed for total and other flavonoid subclasses. These data suggest that higher intake of anthocyanins and flavones are inversely associated with lower arterial stiffness. The intakes of anthocyanins associated with these findings could be incorporated into the diet by the consumption of 1-2 portions of berries daily. Am J Clin Nutr. 2012 Aug 22. PMID: 22914551

Curcuminoids exert a glucose-lowering effect in type 2 diabetes This randomized, placebo-controlled study was conducted to investigate whether curcuminoids have beneficial effects on type 2 diabetic patients and to examine the possible mechanisms of action. Overweight/obese type 2 diabetic patients (BMI ≥ 24.0; fasting blood glucose ≥ 7.0 mmol/L or postprandial blood glucose ≥11.1 mmol/L) were randomly assigned to 300 mg/day curcuminoids or placebo for three months. Bodyweight, glycosylated hemoglobin A(1c) (HbA1c), serum fasting glucose, free fatty acids (FFA), lipids, and lipoprotein lipase (LPL) were determined. One hundred patients

(curcuminoids, N = 50; placebo, N = 50) completed the trial. Curcuminoids supplementation significantly decreased fasting blood glucose (P < 0.01), HbA1c (P = 0.031), and insulin resistance index (homeostasis model of assessment - insulin resistance; HOMA-IR) (P < 0.01). Curcuminoids also led to a significant decrease in serum total FFA (P < 0.01), triglycerides (P = 0.018), and an increase in LPL activity (p < 0.01). The authors concluded that these findings suggest a glucose-lowering effect of curcuminoids in type 2 diabetes. This effect is partially due to a decrease in serum FFA, which may result from promoting fatty acid oxidation and utilization. Mol Nutr Food Res. 2012 Aug 29. PMID: 22930403

Green tea may influence brain function and influence working memory This double-blind, controlled repeated measures within-subject design was conducted to examine the neural effects of green tea extract on human brain activation. Functional magnetic resonance imaging (MRI) was recorded

while 12 healthy volunteers performed a working memory task following administration of 250 or 500 ml of either (1) a whey-based green tea containing soft drink or (2) a whey-based soft drink without green tea (control). A whole-brain analysis was followed by a priori-defined region of interest (ROI) analysis of the dorsolateral prefrontal cortex (DLPFC). Whole-brain analyses revealed no significant effects after correction for multiple comparisons. Using a ROI approach, green tea extract increased activation in the DLPFC relative to the control condition (P<0.001); this neural effect was related to green tea dosage. Green tea extract was not associated with any significant attenuation in regional activation relative to the control condition. These data suggest that green tea extract may modulate brain activity in the DLPFC, a key area that mediates working memory processing in the human brain. Moreover, this is the first neuroimaging study to suggest that functional neuroimaging methods provide a means of examining how green tea extract acts on the brain. Eur J Clin Nutr. 2012 Aug 29. PMID: 22929964

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industry news ‘Flawed’ JAMA omega-3 meta-analysis may harm public health

Tattoo ink linked To serious skin infections

Atrium Innovations announces 2012 second quarter financial results

Income is the great divide when it comes to Canadians’ health

The Global Organization of EPA and DHA (GOED) has stated that the new meta-analysis published in JAMA questioning the heart health benefits of omega3s is flawed. “Our findings do not justify the use of omega-3 as a structured intervention in everyday clinical practice or guidelines supporting dietary omega-3 PUFA administration,” concluded researchers from the University Hospital of Ioannina in Greece. Adam Ismail, GOED executive director, disputed the findings: “Given the flawed design of this meta-analysis, bypassing the advice of the American Heart Association or the 2010 Dietary Guidelines for Americans by stating that omega-3s are not cardioprotective, could be harmful to public health.” Duffy MacKay, ND, vice president, scientific and regulatory affairs for the Council for Responsible Nutrition (CRN) added that many of the studies included in the meta-analysis were conducted on diseased individuals already undergoing treatment with one or more drugs (e.g., statins), which may mask the less potent and more long-term effects of omega-3 fats. “Along these lines, the researchers apparently did not examine within each individual study included in the meta-analysis whether individuals in the placebo group were sufficient or insufficient in their dietary intake omega-3 fats. Without that information, they could not have controlled for this variable.”

Atrium Innovations Inc, a globally recognized leader in the development, manufacturing and commercialization of innovative, science-based dietary supplements, released its results for the quarter ending June 30, 2012. Total revenue growth over last year was recorded at 4.1%, or 7.4% on a currency-neutral basis (all organic). Total branded revenue recorded solid organic growth of 12.2%. “We posted solid organic growth on a global basis with a particularly strong performance from our branded products at 12.2%, reflecting solid momentum in the HCP [health care professional] and Retail channels in North America,” said Pierre Fitzgibbon, President and CEO. “Aligned with our right-sizing initiatives, we have decided to close our manufacturing operations in Penticton, British Columbia by the end of September 2012. Production is in the process of being transferred to our other manufacturing facilities.” Mr. Fitzgibbon concluded, “As indicated over the past year, we face heightened pressure from a regulatory perspective. Associated expenses to elevate our cGMP standards have and will continue to impact margins. However, we are seeing evidence that the industry dynamic is changing which will allow overtime recovering part of these regulatory expenses.”

AIDP been granted U.S. patents for Magtein™

AIDP, Inc., the distributors of Magtein™ magnesium L-threonate, has been awarded two patents for magnesium compositions and uses for cognitive function and neurological disorders. Magnesium L-threoate is expected to be the next breakthrough ingredient and these patents protect Magtein’s unique magnesium compositions and its use for any magnesium L-threonate-containing food, nutritional supplements, and drugs for enhancing cognitive function or ameliorating the effects of a neurological disorder. The use of these products is applicable for improving the health of people suffering from loss of cognitive function, loss of memory, Alzheimer’s disease, depression, attention deficit hyperactivity disorder, Amyotrophic lateral sclerosis (ALS), Parkinson’s disease, migraine, anxiety disorder, and mood disorder, as some examples of cognitive and neurological disorders. “We truly believe that Magtein is a game changing ingredient that will benefit millions of busy and stressed consumers by helping to improve their quality of life,” says Edward Lee Ph.D., AIDP president.

Five clusters of skin infections have been linked to tattoos in the US. Investigators state that the source of bacteria was the ink itself and although tattoo artists should use sterile water and needles, there is no guarantee of safety if the ink is contaminated. The bacteria that caused these outbreaks of tattoo-related infections are Mycobacterium chelonae and Mycobacterium abscessus, which are common in drinking water. “It’s unfortunate that they can do everything right, but if the manufacturer doesn’t supply them with sterile ink product it still results in them giving their clients infections,” says CDC epidemiologist, Tara MacCannell.

A new public opinion survey carried out for the Canadian Medical Association (CMA) indicates that the health of Canadians is increasingly being affected by how much money they earn. Lower income groups reported poorer health and greater use of health services than those with higher incomes. In describing their health, only 39% of those earning <$30,000 a year said it was excellent or very good, compared to 68% of those earning ≥$60,000. This gap represents 29 percentage points whereas the gap represented only 17 points in 2009. The poll also found a disparity in the impact of the economy on Canadians’ ability to take care of their health; of those with household incomes <$30,000 a year, 46% reported that they have spent less time, energy, and money on sustaining their health as a result of the economic downturn compared to only 19% earning ≥$60,000. “When it comes to the wellbeing of Canadians, the old saying that wealth equals health continues to ring true,” said Dr. John Haggie, president of the CMA. “What is particularly worrisome for Canada’s doctors is that in a nation as prosperous as Canada, the gap between the ‘haves’ and ‘have nots’ appears to be widening.”

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industry news New weapon against C. difficile

A team of researchers from Université de Saint-Boniface (USB) in Manitoba has proven the effectiveness of a disinfectant that could revolutionize the fight against superbugs in the hospital system. Mathias Oulé, Ph.D., microbiology professor at Manitoba’s Université de Saint-Boniface, conducted a study revealing that Akwaton tackles spore-forming bacteria, including Clostridium difficile whose heat-tolerant spores can live on surfaces for long periods of time and survive a number of years in a dry environment. Most currently available chemical disinfectants only control or prevent the spread of bacterial spores whereas this study revealed that Akwaton is able to destroy Bacillus subtilis spores at very dilute concentrations, after just 90 seconds’ treatment. According to Dr. Oulé, “Most disinfectants have to be applied at much higher concentrations - typically between 4 and 10% - which may be harmful to humans. Akwaton destroys spores at concentrations well below 1%.” Akwaton is non-corrosive, non-irritating, non-toxic, odourless and environmentally safe.” The USB research team has also shown that Akwaton is effective against strains of Methicillin-resistant Staphylococcus aureus and Escherichia coli.

Supplement use reaches 76% in the US

Seventy-six percent of consumers take a vitamin or supplement, according to a new survey from Wells Fargo Securities LLC Retail Equity Research Department (N = 1,364). Within this group, 71% take a multivitamin, followed by fish oil or omega-3s (45%), vitamin D (40%), and calcium (33%). Interestingly, usage of sports-related supplements (10%) and weight loss supplements (7%) was relatively low. Many consumers (45%) are also considering adding supplements to their diet with fish oil and omega-3s (31%) being the most popular, followed by multivitamins (29%), calcium (18%), weight loss supplements (16%), joint support (16%), vitamin D (16%), and antioxidants (15%). Physician recommendations were the most important factor in the decision to take a supplement, with 42% of respondents relying on their medical doctor’s advice. Research studies and articles (37%) followed as the second most important influence and recommendations from friends/family (16%) was another strong contributor. Information from television or newspapers (4%) and recommendations from a vitamin store associate (2%) did not play a strong role in influencing buyers. Price (43%) and convenience (25%) were the most important factors in determining where consumers buy supplements while most respondents purchased supplements from traditional grocery stores (39%) and drug stores (38%).

Pediatricians decide boys are better off circumcised than not

The American Academy of Pediatrics has concluded that the health benefits of circumcision clearly outweigh any risks. “There is clear evidence that supports the health benefits of circumcision,” said Susan Blank, who led the 14-member task force that formulated the new policy being published in the journal Pediatrics. “The health benefits of male circumcision include a drop in the risk of urinary tract infection in the first year of life by up to 90%,” she says. Blank states that there is a much bigger reason to do it considering that circumcision lowers the risk of a long list of sexually transmitted diseases. “It drops the risk of heterosexual HIV acquisition by about 60%.” In addition, “It drops the risk of human papillomavirus [HPV], herpes virus and other infectious genital ulcers,” she says. “It also reduces the chances that men will spread HPV to their wives and girlfriends, protecting them from getting cervical cancer.” Blank states, “We’ve reviewed the data and, you know, we have gone through them with a fine-tooth comb, and the data are pretty convincing.” This statement and accompanying technical report marks the first revision of the organization’s position since 1999, when the academy backed away from circumcision.

Facebook now campaigning in Canada to boost organ donations

Facebook has taken its campaign to boost organ donations to Canada and Mexico. The feature allows Facebook users to tell their friends and family that they are registered organ donors and it directs people who are not currently signed up as organ donors to the official registries where they live. Between May 1 and the middle of September, around 275,000 Facebook users posted their donor status on the site. “It shows the enormous potential of social media,” said Blair Sadler, an attorney and a senior fellow at the Institute for Healthcare Improvement. He suggests that Facebook’s new feature has the potential to revolutionize the field of organ transplantation because large numbers of people will be expressing publicly what they want to happen to their organs after they die. People are more prone to be influenced by their friends or family than by activists or public health officials.

Thorne Research servicing Canadian customers through Vancouver warehouse facility

In April, Thorne Research initiated a program to distribute products to Eastern Canada by utilizing a warehouse facility in Harrisburg, Pennsylvania. Their hope was to improve delivery times to Eastern Canada so customers would receive orders within 2-3 business days. Unfortunately, this new distribution model did not meet the intended goal. Because of the challenges and difficulties involved with shipping products across the border directly to customers, Thorne has decided to return to a more dependable and stable distribution strategy; Thorne has returned to shipping products to Canadian customers exclusively from a Vancouver, BC warehouse facility. With this change in shipping method also comes an exciting change in their shipping policy, which will hopefully reduce transit times and costs for their customers.

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industry news FDA issues new DMAA warning letter

The US Food and Drug Administration (FDA) has issued another warning letter for DMAA (1,3-Dimethylamylamine, also known as methyl hexaneamine (MHA), and several other names). DMAA has received much press in recent months with the FDA issuing warning letters to 10 manufacturers and distributors of supplements containing DMAA. Manufacturers of some sports supplements are claiming that DMAA is a natural substance derived from geraniums but researchers are showing that it is synthetic, consisting of four stereoisomers. There has been intense debate in the dietary supplement industry and the analytical testing industry about whether DMAA is in fact a constituent of geranium.

Serious omega-3 supply issues are expected

The Global Organization for EPA and DHA (GOED) has warned that the omega-3 sector faces an impending supply crisis as global demand booms for food, pharmaceutical, and nutraceutical products. It is expected that the already maxedout fish stocks are going to struggle to meet omega-3 oil demand forecast at 7-8% annual growth by market analysis completed by Frost & Sullivan. Since the main fisheries in Morocco and Peru are near capacity, the question has to be asked: where is the omega-3 going to come from if it keeps growing at its forecast? There may be a strong place in the industry for algal oils but it is unknown whether they can deliver the high dose EPA oils that are increasingly being demanded by the pharmaceutical sector.

CSPI suggests that Welch’s is using a deceptive health claim

According to the Center for Science in the Public Interest (CSPI), Welch’s should not have a heart-health icon on its grape juice and other products. The group suggests that Welch’s juice does not improve heart health and may actually do harm by contributing to insulin resistance and obesity. Making matters worse, says CSPI, is that Welch’s encourages consumers to drink juice in lieu of eating fresh fruit, stating that “Getting enough fruits and vegetables each day is important for overall health—but everyday life often gets in the way … Welch’s 100% Grape Juice makes it easy to squeeze in more purple fruit each day as part of a healthy diet for the whole family.” CSPI has notified Welch Foods, Inc., that it will face a lawsuit unless it stops making heart-health claims on its juices, spreads, fruit juice cocktails, and fruit snacks.

How does BIO-FEN PLUSTM work?

Specific compounds within the herbal extracts inhibit the 5-alpha-reductase (and therefore reduce DHT) to prevent or slow down the rate of hair loss. This process is the principle by which the prescription drugs such as Propecia (finasteride) work. However, BIO-FEN PLUSTM also contains additional compounds which remove excess cholesterol and testosterone – the building blocks of DHT. BIO-FEN PLUSTM also contains vitamins to increase blood flow to the small capillaries that feed the hair roots, to deliver the active herbal compounds and remove waste. Therefore, BIO-FEN PLUSTM provides a natural, safer alternative to expensive drugs, and/or expensive & painful hair transplants.

As with the prescription alternatives, results vary from person to person, and no one product will work for everyone.

Possible method of removing leukemia stem cells may prevent relapse of AML

New research may provide a new avenue for the treatment of Acute Myeloid Leukemia (AML) and a solution to the high rate of disease relapse experienced by patients. The research found that a protein on the surface of AML cells called CD47 binds to a protein called SIRPα, causing macrophages to develop immune tolerance to AML cells. When SIRPα signalling was absent, macrophages were able to clear human leukemia stem cells (LSC). This finding is significant, as it is believed that relapse of disease is driven by LSCs that survive conventional chemotherapy. The researchers confirmed these results by treating mice that had been engrafted with human AML with a novel protein called SIRPα-Fc that can block CD47 on the leukemia cells. They found that treatment with the protein enhanced phagocytosis of AML cells by macrophages and reduced AML growth in the mice. “This study is an important step forward in our understanding of leukemia stem cells and has opened the door to a new line of therapies that could have a significant clinical impact by preventing relapse of AML,” says Dr. Tom Hudson, President and Scientific Director of Ontario Institute for Cancer Research. ■

www.biofen.com

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PRODUCT mOnOgRaPh

PRODUCT MONOGRAPH OIL OF OREGANO

Oil of Oregano is a hydrophobic extract of Origanum vulgare leaf. Major active constituents include the monoterpene phenolic compounds carvacrol and thymol. Carvacrol and thymol are potent antimicrobials with synergistic bactericidal, fungicidal, and antihelminthic activity.

Human studies

Oil of Mediterranean Oregano had antihelminthic effects when given at 600 mg emulsified oil per day in 14 adults who had tested positive for enteric parasites Blastocystis hominis, Entamoeba hartmanni, and Endolimax nana. After 6 weeks of treatment, there was complete resolution of parasitic infection in 8 cases, while Blastocystis hominis scores decreased in three more cases; gastrointestinal symptoms improved in 7 of the 11 subjects who had presented with Blastocystis hominis infection. (Force 2000)

Animal and In vitro studies

Carvacrol for oral candidiasis in immunocompromised rats was found to be as effective as treatment with Nystatin, reducing the number of colony forming units (CFU’s) and completely clearing hyphae from oral surfaces when given for 8 days (Chami 2004). In vitro, carvacrol was determined to exert an inhibitory effect against 6 different strains of Candida species primarily due to extensive lesion of the plasma membrane (Salgueiro 2003). Carvacrol has potent antimicrobial activity against several microbial species, including Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Psuedomonas aeruginosa, Candida albicans, and Aspergillus niger; out of these, Candida albicans has been found most susceptible (Santoyo 2006). Carvacrol and thymol are thought to exert an additive effect by disrupting bacterial membrane integrity (Lambert 2001). Oregano has been shown to inhibit Methicillin resistant strains of Staph.

Figure 1: Structure of Carvacrol (left) and Thymol (right)

aureus and epidermis, and attenuates biofilm formation in vitro (Nostra 2004; 2007).

Toxicology

Essential oil extracts are categorically known to be toxic in high doses, and are therefore typically given in drop doses; essential oils should not be used internally by pregnant or breastfeeding women. Animal studies to date, however, indicate relative safety of Oregano oil. Carvacrol was shown to be hepatoprotective against ischemia and reperfusion injury in rats; both carvacrol and silymarin had similar beneficial effects on AST and ALT levels (Canbek 2007). Carvacrol also increased liver regeneration rate in rats after partial hepatectomy (Uyanoglu 2008). Mutagenicity studies of carvacrol show only weak activity; carvacrol is excreted in urine after 24 hours in large quantities, unchanged or as glucoronide and sulphate conjugates (De Vincenzi 2004).

References

Canbek M, Uyanoglu M, Bayramoglu G, Senturk H, Erkasap N, Koken T, Uslu S, Demirustu C, Aral E, Husnu Can Baser K. Effects of carvacrol on defects of ischemia-reperfusion in the rat liver. Phytomedicine. 2008 Jan. De Vincenzia M et al. Constituents of aromatic plants: carvacrol. Fitoterapia 2004; 75(7-8): 801-804. Force M et al. Inhibition of enteric parasites by emulsified oil of oregano in vivo. Phytother Res. 2000 May;14(3):213-4. Lambert RJ, Skandamis PN, Coote PJ, Nychas GJ. A study of the minimum inhibitory concentration and mode of action of oregano essential oil, thymol and carvacrol. J Appl Microbiol. 2001 Sep;91(3):453-62. Nostro A, Roccaro AS, Bisignano G, Marino A, Cannatelli MA, Pizzimenti FC, Cioni PL, Procopio F, Blanco AR. Effects of oregano, carvacrol and thymol on Staphylococcus aureus and Staphylococcus epidermidis biofilms. J Med Microbiol. 2007;56(Pt 4):519-23. Nostro A et al. Susceptibility of methicillin-resistant staphylococci to oregano essential oil, carvacrol and thymol. FEMS Microbiol Lett. 2004;230(2):191-5. Salgueiro LR et al. Chemical composition and antifungal activity of the essential oil of Origanum virens on Candida species. Planta Med. 2003 Sep;69(9):871-4. Santoyo S, Cavero S, Jaime L, Ibañez E, Señoráns FJ, Reglero G. Supercritical carbon dioxide extraction of compounds with antimicrobial activity from Origanum vulgare L.: determination of optimal extraction parameters. J Food Prot. 2006;69(2):369-75. Uyanoglu M, Canbed M, Aral E, Husnu Can Baser K. Effects of carvacrol upon the liver of rats undergoing partial hepatectomy. Phytomedicine 2008; 15(3): 226-9. ihpSept10_NAHS_Ad.indd 2 058.IHP NAHS mono.indd 1 IHPAPR2012_10055_North_American_Herb_and_Spice_FP.indd 2

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calendar November

November 21 Urine Steroid Hormone Profile Organized by: Rocky Mountain Analytical Webinar For more information, visit http://www.rmalab.com November 24 Cardio-Metabolic Summit Toronto Organized by: Canadian Heart Research Centre Toronto, Ontario For more information, visit http://www.chrc.net November 25 Dreamwork Organized by: CCNM Toronto, Ontario For more information, visit http://www.ccnm.edu November 28 Regulating the Menstrual Cycle: Addressing Amenorrhea, Dysmenorrhea, and PMS Organized by: Seroyal Webinar For more information, visit www.seroyalseminars.com November 30 A Day of Derm for GPs Organized by: Tamarind Healthcare London, Ontario For more information, visit http://dermdayforgps.ca

DECEMBER

December 1-2 Clinical Applications Using Biotherapeutic Drainage & UNDA Numbered Compounds Organized by: Seroyal Toronto, Ontario For more information, visit www.seroyalseminars.com

December 5 Quenching the Fire Within- Turning Down the Heat of Inflammation and Autoimmune Disease Organized by: Metagenics Webinar For more information, visit http://www.metagenics.com December 6-9 MSK Health in the Infant & Pre-school child Organized by: Anglo-European College of Chiropractic Toronto, Ontario For more information, visit http://www.aecc.ac.uk December 11 Routine HIV Testing: New recommendations and tools for integration into practice Organized by: University of British Columbia Vancouver, British Columbia For more information, visit http://www.ubccpd.ca December 11 Behavioural and Pharmacological Approaches in Managing Insomnia Organized by: HIT Global Delson, Quebec For more information, visit http://www.cfpc.ca December 13-15 20th Annual World Congress on AntiAging and Regenerative Medicine Organized by: American Academy of Anti-Aging Medicine Las Vegas, Nevada For more information, visit http://www.a4m.com

JANUARY

January 1 Parenteral IV Therapy Organized by: CCNM Toronto, Ontario For more information, visit http://www.ccnm.edu

January 19 Routine HIV Testing: New recommendations and tools for integration into practice Organized by: University of British Columbia Vancouver, British Columbia For more information, visit http://www.ubccpd.ca January 24-26 Canadian Pediatric Endocrine Group (CPEG): 2013 Scientific Meeting Organized by: Canadian Pediatric Endocrine Group Quebec City, Quebec For more information, visit http:// www.interprofessional.ubc.ca

FEBRUARY

February 2 Naturopathic Approaches to Epigenetics: Symposium & Professional Product Fair Organized by: Boucher Institute of Naturopathic Medicine Vancouver, British Columbia For more information, visit http://www.binm.org/ February 2 Diagnosis & Therapy using Constitutional Medicine I Fundamentals of Iridology Organized by: Pascoe Canada Toronto, Ontario For more information, visit http:// www.pascoecanada.com February 3 Diagnosis & Therapy using Constitutional Medicine II - In-Depth Iridology Organized by: Pascoe Canada Toronto, Ontario For more information, visit http:// www.pascoecanada.com

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product profiles

Legend

r s y s s e g h n h al ine ine thy alt sur nce ete iatr tric tric itio alt tic llin a c c se ceu edi edi eop He res Ca iab ych edia eria utr e He n r N n D Ps P P u a G l ra n M l M om o s t d t u u a C Nu H or m sc loo sia nic / et Sp Im Va B Di nal . A ota io B ad r rt it T Nu

SISU Vitamin D Are your patients D-prived? It is estimated the economic burden of vitamin D deficiency in Canada is approximately $14.4 billion per year. Vitamin D is essential for bone health and the prevention of many chronic health conditions. SISU Vitamin D is fast-dissolving, sublingual tablets of vitamin D3 1000 IU, and are available in bottles of 90, 200 and a new 400 tablet size. Also available: SISU Kids 400 IU.

pharMAX™fibro Trans-dermal Muscle Pain And Fatigue Relief Cream Used for the temporary relief of muscle and joint pain associated with rheumatoid arthritis or osteoarthritis, and pain of tendons and ligaments. Contains natural oils and extracts that work synergistically for maximum effect: • Capsaicin (Capsicum annuum L.) fruit: Rich in vitamin A, also contains vitamin B6, vitamin E, vitamin C, riboflavin, potassium and manganese • Creatine: Topically applied creatine has been demonstrated to reach dermis, and has been shown to help reduce the appearance of sagging skin, and appears to help protect against oxidative and UV damage • D-Ribose: Used as a humectant and skin-conditioning agent • Pomegranate (Punica granatum) pericarp extract: Contains phenolic punicalagins; gallic acid and other fatty acids; catechin, quercetin, rutin, and other flavonols; anthocyanidins. Pomegranate has been shown to have antioxidant properties.

EGCG SAP Science-based ultra-antioxidant from green tea Epigallocatechin gallate (EGCG) is a powerful natural antioxidant, and the major chemopreventive agent in green tea. Combined with anthocyanidins and lycopene, this standardized, synergistic blend of antioxidants is supported by a wealth of scientific literature. A potent and popular choice of healthcare practitioners for combating oxidative stress; EGCG SAP is designed to address the underlying process behind a myriad of chronic and degenerative conditions, including cancer and cardiovascular disease.

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product profiles

Legend

The Right Multi for Your Patient Progressive MultiVitamins are professionally formulated by Naturopathic Doctor Mikhael Adams to be specific to your age, gender and activity level. Each of the 8 formulas contain select ingredients from nature that have been tested and balanced to provide exactly what your body needs. Featuring green food concentrates, plant enzymes and 100% vegetable capsules, choosing the right multi has never been easier!

SISU Cold & Flu Rescue with Ester-C Reduce the severity of symptoms and shorten the duration of colds or flu with SISU Cold & Flu Rescue with Ester-C®. Cold & Flu Rescue is a potent combination of Ester-C®, echinacea, andrographis, and NAC to effectively relieve cold and flu symptoms and respiratory tract infections – without the side effects that are common with overthe-counter drugs. Visit sisu.com or call 800.663.4163 for more information.

Grape Seed SAP Science-based antioxidant and anti-inflammatory The proanthocyanidins from Grape seed extract (GSE) demonstrate antiinflammatory mechanisms and exhibit cytotoxic behaviour toward human breast, lung and gastric adenocarcinoma cells. With superior free-radical scavenging ability to Vitamins C, E and betacarotene, GSE is a powerful antioxidant, which may protect organs and tissues from the toxic effects of pharmaceutical drugs and environmental stressors, while preventing the development of atherosclerotic plaques.

Cyto-Matrix - Omega-D3 Liquid Forte Evidence based dosages for all indications; High safety profile; Molecularly distilled, ultrapure fish oil; Easy to administer for maximum patient adherence; No fishy aftertaste, light citrus flavour. Each teaspoon (5 mls) contains: Fish Oil Concentrate - 4,377 mg; Omega-3 Fatty Acids 2,845 mg, EPA (Eicosapentaenoic acid) - 1,750 mg; DHA (Docosahexaenoic acid) - 875 mg; Vitamin D3 -1000 IU.

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product profiles

Legend

NEW greens+ O Introducing NEW greens+ O! Containing 75-80% organic ingredients, greens+ O is a great tasting, soy free, dairy free, gluten free, 100% Vegan formulation and like all greens+, is made with non-GMO ingredients. Genuine Health kept the foundation of the award-winning, research-proven greens+ formula, but replaced potential allergens with innovative ingredients, such as organic spirulina, broccoli sprouts, chia seeds, and sunflower lecithin. genuinehealth.com

Immune Support A synergistic formula containing ImmunutrinTM which has been clinically tested and proven effective. Immune Support encourages an optimally functioning immune system. It enhances the body’s immune defenses to help reduce the severity and duration of colds and flu and helps to prevent the occurrence of other bacterial and viral infections.

pharMAX™varicose Trans-dermal Varicose Vein Relief Cream

AHCC AHCC is an extract sourced from mushroom root which offers powerful immune system support. It stimulates and enhances production of immune cells, protects the liver, supports normal cell growth and differentiation and helps control infections. Due to its immunomodulatory effects, it also acts as a potent anti-inflammatory.

Traditionally used in Herbal Medicine as an astringent to help treat varicose veins. Contains natural oils and extracts that work synergistically for maximum effect: • Witch Hazel (Hamamelis virginiana) bark: According to Materia Medica, used for venous congestion and varicose veins • Horse Chestnut (Aesculus Hippocastanum) seed extract: Used as a skin-conditioning agent. Horse chestnut extracts have been shown to contain potent anti-inflammatory and antioxidant compounds • Rutin: Included as an antioxidant and skin-conditioning agent.

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Vitaline CoQ10 ®

the Pure Proven Power of the World’s Most Clinically Studied CoQ10

What Makes Our CoQ10 So Unique? Vitaline CoQ10 was the first to have proven absorption and to be shown to: • Increase serum levels and mitochondrial levels of CoQ10. • Cross the blood-brain barrier. • Have a direct impact on patient health. It is the first choice of researchers across the country and has been the focus of cutting-edge research and the subject of clinical trials showing: • Demonstrated benefits for neurological health. • Benefits for heart and immune health. • Protection to cells from oxidative damage and the effects of aging. It’s the purest, natural form of coenzyme Q10 to support heart, brain, skin and periodontal health and promote healthy aging. • Our special manufacturing process produces a natural, bio-identical CoQ10 for superior absorption. • It’s the purest CoQ10 available and clinically shown to be safe and effective for use at high doses. Our bioavailable form of CoQ10 is proven to restore the CoQ10 depleted by cholesterollowering (statin) drugs.

For more information, please call 800.664.3211 or visit www.integrativeinc.com

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Product MonograPh Bio-Fen Bio-Fen Plus is an oral natural health product used in the treatment of hereditary androgenic alopecia (AGA) for male or female pattern baldness. Without treatment, AGA is progressive, and causes social distress in many affected men and women (Sinclair 1998). Bio-Fen Plus contains extracts DESCRIPTION of fenugreek seeds, saw palmetto berries and flax lignans, as well as specific vitamins. Each ingredient is known to possess inhibitors of the enzyme Vitaline® CoQ10 tablets containare coenzyme Q10for formulated Micosolle®, a proprietary excipient.1 Clinical studies have demonstrated that this 5α-reductase. These inhibitors responsible relieving with symptoms associated with hereditary AGA. process the absorption of CoQ10.2-4 One ofenhances the primary causes of hair loss is a high level of the male hormone dihydrotestosterone (DHT) within the hair follicle (Vierhapper, 2001). For people with AGA, their follicles have a greater number of androgen receptors to which DHT attaches. 5-α-reductase catalyzes the enzymatic Two differentofmethods can be for the productionwhich of coenzyme One method is natural thethan otherthe is synthetic. The natural process1998). utilizes conversion testosterone to used dihydrotestosterone, binds toQ10. the receptor five-fold moreand avidly parent compound (Sinclair living organisms and is referred to as a “biological fermentation/extraction process.” Coenzyme Q10 can also be synthesized by a chemical process, which Vitamins Saw palmetto (Serenoa produces a similar, butrepens) distinctly different product that contains chemical compounds not found in the natural form. Vitaline® CoQ10 contains the Standardized Serenoa natural form (lipophillic) of coenzyme Q10.1extract has been found to be a potent inhibitor In a Polish study of 46 women who had symptoms of diffuse alopecia, calcium of 5α-reductase, resulting in decreased tissue DHT. An open-label, dose response study was conducted on 42 healthy males to determine the effect of a combination

pantothenate was orally administered twice a day in doses of 100 mg for four to five months, and vitamin B6 was injected every day for 20 to 30 days and repeated

STRUCTURE/FUNCTION/USAGE again after six months (Brzezińska-Wcisło 2001). It was determined that vitamin of carotenoid astaxanthin and saw palmetto berry lipid extract on DHT and Vitaline® is a dietary2008). supplement to enhance cellular of CoQ10, with subsequent of CoQ10 affected physical B6 administered parenterally for a support few weeks induces improvement in the hair testosteroneCoQ10 levels (Angwafor The men were divided intomitochondrial two groups: levels systems, of cardiac, neurological,supplement and immune condition in a subset of women and reduces hair loss. one groupincluding received support 800 mg/day of the combination andhealth.* the other group received 2000 mg/day of the supplement for 14 days. ANOVA-RM showed significant within-group increases in serum total testeosterone and significant FORMULA Medicinal Ingredients decreases serum DHT strengths from baseline in both dose groups (P=0.05). There There are in three available of Vitaline® CoQ10 tablets. was no significant difference between dose groups with regard to the increase of Fenugreek (Trigonella foenum graecum) One 25 mg chewable waferofcontains: testeosterone or the decrease DHT; therefore both doses were effective (Angwafor seed extract 4:1mg Coenzyme Q10 (CoQ10) (ubiquinone)…………………………………………...………….25 2008). One 60 mg chewable wafer contains: Saw palmetto berry extract containing Another study liposterolic extract of Serenoa repens (LSESr) and betaCoenzyme Q10tested (CoQ10) (ubiquinone)…………………………………………...………….60 mg 45% free fatty acids sitosterol thechewable treatmentwafer of males (23-64 years of age) with mild to moderate AGA. One 200inmg contains: Flax lignans, standardized to 20% Six of 10 (60%) were(ubiquinone)…………………………………………………….200mg rated as improved at the final visit, thus establishing Coenzyme Q10subjects (CoQ10) secoisolariciresinol diglucoside (SDG) the effectiveness of 5α-reductase inhibitors against AGA (Prager 2002). Chronic Vitaline® Chewable formulated a proprietary process thatAenhances the absorption of CoQ10. inflammation of the hairCoQ10 follicle isisconsidered to with be a contributing factor for AGA. study by Chittur et al sought to determine whether blockade of inflammation using

D-calcium pantothenate (Vitamin B5)

dose Per capsule 260 mg 160 mg

100 mg 10.40 mg

RECOMMENDATIONS LSESr and two anti-inflammatory agents (carnitine and thioctic acid) could alter Niacinamide (Vitamin B3) 10.25 mg theaexpression of molecular take markers inflammation 2009). was found or health care professional. Refer to label for complete instructions. As dietary supplement, 1-2oftablets daily or (Chittur as directed by aIt physician that the combination suppressed lipopolysaccharide-activated gene expression of

Pyridoxine HCl (Vitamin B6)

2 mg

chemokines associated with pathways involved in inflammation and apoptosis. PRECAUTIONS Riboflavin (Vitamin B2) 1.58 mg The study concluded that 5-alpha reductase inhibitors in combination with The safetyofof CoQ10 hasprocesses been evaluated. Dosages in studies have ranged from 100 mg every day to 1200 mg per day. To date, no toxicities have been blockade inflammatory could represent a new two-pronged approach Folic acid 0.095 mg reported. Occasional gastric upset may occur.12, 13 Taking Vitaline® CoQ10 wafers with meals usually alleviates this rare upset.1 in the treatment of AGA.

Biotin

Fenugreek Seeds STORAGE RECOMMENDATIONS Fenugreek seeds contain to 30% protein, steroid sterols, flavonoids Store at controlled room5% temperature, 59° to 86°Fsaponins, (15° to 30°C).

and alkaloids (notably trigonelline and choline). Steroid saponins bind and eliminate extra cholesterol and hormones in the body; DHT is made from testosterone, which is in turn is made from cholesterol. Therefore, when excess cholesterol is eliminated, less DHT can be made (Stark 1993). In a study of 20 adults who consumed 12.5g and 18.0g of germinated fenugreek seed powder for References one month, higher levels of consumption resulted in a significant reduction in total 1. Meese J. President. Vitaline® Corporation. Personal communication (verbal). October 20, 2000. cholesterol and low-density lipoprotein (LDL) levels (Sowmya 1999).

400 mcg

non-Medicinal Ingredients Inert microcrystalline cellulose and vegetable-based magnesium stearate in a veggie-based capsule Recommended adult dose: One capsule per day

2. Nakmura T, Sanma M, Himeno M, Kato K. Transfer of exogenous coenzyme Q10 to the inner membrane of heart mitochondria in rats. In: Folkers K, Yamamura Y, eds. Biomedical and Clinical Aspects of Coenzyme Q. Vol 6. Amsterdam: Elsevier Press; 1980;3-14.

Flax lignans Flax reduces the amount of DHT produced by reducing cholesterol levels in the 4. Joliet P, Simon N, Barre J, et al. Plasma coenzyme Q 10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36:506-509. body. A meta-analysis of 28 studies between 1990 and 2008 showed that flaxseed 5. Mitchell P. The reduces vital protonmotive of coenzyme In: Folkers K, Littarru GP, Yamagami T. Eds. Biochemical significantly circulating totalQ.and LDL-cholesterol concentrations (Pan and Clinical Aspects of Coenzyme Q. Vol 6. Amsterdam: Elsevier Press; 1991:3-10. 6. Sinatra ST, DeMarcointerventions J. Free radicals, oxidative stress, oxidized density lipoprotein (LDL) and the heart: antioxidants and other strategies to limit cardiovascular damage. Conn Med. 1995;59:579-588. 2009). Flaxseed reduced total andlow LDL cholesterol by 0.10 mmol/L (95% CI: 0.00 F,mmol/L) 0.08 mmol/L (95% -0.16, function 0.00 mmol/L), 7. Ravaglia G, -0.20, Forti P, Maioli et al. Effect and of micronutrients on natural killerCI: cell immune in healthy free-living subjects aged >/=90y. Am J Clin Nutr. 2000:71:590-598. respectively. Significant reductions were with whole (-0.21 and of these compounds in rat tissues and mitochondria. J Nutr. 2000;130:2434-2438. 8. Ibrahim WH, Bhagahav HN, Chopra RK, Chow CK.observed Dietary coenzyme Q10 andflaxseed vitamin E alter the status -0.16 mmol/L, respectively) and lignan (-0.28 and -0.16 mmol/L, respectively) 9. Porth CM, Carroll EW. Mitochondria. In: Porth CM. Pathophysiology: Concepts of Altered Health States. 5th ed. Philadelphia, Pa; Lippincott; 1998:8-9. supplements (Pan 2009). 3. Matthews RT, Yang L, Browne S, Baik MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci USA. 1998;95:8892-8897.

10. Guyton AC, Hall JE. Mitochondria. In: Textbook of Medical Physiology. 9th ed. Philadelphia, Pa: WB Saunders; 1996:16-17.

11. Langsjoen PH, Langsjoen A, Willis R, Folkers K. Treatment of hypertrophic cardiomyopathy with coenzyme Q10. Mol Aspects Med. 1997;18 Suppl:S145-S151 12. 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 References Med. 1994;15 Suppl:S287-294. Angwafor F III, Anderson ML. An open label, dose response study to determine the effect of a dietary supplement on dihydrotestosterone, testosterone and estradiol levels in healthy males. J IntSacher Soc Sports NutrML, 2008;5:12. 13. HL, Sacher Landau SW, et al. The clinical and hemodynamic effects of coenzyme Q10 in congestive cardiomyopathy. Am J Ther. 1997;4:66-72. 14. Kim Y, Sawada Y, Fujiwara G, ChibaofH,vitamin Nishimura Therapeutic of co-enzyme Q10 on idiopathic dilated cardiomyopathy: assessment by iodine-123aspects labeled 15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acidWiad myocarBrzezińska-Wcisło L. Evaluation B6T. and calcium effect pantothenate effectiveness on hair growth from clinical and trichographic for treatment of diffuse alopecia in women. dial emission tomography. Eur J Nucl Med. 1997;24:629-634. Leksingle-photon 2001;54:11-8. 15. Littarru Lippa S, Oradei A,G. Fiorni RM, Mazzanti L. Metabolic gene and diagnostic implications of blood CoQ10 In: Folkers K, Littarru GP, Yamagamithioctic T. Eds Biomedical Aspects of Coenzyme Q. Vol 6. Chittur S,GP, Parr B, Marcovici Inhibition of inflammatory expression in keratinocytes using levels. a composition containing carnitine, acid andand sawClinical palmetto extract. Evid Based Amsterdam: Elsevier Press; 1991:167-180. Complement Alternat Med 2009. 16. Carroll EW, Curtis RL. Blood-brain barrier. In: Porth CM. Pathophysiology: Concepts of Altered Health States.5th ed. Philadelphia, Pa; Lippincott; 1998:869. Pan A, Yu D, Demark-Wahnefried W, Franco OH, Lin X. Meta-analysis of the effects of flaxseed interventions on blood lipids. Am J Clin Nutr 2009;90:288-97. 17. Flaherty JF. Blood-brain barrier. In: Young, LY, Koda-Kimble MA. Applied Therapeutics: The Clinical Use of Drugs. 6th ed. Vancouver, Wash: Applied Therapeutics, Inc; 1995: chapter 56, page 2. Prager N, Bickett K, French N, Marcovici G. A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia. J Altern Complement Med 2002;8:143-52. Serenoa repens monograph. Alternative Medicine Review 1998;3:227-9. Sinclair R. Male pattern androgenetic alopecia. BMJ 1998;317:865-9. Sowmya P, Rajyalakshmi P. Hypocholesterolemic effect of germinated fenugreek seeds in human subjects. Plant Foods Hum Nutr 1999;53:359-65. Stark A, Madar Z. The effect of an ethanol extract derived from fenugreek (Trigonella foenum-graecum) on bile acid absorption and cholesterol levels in rats, Br J Nutr 1993;69:277-87. Vierpper H, Nowotny P, Maier H, Waldhausl W. Production rates of dihydrotestosterone in healthy men and women and in men with male pattern baldness: determination by stable isotope/ dilution and mass spectrometry. J Clin Endocrinol Metab 2001;86:5762-4.

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Dr Joseph Gabriele Delivers the future of pain management By Philip Rouchotas, MSc, ND Photography of Dr. Joseph Gabriele by Robyn Russell

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Delivra’s research laboratory grand opening at the National Research Council in Charlottetown PEI. From left to right: Dr. Bryce Wylde, Federal minister Gary Goodyear, Dr. Joseph Gabriele, Premier Robert Ghiz, Bobby Orr, Federal minister Gail Shea

r Joseph Gabriele took a detoured path to a career in academia. Following an undergrad from the University of Toronto and a Masters from McMaster in 1989, he entered a career in footwear importing for the next 19 year. He describes it as a fun time, his sales role having him spend six months of each year traveling across North America and Europe, yet by 2006 he found himself completing his Post Doc at Queens. By the end of 2006 he was a faculty member at McMaster University, conducting important preclinical research with relevance to psychotic and neurodegenerative diseases. Our story begins when a personal tragedy led Dr Gabriele to develop what is now a medical triumph of tremendous significance. Dr Gabriele’s wife was diagnosed with a bone tumour. Following several surgeries, and compounded by a severed branch of the trigeminal nerve, Mrs Gabriele was cancer

free yet suffered debilitating pain. Oral pain relievers were providing little relief and an insufferable list of adverse effects. Mrs Gabriele defiantly chose to discontinue use of pain meds- Dr Gabriele took action. Utilizing his own time, resources and scientific team, Dr. Gabriele developed the cutting edge Delivra™ trans-dermal delivery system - a topical that when combined with any other agent (natural or prescription), can transport these ingredients for deep, localized action. This topical system provides an alternative to oral medication, bypassing the GI tract and any systemic effects associated with digestion, and empowers patient self-medication for enhanced recovery. In the case of his wife, Dr. Gabriele coupled this topical system with natural ingredients traditionally used for pain relief – creating a fast-acting, deep penetrating pain cream – providing the much sought after relief she needed.

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Delivra’s laboratory at the National Research Council This new topical transport system has caused a paradigm shift in promoting a less invasive way to deliver natural and/ or prescription pharmacological medications. The topical delivery system takes advantage of little known scientifically established interactions between plant-product substances, human cellular and nerve tissues, and as such actually has a dual action effect. Not only does it provide a fast-acting response from the actives it transports, but the cream base itself contains natural oils and extracts including rutin and its derivatives, as well as other polyphenols, that have the potential to block five main pain pathways. The delivery system cream has no strong odours, contains no parabens, sodium lauryl sulfate or petrolatum – making it an excellent alternative to emollient, synthetic based creams. Delivra™ has underwent testing for its depth of penetration as a trans-dermal carrier cream. During in vitro studies, using reconstructed epidermis (Epiderm™) (the existing gold standard for testing of topical delivery systems), the Delivra™ cream base was mixed with Naproxen and tested against Pluronic Lecithin Organogel (PLO) – the most common topical base foundation. Regarding delivery depth of Naproxen to the underlying dermis layer, Delivra™ outperformed PLO 6.3 to 1. Dr. Gabriele continues his solid commitment to research in collaboration with an extensive research team. He has partnered with Xenex labs for pharmaceutical applications of the cream, and this partnership services pharmacies across Canada. He has also partnered with natural health product’s giant Atrium Innovations for natural health product applications of the cream. What makes Delivra™ such a novel and important advancement? The cream was developed with the goal of overcoming many obstacles facing existing topical delivery systems; delivering large molecules, delivering active constituents in a targeted manner (selecting between dermis, blood, muscle, or bone delivery), and allowing for the use of actives that are water soluble. Delivra™ has succeeded in all three areas. The cream possesses a fatty acid composition very similar to that of skin... It binds and in many ways “becomes part of” the skin. The union of cream and skin acts to drive active molecules into the dermis. However, the work of this research team was far from done. November/December 2012 l www.ihpmagazine.com 33

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While Delivra™ had succeeded in raising the size limit of molecules for topical delivery from a previous ceiling of 500kDa to over 1000kDa (with work underway to increase this to up to 3000kDa), many of the actives desired for combination with the cream, especially in the realm of natural medicine, remain too large for use. The team succeeded in yet another series of ground- breaking developments, in recognizing that a large antiinflammatory molecule, for example, would retain its therapeutic properties if only a small fragment of the active molecule was isolated and added to the Delivra™ system. This has allowed for the topical delivery of an array

“Our story begins when a personal tragedy led Dr. Gabriele to develop what is now a medical triumph of tremendous significance.” of therapeutic herbal and neutraceutical constituents that until now were beyond the reach of utility as topical agents. The limitless potential of this innovation has not fallen on deaf ears within our government. The NRC, through a natural products and marine biology program in PEI, have offered the Delivra™ team a laboratory within their facility, and funding in the form of a Canadian innovation grant is expected in the near future. We wait with eager anticipation to see how far this incredible team can take “the cream that could”. Dr Gabriele’s accolades do not begin nor end with the creation of the Delivra™ system. He maintains a role as

Researcher and Assistant Professor in the Department of Psychiatry and Behavioural Neurosciences with McMaster University. His lab discovered a novel 40kDa protein tightly linked to dopaminergic activity. The team demonstrated that among patients with psychotic illness there is depressed expression of this protein. Furthermore, among patients who have undergone successful, long-term treatment with antipsychotic medications, the expression of this protein reaches normal or nearnormal levels. Of tremendous interest is how this research has progressed; in preclinical models of psychosis in experimental animals, as well as models of Parkinson’s Disease in animals, injection of an isolate of this protein has been shown to provide tremendous symptomatic relief for both disorders. IHP is grateful to Dr Gabriele for allowing us to showcase his many areas of research to you. It seems like everything this gifted scientist touches turns to gold! An industrychanging innovation in topical medication delivery, an advancement in preclinical psychiatric research that holds promise as a safe and effective solution for two important and debilitating disorders (and likely beyond)... And all of this achieved in what has been a career in science not yet a decade old. We can not help but imagine where Dr Gabriele may have taken us had he chosen to pursue academia instead of clothing sales all those years ago, yet we are certainly grateful he entered the research arena as a second career path. We remain eager to see further advancements of the Delivra™ system, clinical application of the dopaminergic protein, and whatever else Dr Gabriele may chose to apply his efforts to. ■

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Delivraâ&#x20AC;&#x2122;s laboratory at the National Research Council

Delivra compound base for health care practitioners

Delivra creams formulated specifically for health care practitioners

From left to right: Nicole and Sue Gabriele November/December 2012 l www.ihpmagazine.com 35

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How to Read a Fish Oil Label

Don’t stop at 1,000 mg of fish oils — LOOK FURTHER! ✓ NPN number

NPN#80005548

Look for the NPN number to be sure the product is registered and has been approved by Health Canada.

• Carlson Super Omega-3 Fish Oil helps support cognitive health and brain function. / Sup u er Oméga-3 huililile up le de d pois i son de is d Ca C rrlllsson contr tririb tr ibue à lla santé t té cognitititve v et ou aux u ux fo f nctititio ions céré r bra ré r le ra l s. u er up • Carlson Super Omega-3 Fish Oil helps maintain cardiovascular health. / Sup rrd e. t card té diio di ovvascula l irirre la Oméga-3 huililile le de d pois iisson d de Ca C rlrls lson aid iid de à main de i te in t niriri lla santé Each soft gel contains: Medicinal Ingredient:

ttiie ient: t t: Chaque gélule l conti le Ingré r d ré diiie ent médi d diiic ciinal:

Fish Oil 1000 mg {[Anchovy (En E gra En r ulililid ra iddaae - Whole) and Sardine (Cl C Clup u eid ida id dae - Whole)] EPA [Eicosapentaenoic Acid] 300 mg DHA [Docosahexaenoic Acid]} 200 mg

Huiliille le dde Pois i son is {{[[A [Anchois i (E is (En Engra r ulilliid ra ida dae - EEnttiie ierr) et Sa S rd rddiin ine (C (Cl Clup u eid iddaae - En id E titie ier) r] e e] AEP E [[Acid EP iddee EEiic id icosapenta t éénoique] ta ]} ADH [A [ cid iddee Docosahex id exa ex xaén é oique] e]} e]

✓ DHA and EPA Look for substantial amounts of DHA and EPA which support cardiovascular and cognitive health.

Non-medicinal Ingredients: Gelatin, glycerin, water, tocopherols. / Ingré r d ré diie ients t non médi ts diicciinaux di ux: ux x: Géla l ti la tin ine, gly lyc ly ycéri riin ri ne, eau, to t cop o héro op r ls ro l .

✓ Serving Size

Directions: Adults: Take 1 softgel capsule twice per day with meals. / M Mod de d’e ’ mp ’e m lo l i: i Adu d dulltte tes: Pr Pre rendr drre dr e 1 gélu l le lu l de d u ux ffois i par jo j ur ave v cd ve des rre epas. ep Preservative-free. Cholesterol-free. / Sans agents ts va le té t de d conserva v titio ion. Sans chole l sté t ro r l. Do not purchase if safety seal is broken or missing / Ne pas achete t r si le te l sceau sécuri rrita t ir ire re est bri ris ri isé ou manquant. tt.

Check the number of soft gels/capsules in the dosage. (Some products with higher potencies listed on the label may require taking multiple soft gels).

- PURITY GUARANTEED / PUR U ETÉ UR T GA TÉ G RA R NTI T TIIE IE This product is regularly tested (using AOAC international protocols) for freshness, potency and purity by an independent, FDA-registered laboratory rry and has been determined to be fresh, fully-potent and free from detrimental levels of mercury r , cadmium, lead, PCB’s and 28 other contaminants. / Ce ry C pro r d ro du u uiitit fa f iit ré rég égul ulliiè ièrrement l’o ’ bj ’o bje jet de d contr trô tr rôlles (a ( u moy oyye oy en d des pro r to ro t cole l s iinte le t rn r atititio ux ’A C, Associ ci on of Offfffffiiiccciiia al Analy ionaux u de d l’A ’ OA O C cia iatitiio llyyt yttiic ica cal C emis Ch iists ts) s) afiffiiin n d’e ’ n vé ’e v ririfififie ier la l ffrra raîîccch heur, r la r, l pui uis ui issance et la l pure rretté par un u la l bora r to ra t irire re iindé dép épenda d nt enre da rre e eg g giis istr tré ré aup u rè up r s du d Secr cré cr réta t riria iat amérirriiicca cain i aux u pro ux r du ro du uiiitttss alililim imenta ttairire res et pharm r aceutititiq rm iques (F (FD FDA DA A)) et a été tté ju jug ugé comme éta t nt ta fra fr rais is, s, ple l iinement effffffific le icca ace et sans d de e eg gré gr rés nui uis ui isib i le l s de d merc r ure rc r , ca re c dm d iu iu um m, plo l mb, lo b BPC et 2 b, 28 autr ttrrre es conta t min ta i ants in t. ts

✓ Testing Make sure the product is tested for freshness, potency and purity.

Manufactured for / Fa F bri rriiq iqué pour: r r: J.R. Carlson Laboratories, Inc., 888-234-5656 • www.carlsonlabs.com Arlington Heights, IL 60004-1985, USA / ÉÉ U. Imported by / Imp mp rt r: m ort rté té par: r MMP Enterprises Ltd., 1520 Creditstone Road Concord, ON L4K5W2

Be sure it has been tested for contaminants and heavy metals.

POTENCY AND QUALITY GUARANTEED G RA GA R NTI TIIEE DE PUI TI U UIIS ISSA S NCE C ET DE QUA CE U LITÉ UA T TÉ

The leader in Norwegian Fish Oils 888-234-5656 | www.carlsonlabs.com

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Product MonograPh Carlson Norwegian Cod Liver Oil Carlson Norwegian Cod Liver Oil provides EPA and DHA, two very long- chain polyunsaturated omega-3 fatty acids found in fish. The oil also provides naturally occurring vitamin D and preformed vitamin A. EPA and DHA have been the topic of over 12000 published, peer-reviewed journal articles. Clinical intervention studies have shown a wide array of potenial physiological benefits from EPA and DHA consumption, notably improved cardiovascular health, improved mood and well-being, support of fetal development, delay of cachexia associated with cancer and AIDS, and others. Impact to cardiovascular health is the most publicized benefit of EPA and DHA consumption. The single most important outcome delivered by EPA and DHA appears to be their ability to reduce risk of sudden coronary death (SCD), with estimates as high as a 45% reduction in SCD risk among patients whom had recently survived a heart attack (Marchioli 2002). In this large, “megatrial” of EPA and DHA supplementation, 850mg of combined EPA and DHA per day for two years achieved a 45% reduction in SCD risk as well as a 25% reduced risk of all-cause mortality. It has been suggested that as little as 250mg per day of combined EPA and DHA are sufficient to achieve the very profound impact to SCD risk described above (Mozaffarian 2006). Other experts believe a dosage of 600-900mg of combined EPA and DHA per day is required to achieve this outcome (KrisEtherton 2003). While low dosages of EPA and DHA appear to deliver a large magnitude of benefit to SCD risk and subsequent risk of all-cause mortality, there appears to be added benefit in consuming larger dosages (Mozaffarian 2007). At a dosage range of 2000-4000mg of combined EPA and DHA per day, benefit to cholesterol levels is achieved, an outcome not delivered at the lower dosages described above. When consumed at this larger dosage range, EPA and DHA powerfully reduce fasting triglyceride levels (20-45%) while simultaneously achieving increases to HDL-C levels of 5-15% (Harris 1997). LDL-C levels are typically unchanged, but may increase 5-10% (Harris 1997). In a large intervention trial spanning five years, large dosages of EPA (1800mg per day) were supplemented to a Japanese population, estimated to be consuming a mean of 900mg of EPA and DHA per day through diet alone. While mechanistic detail remains speculative, the trial reported a 19-28% reduced risk of non-fatal major coronary events among EPA supplemented subjects (Yokoyama 2007). Therefore, while low-dose EPA and DHA have been reproducibly demonstrated to reduce SCD risk, this large landmark study highlights that at higher dosages, EPA and DHA begin to reduce risk of non-fatal cardiovascular events (Mozaffarian 2007, Yokoyama 2007).

Carlson Norwegian Cod Liver Oil – Supplement Facts Serving size 1 teaspoon (5ml)

amount per teaspoon

Calories

Vitamin A

850 IU

Vitamin D

400 IU

Vitamin E

10 IU

Omega-3 fatty acids DHA (docosahexaenoic acid) EPA (eicosapentaenoic acid) ALA (alpha linolenic acid)

1100 mg 500 mg 400 mg 40 mg

References Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997 May;65(5 Suppl):1645S-1654S. Kris-Etherton PM, Harris WS, Appel LJ; AHA Nutrition Committee. American Heart Association. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):151-2. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, Franzosi MG, Geraci E, Levantesi G, Maggioni AP, Mantini L, Marfisi RM, Mastrogiuseppe G, Mininni N, Nicolosi GL, Santini M, Schweiger C, Tavazzi L, Tognoni G, Tucci C, Valagussa F; GISSI-Prevenzione Investigators. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002 Apr 23;105(16):1897-903. Mozaffarian D. JELIS, fish oil, and cardiac events. Lancet. 2007 Mar 31;369(9567):1062-3. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006 Oct 18;296(15):1885-99. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K; Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007 Mar 31;369(9567):1090-8.

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clinic profile

From left to right: Nara Simmonds, Lana McMurrer, and Kali Simmonds

Simmonds McMurrer Integrating naturopathic medicine into “the island way of life”

By Angela MacNeil, MSc, ND • Photography by Alanna Jankov

immonds McMurrer Naturopathic Medicine is a naturopathic clinic located in a beautifully restored heritage building in historic downtown Charlottetown, Prince Edward Island. Dr. Kali Simmonds always envisioned starting and raising a family back home in PEI. However, she was concerned with a general lack of knowledge surrounding the profession. In June 1999 when The Root Cellar, a grassroots health food store founded in 1972, was put on the market, Dr. Simmonds decided to gauge this small province’s interest in naturopathic medicine. She advertised in a small local newspaper that she would be conducting patient visits while vacationing for 10 days in July. Conducting 44 initial 1.5 hour visits during this 10-day period, she was shocked by the response! Reassured by this immense interest, Kali and her husband were highly motivated and bought The Root Cellar and the threestorey heritage building in which it was housed in November 1999. Initially, Dr. Simmonds concentrated a lot of her time in the store to help educate the public about naturopathic medicine. While awareness about the value of naturopathic medicine has grown tremendously, she notes that education must be ongoing given the tendency to lump alternative health care practitioners under the category of “naturopathic doctor” or “naturopath” despite the significant educational disparities among this wide and diverse group of practitioners. The Root Cellar occupied the 1,600 square foot ground floor of the building and apartments occupied the second and third floors. In February 2000, the 1,000 square foot apartment on the second floor was renovated into four offices and a sauna in which Dr. Simmonds, a psychologist, a counsellor, and a massage therapist practiced. By the Fall of 2006, Dr. Simmonds had roughly 1,500 patient files and having recently had her fourth child out of an eventual six children, the need for another naturopathic doctor in the clinic was obvious. Consequently, Dr. Lana McMurrer joined the practice. The partnership between Dr. Simmonds and Dr. McMurrer led to an exciting opportunity with Easlink TV. The two

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clinic profile naturopathic doctors launched a regional weekly community television show called “Au Natural”. As co-hosts, they discuss a large range of health topics and feature a variety of different guests, including medical specialists, family physicians, pharmacists, physiotherapists, psychologists, etc. The practitioners make themselves relatable during this program and aim to make naturopathic medicine part of the everyday. Now entering their fifth season and having recorded over 100 shows, “Au Natural” has been very well received. Although no payment is received for hosting the show, the practitioners acknowledge that the show has been a big part of the clinic’s success and has been excellent for mainstreaming naturopathic medicine. Dr. Simmonds’ sister, Dr. Nara Simmonds, joined Simmonds McMurrer in the Fall of 2010, at which point the clinic changed from a multi-disciplinary clinic into primarily a naturopathic clinic. Currently, the clinic is comprised of the three naturopathic doctors, a massage therapist, and an office manager. Even with Dr. Kali Simmonds and Dr. McMurrer practicing part-time, the clinic has over 3,000 patient files. Half of the clinic visits are new patient visits, which mean fewer visits per patient than what might be common in naturopathic practice but this highlights the tremendous growth the clinic continues to observe. The television show, a newspaper column, and many public and private seminars act as the clinic’s main sources of advertising. The success of Simmonds McMurrer is due to its strong presence in the community. In addition, the three naturopathic doctors have very close personal and professional relationships, which has resulted in similar practice styles. This has allowed for strong continuity of care for patients during numerous maternity leaves; while Dr. Kali Simmonds has completed her family, Dr. Lana McMurrer and Dr. Nara Simmonds have just begun with Dr. McMurrer having one child and Dr. Nara Simmonds expecting her first. The practitioners generally take an orthomolecular approach to medicine

and concentrate on nutrition, botanical medicine, and counseling. They are constantly challenged with meeting patient needs while remaining cognizant of financial constraints given relatively low average incomes in PEI. Therefore, high quality retail brands, such as Trophic and Natural Factors are often recommended. Several professional lines are also available to patients over-the-counter in The Root Cellar, including Douglas Labs, Mediherb, WTSmed Formulations, Thorne, and custom formulations from Signature Supplements. The clinic also utilizes a number of laboratory analyses, including saliva hormones, 24-hour urine testing, IgG and IgE allergy testing, hair analysis, and Candida antibodies through Rocky Mountain Analytical in Alberta. In addition, the clinic utilizes Genova Diagnostics for stool yeast and parasite culturing and FFP Laboratories for halogen and heavy metal urine testing. Roughly twelve medical doctors regularly refer patients to Simmonds McMurrer; this is significant in a province of only 130, 000 people. The naturopathic doctors work with patients daily to coordinate thyroid and bioidentical sex hormone treatment through their family physicians. In fact,

Dr. Kali Simmonds has actually attended medical visits with patients! Medical doctors are generally receptive to blood testing requests when patients present professionally justified test requests from the naturopathic practitioners, which is important since there are no private laboratories on the Island. Educating the public is an ongoing issue because naturopathic medicine is not a regulated profession in PEI but the six residing naturopathic doctors are hopeful that legislation could come as soon as Spring 2013. According to the CAND, the PEI Association of Naturopathic Doctors is the only association ever invited to speak to the Board of Directors of the College of Family Physicians and Surgeons of PEI or to be granted written support from the board of the PEI medical society to the ministry of health for the need for legislation for naturopathic medicine in this province. IHP would like to thank the practitioners of Simmonds McMurrer for taking time out of their hectic schedules to allow us a glimpse into this highly successful naturopathic practice. We are extremely impressed with how they have integrated the clinic into the community. We wish them all the best! ■

CLINIC TEAM Dr.Kali Simmonds, ND: Naturopathic Doctor, Clinic Director Dr.Lana McMurrer, ND: Naturopathic Doctor Dr.Nara Simmonds, ND: Naturopathic Doctor Kelsie MacEachern, RMT: Registered Massage Therapist Mary Anne DeMone: Office manager

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One of the primary causes of hair loss is a high level of the male hormone, dihydrotestosterone (DHT) within the hair follicle (Hoffmann 2002). DHT is produced from Sawfor palmetto (Serenoa repens) the and elimination offollicle. invading pathogens and foreignofcells suchtheas and bacteria. testosterone in thedetection testes (males), the adrenal glands, and the After a period of time, anVitamins over abundance DHT causes hairviruses follicle to degrade and shortens the active phase of the hair,(lipophillic) eventually leading to thinning hairbeen and eventual Thereinhibitor is a familial In tendency forstudy stepwise the hair follicle and an increase the calcium ratio a Polish of miniaturization 46 women whoof had symptoms of diffuse alopecia, Standardized Serenoa extract has found tohair be loss. a potent Immune Support is a potent immune system support formula containing well researched ingredients ininwith of of telogen (resting phase) to anagen (growthtissue phase)DHT. hairs, which is promoteddose by systemic effects of was androgens. Althou gh everyone thosemg pantothenate orally administered twiceproduces a day inDHT, dosesonly of 100 fora four to 5α-reductase, resulting in decreased An open-label, responseand local higher number of androgen in their binding sitesof for greater five androgen sensitivity experience hairinjected loss (Prager 5AR forrepeated the clinically effective dosages. It is designed toa DHT, helpandimprove immune promote the months, and system vitamin B6activity, was every2002). day for 20istoresponsible 30 days and study was conducted onreceptors 42 healthy maleshair to follicles, determine the effect combination conversion of testosterone to dihydrotestosterone, binds to the sameon androgen but with five-fold greater(Brzezińska-Wcisło affinity. (Hoffmann 2001). 2002, Trueb after six months It was2002) determined that vitamin again of carotenoid astaxanthin and saw palmettowhich berry lipid extract DHT receptor, and

proliferation of immune system cells, help prevent the occurrence of bacterial and viral infections, and is

testosterone levels (Angwafor 2008). The men were divided into two groups:

B6 administered parenterally for a few weeks induces improvement in the hair

Flax excellent for anyone looking to improve their health and boost their defenses against colds, flus and other condition in subset women and Flax reduces hair are loss. onelignans groupinhibit received 800 mg/day of the combination supplement the other Flax the enzyme 5AR, thus balancing formation of the maleand hormones that are responsible fora hair lossof(Evans 1995). lignans converted by the body to group received mg/daywith of the supplement for 14 days. ANOVA-RM types of2000 infections. enterolactones, which compete estrogen and testosterone for receptor binding,showed and increase sex hormone binding globulin (SHBG), resulting in lower levels of free (ie active) significant within-group increases in serum testeosterone and significant estrogen and testosterone. Flaxseed been shown total toof reduce serum levels of 17-beta-estradiol andingredients estrone sulfate (Hutchins 2001), and results in a shift to in estrogen metabolism to Immune support ishas comprised carefully selected natural that are both designed Medicinal Ingredients Doseencourage Per Capsule decreases serum DHT baseline in both favor the lessin biologically activefrom estrogens (Brooks 2004).dose groups (P=0.05). There

optimaldifference functioning of the immune system and which are backed by extensive scientific was the no significant between dose groups with regard to the increase of Fenugreek (Trigonella foenum graecum)

research. The

Fenugreek mg testeosterone the decrease of DHT; therefore both doses were effective (Angwafor active or ingredients in Immune Defense include Holy Basil,seed Andrographis paniculata extract,260 Emblica extract 4:1 Fenugreek 2008). has been used traditionally as an oral and topical treatment for hair loss. Plant sterols contained in fenugreek such as -sitosterol have been shown to block DHT receptor sites (Prager 2002, see below). officinalis extract and Immunutrin TM which is a combination of mushrooms including Maitake (Grifola

Saw palmetto berry extract containing

160 mg

Another study tested liposterolic extract of Serenoa repensReishi (LSESr) (Ganoderma and betafrondosa), Shitake (Lentinula edodes), lucidum), and Brazilian (Agaricus Blazei) 45% free fatty acids Saw Palmetto (men’s product) sitosterol inextract the treatment of males (23-64 years of age)resulting with mild to moderate AGA. Saw palmetto is a potent inhibitor of 5 -reductase, in decreased tissue DHT (Prager 2002). In a pilot study of 26 men with mild to moderate AGA, treatment with along with rice bran, olive leaf and wild yam. Each of these ingredients in this bioavailable Flax lignans, standardized tohighly 20% assessors Six of 10 (60%) subjectssaw were rated asextract improved at and the beta-sitosterol final visit, thus50mg establishing a combination of lipophilic palmetto 200mg improved symptoms by up to 60%, as scored by blinded (Prager 2002). In a meta 100 mg secoisolariciresinol diglucoside (SDG) isof able modulate thebeen immune system and to assist the body in(Wilt fighting infection and the formula effectiveness 5α-reductase inhibitors AGA (Prager 2002). Chronic analysis by the Cochrane group,to saw palmetto hasagainst also found to be effective as a treatment for symptoms of BPH 2002). illness, inflammation of the of hairdisease. follicle is considered to be a contributing factor for AGA. A symptoms

D-calcium pantothenate (Vitamin B5) 10.40 mg Silica (women’s product) study by Chittur et al sought to determine whether blockade of inflammation using Silica is a and tracetwo mineral that has been found to increase hydroxyproline in connective tissue (Barel 2005). In a randomized, double blind, placebo controlled study, 50 LSESr anti-inflammatory agents (carnitine and thiocticconcentration acid) could alter Niacinamide (Vitamin B3) 10.25 mg women with damaged skin weremarkers treated orally with 10mg silica as orthosilicic the expression of molecular of inflammation (Chittur 2009). It acid was (OSA) found daily for 20 weeks. The treatment group reported a significant decrease in visual analog Ingredients: scale ratings of hair brittleness (Barel 2005). A second randomized, double blind, placebo controlled trial conducted in 50 women with brittle hair found that 10mg silica as OSA Pyridoxine HCl (Vitamin B6) 2 mg that the combination suppressed lipopolysaccharide-activated gene expression of for 9 months significantly improved Immunutrin TM hair elasticity, breakage, and diameter (thickness) (Wickett 2007). chemokines associated with pathways involved in inflammation and apoptosis.

Immunutrin TM has been increase the activity study thatcell 5-alpha reductase inhibitors in to combination with B The vitamins are concluded support healthy growth and demonstrated division, and facilitate optimal hormone metabolism.

Riboflavin B2) of(Vitamin the immune

1.58 mg which system macrophages

blockade of inflammatory processes could representof a new two-pronged approach engage in the important process phagocytosis. In one study conducted to examine this process, after Folic acid 0.095 mg Medicinal ingredients per capsule in both the men’s and women’s: in the treatment of AGA. just one hour of incubation with ImmuNutrin TM the activity level of macrophages increased by 65% Fenugreek (Trigonella foenum graecum) seed extract 4:1 ....................................................260 mg Biotin 400 mcg (dry equiv 1040mg) Fenugreek Seeds (Ooi VE and Lui F, 2000). This result has also been observed when the independent mushroom Flax lignans, standardized to 50%to SDG ...............................................................................100 mg Non-Medicinal Ingredients Fenugreek seeds contain 30% protein, steroid saponins, sterols, flavonoids constituents of5% theB5)formula were tested in another study in d-calcium pantothenate (Vitamin ..................................................................................10.4 mg order to determine the immunomodulatory and alkaloids (notably trigonelline and choline). Steroid saponins bind and Niacinamide (Vitamin B3) ...................................................................................................10.3 mg Inert microcrystalline cellulose and vegetable-based magnesium activities of mushroom glucans polysaccharidecomplexes in animals and humans (Rowan, eliminate extra cholesterol and hormones in theand body; DHT is made fromprotein Pyridoxine HCl (Vitamin B6) ...............................................................................................2.0 mgstearate in a veggie-based capsule testosterone, which is in turn is made from cholesterol. Therefore, when excess (Vitamin .......................................................................................................1.6 mg Riboflavin N.J., et al.B2)2003). Previous studies have shown the β-glucans in mushrooms are capable of activating is eliminated, less DHT can be made (Stark 1993). In a study of 20 mcg cholesterol Folic acid ..............................................................................................................................95 dormant macrophages. In an open-label human study involving 18 subjects, 2 months Recommended adult dose: One capsule perof daysupplementation adults who consumed 12.5g and 18.0g of germinated fenugreek seed powder for Biotin ....................................................................................................................................250 mcg one with month,1000mg higher levelsdaily of consumption resulted in a significant reductionin in total of ImmuNutrinTM resulted an 18% increase in immune cell levels, 16 of the 18 Men’s also has: cholesterol and low-density lipoprotein (LDL) levels (Sowmya 1999).

throughout the study (Chavoustie SE, et al., of ImmuNutrinTM per day. After two Flax reduces the amount of DHT produced by reducing cholesterol levels in the weeks, the subjects’ levels of natural killer cells had increased by 19% and natural killer cell activity, or Women’s also has: body.(silicon A meta-analysis of 28 studies between 1990 and 2008 showed that flaxseed mg Silicon dioxide) ........................................................................................................40 cytotoxicity, had increased by 17%. Olive leaf is included significantly reduces circulating total and LDL-cholesterol concentrations (Pan mg in Immunutrin as it has demonstrated Iron (ferric citrate) ................................................................................................................20 2009). Flaxseed interventions reduced and LDL cholesterol by 0.10 mmol/L antimicrobial activity intotal several studies including one that investigated the successful antimicrobial effect Recommended use:0.00 one mmol/L) capsule twice capsules perCI: bottle). Bio-Fen® Plus capsules are usually effective (95% CI: -0.20, and daily 0.08 (60 mmol/L (95% -0.16, 0.00 mmol/L), of olive against bacteria and fungi (Markin, D.,see etital. 2003) Hydrolized Rice Bran (HRB) has at respectively. stopping hair Significant lossleaves within the first two were months. Anyone experiencing new growth within four months. reductions observed with whole flaxseed (-0.21should and Once Bio-Fen is stopped, thein hairreducing growth pattern willphysical slowly return to its original point, however some people respiratory may -0.16 mmol/L, respectively) and lignan (-0.28 and -0.16 mmol/L, respectively) shown benefit the stress associated with acute tract infection. The besupplements able to continue with a lower maintenance dose. (Pan 2009). preventive effect of Hydrolyzed Rice Bran against the common cold syndrome was examined in elderly Bio-Fen has been (Maeda approved by H Health and has and received a unique NPN number. In addition to being approved people et Canada al., 2004) the immunomodulatory action of the HRB was also observed in their for hair growth applications, Bio-Fen has been approved for additional health benefits. laboratory tests. Angwafor F III, Anderson ML. An open label, dose response study to determine the effect of a dietary supplement on dihydrotestosterone, testosterone and estradiol levels in healthy males. J Int Soc Sports Nutr 2008;5:12. Botanical Ingredients Contraindications: The ingredient combination in Bio-Fen Plus for Men/Women is generally safe for most adults. Bio-Fen should not be used by paniculata patients withB6 diabetes, known hypersensitivity to any ingredients. Brzezińska-Wcisło L. Evaluation of vitamin andis calcium pantothenate effectiveness onflu hair growth from used clinical and aspects for treatment of diffuse Andrographis aorcommon cold and remedy intrichographic traditional Ayurvedic, Thaialopecia and in women. Wiad Lek 2001;54:11-8. Chinese medicine. Andrographis possesses anti-inflammatory, fever reducing, anti-cancer, anti-viral, antiReferences Chittur S, Parr B, Marcovici G. Inhibition of inflammatory gene expression in keratinocytes using a composition containing carnitine, thioctic acid and saw palmetto extract. Evid Based Brooks JD, et al. Am J Clin Nutr. Complement Alternat Med 2009. 2004 Feb;79(2):318-25. malaria and immune system stimulating properties. In humans, Andrographis has been studied for its Evans BA, et al. 1995 Nov;147(2):295-302. Pan ability A, YuR.D,Clin Demark-Wahnefried W, Franco OH,cold Lin X. Meta-analysis of the effects of flaxseed interventions on blood lipids. Am J Clin Nutr 2009;90:288-97. toExptreat and2002 prevent and flu infections. At least seven placebo-controlled clinical trials, Hoffmann Dermatol. Jul;27(5):373-82. 2001;39(1):58-65. Hutchins AM,et al. Nutr Cancer. Prager N, Bickett K, French N, Marcovici G. A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors 5-alpha-reductase in the including a total of over 800 patients, have been conducted with Andrographis paniculata, andofhave Prager N, etof al.androgenetic 2002 Apr;8(2):143-52. treatment alopecia. J Altern Complement Med 2002;8:143-52. very positive results (Coon JT and Ernst E, 2004). In one of these trials 208 men and women with Trüeb shown RM. Exp Gerontol. 2002 Aug-Sep;37(8-9):981-90. Serenoa repens monograph. Alternative Medicine Review 1998;3:227-9. Wickett RR, et al Arch Dermatol Res. 2007 Dec;299(10):499-505. upper respiratory tract infections were given 60 mg of Andrographis or a placebo per day. Following just Wilt T et al. Database Syst Rev. 2002;(3):CD001423. Sinclair R. Cochrane Male pattern androgenetic alopecia. BMJ 1998;317:865-9. two days of supplementation, symptoms of sore throat, fatigue, sleep disturbance and nasal secretion were Sowmya P, Rajyalakshmi P. Hypocholesterolemic effect of germinated fenugreek seeds in human subjects. Plant Foods Hum Nutr 1999;53:359-65. significantly improved compared to the placebo group. Stark A, Madar Z. The effect of an ethanol extract derived from fenugreek (Trigonella foenum-graecum) on bile acid absorption and cholesterol levels in rats, Br J Nutr 1993;69:277-87.

subjects no symptoms of viral or bacterial infection Saw palmetto berry reported extract 4:1 .............................................................................................125 mg (dry 500 mg) Inequiv. a follow-up study, five subjects were given 3000mg Flaxn.d.). lignans

Vierpper H, Nowotny P, Maier H, Waldhausl W. Production rates of dihydrotestosterone in healthy men and women and in men with male pattern baldness: determination by stable isotope/ dilution and mass spectrometry. J Clin Endocrinol Metab 2001;86:5762-4.

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The Journal of

The Journal of Integrated Healthcare Practitioners presents peer- reviewed articles on clinically relevant topics to healthcare providers. As advised by our Editorial Board, the separation of peer- reviewed material from news/stories/profiles delivers a message of strict academic rigor accompanying the compilation, review and publication of these clinically applicable scientific reviews.

1 2

2 3

4 CE

A natural, targeted approach to preventing and treating cancer

Female Fertility

Oxidant stress and a potential role for antioxidant therapy by: Gillian Flower, ND Naturopathic Doctor, Ottawa Integrative Cancer Centre

Salvestrols

William R. Ware, Ph.D. Faculty of Science, University of Western Ontario

A Hot Topic

by: Christopher Habib, ND and Gurdev Parmar, ND, FABNO Clinic Director, Mahaya Forest Hill Integrative Clinic Co-Founder & Medical Director, Integrated Health Clinic

Hyperthermia in Oncology

Parkinsonâ&#x20AC;&#x2122;s Disease An eclectic approach

by: Maria Shapoval, ND Research Resident, Canadian College of Naturopathic Medicine

by: Philip Rouchotas, MSc, ND and Heidi Fritz, MA, ND Editor-in-Chief, Integrated Healthcare Practitioner Research Fellow, Canadian College of Naturopathic Medicine

CE p73 What not to do Vitamin A and Beta Carotene

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editor’s letter

A Chill in the Air

horter, colder days seem to cause an influx of psychiatric concerns in our clinic... Patients seem to be getting younger and younger... Congratulations to integrated healthcare providers who work in this area. It requires a humble practitioner who accepts that not every case will be a success. Yet each time we successfully spare a patient a lifetime of antidepressant/ antipsychotic prescription, we are reminded why our role in these debilitating and chronic illnesses is so important. This issue of the Journal of Integrated Healthcare Practitioners showcases a selection of important reviews that invariably impact the course of integrated healthcare practice. Dr’s Habib and Parmar continue to set the bar in education on integrative cancer care by following up their article on DCA (IHP September 2012) with an excellent review of evidence regarding the role of local- regional hyperthermia as adjunctive and standalone therapy. Dr Ware adds to the formulary available to the provider of integrative oncology with an excellent review of a novel agent for cancer management; salvestrols. Following a review of strategies for enhancement of male fertility by Dr Cherevaty in the October issue of IHP, Dr Flower presents strategies for enhancing female fertility. Dr Shapoval highlights several important interventions that may help slow the course of Parkinson’s disease. Dr Fritz and myself have compiled the continuing education article for the issue, reminding integrative healthcare providers of the immense body of sound evidence demonstrating profound detriment from supplemental vitamin A and beta carotene in hopes of having these molecules removed from day-to-day practice.

Best Regards, Philip Rouchotas, MSc, ND Editor-in-Chief We invite questions or comments. philip@ihpmagazine.com

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Publisher | Sanjiv Jagota (416) 203-7900 ext 6125 Editor-in-Chief | Philip Rouchotas, MSc, ND (416) 203-7900 ext. 6109 Associate Editor | Angela MacNeil, MSc, ND Art Director | Scott Jordan Design | Sarah Vincett Production | Erin Booth (416) 203-7900 ext. 6110 Contributors Angela MacNeil, MSc, ND, Christopher Habib, ND Philip Rouchotas, MSc, ND, Heidi Fritz, MA, ND William R. Ware, PhD, Maria Shapoval, ND Gurdev Parmar, ND, FABNO, Gillian Flower, ND

President | Olivier Felicio (416) 203-7900 ext. 6107 Vice President Operations | Frank Shoniker (416) 203-7900 ext. 6109 Controller & Operations | Melanie Seth (416) 203-7900 ext. 6114 Finance Administrator | Henry Fonseca (416) 203-7900 ext. 6127 Advertising Information Sanjiv Jagota | Tel: (416) 203-7900 ext 6125 Email: sanjiv@ihpmagazine.com Paul Airut | Tel: (416) 203-7900 ext 6103 Email: paul@gorgmgo.com Jeff Yamaguchi | Tel: (416) 203-7900 ext 6122 Email: jeff@gorgmgo.com Erin Poredos | Tel: (416) 203-7900 ext 6128 Email: erin@gorgmgo.com Circulation Garth Atkinson | Publication Partners 345 Kingston Rd., Suite 101 Pickering, Ontario, L1V 1A1 Telephone: 1-877-547-2246 Fax: 905-509-0735 Email: ihp@publicationpartners.com

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44 www.ihpmagazine.com l November/December 2012

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peer review

Peer Review Board Members Aoife Earls, MSc, ND Trafalgar Ridge Chiropractic and Acupuncture 2387 Trafalgar Rd, Unit 7A Oakville, Ontario L6H 6K7 aearlsnd@gmail.com

Erin Balodis, BSc, MSc, ND Kingswood Chiropractic Health Centre 1210 Hammonds Plains Road Hammonds Plains, NS B4B 1B4 erinbalodis@gmail.com

Berchman Wong, ND 718 - 33 Canniff St Toronto, Ontario M6K 3M5 berchman.nd@gmail.com

Erin Psota, BSc, ND 626 King St West, Suite 201 Toronto, Ontario M5V 1M7 drpsota@gmail.com

Betty Rozendaal, BES, MA, ND Thornhill Naturopathic Health Clinic 12A Centre Street Thornhill, Ontario L4J 1E9 rozendaal@sympatico.ca

Faryal Luhar, ND Healthwise Wellness 4250 Weston Rd Toronto, Ontario M9L1W9 ndluhar@hotmail.com

Carol Morley, ND Zawada Health 201 City Centre Drive Suite 404 Mississauga, Ontario L5B 2G6 info@zawadahealth.comaa

Heidi Fritz, MA, ND Research Fellow Canadian College of Naturopathic Medicine 1255 Sheppard Ave East Toronto, Ontario M2K 1E2 hfritz@ccnm.edu

Colin MacLeod, ND Alderney Chiropractic 164 Ochterloney St. Dartmouth, NS B2Y 1E1 info@drcolinmacleod.com Daniel Watters, BSc, ND Rosedale Wellness Centre 365 Bloor St East Toronto, Ontario M4W 3L4 wattersdaniel@hotmail.com David W Lescheid, BSc, PhD, ND Lichtentaler Strasse 48 76530 Baden-Baden, Germany David Miller, BSc, ND 662 Gustavus St. Port Elgin ON N0H2C0 davidjmillernd@gmail.com Elizabeth Cherevaty, BSc, ND Healing Foundations Naturopathic Clinic 111 Norfolk St., 2nd Floor Guelph, Ontario N1H 4J7 drliz@guelphnaturopathic.com Karam Bains, BSc, ND Elixir Health, Multiple Clinics karam@elixirhealth.ca

Isaac Eliaz, MD, MS, LAc Amitabha Medical Clinic & Healing Center 7064 Corline Ct # A Sebastopol, CA 95472-4528 ieliaz@sonic.net Jacob Scheer, DC, ND, MHSc 2100 Finch Ave. W. #206 North York, Ontario M3N 2Z9 Jacob.Scheer@utoronto.ca Jiselle Griffith, BSc, ND The Health Hub Integrated Clinic 35 Hayden St, Suite 109 Toronto, Ontario M4Y 3C3 info@jisellegriffith.ca Jordan Robertson, BSc, ND Lakeshore Clinic 2159 Lakeshore Road Burlington, Ontario L7R 1A5 jordanrobertsonnd@gmail.com Judah Bunin, BSc, MSc, ND, DrAc Fredericton Naturopathic Clinic 10-150 Cliffe St Fredericton, NB E3A0A1 frednatclin@yahoo.ca

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peer review Kelly Brown, BSc, ND Healthview Therapy Centre 5118 Roblin Blvd Winnepeg, Manitoba R3R 0G9 drkbrownnd@gmail.com

Rochelle Wilcox, BA, ND Living Well Integrative Health Centre 2176 Windsor Street Halifax, NS B3K 5B6 drwilcox@balancehealthcentre.ca

Leigh Arseneau, ND The Naturopathic Institute of Advanced Medicine 122 Simcoe St North Oshawa, Ontario L1G 4S4 docleigh@gmail.com

Sarah Vadeboncoeur, ND Ottawa Integrative Health Centre 1129 Carling Ave Ottawa, Ontario K1Y 4G6 sarahmvadeboncoeur@gmail.com

Lindsay Bast, BSc, ND Greenwood Wellness Clinic PO Box 189 1400 Greenwood Hill Rd. Wellesley, ON N0B 2T0

Scott Clack, ND Touchstone Naturopathic Centre 950 Southdown Rd, Unit B5 Mississauga, Ontario L5J 2Y4 sclack.nd@touchstonecentre.com

Louise Wilson, BSc, ND 320 Queen St S Bolton, Ontario L7E 4Z9 Dr.louisewilsonnd@gmail.com

Shawna Clark, ND Forces of Nature Naturopathic Clinic 2447 1/2 Yonge St Toronto, Ontario M4P 2E7 info@shawnaclarknd.com

Makoto Trotter, ND Zen-tai Wellness Centre 120 Carlton Street, Suite 302, Toronto, ON M5A 4K2 makoto@zen-tai.com

Stephanie Swinkles, DDS Elmsdale Dental Clinic 4-269 Highway 214 Elmsdale, Nova Scotia N2S 1K1 steph_moroze@hotmail.com

Mandana Edalati, BA, ND Wellness Naturopathic Centre Suite 213-1940 Lonsdale Ave North Vancouver, British Columbia V7M 2K2 dredalati@gmail.com

Susan Coulter, BSc, ND Roots of Health 2-497 Laurier Ave Milton, ON L9T 3K8 scoulter@rootsofhealth.ca

Melanie DesChatelets, BSc, ND True Health Studio 200-4255 Arbutus St Vancouver, British Columbia V6J 4R1 melanie@drdeschat.com

Sylvi Martin, BScN, ND Fusion Chiropractic and Integrative Health 735 Danforth Avenue Toronto, Ontario M4J 1L2 martin.sylvi@gmail.com

Misa Kawasaki, BSc, ND Meridian Wellness 13085 Yonge Street, Suite 205 Richmond Hill, ON L4E 3S8 drkawasaki@meridianwellness.ca

Tanya Lee, BSc, ND The Health Centre of Milton 400 Main St East Suite 210 Milton, Ontario L9T 1P7 tanyalee.nd@gmail.com

Nicole Egenberger, BSc, ND Remede Naturopathics 214 Sullivan Street Suite 3B New York, New York 10012 info@remedenaturopathics.com

Terry Vanderheyden, ND Bayside Naturopathic Medicine 118 Bay Street Barryâ&#x20AC;&#x2122;s Bay, Ontario KOJ 1B0 doctrv@gmail.com

Raza Shah, BSc, ND St. Jacobs Naturopathic 1-9 Parkside Drive St. Jacobs, Ontario N0B 2NO stjacobs.nd@gmail.com

Theresa Jahn, BSc, ND Living Well Integrative Health Centre 2176 Windsor Street Halifax, NS B3K 5B6 info@theresajahn.com

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editorial board

IHP Editorial Board Members The purpose of our Editorial Board is to help guide the direction of the publication, in a manner that A) improves academic quality and rigor, B) exerts a positive impact on patient outcomes, C) contributes to knowledge of integrative healthcare, and D) showcases evolving trends in the healthcare industry. We have appointed a dynamic mix of individuals representing integrative MD’s, profession-leading ND’s, and members of academia. This unique blend of minds comes together and has already provided

insight that is actively shaping the manner in which IHP is compiled. Our goal remains successful listing with the PubMed database of scientific literature, and the contributions of this incredible team are an important step in the right direction. IHP is grateful to the donation of time and expertise made by these incredible professionals. The best way we can think of honouring their contribution is to effectively implement their suggestions and thus continuously elevate the quality of delivery of this publication.

Ben Boucher, MD

Dr. Boucher is a Nova Scotian of Acadian-Metis heritage who spent his early years in Havre Boucher, NS. He attended St. Francis Xavier University where he graduated in 1973. In 1978, he obtained a Doctor of Medicine degree from Dalhousie University, NS. Since 1979, he has practiced rural medicine in Cape Breton, NS. Although he has a very large general practice, he has special interests in chelation therapy and metal toxicity. In the past three years, he has been recognizing and treating vector- transmitted infections. Dr. Ben does his best to help patients by following Sir William Osler’s approach whereby if one listens long enough to a patient, together the answer will be found.

Jason Boxtart, ND

Dr Boxtart is currently serving as Chair to the Board of Directors for the Canadian Association of Naturopathic Doctors, the national association of naturopathic medicine in Canada. In that position he also chairs the Canadian Naturopathic Coordinating Council, the national stakeholder group in Canada. He also is a Board member of the Canadian Naturopathic Foundation, the national naturopathic charity. For the last eight years Dr. Boxtart has held a Faculty of Medicine post with the University of Northern British Columbia. Jason, and his wife Dr. Cher Boomhower, ND, share the role of Medical Director for the Northern Center for Integrative Medicine, a multi-practitioner clinic in Prince George, BC.

Roger A. Brumback, MD

Dr Brumback completed his residency in paediatrics at John Hopkins Hospital as well as in child neurology at Washington University, St Louis Children’s Hospital. He also completed a fellowship in neurology and neuropathology at the National Institutes of Health. This was preceded by undergraduate and medical training at Pennsylvania State University. Roger has been a Professor of Pathology at the Creighton University School of Medicine in Omaha, Nebraska since 2001. In 1986 he founded the Journal of Child Neurology and has maintained his position as Editor-in-Chief to this day. He likewise accepted the appointment as Editorin-Chief of the Journal of Evidence- Based Complimentary and Alternative Medicine in 2011.

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editorial board

Pardeep Nijhawan, MD, FRCP(C), FACG

Dr. Nijhawan completed his medical school training at the University of Ottawa and proceeded to complete an internal medicine internship at Yale-Norwalk, CT. He completed his internal medicine residency and Gastroenterology and Hepatology fellowship at the Mayo Clinic in Rochester, MN. There he was awarded the Calgary fellowship for outstanding achievements. He is a member of the Royal College of Physicians and Surgeons of Canada, American Board of Gastroenterology, and American Board of Internal Medicine. In 2003, Dr. Nijhawan established the Digestive Health Clinic to help bring leading edge technology to Canada. He specializes in therapeutic endoscopy, irritable bowel and celiac disease.

Gurdev Parmar, ND, FABNO

Dr. Parmar is a respected leader in the field of Integrative Oncology. He and his wife, Dr. Karen Parmar, launched the Integrated Health Clinic in 2000 and have since facilitated its growth to become one of the largest and most successful integrated health care facilities in Canada. Dr. Parmar was the first Canadian naturopathic physician to hold a fellowship to the American Board of Naturopathic Oncology (FABNO), a board certification as a cancer specialist. Dr. Parmar has been a consulting physician at the Lions Gate Hospital chemotherapy clinic since 2008, creating the first Integrative Oncology service in any chemotherapy hospital in the country.

Kristy Prouse, MD, FRCSC

Dr. Prouse has practiced as an Obstetrician/Gynaecologist for over 10 years and currently holds the position of assistant professor at the University of Toronto and the Northern Ontario School of Medicine. Dr. Prouse completed her medical degree at Queen’s University and residency training at the University of Calgary. Additionally, Dr. Prouse has trained in bio-identical hormone replacement therapy and anti-aging and regenerative medicine through the University of Southern Florida-College of Medicine. She is the Founder and Chief Medical Officer at the Institute for Hormonal Health, an integrative medical practice in Oakville, Ontario that focuses on hormonal imbalances in both women and men. Kristy completed her residency training at the University of Calgary, while obtaining her medical degree from Queen’s.

Dugald Seely, ND, MSc

Dr Seely is a naturopathic doctor and director of research at the Canadian College of Naturopathic Medicine (CCNM). Dugald completed his masters of science in cancer research from the University of Toronto with a focus on interactions between chemotherapy and natural health products. In his current role as director of research, Dugald is the principal investigator for a number of clinical trials, and is actively pursuing relevant synthesis research in the production of systematic reviews and meta-analyses. Ongoing projects include three multicentred randomized clinical trials and a comprehensive CIHR synthesis review of natural health products used for cancer. Dugald is currently a member of Health Canada’s Expert Advisory Committee for the Vigilance of Health Products and is a peer reviewer for the Canadian Adverse Reaction Newsletter. 48 www.ihpmagazine.com l November/December 2012

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The Journal of IHP

Hyperthermia in Oncology A Hot Topic By Christopher Habib, ND Clinic Director Mahaya Forest Hill 102-73 Warren Road Toronto, ON M4V 2R9 info@chrishabibnd.com Gurdev Parmar, ND, FABNO Co-Founder, Medical Director Integrated Health Clinic 2nd Floor- 23242 Mavis Ave Fort Langley, BC V1M2R4 info@integratedhealthclinic.com

Hyperthermia (HT), or thermal therapy, is the use of high temperature or heat against cancerous tissues. This article will look at local-regional HT, which has historically been used in some form or another across most ancient medical traditions. Naturopathic training includes the use of various local therapeutic heat treatments including hydrotherapy, moxibustion, herbs such as cayenne, heating pads, diathermy, and others. More recently, HT has been studied alongside radiotherapy and chemotherapy, and has been shown to act as a chemotherapy and radiotherapy sensitizer. There has also been a significant amount of literature published on the immune effects of HT, including HTâ&#x20AC;&#x2122;s ability to modulate cells of the innate and adaptive immune systems. By multiple mechanisms, HT treatments have been shown to significantly improve local tumour control and provide a survival advantage in many solid cancers. Some human trials published in the literature have been contradictory, largely due to differing experimental temperatures and exposure times. This article reviews the evidence available and describes various potential mechanisms of action that HT exerts on the immune system. Clinical pearls from the practice of a Fellow of the American Board of Naturopathic Oncology are provided. November/December 2012 l www.ihpmagazine.com 49

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Introduction HT is a procedure whereby the temperature of cancerous tissue is increased above what is considered normal, most often in the 40-43 degrees Celsius range (Wust 2002). Through multiple mechanisms, including direct cell killing, treatments have the ability to significantly improve local tumour control and provide a survival advantage to cancer patients (Dewey 1994). HT can also act as a chemotherapy and radiation sensitizer (Jones 2003). HT can modulate directly or indirectly the cells of the innate and adaptive immune systems (Frey 2012). HT can improve tumour oxygenation, in both diffusion-limited and perfusionlimited hypoxic cells, which reverses the incapacitating effects of hypoxia in the tumour microenvironment and improves treatment outcomes (Song 2001). Finally,

â&#x20AC;&#x153;HT can improve tumour oxygenation, in both diffusion-limited and perfusionlimited hypoxic cells, which reverses the incapacitating effects of hypoxia in the tumour microenvironment and improves treatment outcomesâ&#x20AC;? HT can inactivate superoxide dismutase (SOD) and allow tumours can be destroyed by inducing oxidative stress (Lehmann 2012). There are multiple forms of HT, such as whole body HT, but this paper will focus on local-regional HT. Even though HT may appear to be a promising adjunctive therapy, there have been contradictory results published in the literature. One argument is that the inconsistent outcomes after HT are due to differing experimental temperatures and exposure times (Frey 2012). The challenges in utilizing HT include heating tumours to high temperatures in a precise and reproducible manner, defining and calculating the required thermal dose for efficacy, and appropriately measuring

temperature. There has been significant progress on all these issues, particularly in the last decade. This article will review the evidence available and describe various potential mechanisms of action of HT on the immune system. Clinical pearls from the practice of a Fellow of the American Board of Naturopathic Oncology will be provided. Immune Effects of Hyperthermia HT has general and specific effects on the innate and adaptive immune responses, similar and beyond that of fever. Studies have shown that HT has beneficial effects on macrophages. In one trial, the experimenters measured the response of macrophages to phytohaemagglutinin, a lectin that is used to measure cell-mediated immunity (Manzella 1979). It was found that even mild HT increased macrophage responsiveness. Higher temperatures, even if not above 40 degrees Celsius, can influence lymphocyte transformation and mitogenesis, both of which increase the activity of the immune system (Skeen 1983). A study that examined whole body HT in mice showed that HT influences the migration of Langerhans cells (Ostberg 2000). Langerhans cells are the dendritic cells of the skin and mucosa. As such, they are responsible for taking up microbial antigens and other antigens and acting as antigen-presenting cells. The systemic activation of the immune system by HT may help target metastatic tumour cells (von Ardenne 1972). Heat shock proteins (HSPs) are proteins than can be induced by physiological stress, including environmental stresses and pathological states such as fever and inflammation (Morimoto 1993). They have immunomodulatory functions and can have positive and negative effects on regulating macrophage function, depending on the cellular location of the HSPs. Extracellular or membrane-bound HSPs might serve as a danger signal to stimulate the immune response (Schmitt 2007). HSPs are synthesized in response to HT treatments. In one study looking at HSP72, it was

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The Journal of IHP

found to be expressed on the surface of malignant cells but not on normal cells (Multhoff 1995). HSPexpressing cells are more susceptible to lysis by natural killer (NK) cells. HSPs are released after necrosis and in turn then stimulate macrophage and dendritic cells to secrete cytokines, which can inhibit tumour development and progression (Basu 2000). HSPs may also act to repair or limit damage to otherwise healthy cells, protect them from or prevent future damage, or place the cells in a state that limits expression or fixation of damage (Tomasovic 1989). The exact mechanism is unclear. Macrophage function can also be enhanced through an increased secretion of tumour necrosis factor (TNF), formerly known as TNF-alpha. Mild acute or chronic HT can increase tumour cell susceptibility to TNF (Tomasovic 1989). In vitro, TNF has effects on tumour vasculature and TNF-mediated cell killing is stimulated by chronic heating (Ruff 1981). Studies that have examined the effects on macrophages of potential treatment sequences have shown that appropriately constructed sequences for macrophage priming and triggering combined with HT could augment the cytotoxic actions of macrophages, which could have important clinical implications (Tomasovic 1989). NK cells have the ability to detach from tumour cells and kill novel tumour cells (Bhat 2007). However, there is some conflicting evidence on the way HT influences them. NK cell activity is modified by their environment and seems to be impaired in various cancer types, including lymphoma, breast cancer, and multiple myeloma (Konjevic 2012). HT at temperatures above 40 degrees Celsius has been shown to decrease NK cell activity in many in vitro studies (Azocar 1982). However, whole body HT has been shown to increase NK cell activity in vivo (Zanker 1982). Despite the conflicting evidence at higher temperature ranges, there is evidence that fever-range thermal stress at a temperature of 39.5 degrees enhances NK cell cytotoxicity against tumour cells (Dayanc 2008). Hyperthermia Trials Several older non-randomized trials have looked at the use of HT alone and in combination with other therapies. A review of 14 studies looking at HT by itself with 343 patients demonstrated complete response rates varying from 0-40%, with an overall complete response rate of 13% (Hetzel 1987). However, these studies found that using HT alone resulted in a

short duration of response. The first two randomized studies failed to show a beneficial effect of adding HT to radiotherapy (van der Zee 2002). One criticism of these initial randomized trials was that the treatment techniques were inadequate for the patients included. Since then, many trials have examined the use of HT in conjunction with either chemotherapy, radiotherapy, or with both. The large majority have shown significantly better results with the HT group (van der Zee 2002). A review looking at selected phase I, II, and III trials investigated the effects of HT combined with radiotherapy, chemotherapy, or both, obtained data on 2200 patients (Falk 2001). The trials it analyzed had been performed in patients with a variety of solid tumours including: melanoma, head and neck cancer, breast cancer, cancer of the gastrointestinal tract or urogenital tract, glioblastoma, and sarcoma. The authors concluded that although the effects of HT vary depending on cancer type, complete response rates with HT, alone or in combination with other therapies is possible (Falk 2001). One of the most compelling studies involved randomizing patients with metastatic stage IV squamous cell cancer of the head and neck to radiotherapy, or to radiotherapy plus HT (Overgaard 1995). In this trial, the complete response rate improved from 41% to 83%, with 5-year overall survival increasing from 0% to 53% with the addition of HT (Valdagni 1993). Another compelling study analyzed the results of five randomized controlled trials in the treatment of superficial localized breast cancer (Vernon 1996). This study included over 300 patients who had advanced primary or recurrent breast cancer and in which local radiotherapy was indicated. Not all trials demonstrated an advantage for the combined treatment, but the overall complete response rate for radiotherapy alone was 41% and for the combined treatment was 59%. The greatest effect was in patients with recurrent lesions where further irradiation was limited to low doses (Vernon 1996). Local HT appears to follow a dose-response relation, in that the number of treatments is related to the degree of local tumour control (Wust 2002). There are doseresponse relationships between temperature and killing effects as well. These vary depending on cell lines and tumour types (Dewhirst 1980). Another study examined the effect of adjuvant interstitial HT in patients with glioblastoma undergoing brachytherapy boost after conventional radiotherapy (Sneed 1998). In this study, adults with newly-diagnosed

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glioblastoma were randomized and treated with partial brain radiotherapy. Those patients whose tumour was still implantable after teletherapy were randomized to brachytherapy boost with or without HT for 30 minutes immediately before and afterwards. 79 patients were randomized between the two groups. Both endpoints that were measured (time to progression and survival) were significantly longer for HT than without HT, regardless of the use of brachytherapy (Sneed 1998). HT can be utilized for many types of malignancy. In one study, patients with advanced adenocarcinoma and severely symptomatic benign prostatic hyperplasia received transrectal microwave HT of the prostate (Szmigielski 1991). Local HT was given twice a week for a total of six sessions and the treatments were administered using a water-cooled rectal applicator. Each session lasted for 30 minutes and the rectal mucosa temperature was controlled at 45 degrees Celsius. The results indicated a significant increase in NK cell cytotoxic activity in the adenocarcinoma patients, indicating a transient stimulation of cell-mediated immune reaction (Szmidielski 1991). Finally, a more recent randomised phase 3 multicentre study investigated the use of regional HT with chemotherapy in high-risk soft-tissue sarcoma (Issels 2010). Prior to these, phase 2 studies showed that the combination of HT and chemotherapy improved local control compared to chemotherapy alone. In the phase 3 study, patients were randomly assigned to receive chemotherapy alone or combined with regional HT in addition to local therapy. 341 patients were enrolled in total, with approximately half in each group. Patients had higher progression rates and death rates with chemotherapy alone. The treatment response rate in the group that received HT was 28.8%, compared with 12.7% in the chemotherapy alone group. The adverse events associated with HT included pain, pressure, and skin burn (Issels 2010). Overall, HT appeared to improve patient outcomes and was a valuable addition to chemotherapy. Clinical Pearls Dr. Gurdev Parmar, ND, FABNO is the co-founder and medical director of the Integrated Health Clinic (IHC) in Fort Langley, British Columbia. Dr. Parmar has been using local-regional HT with patients since 2009 and fever-range whole body HT for the past year. At the IHC, local-regional HT has now been used with over 250 patients, totalling over 3500 treatments. This has given Dr. Parmar and his team an opportunity to use this treatment against many different tumour types and at varying stages of disease. The IHC is finalizing a database for all patients treated thus far with HT. Dr. Parmar will be presenting the basic data from this database soon at the 41st annual International Clinical

Hyperthermia Society conference in Budapest. The rest of the more detailed retrospective data is slated to be published in early 2013. Dr. Parmar is also working on a prospective study that is moving forward. He reports having noticed a significant benefit to many of his patientâ&#x20AC;&#x2122;s quality of life and overall survival when adding HT to their treatment plan. He looks forward to the day that HT is widely available to patients across the country and the world. It is Dr. Parmarâ&#x20AC;&#x2122;s contention that HT will be the fourth pillar of conventional oncology care, as it improves the efficacy of chemotherapy and radiotherapy without any risk of interference. It also can be used as a salvage therapy once conventional measures have been exhausted, while maintaining a good quality of life, as there are few potential side effects or risks. Conclusion HT is a treatment strategy whereby the temperature of cancerous tissues is increased above normal. This paper focused largely on local-regional HT. HT is best used in combination with chemotherapy and radiotherapy, and can also be utilized in the late treatment of various cancers as a standalone therapy, or as a salvage therapy. Among its various possible mechanisms of action, much research has been conducted on the stimulating effects of HT on the innate and adaptive immune systems. HT appears to stimulate the activity of macrophages, NK cells, and also has immunomodulatory functions via the creation of HSPs. Elevated temperatures influence lymphocyte transformation and mitogenesis, both of which increase the activity of the immune system. The systemic activation of the immune system by HT may help target metastatic tumour cells. HT is an effective chemosensitizer and radiosensitizer. HT also increases the amount of oxygen in the target tissue, which makes chemotherapy and radiotherapy function more effectively. In studies where HT has been used as a standalone therapy, response rates have been varied but impressive. HT has been studied in numerous cancer types, including melanoma, head and neck cancer, breast cancer, cancer of the gastrointestinal tract or urogenital tract, glioblastoma, sarcoma, and others. It is encouraging that the large majority of the research across various cancer types demonstrates that HT is an effective oncological treatment that can improve response rates and patient survival. Clinical experience from the practice of a Fellow of the American Board of Naturopathic Oncology in the treatment of over 250 patients has mirrored these findings. Finally, the most recent and best-conducted trials have shown that HT provides benefits above and beyond conventional oncological treatment approaches with minimal side effects. â&#x2013;

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References Azocar J, Yunis EJ, Essex M. Sensitivity of human natural killer cells to hyperthermia. Lancet. 1982;1(8262):16-7. Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol. 2000;12(11):1539-46. Bhat R, Watzl C. Serial killing of tumor cells by human natural killer cells--enhancement by therapeutic antibodies. PLoS One. 2007;2(3):e326. Dayanc BE, Beachy SH, Ostberg JR, Repasky EA. Dissecting the role of hyperthermia in natural killer cell mediated anti-tumor responses. Int J Hyperthermia. 2008;24(1):41-56. Dewey WC. Arrhenius relationships from the molecule and cell to the clinic. Int J Hyperthermia. 1994;10(4):457-83. Dewhirst MW, Ozimek EJ, Gross J, Cetas TC. Will hyperthermia conquer the elusive hypoxic cell? Implications of heat effects on tumor and normal-tissue microcirculation. Radiology. 1980;137(3):811-7. Falk MH, Issels RD. Hyperthermia in oncology. Int J Hyperthermia. 2001;17(1):1-18. Frey B, Weiss EM, Rubner Y, Wunderlich R, Ott OJ, Sauer R, Fietkau R, Gaipl US. Old and new facts about hyperthermiainduced modulations of the immune system. Int J Hyperthermia. 2012;28(6):528-42.

Ostberg JR, Patel R, Repasky EA. Regulation of immune activity by mild ( fever-range) whole body hyperthermia: effects on epidermal Langerhans cells. Cell Stress Chaperones. 2000;5(5):458-61. Overgaard J, Gonzalez Gonzalez D, Hulshof MC, Arcangeli G, Dahl O, Mella O, Bentzen SM. Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology. Lancet. 1995;345(8949):540-3. Redmann K, Burmeister J, Jenssen HL. The influence of hyperthermia on the transmembrane potential, zeta-potential and metabolism of polymorphonuclear leukocytes. Acta Bio Med Ger. 1974;33(2):187-96. Ruff MR, Gifford GE. Rabbit tumor necrosis factor: mechanism of action. Infect Immunol. 1981;31(1):380-5. Schildkopf P, Ott OJ, Frey B, Wadepohl M, Sauer R, Fietkau R, Gaipl US. Biological rationales and clinical applications of temperature controlled hyperthermia--implications for multimodal cancer treatments. Curr Med Chem. 2010;17(27):3045-57. Schildkopf P, Frey B, Ott OJ, Rubner Y, Multhoff G, Sauer R, Fietkau R, Gaipl US. Radiation combined with hyperthermia induces HSP70-dependent maturation of dendritic cells and release of proinflammatory cytokines by dendritic cells and macrophages. Radiother Oncol. 2011;101(1):109-15.

Harris JW, Meneses JJ. Effects of hyperthermia on the production and activity of primary and secondary cytolytic T-lymphocytes in vitro. Cancer Res. 1978;38(4):1120-6.

Skeen MJ, Olkowski ZL, DuPre JR, McLaren JR. Mitogenesis in human lymphocytes following brief exposure to hyperthermia. Int J Radiat Oncol Biol Phys. 1983;9(1):61-6.

Hetzel FW, Mattielo J. Interactions of hyperthermia with other modalities. In Paliwal BR, Hetzel FW, Dewhirst MW, eds. Medical Physics Monograph no. 16: Biological, physical and clinical aspects of hyperthermia. College Park, MD: American Institute of Physics. 1987;30-56.

Sneed PK, Stauffer PR, McDermott MW, Diederich CJ, Lamborn KR, Prados MD, Chang S, Weaver KA, Spry L, Malec MK, Lamb SA, Voss B, Davis RL, Wara WM, Larson DA, Phillips TL, Gutin PH. Survival benefit of hyperthermia in prospective randomized trial of brachytherapy boost +/- hyperthermia for glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 1998;40(2):287-95.

Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem BC, Abdel-Rahman S, Daugaard S, Salat C, Wendtner CM, Vujaskovic Z, Wessalowski R, Jauch KW, Durr HR, Ploner F, Baur-Melnyk A, Mansmann U, Hiddemann W, Blay JY, Hohenberger P, European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG), European Society for Hyperthermic Oncology (ESHO). Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancel Oncol. 2010; 11(6):561-70. Jones EL, Samulski TV, Dewhirst MW, Alvarez-Secord A, Berchuk A, Clarke-Pearson D, Havrilesky LJ, Soper J, Prosnitz LR. A pilot Phase II trial of concurrent radiotherapy, chemotherapy, and hyperthermia for locally advanced cervical carcinoma. Cancer. 2003;98(2):277-82. Konjevic G, Jurisic V, Jovic V, Vuletic A, Mirjacic Martinovic K, Radenkovic S, Spuzic I. Investigation of NK cell function and their modulation in different malignancies. Immunol Res. 2012;52(12):139-56. Lehmann K, Rickenbacher A, Jang JH, Oberkofler CE, Vonlanthen R, von Boehmer L, Humar B, Graf R, Gertsch P, Clavien PA. New insight into hyperthermic intraperitoneal chemotherapy: induction of oxidative stress dramatically enhanced tumor killing in vitro and in vivo models. Ann Surg. 2012;256(5):730-8. Manzella JP, Roberts NJ Jr. Human macrophage and lymphocyte responses to mitogen stimulation after exposure to influenza virus, ascorbic acid, and hyperthermia. J Immunol. 1979;123(5):1940-4. Morimoto RI. Cells in stress: transcriptional activation of heat shock genes. Science. 1993;259(5100):1409-10. Multhoff G, Botzler C, Wiesnet M, Muller E, Meier T, Wilmanns W, Issels RD. A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. Int J Cancer. 1995;61(2):272-9.

Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C. Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol. 2007;81(1):15-27.

Song CW, Park H, Griffin RJ. Improvement of tumor oxygenation by mild hyperthermia. Radiat Res. 2001;155(4):515-28. Szmigielski S, Sobczynski J, Sokolska G, Stawarz B, Zielinski H, Petrovich Z. Effects of local prostatic hyperthermia on human NK and T cell function. Int J Hyperthermia. 1991;7(6):869-80. Takada Y, Sato EF, Nakajima T, Hosono M, Tsumura M, Inoue M, Yamada R. Granulocyte-colony stimulating factor enhances anti-tumour effect of hyperthermia. Int J Hyperthermia. 2000;16(3):275-86. Tomasovic SP, Klostergaard J. Hyperthermic modulation of macrophagetumor cell interactions. Cancer Metastasis REv. 1989;8(3):215-29. Wust P, Hildebrandt B, Sreenivasa G, Rau B, Gellermann J, Riess H, Felix R, Schlag PM. Hyperthermia in combined treatment of cancer. Lancet Oncol. 2002;3(8):487-97. Valdagni R, Amichetti M. Report of long-term follow-up in a randomized trial comparing radiation therapy and radiation therapy plus hyperthermia to metastatic lymph nodes in stage IV head and neck patients. Int J Radiat Oncol Biol Phys. 1994;28(1):163-9. van der Zee J. Heating the patient: a promising approach? Ann Oncol. 2002;13(8):1173-84. Vernon CC, Hand JW, Field SB, Machin D, Whaley JB, van der Zee J, van Putten WL, van Rhoon GC, van Dijk JD, Gonzalez Gonzalez D, Liu FF, Goodman P, Sherar M. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys. 1996;35(4):731-44. von Ardenne M. Selective multiphase cancer therapy: conceptual aspects and experimental basis. Adv Pharmacol Chemother. 1972;10:339-80. Zanker KS, Lange J. Whole body hyperthermia and natural killer cell activity. Lancet. 1982;1(8280):1079-80.

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Salvestrols

A natural, targeted approach to preventing and treating cancer By William R. Ware, Ph.D. Faculty of Science University of Western Ontario London, Ontario, Canada warewr@rogers.com

The ultimate goal in cancer research is to find a way to kill cancer cells present as tumors, precancerous lesions, or circulating cancer cells, and to accomplish this with minimal systemic toxicity. Any realistic evaluation of the current status to cancer therapy suggests that this goal is far from being achieved, although for a small number of cancers, achieving a complete and durable cure is possible. This article describes an alternative approach to cancer prevention and therapy based on the remarkable properties of an enzyme highly expressed at the protein level in cancer cells and present only in negligible amounts in normal cells. This statement applies to at least 26 different cancer types. The reason this is important is that naturally occurring substrates for this enzyme exist which when metabolized in the cancer cell yield a cytotoxin that kills the cell. Research over the past decade has identified extracts of certain fruits that have been demonstrated in cell culture studies to provide highly active cytotoxic metabolites generated by this enzyme. In addition, serum variations in substrate and metabolite have been demonstrated to provide evidence of the presence of cancer, to some extent its stage, and when the substrate is observed to

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be metabolized and the metabolite detected, an indication of the success of the therapeutic intervention is evident. This provides compelling biological plausibility for the therapy and the action of this enzyme. Human studies at this point in time involve case histories of 15 patients cured, in the opinion of the specialists involved, by the use of this oral therapy. The success of the therapy appears independent of the site. Given that this is a natural product, it is unrealistic at this time to expect more comprehensive clinical evidence, and to ignore this approach appears to be a serious mistake. Introduction The natural history of cancer indicates initiation via a modified cell is followed over a number of years by abnormal cell growth before there is any clinical evidence of the disease. Current technology involving either scanning or the use of biomarkers or reliance on clinical manifestation (e.g. a lump) has a threshold for detection of somewhere between 1/10th of a billion and one billion cells. The time from initiation to this tumor size ranges from a few years to as many as 20 years. An important feature of this process is that it is well advanced before diagnosis is currently possible (Burke 2009, Oâ&#x20AC;&#x2122;Shaughnessy 2002). Multiple cancers may be present at a variety of stages of development, and patients may also already have established metastasis from the primary cancer prior to diagnosis or treatment. Millions of individuals currently have undetected, silent cancer that is somewhere between the initiation of a cancer cell and manifestation of the disease (Hyman 2007). The challenge of primary prevention involves preventing the formation of the initial modified cells or detecting and destroying their progeny. Primary carcinogenesis appears to occur constantly due to mutations induced by natural background radiation or by cell changes induced by a variety of endogenous and exogenous factors. The fact that the human race is here today suggests the existence of one or more protective mechanisms. Put another way, why donâ&#x20AC;&#x2122;t we all get cancer? For existing tumours, the challenge is targeting with a localized therapy with low or negligible systemic toxicity, an approach attracting intense research interest at present (NIH 2012). It is well established that the consumption of fruits and vegetables offers protection from cancer, and various constituents such as polyphenols have been suggested as responsible, partially mediated through the ability to counteract, reduce and also repair damage resulting from inflammation and oxidative stress (Reiss 2012,

Seeram 2008, Vainio 2006, Ware 2009a). However, there is another mechanism which may be much more important. This is based on the fact that cancer cells express at the protein level an enzyme that is capable of metabolizing chemicals found in fruits and generating cytotoxic metabolites within the same cell. The enzyme belongs to the large P450 class and is designated CYP1B1. Already in 2002 it was reported that this enzyme converted resveratrol into the anticancer agent piceatannol (Potter 2002). So far, there are 26 cancer types where tumour cell overexpression of CYP1B1 has been demonstrated, but its presence in normal cells is negligible. In Appendix 1 of his book Linking Diet and Cancer. Salvestrols, Natureâ&#x20AC;&#x2122;s Defence Against Cancer, Dr. Brain Schaefer cites 62 studies (Schaefer 2012b). Taking advantage of this cytotoxin generating ability provides a targeted therapy independent of cancer type (Tan 2007). The literature associated with exploiting the beneficial aspects of CYP1B1 is sparse and some appears in journals not covered by MEDLINE (PubMed). However, the book cited above provides a detailed, documented review of the issues being discussed here and also includes considerable unpublished information (Schaefer 2012b).

The search for the best CYP1B1 substrates The remarkable property of CYP1B1 prompted two researchers, Professors Gerald Potter and Danny Burk in Leicester, U.K. to search for both synthetic and natural substrates using cancer cell culture techniques (Androutsopoulos 2008, Potter 2002, Potter 2006). A prodrug was developed and substrates for CYP1B1 yielding potent natural cytotoxic metabolites identified. In comparison with organically grown produce, produce grown with insecticides and from highly inbred varieties or hybridized to decrease bitterness had remarkably low levels of these substrates, an observation of great significance. The name Salvestrol was given to these November/December 2012 l www.ihpmagazine.com 55

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active compounds or extracts (Schaefer 2012b, Tan 2007). They are vastly more selective than conventional chemotherapy because they target CYP1B1. Summary of case studies The evidence for human efficacy derives from a number of case studies. (Schaefer 2012a, Schaefer 2012b, Schaefer 2007, Schaefer 2010, Schaefer 2012c). In all cases listed in the table below, the cancer was considered cured by the oncologists involved. Additional cases have been collected including lung and pancreatic cancer (Schaefer 2012a). Salvestrols of various potency were used by the individuals in these case studies which spanned a considerable time. Complete success is not always achieved by individuals using salvestrols, and dose, potency and adherence may be among the responsible factors. European experience with dose escalation suggests that there is a range of a factor of about two in the dose that produces response (Schaefer 2012a). Also, the currently available commercial extract is

â&#x20AC;&#x153;Given that this is a natural product, it is unrealistic at this time to expect more comprehensive clinical evidence, and to ignore this approach appears to be a serious mistake.â&#x20AC;? much more potent than earlier formulations. Dismissing or ignoring these case studies because they are not proper clinical trials is unrealistic considering a natural product is involved. The author of this article attempted to give wider recognition to the remarkable property and potential of CYB1B1 and some of these results by publishing two articles, but there appears to be little interest (Ware 2009a, Ware 2009b). Instead, research interest is focused on inhibiting this enzyme because it is implicated in carcinogenesis, especially involving aromatic hydrocarbons and estrogen, or on research involving stimulating immune activity against CYP1B1 (McFadyen 2005, Swanson 2010). However, once one

has cancer, this seems irrelevant. Inhibition of CYP1B1 would address only a very minor aspect of carcinogenesis while eliminating what appears to be a very important human defence mechanism against this disease. Also, smoking is an avoidable risk and the major source of exogenous aromatic hydrocarbons. Given the apparently universal phenomenon of CYTP1B1 overexpression in cancer cells, it is hard to see how this enzyme could have evolved to be anything other than mostly beneficial, and thus not a target for inhibition or a vaccine (which exists, incidentally). Diagnosis by detecting CYP1B1 in serum The original observation that CYP1B1 was not expressed in normal cells was found to be not universally true when highly sensitive detection methods were used, although the levels were still vastly lower than found in tumour tissue (Schaefer 2012b) Eventually the researchers developed a highly sensitive serum assay specific for human CYP1B1 protein. A proteomic approach was involved and it was possible to establish a baseline CYP1B1 level in individuals believed to be free of cancer which was minute but not zero. This background of CYP1B1 may reflect adventitious cancer cells constantly being generated. Based on thresholds derived from this background level, Schaefer estimates that the present level of sensitivity allows cancer detection about six years prior to clinical manifestation. For example, CYP1B1 at between 100 and 6000 times normal background was measured in lung cancer patients with levels providing a good correlation with the extent of disease (Schaefer 2012b). Monitoring the success of therapy with serum CYP1B1 metabolites Schaefer describes a second blood test termed the metabolic approach (Schaefer 2012b). A sensitive analytical method for testing in blood and urine for both the salvestrol (substrate) and its CYP1B1 metabolite was developed, and provided the opportunity to detect the presence of the enzyme and measure the extent of the cancer by the change in substrate concentration and the appearance of metabolite. A salvestrol was used that produced large amounts of metabolite with no confounding from

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The Journal of IHP

Summary of case studies Site

Stage

Cases*

2-3

Melanoma

Prostate (one Gleason 3+3)

Breast, (one aggressive)

Breast

Squamous-cell carcinoma (lung)

Bladder Liver

1 2

Colon Hodgkin’s Lymphoma

1 1

Squamous cell carcinoma (anus)

Lymphocytic leukemia

Primary peritoneal carcinoma

*Cases considered cured or in total remission

dietary sources, and upon testing a group of healthy individuals it was found the salvestrol was recovered unmetabolized in the blood and urine. When cancer patients were given the salvestrol, the metabolite was found and the amount of substrate decreased with the magnitude of the effect dependent on the severity of the disease as estimated from the clinical presentation. For severe disease, the researchers were unable to detect any substrate, only the metabolite. These observations were made on individuals with breast, stomach, kidney, and prostate cancer with an array of stages but skewed towards more advanced cases. This approach does not yield site-specific information if the presence of cancer is indicated. The metabolic approach obviously offers the opportunity to measure the effectiveness of any given salvestrol mixture, as well as the ability to examine and adjust for individual dose dependence. Finally a noninvasive judgment is possible regarding when a “cure” or significant regression has been achieved by this alternative approach. This can then be confirmed by conventional methods. The proteomic approach is exquisitely sensitive and close to the state of the art for detection of a chemical in the circulation. Thus if screening is done and a positive result is obtained, where is the cancer? A serious problem since it may be small enough as to escape all modern attempts to locate it. Also, there is no non-specific anticancer treatment in so-called evidence based or officially sanctioned cancer therapy that could be used in the absence of knowledge of the identity of the tumour site. But the metabolic approach allows testing the most modern and powerful salvestrol on patients with cancer, even if not clinically evident,

to determine if the metabolic markers change, thus potentially justifying and encouraging an alternative therapeutic program, independent of the lack of knowledge of the actual site. The future Mainstream medicine thinks only in terms of their holy grail, the randomized, controlled trial as evidence for even considering a new therapy. Held in high contempt is the case study. Consider the obstacles facing salvestrols. Naturally occurring chemicals generally cannot be patented. Companies selling products such as salvestrols are tightly regulated as to what claims can be made concerning efficacy. Clinical trials required for regulatory approval are very expensive. Only a synthetic salvestrol has a chance of becoming an approved prescription drug or approved “medicinal food.” It would be hard to find a physician who would take the professional risk of recommending to a cancer patient a natural product rather than the conventional approach. Combining salvestrols with conventional treatment is interesting but probably would be hard to implement in the face of negative attitudes. A trial can be visualized that might satisfy integrative physicians demanding more concrete evidence. It would involve patients who have rejected conventional treatment or found it failed them. These individuals could be recruited for an uncontrolled study or an old-fashioned study where the control is based on the average life expectancy or cancer progression of multiple matched untreated patients. Taking low doses of salvestrols for cancer prevention also appears reasonable and this may be significantly superior to taking fruit extracts available at the health food store or online because salvestrols are selected extracts which have laboratory-proven cancer cell cytotoxicity. The above discussion provides justification for the role of salvestrols in prevention. However, the optimum dose is still unknown.

Conclusions The underlying theory of salvestrols is that CYP1B1 represent a rescue enzyme that evolved in humans eons ago, partly in order to deal with cancer cells and destroy them with substances derived from the normal diet. The evidence is compelling that this enzyme is overexpressed in cancer cells and present only in minute and insignificant levels in normal cells. Furthermore, related to diagnosis and prognosis, the enzyme is present at vastly higher levels in the blood of individuals with cancer as compared to those who are cancer free. The observations based on cell culture studies involving cancer and normal cells confirm the presence of cytotoxic metabolites of CYP1B1 and the indifference of normal cells to the substrate. When November/December 2012 l www.ihpmagazine.com 57

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cancer patients are compared to normal controls, after dosing with salvestrols the serum salvestrol levels, rather than being unchanged, are lower and can be driven to near zero in advanced cancer patients, while evidence of toxic metabolites increases in step with these decreases. These observations significantly support the biological plausibility of the therapy. The modern salvestrols used in today’s preparations contain fruit-derived CYP1B1 substrates proven in cell culture studies to yield high levels of cancer cell cytotoxicity, whereas commercially available fruit extracts and polyphenols mixtures sold as supplements have never been graded for efficacy by this standard. Evidence of salvestrol induced remission or cure consists of 15 specialist verified human case studies covering 11 cancer types. More are about to be reported. At this stage in the evolution of salvestrol therapy, this is the only clinical evidence one should expect. These case studies along with serum metabolite and proteomic studies support the salvestrol concept. While it is understandable that practitioners would be less than happy about such a modest clinical evidence base, it must be remembered that this is a natural product. There are even restrictions on the extent to which it can be promoted as effective against cancer and represents a therapy resisted a priori by conventional medicine. There will no doubt be small clinical trials in the near future, but given the absence of side effects of, waiting for such trials seems unnecessary. There are fewer regulatory barriers to the acceptance of the metabolic and proteomic approaches to cancer detection and monitoring therapy. This in fact is a principal focus at present with research ongoing at University of Victoria and University of British Columbia (Schaefer 2012a). Issues such as the use of salvestrols for primary and metastatic cancer prevention will no doubt remain theoretical for a long time, given the natural history of cancer and nature of the product, and the huge cost of human studies. Nevertheless, to ignore the possibility that this is a true magic bullet with minimal or no side effects may be to ignore one of the most important developments in cancer detection and therapy in decades. Salvestrols are availble at www.salvestrol.ca. Dr. Schaefer’s book can be ordered via this link: http:// www.salvestrolbook.com. Disclaimer and conflict of interests The author of this article has no financial interest in any commercial or research aspect of salvestrols, does take daily low dose of Salvestrol “Platinum” for prevention, and emphasizes that the above review does not constitute a recommendation or advice but merely provides information. ■

References Androutsopoulos,V., Arroo,R.R., Hall,J.F., Surichan,S. and Potter,G.A. Antiproliferative and cy-tostatic effects of the natural product eupatorin on MDA-MB-468 human breast cancer cells due to CYP1-mediated metabolism. Breast Cancer Res 2008; 10(3): R39. Burke,D. The silent growth of cancer and its implications for nutritional protection. British Neu-ropathic Journal 2009; 26(1): 15-18. Hyman,M.A. Cancer--treatment through the continuum. Altern. Ther Health Med 2007; 13(1): 10. McFadyen,M.C. and Murray,G.I. Cytochrome P450 1B1: a novel anticancer therapeutic target. Future Oncol 2005; 1(2): 259-263. NIH, 2012. Targeted Cancer therapies. Fact sheet, National Institutes of Health. http://www.cancer.gov/cancertopics/factsheet/Therapy/ Fs7_49.pdf. O’Shaughnessy,J.A., Kelloff,G.J., Gordon,G.B., Dannenberg,A.J., Hong,W.K., Fabian,C.J., Sig-man,C.C., Bertagnolli,M.M., Stratton,S.P., Lam,S., Nelson,W.G., Meyskens,F.L., Alberts,D.S., Follen,M., Rustgi,A.K., Papadimitrakopoulou,V., Scardino,P.T., Gazdar,A.F., Wattenberg,L.W., Sporn,M.B., Sakr,W.A., Lippman,S.M. and Von Hoff,D.D. Treatment and prevention of intraepi-thelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res 2002; 8(2): 314-346 see Fig.1. Potter,G.A. and Burke,M.D. Salvestrols--Natural products with tumour selective activity. Journal of Orthomolecular Medicine 2006; 21(1): 34-36. Potter,G.A., Patterson,L.H., Wanogho,E., Perry,P.J., Butler,P.C., Ijaz,T., Ruparelia,K.C., Lamb,J.H., Farmer,P.B., Stanley,L.A. and Burke,M.D. The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1. Br. J Cancer 2002; 86(5): 774-778. Reiss,R., Johnston,J., Tucker,K., Desesso,J.M. and Keen,C.L. Estimation of cancer risks and benefits associated with a potential increased consumption of fruits and vegetables. Food Chem Toxicol 2012. Schaefer,B., 2012a. Personal communication. Schaefer,B., 2012b. Salvestrols. Nature’s Defence Against Cancer. Linking diet and cancer. Clini-cal Intelligence Corp. Schaefer,B.A., Hoon.L.T., Burke,M.D. and Potter,G.A. Nutrition and Cancer: Salvestrol Case Studies. Journal of Orthomolecular Medicine 2007; 22(4): 177. Schaefer,B., Dooner,C., Burke,D. and Potter,G. Nutrition and Cancer: Further case studies involv-ing savlestrol. Journal of Orthomolecular Medicine 2010; 25(1): 17-23. Schaefer,B., Potter,G., Wood,R. and Burke D Cancer and related case studies involving salvestrol and CYP1B1. Journal of Orthomolecular Medicine 2012c; 27(3): 131-138. Seeram,N.P. Berry fruits for cancer prevention: current status and future prospects. J Agric. Food Chem. 2008; 56(3): 630-635. Swanson,H.I., Njar,V.C.O., Yu,Z., Castro,D.J., Gonzalez,F.J., Williams,D.E., Huang,Y., Kong,A.N., Doloff,J.C., Ma,J., Waxman,D.J. and Scott,E.E. Targeting drug-metabolizing en-zymes for effective chemoprevention and chemotherapy. Drug Metabolism and Disposition 2010; 38(4): 539-544. Tan,H.L., Butler,P.C., Burke,M.D. and Potter,G.A. Salvestrols: A New Perspective in Nutritional Research. Journal of Orthomolecular Medicine 2007; 22(1): 39-47. Vainio,H. and Weiderpass,E. Fruit and vegetables in cancer prevention. Nutr Cancer 2006; 54(1): 111-142. Ware,W.R. Nutrition and the prevention and treatment of cancer: association of cytochrome P450 CYP1B1 with the role of fruit and fruit extracts. Integr Cancer Ther 2009a; 8(1): 22-28. Ware,W.R. P450 CYP1B1 mediated fluorescent tumor markers: a potentially useful approach for photodynamic therapy, diagnosis and establishing surgical margins. Med Hypotheses 2009b; 72(1): 67-70.

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Progressive MultiVitamins are designed with you and your patients in mind. They have been formulated and balanced by Dr. Mikhael Adams to include the right ingredients and dosages, along with age, gender and activity specific nutrients that make Progressive the smarter choice.

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PRODUCT MONOGRAPH Bio-Fen Bio-Fen Plus is an oral natural health product used in the treatment of hereditary androgenic alopecia (AGA) for male or female pattern baldness. PROGRESSIVE NUTRITIONAL SUPPLEMENTS MULTIPLE VITAMINS & MINERALS Without treatment, AGA is progressive, and causes social distress in many affected men and women (Sinclair 1998). Bio-Fen Plus contains extracts BIO-FEN for Men and Women The Progressive family offers age, gender, and activity specific vitamin and mineral formulas. Each formula is designed specifically to target of fenugreek seeds, saw palmetto berries and flax lignans, as well as specific vitamins. Each ingredient is known to possess inhibitors of the enzyme the unique nutritional demands throughout a lifespan. 5α-reductase. are responsible for relieving symptoms associated withPlus hereditary AGA. Bio-Fen represents aThese line of inhibitors products approved by Health Canada for hair growth and restoration. Bio-Fen for Men and Bio-Fen Plus for Women are both oral natural health Multiple Vitamins Minerals the Maintenance Good Healthalopecia One of the primary causes ofgrowth hair loss isinand a high level of hereditary the of male hormone dihydrotestosterone (DHT) within the hair follicle (Vierhapper, 2001). products (NHPs) which support hairand in men women with androgenic (AGA), or female/male pattern baldness. Bio-Fen contains a combination of herb extracts and vitamins & minerals that arethe known inhibit the enzymeof 5supplement -reductase (5AR), a keyfunction pathway implicated in the progression of AGA. Vazir, etAGA, al (2006) evaluated effect of a micronutrient on mental childrenattaches. (aged 6 –5-α-reductase 15 years). Thiscatalyzes double blind, For people with their follicles have atogreater number androgen receptors to whichin DHT the enzymatic placebo-controlled, matched-pair, cluster, randomized trial assessed a cohortfive-fold of 608 children for intelligence, and concentration, conversion of testosterone to dihydrotestosterone, which binds to the receptor more avidly than theattention parent compound (Sinclair 1998). AGA Pathophysiology memory, and school achievement, before and after 14 months of micronutrient supplementation. Results indicated that supplementation One of the primary loss is a high significantly level of the male hormone, dihydrotestosterone (DHT) the hair (Hoffmann 2002).aged DHT6is– produced with acauses rangeofofhair micronutrients improved attention-concentration overwithin the period of follicle 14 months in children 15 years.from Saw palmetto repens) testosterone in the(Serenoa testes (males), the adrenal glands, and the follicle. After a period of time, anVitamins over abundance of DHT causes the hair follicle to degrade and shortens the active Increasing bone mineral content (BMC) duringtoperiods ofThere rapid (childhood & may effectively prevent osteoporosis and phase of the hair, eventually leading to thinning hair and eventual hair isgrowth a familial tendency foradolescence) stepwise the hair follicle and an increase in the calcium ratio In a Polish study of miniaturization 46 women whoof had symptoms of diffuse alopecia, Standardized (lipophillic) Serenoa extract has been found be loss. a potent inhibitor age-related loss. Shatrugna, et al (2006) effectand of alocal micronutrient supplementation BMC, andonly bone of of telogen (resting phase) tobone anagen (growth phase)DHT. hairs, which isinvestigated promoteddose by the systemic effects of was androgens. Althou ghon everyone produces thosemg with pantothenate orally administered twicebone a dayarea, inDHT, doses of 100 fora four to 5α-reductase, resulting in decreased tissue An open-label, response mineral density (BMD)inat variousfollicles, sites in binding childrensites (aged 6 – 16and years). The micronutrient supplement was found to increase tissue higher of androgen their fora DHT, greater androgen sensitivity experience hairinjected loss (Prager 2002). 5AR istogrowth responsible forrepeated the five months, and vitamin B6increases was every dayoffor 20femur. 30 days and studynumber was conducted onreceptors 42 healthy maleshair to determine the effect of combination skeletaltoshell in apparently normal children over a 14-month period, including site-specific BMD at the neckTrueb the conversion of and testosterone dihydrotestosterone, which binds to the same androgen receptor, but with five-fold greater affinity. (Hoffmann 2002, 2002)

of carotenoid astaxanthin and saw palmetto berry lipid extract on DHT and

again after six months (Brzezińska-Wcisło 2001). It was determined that vitamin

SHEEP study examined themen association between thetwo usegroups: a multivitamin supplements parenterally and the risk for of myocardial infarction Results in the hair B6 administered a few weeks induces(MI). improvement testosteroneThe levels (Angwafor 2008). The were divided into Flax were based data from a large population-based, case-control study ofcondition subjects aged 45 – 70 years. The included 1296 cases (910 subset women andstudy reduces hair are loss. onelignans groupinhibit received 800onmg/day of the combination supplement the other Flax the enzyme 5AR, thus balancing formation of the maleand hormones that are responsiblein fora hair lossof(Evans 1995). Flax lignans converted by the body to men,2000 386 mg/day women)ofwith asupplement first nonfatal 1685 controls (1143 men, 542 women) frequency-matched to the cases by sex, age and group received forMI 14and days. ANOVA-RM enterolactones, which compete with the estrogen and testosterone for receptor binding,showed and increase sex hormone binding globulin (SHBG), resulting in lower levels of free (ie active) hospital catchments areain(Holmquist, et testeosterone al 2003). The and results from this study indicate that use of a multivitamin supplements may aid in the significant within-group increases serum significant estrogen and testosterone. Flaxseed has been shown total to reduce serum levels of 17-beta-estradiol and estrone sulfate (Hutchins 2001), and results in a shift in estrogen metabolism to primary prevention of MI. Medicinal Ingredients Dose Per Capsule decreases serum DHT baseline in both favor the lessin biologically activefrom estrogens (Brooks 2004).dose groups (P=0.05). There was no significant difference between dose groups with regard to the increase of The elderly are an epidemic of deficiency, and multivitamins and minerals are extremely(Trigonella helpful in reducing of a variety of diseases in Fenugreek foenum risk graecum) Fenugreek 260inmg this by Girodon, et al (1997)(Angwafor examined the impact of trace 4:1 element and vitamin supplementation 81 elderly testeosterone orpopulation. the decreaseAofstudy DHT;conducted therefore both doses were effective seed extract Fenugreek has been used traditionally as an oral and topical treatment for hair loss. Plant sterols contained in fenugreek such as -sitosterol have beendeficiencies. shown to block DHT subjects over a 2-year period. Before supplementation more than 2/3 of the elderly subjects were found to have significant 2008). receptor sites (Prager 2002, see below). After only 6 months of supplementation, significant increases in these vitamins minerals wereextract observed. Furthermore, a160 200% Sawand palmetto berry containing mg reduction inliposterolic infectious disease subjects administered multivitamin was demonstrated. Another study tested extract incidence of Serenoaamong repenselderly (LSESr) and beta45% free fatty acids Saw Palmetto (men’s product) sitosterol inAgeing the treatment of males (23-64 years of age) with mild to moderate AGA. with in micronutrient intake,tissue making malnutrition an increasing public health the elderly. Saw palmetto extract isisaassociated potent inhibitor ofa 5reduction -reductase, resulting in decreased DHT (Prager 2002). In a pilot study of 26 men problem with mildamong to moderate AGA, treatment with Flax lignans, standardized to 20%found Six of 10 (60%) subjects were rated asextract improved at and the final visit, thus50mg establishing Grieger, et alsaw (2007) examined the use of abeta-sitosterol multivitamin supplement forsymptoms 6 months 92toelderly Itblinded was that multivitamin a combination of lipophilic palmetto 200mg improved byinup 60%, assubjects. scored by assessors (Prager 2002). In a meta 100 mg diglucoside (SDG) improved micronutrient status in vulnerable may of reduce the risk of micronutrient-related diseases. the effectiveness of 5α-reductase inhibitors AGA (Prager 2002). Chronic analysis by thesupplementation Cochrane group, saw palmetto hasagainst also been found to this be effective as a population, treatment secoisolariciresinol forwhich symptoms BPH (Wilt 2002). a positive effect Multivitamin also to havefactor inflammation of the hairsupplementation follicle is considered toappeared be a contributing for AGA. A on bone quality, which may also reduce the risk of osteoporosis. D-calcium pantothenate (Vitamin B5) 10.40 mg Silica (women’s product) study by Chittur et al sought to determine whether blockade of inflammation using Silica is a and traceDosage mineral that has been found to increase hydroxyproline concentration in connective tissue (Barel 2005). In a randomized, double blind, placebo controlled study, 50 LSESr two anti-inflammatory agents (carnitine and thioctic acid) could alter Niacinamide (Vitamin B3) 10.25 mg Indication: in the maintenance of good health. women with damaged skin Aids weremarkers treated orally with 10mg silica as orthosilicic the expression of molecular of inflammation (Chittur 2009). It acid was (OSA) found daily for 20 weeks. The treatment group reported a significant decrease in visual analog controlled trial conducted in 50 women with brittle hair found that 10mg silica as OSA scale ratings ofProgressive hair brittleness (Barel 2005). A second Multiple Agerandomized, double blind, placebo Dosage Pyridoxine HCl (Vitamin B6) 2 mg that the combination suppressed lipopolysaccharide-activated gene expression of for 9 months significantly improvedFormula hair elasticity, breakage, and diameter (thickness) (Wickett 2007). Vitamin & Mineral chemokinesKids associated with pathways involvedChildren in inflammation and apoptosis. (4 – 8 years) ChewRiboflavin ½ tablet with breakfast a total (Vitamin B2)and ½ tablet with dinner for 1.58 mg of study thatcell 5-alpha inhibitors in combination withmetabolism. B The vitamins are concluded support healthy growthreductase and division, and facilitate optimal hormone one tablet daily. blockade of inflammatory processes could represent a new two-pronged approach Adolescents (9 – 18 years) ChewFolic one tablet for amg total acid with breakfast and one tablet with dinner 0.095 Medicinal ingredients per capsule in both the men’s and women’s: in the treatment of AGA. of two tablets daily. Fenugreek (Trigonella foenum graecum) seed extract 4:1 ....................................................260 Biotin mcg Takemg one capsule with breakfast, lunch, and dinner, for400 a total of Active Women (19 – 50 years) Active Women (dry equiv FenugreekActive Seeds three capsules daily. Active Men (19 – 50 years) Men1040mg) Flax lignans, standardized to 50% SDG ...............................................................................100 mg Non-Medicinal Ingredients Fenugreek seeds contain steroid saponins, sterols, flavonoids (19 – 50 years) Adult Women 5% to 30% protein, Women d-calcium pantothenate (Vitamin B5) ..................................................................................10.4 mg and alkaloids trigonelline and choline). saponins bind and Men (19Steroid – 50 years) Adult(notably Men Niacinamide (Vitamin B3) ...................................................................................................10.3 mg Inert microcrystalline cellulose and vegetable-based magnesium Women (19 – DHT 50 years) one tablet with breakfast, lunch, and dinner, for a total of three Adult Women eliminateHCl extra cholesterol and hormones in the body; is made fromChew Pyridoxine (Vitamin B6)(Chewable) ...............................................................................................2.0 mgstearate tablets daily. in a veggie-based capsule Men (19 – 50 years) Adult Men (Chewable) testosterone, which is in turn is made from cholesterol. Therefore, when excess Riboflavin (Vitamin B2) .......................................................................................................1.6 mg Women (≥ 50 years) Take one Women 50 Plus is eliminated, less DHT can be made (Stark 1993). In a study of 20 cholesterol Folic acid ..............................................................................................................................95 mcg capsule with breakfast, lunch, and dinner, for a total of capsules daily.adult dose: One capsule per day Men (≥ 50fenugreek years) seed powder forthree 50 Plus12.5g and 18.0g of germinated Recommended adults....................................................................................................................................250 whoMen consumed Biotin mcg

one month, higher levels of consumption resulted in a significant reduction in total

Interactions Men’s also has: cholesterol and low-density lipoprotein (LDL) levels (Sowmya 1999). dose each vitamin & mineral is included above the minimum mg dosage value and at or below the maximum dosage value as Saw palmetto The berrydaily extract 4:1 of .............................................................................................125 established the Natural Health Products Directorate (NHPD). The general combinations of vitamins, minerals, and herbal components (dry equiv. 500by mg) Flax lignans are safe (NHPD monograph: Multi-Vitamin/Mineral Supplement). Flax reduceshas: the amount of DHT produced by reducing cholesterol levels in the Women’s alsoDue to potential toxicity from some of the vitamins, minerals and herbal components, children under 19 years of age are not recommended body.(silicon A meta-analysis of 28 studies between 1990 and 2008 showed that flaxseed mg Silicon ........................................................................................................40 todioxide) take any of the adult specific formulas (NHPD monograph: Multi-Vitamin/Mineral Supplement). significantly reduces circulating total and LDL-cholesterol concentrations (Pan mg Iron (ferric citrate) ................................................................................................................20 Due to the potential of toxicity and adverse effects of some of the vitamins, minerals and herbal components, none of the formulas are 2009). Flaxseed interventions reduced total and LDL cholesterol by 0.10 mmol/L recommended for use in pregnant or breastfeeding women (NHPD monograph: Multi-Vitamin/Mineral Supplement). Recommended use:0.00 one mmol/L) capsule twice capsules perCI: bottle). Bio-Fen® Plus capsules are usually effective (95% CI: -0.20, and daily 0.08 (60 mmol/L (95% -0.16, 0.00 mmol/L), Some of the the vitamins, and herbal components may interact diseases and conditions, and/or lab test results. It is at respectively. stopping hair loss within first twominerals, months. Anyone experiencing new growth see itmedication, within four months. Significant reductions were observed with whole flaxseed (-0.21should and with recommended that all ingredients be reviewed before use in an individual under medical taking prescription medication, Once Bio-Fen is stopped, the hairand growth pattern will and slowly return to its original point, however some peoplesupervision, may -0.16 mmol/L, respectively) lignan (-0.28 -0.16 mmol/L, respectively) suffering a serious and/or pre-existing medical condition (NHPD monograph: Multi-Vitamin/Mineral Supplement). be able to continue with from a lower maintenance dose.

supplements (Pan 2009).

Quality Assurance Bio-Fen has been approved by Health Canada and has received a unique NPN number. In additionReferences to being approved Test Specifications Girodon F, et al (1997). Effect of micronutrient supplementation on for hair growthParameter applications, Bio-Fen has been approved for additional health benefits. infection in institutionalized elderly subjects: a controlled trial. Ann Nutr Microbial 41(2):on98-107. Angwafor F Total III, Anderson response study to than determine thecfu/g effect of a dietary Metab, supplement dihydrotestosterone, testosterone and estradiol levels in healthy males. J Count ML. An open label, dose USP Less 5,000 Grieger JA, et al (2007). Effect of multivitamin on vitamin D status and Int Soc Sports Nutr 2008;5:12. Contraindications: The ingredient combination in Bio-Fen Plus Men/Women most adults. Yeast & Mold USP Lessfor than 100 cfu/g is generally safe heelfor ultrasound bone density in Australian aged care residents. Bio-Fen should not be used coli by patients withB6 diabetes, or known hypersensitivity to any ingredients. USP Negative Brzezińska-Wcisło L. Evaluation of vitamin and calcium pantothenate effectiveness on hair growth International from clinical Congress and trichographic aspects for treatment of diffuse alopecia in women. Wiad Escherichia Series, 1297: 109-119. Lek 2001;54:11-8. Holmquist C, et al (2003). Multivitamin Supplements Are Inversely USP Negative Salmonella sp Associated with Risk of Myocardial Infraction in Men and Women – References USP Staphylococcus aureus of inflammatory Chittur S, Parr B, Marcovici G. Inhibition geneNegative expression in keratinocytes using a composition carnitine, Program thioctic acid and saw palmetto Stockholm containing Heart Epidemiology (SHEEP). J Nutr, 133:extract. 2650- Evid Based Brooks JD, et Heavy al. Am JMetal Clin Complement Alternat Med Nutr. 2009. 2004 Feb;79(2):318-25. 2654. Evans BA, et al. 1995 Nov;147(2):295-302. Arsenic USEPA < 1.0 ppm NHPD monograph. (2007). supplement, October 22. Pan A, YuR.D,Clin Demark-Wahnefried W, Franco OH, Lin X. Meta-analysis of the effects of flaxseed interventions on blood lipids. AmMulti-vitamin/mineral J Clin Nutr 2009;90:288-97. Hoffmann Exp Dermatol. 2002 Jul;27(5):373-82. Shatrugna V, et al (2006). Effect of a micronutrient supplement on health Cadmium USEPA < 0.5 ppm 2001;39(1):58-65. Hutchins AM,et al.K, Nutr Cancer. and nutritional status of school children: bone health and body Prager N, Bickett French N, Marcovici G. A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the Lead USEPA < 1.0 ppm Prager N, etof al.androgenetic 2002 Apr;8(2):143-52. composition. Nutrition, 22: S33-S39. treatment alopecia. J Altern Complement Med 2002;8:143-52. Total Mercury USEPA < 1.0 ppm Vazir S, et al (2006). Effect of micronutrient supplement on health and Trüeb RM. Exp Gerontol. 2002 Aug-Sep;37(8-9):981-90. Chemical Serenoa repens Alternative Medicine Review 1998;3:227-9. nutritional status of schoolchildren: mental function. Nutrition, 22: S26Wickett RR, et almonograph. Arch Dermatol Res. 2007 Dec;299(10):499-505. S32. Pesticides USP Absent Wilt T et al. Database Syst Rev. 2002;(3):CD001423. Sinclair R. Cochrane Male pattern androgenetic alopecia. BMJ 1998;317:865-9. Solvents USP Conforms to limits Sowmya P, Rajyalakshmi P. Hypocholesterolemic effect of germinated fenugreek seeds in human subjects. Plant Foods Hum Nutr 1999;53:359-65. Stark A, Madar Z. The effect of an ethanol extract derived from fenugreek (Trigonella foenum-graecum) on bile acid absorption and cholesterol levels in rats, Br J Nutr 1993;69:277-87. Vierpper H, Nowotny P, Maier H, Waldhausl W. Production rates of dihydrotestosterone in healthy men and women and in men with male pattern baldness: determination by stable isotope/ dilution and mass spectrometry. J Clin Endocrinol Metab 2001;86:5762-4.

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Female Fertility Oxidant stress and a potential role for antioxidant therapy By Gillian Flower, ND Ottawa Integrative Cancer Centre 29 Bayswater Avenue Ottawa, ON, K1Y2E5 gflower@ccnm.edu

Infertility affects up to 15% of Canadian couples and may be attributed to a number of diverse factors. Recent evidence suggests that while oxidative processes play an essential role in human reproduction, a state of oxidative stress may contribute significantly to the inability to conceive.Oxidative stress has been implicated in endometriosis, recurrent pregnancy loss and poor embryo quality. Human studies into the effect of antioxidants upon reproductive outcomes have shown some promising results. Interventions including vitamin A, vitamin E, n-acetyl cysteine, and melatonin may quench oxidative stress, while observational data suggests a possible role for CoQ10. Antioxidants may offer novel therapeutic options in the management of female infertility. November/December 2012 l www.ihpmagazine.com 61

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Infertility is defined as a â&#x20AC;&#x153;failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourseâ&#x20AC;? (PCASRM 2008). Recent surveys suggest that between 11.5% and 15.7% of Canadian couples attempting to get pregnant are dealing with an inability to conceive, with prevalence rates increasing with advancing maternal age (Bushnik 2012). It is estimated that approximately 30% of infertility causes may be attributed to male factors and 40% to female factors. In the remainder of cases, a combination of influences or an undetermined cause are deemed to be responsible (AHRC 2010). Through diagnostic imaging and laboratory assessment, many causes of female infertility may be identified and treated. Common causes include disturbances to ovulation caused by polycystic ovarian syndrome (PCOS) and its accompanying insulin resistance and androgen dominance, and disruptions to the physical structure of the reproductive tract as a result of fibroids, endometriosis and pelvic inflammatory disease. Factors external to the reproductive tract such as age, genetics, smoking status and toxin exposure history can also influence the viability of reproductive cells and the success of attempts at pregnancy. Endocrine functioning, involving the complex interplay of reproductive hormones (estrogen, progesterone, luteinizing hormone and follicle stimulating hormone), thyroid hormones (thyroid stimulating hormone, T3, T4, reverse T3), prolactin, melatonin, insulin and cortisol, has an equally important role in determining the success or failure of any attempts at conception. This component presents perhaps the greatest challenge to those working to support conception. Factors such as body composition, dietary choices, exercise and exposure to stress may have significant impacts on the functioning of this elegant, dynamic system. In spite of our ability to image, measure and quantify so many aspects of the reproductive tract, a clear cause of infertility cannot be identified in a number of cases (Ledger 2009). These unexplained cases may be attributed in the future to other pathological processes that are the subject of current research including immune functioning (Siam 2011), genetic enzymatic variants (Eloualid 2012) and signaling peptides (Sadeu 2012). A role of oxidative stress in infertility has also been proposed by numerous authors (Agarwal 2005, Ruder 2009, Visioli 2011) and forms the focus of this present analysis.

significant tissue damage and disease. For this reason, mechanisms within the body work to stabilize free radicals and to neutralize the damage they may cause. Antioxidant compounds and enzymes accomplish this function on an ongoing basis (Agarwal 2005). When the burden of reactive species overwhelms the compensatory mechanisms of the body, oxidative stress occurs, causing damage to cellular structures and DNA (Valko 2007).

Free radicals and oxidative stress Free radicals, comprising two main classes of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are unstable compounds that are produced through many physiological processes. While they are essential to some functions of the body such as infection control (Valko 2007), free radicals have the potential to cause

Recurrent pregnancy loss (RPL) Recurrent pregnancy loss, the spontaneous termination of three or more pregnancies under 20 weeks gestation (Gupta 2007), may also prove to have an association with oxidative mechanisms. One study of 45 women that had experienced recurrent pregnancy loss found significantly decreased total antioxidant capacity (TAC) and increased

Oxidative processes in reproduction As in the rest of the body, oxidative processes are integral to the proper functioning of the reproductive system. Key functions such as follicle and oocyte follicular development, embryonic development and implantation (Agarwal 2005, Wiener-Megnazi 2011) involve ROS. However, as oxidative stress has also been implicated as a causative factor in age-related fertility decline (Keefe 2009), it is clear that oxidative processes are not wholly supportive of reproductive processes. Oxidative stress and endometriosis Oxidative stress has been put forth as a contributing factor in women with endometriosis, a significant cause of female infertility (Augoulea 2009). Women with this presentation have been found to have a lower antioxidant capacity, as evidenced by decreased levels of plasma superoxide dismustase in one recent investigation (Prieto 2012). Oxidative processes, originating in the peritoneum, are thought to contribute to the development of endometriosis (Gupta 2005, Lousse 2012) and affect not only the structure of the reproductive tract, but oocyte quality in these women (Saito 2002). It has also been suggested that more advanced cases are associated with more evidence of systemic oxidative stress (Andrade 2010). The administration of antioxidant therapies may provide a novel strategy for the management of this reproductive concern. One recent trial demonstrated that levels of malondialdehyde (MDA), a marker of oxidative stress, could be significantly attenuated by low doses of vitamins A and E (343mg and 84mg respectively) over a six-month period (Mier-Cabrera 2008). At the end of the study, pregnancy rates were slightly higher in the treatment group but results did not reach significance. Future trials with higher doses of targeted antioxidant compounds may hold promise in the treatment of this common cause of female infertility.

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total oxidative status (TOS) among these women compared to healthy pregnant controls (Toy 2010). This evidence is supported by an earlier study identifying low activity of the paraoxonase-1 enzymatic system that prevents lipid oxidation compared to healthy controls (p<0.01). High levels of lipid hydroperoxide in these same women demonstrated increased levels of oxidative stress in these individuals (p<0.01). It should be noted here that other studies have identified oxidative stress as a result rather than a cause of RPL (Baban 2010). N-acetyl cysteine (NAC) is a mucolytic compound that has been discussed previously in reference to its application in polycystic ovarian syndrome (PCOS) (Flower 2011), where it appears to improve insulin sensitivity and reduce resistance to clomiphene therapy (Abu Hashim 2010). A recent prospective study (Amin 2008) assessed the suitability of NAC in the treatment of RPL, reporting a significant decrease in the risk of pregnancy loss when treatment with a combination of NAC (0.6g) and folic acid (500mcg) was initiated at the time of pregnancy confirmation. In comparison to folic acid therapy alone, the addition of NAC greatly improved the rate of pregnancy maintenance up to 20 weeks (RR 2.9, 95% confidence interval (CI) 1.5-5.6). Perhaps most importantly, the so-called take home baby rate was significantly higher in the NAC-treated group (RR 1.98, 95%CI 1.3-4.0). Given the established antioxidant activity of NAC (Amin 2008), coupled with the evidence of increased oxidative stress in women suffering RPL, it is reasonable to postulate that this intervention improved pregnancy outcomes by attenuating the predominance of oxidative reactions in the body. It is not yet known whether this effect is achieved through direct action of NAC as a scavenger of free radicals or whether it counters oxidation more indirectly by increasing endogenous glutathione levels (Amin 2008). NAC and other antioxidants may have an important role to play in the management of this devastating condition. Oxidative factors and in-vitro fertilization (IVF) IVF, with or without intracytoplasmic sperm injection (ICSI), provides hope for many couples struggling with fertility challenges. A review of the literature pertaining to the oxidative status of women undergoing IVF indicates that this population may be another arena where intervention with antioxidant therapies may be appropriate. Observational data from a series of prospective trials have examined markers of oxidative activity in women undergoing both IVF and ICSI (Bedaiwy 2010, Bedaiwy 2011, Liu 2010) and their relationship to pregnant cycles. All reviewed trials report similar findings. In their assessment of follicular fluid, Bedaiwy et al. (2011)

report significant associations between both lower levels of ROS and higher TAC and pregnant cycles. Non-pregnant patients in the study by Liu et al. had higher MDA measurements (p<0.05) and lower SOD levels (p<0.05), indicating higher amounts of oxidative activity. An earlier study of ROS levels in embryo culture dishes found that lower levels on day three were significantly associated with pregnant cycles (Bedaiwy 2010). A milieu dominated by oxidative processes does not appear to favour conception. Some researchers have taken this concept of hindrance by oxidation a step further and have declared a cut point for ROS levels in follicular fluid (Jana 2010). After assessing ROS in women with a range of fertility concerns (PCOS, endometriosis, tubal factor infertility), Jana et al. propose that ROS levels over 107cps/400micromol follicular fluid do not favour the growth of viable embryos. One may speculate that these findings could eventually translate into improved clinical tools for predicting IVF success rates. Melatonin and IVF Melatonin is a hormone that is naturally secreted by the pineal gland to manage sleep/wake cycles in humans. This compound has also been studied extensively for its antioxidant properties (Tan 2007). In light of the evidence suggesting a detrimental effect of oxidation in IVF cycles, it is not surprising that this antioxidant hormone may promote favourable outcomes for individuals undergoing this therapy. Three recent randomized controlled trials (RCTs) have evaluated the effect of 3mg of melatonin upon IVF-related parameters (Eryilmaz 2011, Rizzo 2010, Tamura 2008). A fourth trial did not specify dose in the abstract that was available for review (BatioÄ&#x;lu 2012). Trials reported significantly higher numbers of mature oocytes at pickup and higher quality embryos in treated patients (BatioÄ&#x;lu 2012, Rizzo 2010, Eryilmaz 2011). Trends towards higher pregnancy rates were also reported. When comparing current and previous IVF cycles, improved fertilization rates were seen among participants receiving melatonin (Tamura 2008). The benefit of melatonin to parameters of successful IVF therapy may be attributed at least in part to its action as an antioxidant (Eryilmaz 2011, Rizzo 2010). This theory is supported and elaborated upon by a randomized trial (Taketani 2011) that demonstrates a protective effect of melatonin against reactive oxygen species (ROS) such as H2O2. The production of progesterone by luteinized granulosa cells was inhibited in vitro by H2O2 but this effect was reversed with the addition of melatonin. This effect was demonstrated in vivo by the same authors, through the restoration of deficient progesterone levels in some participants treated with 3mg of melatonin (see Figure 1).

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Table 1. Melatonin and oocyte maturation, embryo quality, pregnancy rates and progesterone Reference

Population

Intervention

Control

Outcomes

Rizzo 2010 (RCT; n=65)

Women with low oocyte quality undergoing IVF

Melatonin (MLT) 3mg + Inositol 2g + Folic acid 200mcg

Inositol 2g + Folic acid 200mcg

Greater mean number of mature oocytes, MLT vs. control (6.56 ± 1.64 vs 5.76 ± 1.56; p=0.047) and high-quality embryos (p<0.01). NS higher clinical pregnancy rate in MLT group.

Batioglu 2012 [abst] (RCT; n=85)

Women undergoing IVF

MLT (dose unspecified)

No MLT

Higher percentage of mature oocytes in MLT-treated group (p<0.05); greater number of class 1 embryos with MLT treatment vs. placebo (3.28 vs. 2.53; p < 0.05). NS trend to higher pregnancy rate with MLT.

Eryilmaz 2011 (RCT; n=60)

Women undergoing IVF with sleeping problems

MLT 3mg

No MLT

Higher mean mature oocyte count, MLT vs. control (9.0±5.6 vs. 4.4±3.3 (p=0.0001). Higher transfer ratio of grade 1 embryos with MLT (69.3 vs 44.8,; p<0.05). Similar pregnancy rates.

Tamura 2008 (n=115)

Women with low fertilization rate in prior IVF

MLT 3mg

No MLT

Improved fertilization rates compared to previous IVF cycle in MLT treated group (p-value NR, but reported as NS in nontreated group)

Taketani 2011 (n=25)

Women with progesterone deficiency (<10ng/mL in mid-luteal phase)

MLT 3mg

No MLT

Improved serum progesterone levels(>10 ng/mL) in 9/14 treated women; same result in 2/11untreated women.

Viewed from this perspective, melatonin may benefit women undergoing IVF, and presumably those trying to conceive naturally as well, through two related mechanisms. First, acting as a free-radical scavenger, melatonin may quench some of the oxidative stress that has been shown to be higher in women with diverse fertility challenges. Secondly, melatonin may reduce the activity of ROS such as H2O2 at the level of the ovary, preventing interference with endogenous progesterone production. Future directions – CoQ10 While intervention studies have not yet been conducted, coenzyme Q10 (CoQ10) is another antioxidant that may also hold some promise in the treatment of infertility. A recent study investigated CoQ10 levels in the follicular fluid of women undergoing oocyte retrieval. Women with higher levels of CoQ10 had significantly increased numbers of mature oocytes and grade I-II embryos (Turi 2012), suggesting that the presence of this antioxidant compound may also contribute to positive fertility-associated outcomes.

Conclusions Although oxidative processes are required for numerous essential physiological functions, a state of oxidative stress appears to be associated with conditions that may present barriers to successful conception. Markers of oxidative activity may be higher in women with endometriosis and a history of EPL. While antioxidant therapy has not been fully evaluated for either condition, treatment with 600mg of NAC may help women with EPL to prolong and preserve their pregnancies. In women undergoing IVF treatments, increased levels of oxidative stress have been observed and may be associated with the success of individual IVF cycles. Melatonin administration at a dose of 3mg per night has been significantly associated with improved oocyte maturity and embryo quality. CoQ10 may also contribute positively to these outcomes but intervention studies are needed to support observational data. While the association between oxidation and female fertility is not entirely understood, this relationship offers some novel therapeutic options to care providers and may further our understanding of infertility that is otherwise unexplained. ■

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References Abu Hashim H, Anwar K, El-Fatah RA. N-acetyl cysteine plus clomiphene citrate versus metformin and clomiphene citrate in treatment of clomiphene-resistant polycystic ovary syndrome: a randomized controlled trial. J Womens Health (Larchmt). 2010 Nov;19(11):2043-8. Agarwal A, Gupta S, Sharma RK. Role of oxidative stress in female reproduction.ReprodBiolEndocrinol. 2005 Jul 14;3:28. Amin AF, Shaaban OM, Bediawy MA. N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss.Reprod Biomed Online. 2008 Nov;17(5):722-6. Andrade AZ, Rodrigues JK, Dib LA, Romão GS, Ferriani RA, Jordão Junior AA, Navarro PA.[Serum markers of oxidative stress in infertile women with endometriosis]. [Article in Portuguese] Rev Bras Ginecol Obstet. 2010 Jun;32(6):279-85. Assisted Human Reproduction Canada (AHRC). Infertility and Assisted Human Reproduction (AHR) [Internet] 2010 Aug 26 [cited 2012 Sep 23]. Available from: http://www.ahrc-pac.gc.ca/v2/patients/infertilityinfertilite-eng.php Augoulea A, Mastorakos G, Lambrinoudaki I, Christodoulakos G, Creatsas G. The role of the oxidative-stress in the endometriosis-related infertility.GynecolEndocrinol. 2009 Feb;25(2):75-81. Baban RS. Oxidative stress in recurrent pregnancy loss women. Saudi Med J. 2010 Jul;31(7):759-63. Batioğlu AS, Sahin U, Gürlek B, Oztürk N, Unsal E. The efficacy of melatonin administration on oocyte quality.GynecolEndocrinol. 2012 Feb;28(2):91-3. [abst] Bedaiwy MA, Elnashar SA, Goldberg JM, Sharma R, Mascha EJ, Arrigain S, Agarwal A, Falcone T. Effect of follicular fluid oxidative stress parameters on intracytoplasmic sperm injection outcome. GynecolEndocrinol. 2012 Jan;28(1):51-5. Bedaiwy MA, Mahfouz RZ, Goldberg JM, Sharma R, Falcone T, Abdel Hafez MF, Agarwal A. Relationship of reactive oxygen species levels in day 3 culture media to the outcome of in vitro fertilization/intracytoplasmic sperm injection cycles.FertilSteril. 2010 Nov;94(6):2037-42. Bushnik T, Cook JL, Yuzpe AA, Tough S, Collins J. Estimating the prevalence of infertility in Canada. Hum Reprod. 2012 Mar;27(3):73846. Eloualid A, Abidi O, Charif M, El Houate B, Benrahma H, Louanjli N, Chadli E, Ajjemami M, Barakat A, Bashamboo A, McElreavey K, Rhaissi H, Rouba H. Association of the MTHFR A1298C variant with unexplained severe male infertility. PLoS One. 2012;7(3):e34111. Eryilmaz OG, Devran A, Sarikaya E, Aksakal FN, Mollamahmutoğlu L, Cicek N. Melatonin improves the oocyte and the embryo in IVF patients with sleep disturbances, but does not improve the sleeping problems. J Assist Reprod Genet. 2011 Sep;28(9):815-20. Flower G. Polycystic ovarian syndrome – Clinical considerations and therapeutic options. Integrated Healthcare Practitioners. 2011 April/ May;20:68-72. Gupta S, Agarwal A, Banerjee J, Alvarez JG. The role of oxidative stress in spontaneous abortion and recurrent pregnancy loss: a systematic review. ObstetGynecolSurv. 2007 May;62(5):335-47; quiz 353-4. Gupta S, Agarwal A, Krajcir N, Alvarez JG. Role of oxidative stress in endometriosis.Reprod Biomed Online. 2006 Jul;13(1):126-34. Jana SK, K NB, Chattopadhyay R, Chakravarty B, Chaudhury K. Upper control limit of reactive oxygen species in follicular fluid beyond which viable embryo formation is not favorable. ReprodToxicol. 2010 Jul;29(4):447-51. Keefe DL, Liu L. Telomeres and reproductive aging.ReprodFertil Dev. 2009;21(1):10-4. Ledger WL. Demographics of infertility.Reprod Biomed Online. 2009;18Suppl 2:11-4.

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Taketani T, Tamura H, Takasaki A, Lee L, Kizuka F, Tamura I, Taniguchi K, Maekawa R, Asada H, Shimamura K, Reiter RJ, Sugino N. Protective role of melatonin in progesterone production by human luteal cells. J Pineal Res. 2011 Sep;51(2):207-13. doi: 10.1111/j.1600079X.2011.00878.x. [abst] Tamura H, Takasaki A, Miwa I, Taniguchi K, Maekawa R, Asada H, Taketani T, Matsuoka A, Yamagata Y, Shimamura K, Morioka H, Ishikawa H, Reiter RJ, Sugino N. Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res. 2008 Apr;44(3):280-7. [abst] Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res. 2007 Jan;42(1):28-42. Toy H, Camuzcuoglu H, Camuzcuoglu A, Celik H, Aksoy N. Decreased serum prolidase activity and increased oxidative stress in early pregnancy loss. GynecolObstet Invest. 2010;69(2):122-7. Turi A, Giannubilo SR, Brugè F, Principi F, Battistoni S, Santoni F, Tranquilli AL, Littarru G, Tiano L.Coenzyme Q10 content in follicular fluid and its relationship with oocyte fertilization and embryo grading. Arch Gynecol Obstet. 2012 Apr;285(4):1173-6. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44-84. Visioli F, Hagen TM. Antioxidants to enhance fertility: role of eNOS and potential benefits. Pharmacol Res. 2011 Nov;64(5):431-7. Wiener-Megnazi Z, Reznick AZ, Lahav-Baratz S, Shiloh H, Koifman M, Grach B, Arnon T, Avraham L, Auslander R, Dirnfeld M. [Oxidation and female reproduction: the good, the bad and what’s between]. [Article in Hebrew] Harefuah. 2011 Mar;150(3):255-9, 303.

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Parkinsonâ&#x20AC;&#x2122;s Disease An eclectic approach By Maria Shapoval, ND Research Resident Canadian College of Naturopathic Medicine Integrated Healthcare Centre 1255 Sheppard Ave E Toronto, Ontario, Canada M2K 1E2 mshapoval@ccnm.edu

Parkinsonâ&#x20AC;&#x2122;s disease (PD) is a complex problem affecting multiple body systems. Its impact includes muscle control, balance, mood, temperature and blood pressure regulation, peristalsis, sleep, sense of smell and others. The etiology of PD is also complex involving several different hypotheses including genetic predisposition, oxidative stress, alpha-synuclein aggregation, iron accumulation, inflammation, heavy metal and pesticide exposure, blood brain barrier disruption and autoimmunity. Invariably the etiology is dependent on a combination of these factors, as well as others that remain as- yet unidentified. Though this review will not attempt to address or truly explore the root of this complex problem, it will explore a wide range of therapeutic options.

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Introduction Parkinson’s disease is a complex problem affecting multiple body systems. An appropriate treatment approach to this problem must also be complex and affect multiple systems. Parkinson’s disease (PD) is a neurodegenerative motor disorder affecting 2% of the North American population over 60 years of age (Liepelt 2011). The degeneration occurs within the basal ganglia; specifically the dopaminergic neurons of the substantia nigra (SN) undergo apoptosis (Zhu 2010). According to Jankovic (2008) the primary symptoms of PD are TRAP: tremor at rest, rigidity, akinesia (bradykinesia) and postural instability, but patients may also present with shuffling gate, micrographia, pain, difficulty rising from a seated position and other symptoms. Typically these symptoms develop when 60-80% of the SN dopaminergic neurons are already destroyed making treatment challenging (Jankovic 2008, Prediger 2010). The neurological degeneration of PD does not originate in the SN; rather it begins in the dorsal motor nucleus and olfactory bulb and nucleus, progresses to the locus coeruleus and then arrives at the pars compacta of the SN (Schapira 2006). Even more significant is the finding that patients with PD develop non-motor symptoms of constipation, olfactory dysfunction and REM sleep disturbances 10-20 years prior to their motor symptoms (Ahlskog 2007, Gaig 2009). Da Silva (2008) argues that depression, in those that concomitantly suffer it, also develops prior to the motor symptoms. Oxidative damage has been frequently cited to be an integral part of the etiology of PD. Multiple factors can lead to oxidative stress including the accumulations of iron and insoluble aggregates of the α-synuclein (α-syn) protein within the degenerating neurons and inflammation within and surrounding the degenerating region (Schapira 2006, Zhu 2010). Though this review will not attempt to address or truly explore the root of this problem, it will explore a wide range of therapeutic options. Botanical Medicine Gingko biloba (Gb) Gingko biloba is considered a potent vascular tonic commonly prescribed as a memory aid or circulatory stimulant. Its role as a potent antioxidant may be less known. A series of preclinical investigations has suggested a potential role for ginkgo in the management of PD. Yang (2001) demonstrated a reduction in malondialdehyde (MDA), a marker of oxidative damage, and increase in the activity of superoxide dismutase (SOD); an antioxidant enzyme, within the rat SN following supplementation with Gb extract at 50 and 100mg/kg for 20 days. The loss of dopaminergic neurons induced by MPTP (1-methyl-4-phenyl-1,2,3,6trtrahydropyridine) was also reduced. A dose- ranging animal study by Rojas and colleagues (2008) found

40mg/kg to be the ideal dose for enhancing antioxidant activity, inhibiting lipid peroxidation, and achieving neuroprotection. Alternatively studies by Cao (2003) and Kim (2004) utilized doses of 50mg and 100mg demonstrating a decrease in apoptosis and increase in dopamine levels as well as improvements in akinesia. The capacity of Gb to prevent oxidative damage may be the reason for the observed decrease in neuronal death. Although the evidencebase in favour of ginkgo specifically in PD is based on preclinical evidence, a multicentre observational study of 22 primary care physicians in Germany found ginkgo to be the most commonly prescribed medication for dementia (including dementia of Parkinson’s origin) (67.6% of all prescriptions) followed by cholinesterase inhibitors (17.6% of all prescriptions) (Jeschke 2011). Withania somnifera Withania somnifera contain 0.19mg of L-DOPA per kg of dried root (Nagashayana 2000), which may contribute to the benefit it provides. However a study by RajaSankar (2009) demonstrates antioxidant activity that may add preventative value to this herb. Mice given 100mg/kg for either seven or 28 days combined with MPTP had increased levels of dopamine and its metabolites, compared to MPTP alone (RajaSankar 2009). The mice also performed better on motor tasks focusing on balance and had reduced levels of lipid peroxidation. The dose of 100mg/kg would translate to 7g for an average weight human and is above the regularly prescribed dose. Given its content of L-DOPA it may work synergistically with standard dopamine replacement and agonist medications; however the possibility of increase in diskinesia cannot be rejected. Ganoderma lucidum An alternative hypothesis to the pathogenesis of PD explores the role of microglial inflammation. Increased numbers of microglia, seen with PD, potentially attracted to the Lewy body depositions, produce inflammatory cytokines, nitric oxide (NO) and TNFα, which further the apoptotic cascade. Incubation of rat dopaminergic cells with MPP+ and 100 or 400µg/mL of Ganoderma lucidum extract resulted in a decrease of NO, TNFα and IL-1β (Zhang 2011).

EGCG/ Green tea Whether by its antioxidant activity or its iron chelation capacity, (-)-epigallocatechin-3-gallate (EGCG) has been shown to offer neuroprotection to dopaminergic neurons and affect gene expression. Pan (2003) reviews the literature surrounding EGCG and reports evidence of decreased lipid peroxidation and reduction of pro-apoptotic gene expression. November/December 2012 l www.ihpmagazine.com 67

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In an animal study, Mandel (2004) demonstrates preservation of dopaminergic neurons against MPTP toxicity and subsequent reduction in the depletion of dopamine. Incubating dopaminergic cells (Chao 2010) with EGCG offered protection against a different PD inducer, 6-hydroxydopamine (6OHDA), by reducing the associated toxicity. Whether EGCG can impact the prognosis of PD in humans and affect motor functions remains to be explored. Acupuncture Though the protocols described in acupuncture studies are diverse, they demonstrate significantly positive results. Animal studies (Kim 2011, Wang 2011) report improved balance, neuroprotection and antioxidant achievements. Human studies range in the degree of improvement associated with electro-acupuncture of scalp and regular acupuncture with or without additional therapies like Qi Gong and massage. While an open label trial by Eng (2006) observed a worsening of motor symptoms and improvement of quality of life and mood, a systematic review by Lam (2008) reported improvements in motor symptoms in addition to quality of life. The review does report significant methodological flaws within the acupuncture studies and cautions regarding the high publication bias associated with them. Exercise An increasing number of studies report significant improvements with therapeutic exercise; however different exercise regimes seem to benefit PD patients differently. Nordic walking has been shown to increase walking speed, improve ability to make turns while walking, and improve ability to get up from a sitting position (Fritz 2011, Van Eijkeren 2008). However, achieving these benefits requires obtaining a mastery of the walking technique, which often proves challenging (Fritz 2011, Van Eijkeren 2008). Inability to reproduce this technique limits the benefits to cardiovascular and musculoskeletal systems, not addressing motor function. Tai chi, while not as challenging, does not improve walking gait (Li 2012). It does, however, significantly improve balance, which is typically not addressed by conventional medications (Hackney 2008). In addition it offers improvements in walking speed and

scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) (Hackeny 2009, Li 2012). Argentinean Tango offers a wide array of benefits as it improves UPDRS, increased walking velocity, reduced bradykinesia and tremor and also improved balance (Duncan 2012, Hackney 2009). The above outcomes were seen with a regime of 1hr 2x/wk, ranging in duration from 10 weeks to one year. Performed in a group setting it may enhance compliance and offer social support. Exercise in water offers the challenge of increased resistance and the benefit of buoyancy. After 12 weeks of exercises at 30 minutes 2x/wk both motor symptoms and quality of life measures showed improvements (Ayan 2012). In addition to palliation, exercise may slow down the progression of PD as it also increases activity of antioxidant enzymes SOD and glutathione peroxidase (Gpx), and decreases markers of lipid peroxidation (Bloomer 2008). Bright Light Therapy Whether through the inhibition of melatonin release or via a different mechanism altogether, bright light therapy improves not only mood, but also motor function of patients with PD (Paus 2007). While Paus (2007) reports no changes in motor function, yet significant improvement in quality of life and depression scales, a case series by Willis (2007) demonstrated improvement in bradykinesia and rigidity. The discrepancy between these studies may be due to the differences in the duration of exposure. Paus’ study exposed patients to lower intensity (750lux) for 30 minutes/day, while patients in Willis’ study had almost double the intensity (1000-1500lux) for 60-90 minutes/ day. Whether the improvements are transient remains to be seen as both studies lasted for no more than two weeks. Nutritional Supplements Vitamin B12 While studies with cognitive dementia and Alzheimer’s disease illustrate the significance of vitamin B12 on cognitive function and mood (Fauz 2011, Moore 2012), a study by Lee (2010) demonstrates its effect on minimizing homocysteine levels (increased by levodopa treatments) and maintaining bone mineral density (BMD). Subjects were assigned to one of three groups; 1500μM methylcobalamin and 500mg folate/day, 600mg of alpha-lipoic acid/day, and a control group. All three groups

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The Journal of IHP

experienced decreases in BMD, however, the decrease was significantly less with vitamin B12 supplementation (p=0.023 lumbar spine, p=0.021 total femur and p=0.005 femur shaft). As patients with PD are already at risk for falling, due to postural instability, maintaining adequate BMD becomes very important in preventing fractures, which may further challenge the patient’s mobility as well as increase mortality risk. Melatonin Conflicting results are seen with respect to melatonin and its effect on the motor symptoms of PD as well as PD pathogenesis. While a study reports a reduction in formation of α-syn aggregates (Ono 2012), other studies demonstrate its capacity to promote this aggregation and associated toxicity (Pandi-Perumal 2012). Alternatively an animal study (GutierrezValdez 2012) shows melatonin at 10mg/kg preserving dopaminergic neurons and improving motor function. However at the same time, Mendes- Mendeiros (2007) in a randomized clinical trial observes no statistically significant change in UPDRS, which includes motor function assessments, though an improvement in sleep quality at 3mg/d of melatonin was noted. Sleep seems to be consistently affected by melatonin (Dowling 2005), though the dose is diverse, ranging from 3 to 50mg. Polyunsaturated Fatty Acids (PUFAs) The effect of omega 3 on PD is also unclear. Animal studies of docosahexaenoic acid (DHA) (Hacioglu 2012, Ozsoy 2011) at 36mg/kg/d demonstrate protection against MPTP in the form of decreased cell death, preservation of motor function and anti-inflammatory effects. An animal study with eicosapentaenoic acid (EPA) (Lutchman 2012) also demonstrates anti-inflammatory effects against MPTP. Alternatively studies with other PD inducers, such as 6-hydroxydopamine (6-OHDA) and hydrogen peroxide (H2O2), and DHA demonstrate an alarming potential to promote oxidative damage, increase aggregation of αsyn and further reduce dopamine levels (Kabuto 2009, Riedel 2011). There may be more than one pathological mechanism that can result in PD. Thus it is possible that there may exist a subtype of PD patients that will benefit from DHA and others that may be harmed by it. Alternatively it may also be a question of dose. Regardless, a human study with fish oil (Da Silva 2008) continues to demonstrate the positive effect of omega 3 on depression, which affects around 40% of patients with PD. A review of human trials of fish oil supplementation across an array of neurodegenerative diseases concluded that a 1.5:1 to 2:1 ratio of EPA: DHA appears ideal based on available evidence (Rouchotas 2010). However trials of DHAbased fish oils, and likewise trials with very high levels of EPA relative to DHA, were found to fail or produce

benefit of unexpectedly small magnitude (Rouchotas 2010). Conclusion Parkinson’s disease is complex in its presentation and pathogenesis. Combinations of the different therapeutic approaches may offer unpredictably positive results when synergistically combined at appropriate dosages and frequencies. Therapeutic approaches include reducing inflammation, increasing the activity of antioxidant enzymes and targeting the motor symptoms, such as postural instability and muscle rigidity. Other therapeutic options available but not discussed in this review include caffeine, coenzyme Q10, creatine, NADH, vitamins C and E, which were previously reviewed in this journal (Prousky 2010), as well as curcumin, meditation, and vitamin D. Thus the therapeutic tool kit continues to grow in diversity and complexity ■ References Ahlskog, JE. Beating a dead horse: dopamine and Parkinson disease. Neurology. 69 (2007): 1701-1710. Ayan C, Cancela J. Feasibility of 2 different water-based exercise training programs in patients with Parkinson’s disease; a pilot study. Arch Phys Med Rehabilitation. 2012; Oct; 93(10): 1709-14 Bloomer RJ, Schilling BK, Karlage RE, Ledoux MS, Pfeiffer RF, Callegari J. Effect of resistance training on blood oxidative stress in Parkinson’s disease. Medicine & Science in Sports & Exercise. 2008; Aug; 40(8): 1385-1389. Cao F, Sun S, Tong ET. Experimental study on inhibition of neuronal toxical effect of levodopa by ginkgo biloba extract on Parkinson disease in rats. J Huazhong Univ Sci Technolog Med Sci. 2003; 23(2):151-3. Chao J, Lau WK, Huie MJ, Ho YS, Yu MS, Lai CS, Wang M, Yuen WH, Lam WH, Chan TH, Chang RC. A pro-drug of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) prevents differentiated SH-SY5Y cells from toxicity induced by 6-hydroxydopamine. Neurosci Lett. 2010 Jan; 469(3): 360-4. Da Silva TM, Munhoz RP, Alvarez C, Naliwaiko K, Kiss A, Andreatini R, Ferraz AC. Depression in Parkinson’s disease: a double blind, randomized, placebo-controlled pilot study of omega3 fatty acid supplementation. Journal of Affective Disorders. 2008; 111: 351-359.

Dowling GA, Mastick J, Colling E, Carter JH, Singer CM, Aminoff MJ. Melatonin for sleep disturbances in Parkinson’s disease. Sleep Medicine. 2005; 6: 459-466. Duncan RP, Earhart GM. Randomized controlled trial of community-based dancing to modify disease progression in Parkinson’s disease. Neurorehabilitation and Neural Repair. 2012; 26(2): 132-143. Eng ML, Lyons KE, Greene MS, Pahwa R. Open-label trial regarding the use of acupuncture and yin tui na in Parkinson’s disease outpatients: a pilot study on efficacy, tolerability, and quality of life. J Altern Complement Med. 2006 May;12(4):395-9. Faux NG, Ellis KA, Porter L, Fowler CG, Laws SM, Martins RN, Pertile KK, Rembach A, Rowe CC, Rumble RL, Szoeke C, Taddei K, Taddei T, Trounson BO, Willemagne VL, Ward V, Ames D, Masters CL, Bush Al. Homocysteine, vitamin B12, and folic acid levels in Alzheimer’s disease, mild cognitive impairment, and healthy elderly: baseline characteristics in subjects of the Australian Imaging Biomarker Lifestyle study. J Alzheimers Dis. 2011; 27(4): 909-22.

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Fritz B, Rombach S, Godau J, Berg D, Horstmann T, Grau S. The influence of Nordic Walking training on sit-to-stand transfer in Parkinson patients. Gait & Posture. 2011; 34: 234-238. Gaig, C., Tolosa, E. When does Parkinson’s disease begin? Movement Disorder. 24 Suppl 2 (2009): S656-64. Guiterrez-Valdez AL, Anaya-Martinez V, Ordonez-Librado JL, GarciaRuiz R, Rorres-Esquivel C, Moreno-Rivera M, Sanchez-Betancourt J, Montiel-Flores E, Avila-Costa MR. Effect of chronic L-DOPA or melatonin treatments after dopamine deafferentation in rats: dyskinesia, motor performance, and cytological analysis. International Scholarly Research Network. 2012. Hacioglu G, Seval-Celik Y, Tanriover G, Ozsoy O, Saka-Topcuoglu E, Balkan S, Agar A. Docosahexaenoic acid provides protective mechanism in bilaterally MPTP-lesioned rat model of Parkinson’s disease. Folio Histochem Cytobiol. 2012; 50(2): 228-238. Hackney ME, Earhart GM. Tai Chi improves balance and mobility in people with Parkinson disease. Gait Posture. 2008 Oct; 28(3): 456-460. Hackney ME, Earhart GM. Health related quality of life and alternative forms of exercise in Parkinson’s disease. Parkinsonism Related Disorders. 2009 Nov; 15(9): 644-648. Jankovic, J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 79 (2008): 368-376. Jeschke E, Ostermann T, Vollmar HC, Tabali M, Schad F, Matthes H. Prescribing patterns in dementia: a multicentre observational study in a German network of CAM physicians. BMC Neurol. 2011 Aug 8;11:99. Kabuto H, Amakawa M, Mankura M, Yamanushi TT, Mori A. Docosahexaenoic acid ethyl ester enhances 6-hydroxydopamine-induced neuronal damage by induction of lipid peroxidation in mouse striatum. Neurochem Res. 2009; 34: 1299-1303. Kim MS, Lee JI, Lee WY, Kim SE. Neuroprotective effect of Ginkgo biloba L. extract in a rat model of Parkinson’s disease. Phytother Res. 2004 Aug;18(8):663-6. Kim SN, Doo AR, Park JY, Bae H, Chae Y, Shim I, Lee H, Moon W, Lee H, Park HJ. Acupuncture enhances the synaptic dopamine availability to improve motor function in a mouse model of Parkinson’s disease. PLoS One. 2011; 6(11): e27566. Lam YC, Kum WF, Durairajan SS, Lu JH, Man SC, Xu M, Zhang XF, Huang XZ, Li M. Efficacy and safety of acupuncture for idiopathic Parkinson’s disease: a systematic review. J Altern Complement Med. 2008 Jul; 14(6): 663-71. Lee SH, Kim MJ, Kim BJ, Kim SR, Chun S, Ryu JS, Kim GS, Lee MC, Koh JM, Chung SJ. Homocysteine-lowering therapy or antioxidant therapy for bone loss in Parkinson’s disease. Movement Disorders. 2010; 25(3): 332340. Li F, Harmer P, Fitzgerald K, ckstrom E, Stock R, Galver J, Maddalozzo G, Batya SS. Tai Chi and postural stability in patients with Parkinson’s disease. New England Journal of Medicine. 2012 Feb; 366(6): 511-519. Liepelt, I., Behnke, S., Schweitzer, K., Wolf, B., Godau, J., Wollenweber, F., Dillmann, U., Gaenslen , A., Di Santo, A., Maetzler, W., Berg, D. Premotor signs of PD are related to SN hyperechogenicity assessed by TCS in an elderly population. Neurobiology of Aging. 32, 9 (2011): 1599-606. Lutchman DW, Meng Q, Song C. Ethyl-eicosapentaenoate (E-EPA) attenuates motor impairments and inflammation in the MPTP-probenecid mouse model of Parkinson’s disease. Behavioural Brain Research. 2012; 226: 386-396. Mandel S, Maor G, Youdim MBH. Iron and alpha-synuclein in the substantia nigra of MPTP-treated mice. Journal of Molecular Neuroscience. 2004; 24(3): 401-16. Mendes-Medeiros CA, Carvalhedo de Bruin PF, Lopes LA, Magalhaes MC, Seabra ML, Sales de Bruin VM. Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease. J Neurology. 2007 April; 254(4): 459-464. Moore E, Mander A, Ames D, Carne R, Sanders K, Watters D. Cognitive impairment and vitamin B12: a review. Int Psychogeriatr. 2012 Jan 6: 1-16.

Nagashayana N, Sankarankutty P, Nampoothiri MR, Mohan PK, Mohanakumar KP. Association of L-DOPA with recovery following Ayurveda medication in Parkinson’s disease. J Neurol Sci. 2000 Jun 15;176(2):124-7. Ono K, Mochizuki H, Ikeda T, Nihira T, Takasaki J, Teplow DB, Yamada M. Effect of melatonin on alpha-synuclein self-assembly and cytotoxicity. Neurobiology of Aging. 2012; 33: 2172-2185. Ozsoy O, Tanriover G, Derin N, Uysal N, Demir N, Gemici B, Kencebay C, Yargicoglu P, Agar A, Aslan M. The effect of docosahexaenoic acid on visual evoked potentials in a mouse model of Parkinson’s disease: the role of cyclooxygenase-2 and nuclear factor kappa-B. Neurotox Res. 2011; 20: 250262. Pan T, Jankovic J, Le W. Potential therapeutic properties of green tea polyphenols in Parkinson’s disease. Drugs Aging. 2003; 20(10): 711-21. Pandi-Perumal SR, BaHammam AS, Brown GM, Spence DW, Bharti VK, Kaur C, Hardeland R, Cardinali DP. Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes. Neurotox Res. 2012 June. Paus S, Schmitz-Hübsch T, Wüllner U, Vogel A, Klockgether T, Abele M. Bright light therapy in Parkinson’s disease: a pilot study. Mov Disord. 2007 Jul 30;22(10):1495-8. Prediger, RD. Effects of caffeine in Parkinson’s disease: from neuroprotection to the management of motor and non-motor symptoms. J Alzheimer’s Disease. 20, Suppl1 (2010): S205-20. Prousky J. Parkinson’s disease: contemporary and natural therapeutic interventions. Integrated Healthcare Practitioners. 2010;April/May: 84-90. RajaSankar S, Manivasagam T, Sankar V, Prakash S, Muthusamy R, Krishnamurti A, Surendran S.Withania somnifera root extract improves catecholamines and physiological abnormalities seen in a Parkinson’s disease model mouse. J Ethnopharmacol. 2009 Sep 25;125(3):369-73. Riedel M, Goldbaum O, Wille M, Richter-Landsberg C. Membrane lipid modification by docosahexaenoic acid (DHA) promotes the formation of alpasynuclein inclusion bodies immunopositive for SUMO-1 in oligodendroglial cells after oxidative stress. J Mol Neuroscience. 2011; 43: 290-302. Rojas P, Serrano-García N, Mares-Sámano JJ, Medina-Campos ON, Pedraza-Chaverri J, Ogren SO. EGb761 protects against nigrostriatal dopaminergic neurotoxicity in 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine-induced Parkinsonism in mice: role of oxidative stress. Eur J Neurosci. 2008 Jul;28(1):41-50. Rouchotas P. Fish oil; overview of intervention trials in neurodegenerative disease. Integrated Healthcare Practitioners. 2010; Apr/May:53-57. Schapira, AHV. Etiology of Parkinson’s disease. Neurology. 66 (Suppl 4) (2006): S10-S23. Van Eijkeren FJM, Reimers RSJ, Kleinveld MJ, Minten A, Bruggen JP, Bloem BR. Nordic walking improves mobility in Parkinson’s disease. Movement Disorders. 2008 Sept; 23(15): 2239-2243. Wang H, Pan Y, Xue B, Wang X, Zhao F, Jia L, Liang X, Wang X. The antioxidative effect of electro-acupuncture in a mouse model of Parkinson’s disease. PLoS One. 2011; 6(5):e19790. Willis GL, Turner EJ. Primary and secondary features of Parkinson’s disease improve with strategic exposure to bright light: a case series study. Chronobiol Int. 2007;24(3):521-37. Yang SF, Wu Q, Sun AS, Huang XN, Shi JS. Protective effect and mechanism of Ginkgo biloba leaf extracts for Parkinson disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Acta Pharmacol Sin. 2001 Dec;22(12):1089-93. Zhang R, Xu S, Cai Y, Zhou M, Zuo X, Chan P. Ganoderma lucidum protects dopaminergic neuron degeneration through inhibition of microglial activation. Evidence-Based Complementary and Alternative Medicine. 2011. Zhu, W., Li, X., Xie, W., Luo, F., Kaur, D., Andersen, JK., Jankovic, J., Le, W. Genetic iron chelation protects against proteasome inhibition-induced dopamine neuron degeneration. Neurobiology of Disease. 2010 Feb; 37(2): 307-313.

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One of the primary causes of hair loss is a high level of the male hormone, dihydrotestosterone (DHT) within the hair follicle (Hoffmann 2002). DHT is produced from Saw palmetto repens) testosterone in the(Serenoa testes (males), the adrenal glands, and the follicle. After a period of time, anVitamins over abundance of DHT causes the hair follicle to degrade and shortens the active by Metagenics features special Siberian rhubarb root (RheumIn rhaponticum) designed reduce hot flashes andfollicle other menopausal symptoms phase of theEstrovera hair,(lipophillic) eventually leading to thinning hairbeen andextract eventual hair Thereinhibitor is a familial tendency forstudy stepwise the hair and an increase in the calcium ratio a Polish of miniaturization 46towomen whoof had symptoms of diffuse alopecia, Standardized Serenoa extracta has foundofto be loss. a potent withoutphase) potential serious(growth adversephase) eventshairs, associated with conventional hormoneand therapies (HT).of androgens. Althou gh everyone produces DHT, only those with a of of telogen (resting to anagen which is promoted by systemic local effects pantothenate was orally administered twice a day in doses of 100 mg for four to 5α-reductase, resulting in decreased tissue DHT. An open-label, dose response higher of androgen receptors in their hair follicles, binding sitesof fora DHT, and greater five androgen sensitivity experience hairinjected loss (Prager 5AR istoresponsible forrepeated the months, and vitamin B6 was every2002). dayInfor 20 30 days and studynumber wasMenopause conducted 42clinical healthy males determine the effect combination ison the term usedtoafter menstruation hassame ceased for onereceptor, year, after women are considered postmenopausal [1].Trueb the2002) Western world, the conversion of testosterone to dihydrotestosterone, which binds to the androgen butwhich with five-fold greater affinity. (Hoffmann 2001). 2002, after six months (Brzezińska-Wcisło It was determined that vitamin again of carotenoid astaxanthin and saw palmetto berry lipid extract on DHT and age range for natural menopause is 40 to 58 years, with 51 being the median age for menopause. The average age of menopause in Canada is also 51, and it is B6 administered parenterally foralla the fewmenopausal weeks induces improvement testosterone levels that (Angwafor 2008). The were almost divided two(22%) groups: estimated women over age 50 willmen comprise oneinto quarter of the population by the year 2026 [2]. Of symptoms, hot flashesin the hair Flax condition subset of(Evans women and reduces hairfrom loss. one group received 800 of the supplement the other referred to asmg/day hot flushes) arecombination the most common debilitating. 80%in ofawomen Western countries suffer hot flashes, 30% to Flax lignans(also inhibit the enzyme 5AR, thus balancing formation ofand the potentially maleand hormones that are Nearly responsible for hair lossin 1995). Flax lignans are converted bywith the body reporting hot flasheswith severe and frequent enough tofor seriously affect quality life [3].sex hormone binding globulin (SHBG), resulting in lower levels of free (ie active) group received 2000 mg/day of the supplement for 14 days. ANOVA-RM showed enterolactones, which compete estrogen and testosterone receptor binding, and of increase significant within-group increases in serum testeosterone significant estrogen and testosterone. Flaxseed has been shown total to reduce serum levelsand of 17-beta-estradiol and estrone sulfate (Hutchins 2001), and results in a shift in estrogen metabolism to Ingredients Per Capsule HT isserum considered thefrom most baseline effective medical treatment option(P=0.05). for relief of hot flashesMedicinal and other menopausal symptoms [4]. However, HT isDose currently recommended decreases in DHT in both dose groups There favor the less biologically active estrogens (Brooks 2004). only for moderate to severe vasomotor symptoms to potential risk of breast cancer, cardiovascular events and other unwanted side effects [1]. The was no significant difference between dose groups withdue regard to the increased increase of (Trigonella foenum graecum) North American Menopause Society recommends using the lowest possible dose forFenugreek the shortest duration possible [3]. The Society for Obstetricians Fenugreek 260 mg and testeosterone or the decrease of DHT; therefore both doses were effective (Angwafor seed extract 4:1 Gynaegologists of Canada as also recommends using the lowest effective dose for HT [2]. Women with a history of as cardiovascular events, venous Fenugreek has been used traditionally an oral and topical treatment for hair loss. Plant sterols contained in fenugreek such -sitosterol have been shownthromboembolism, to block DHT 2008). breast or uterine cancer, or liver disease, should not use estrogen to alleviate vasomotor symptoms [1]. receptor sites (Prager 2002, see below).

Saw palmetto berry extract containing

160 mg

Another study tested liposterolic extract of therapies, Serenoa phytoestrogens repens (LSESr)areand beta-popular45% free fatty acids Among theproduct) natural non-pharmalogical the most and the most studied category. Phytoestrogens are plant substances found in Saw Palmetto (men’s sitosterol inextract the of males of possess age)resulting with mild to moderate AGA. soy, redtreatment clover, flax, hops, (23-64 andofothers, that weak activity by binding estrogen (ER). However, systematic review ofAGA, literature foundwith Saw palmetto is a potent inhibitor 5 years -reductase, inestrogenic decreased tissue DHT (Pragerto2002). In areceptors pilot study of 26 men with mild to moderate treatment Flax standardized toblinded 20% such as isoflavones, lignans, and have, atsymptoms best, onlylignans, modest in scored ameliorating menopausal symptoms [5-7]. In a meta Six of 10that (60%) subjectssaw were rated asextract improved at and the beta-sitosterol final8-prenylnaringenin visit, thus50mg establishing a combination ofphytoestrogens lipophilic palmetto 200mg improved by up to effect 60%, as by assessors (Prager 2002). 100 mg diglucoside the effectiveness of 5α-reductase inhibitors AGA (Prager 2002). Chronic analysis by the Cochrane group, saw palmetto hasagainst also been found to be effective as a treatment secoisolariciresinol for symptoms of BPH (Wilt 2002). (SDG) Sinceof 1993, a special phytoestrogen the root offactor Siberian inflammation the hair follicle is consideredextract to be from a contributing for rhubarb AGA. A(Rheum rhaponticum) known in scientific literature as ERr 731™ has been pantothenate (Vitamin mg R. recommended by healthcare practitioners in Germany for menopausal hot flashes andD-calcium related complaints [8]. Unlike Chinese B5) rhubarb (e.g.,10.40 R. palmatum, Silica (women’s product) study by Chittur et al sought to determine whether blockade of inflammation using officinale) orthat other rhubarb species that contain strong laxativesinanthraquinones, the(Barel main constituents of ERr 731 are hydroxystilbenes, Silica is a and trace mineral hasmedicinal been found to increase hydroxyproline concentration connective tissue 2005). In a randomized, double blind, placeboincluding controlled study, 50 LSESr two anti-inflammatory agents (carnitine and thioctic acid) could alter Niacinamide (Vitamin B3) 10.25 desoxyrhaponticin, rhapontigenin, and desoxyrhapontigenin [8]. They to be The agonists of estrogen and do notmg display ERαanalog women withrhaponticin, damaged skin weremarkers treated orally with 10mg silica as orthosilicic acid (OSA) dailyare forfound 20 weeks. treatment group receptor reported βa (ERβ) significant decrease in visual the expression of molecular of inflammation (Chittur 2009). It was found endometrial tissue in laboratory [9]. ERβ activation is involved in the estradiol-mediated reduction hot brittle flasheshair [10]. In tissues that express blind, placebo controlled trial conducted in 50 womenofwith found that 10mg silica asboth OSA scale ratingsactivity of hair in brittleness (Barel 2005). A second studies randomized, double Pyridoxine HCl (Vitamin B6) 2 mg that the combination suppressed lipopolysaccharide-activated gene expression of and ERβ, improved ERβ acts as a negative ofand ERαdiameter and offers protection against 2007). ERα-mediated effects in the breast and endometrium [11, 12]. for 9 monthsERα significantly hair elasticity,regulator breakage, (thickness) (Wickett chemokines associated with pathways involved in inflammation and apoptosis.

Riboflavin (Vitamin B2)

1.58 mg

Clinical trials have that 1 tablet (4 mg) daily of ERr 731 offers effective relief for common menopausal symptoms, including hot flashes [8, 10, 13study thatdemonstrated 5-alpha inhibitors in combination withmetabolism. B The vitamins are concluded support healthy cell growthreductase and division, and facilitate optimal hormone For example, in a multicenter, trial in which 112 perimenopausal women with menopausal symptoms received either 1 blockade 15]. of inflammatory processes couldrandomized, represent a placebo-controlled new two-pronged clinical approach Folic acid 0.095 mg tablet of of ERr 731capsule (n=56)in orboth placebo weeks, ERr 731 treatment compared with placebo treatment resulted in [15]: Medicinal ingredients per the (n=56) men’s for and12 women’s: in the treatment AGA. • A significant reduction of the Menopause Rating Scale (MRS) total score and in each individual MRS item score Fenugreek (Trigonella foenum graecum) seed extract 4:1 ....................................................260 mg Biotin 400 mcg •equiv A significant reduction in the number of hot flashes, from an average of 12 per day at baseline to 2.8 ±2.8 (mean ± SE) per day at 12 weeks 1040mg) Fenugreek (dry Seeds • A significant reduction in the hot flash weekly weighted score Flax lignans, standardized to 5% 50%to SDG ...............................................................................100 mg Non-Medicinal Ingredients Fenugreek seeds contain 30% protein, steroid saponins, sterols, flavonoids d-calcium pantothenate (Vitamin B5) ..................................................................................10.4 mg and alkaloids (notablyclinical trigonelline andsubjects choline). Steroid saponins bind and women reported continued symptom reduction to help improve quality of life In a long-term study with taking ERr 731 for up to 24 months, Niacinamide (Vitamin B3) ...................................................................................................10.3 mg Inert microcrystalline cellulose and vegetable-based magnesium eliminateHCl extra cholesterol and negative hormones in and thesleep body; DHT is [10]. made from mg through reduced mood, disturbances Pyridoxine (Vitamin B6)anxiety, ...............................................................................................2.0 stearate in a veggie-based capsule testosterone, which is in turn is made from cholesterol. Therefore, when excess Riboflavin (Vitamin B2) .......................................................................................................1.6 mg Data from these clinical trials also show that ERr 731 is well tolerated; no ERr 731-related adverse events are observed. [8, 10, 13-15] is eliminated, less DHT can be made (Stark 1993). In a study of 20 cholesterol Folic acid ..............................................................................................................................95 mcg Recommended adult dose: One capsule per day adults....................................................................................................................................250 who consumed 12.5g and 18.0g of germinated fenugreek seed powder for Biotin mcg ERrhigher 731, the active ingredient in Estrovera, is available to healthcare in North America, exclusively from Metagenics, Inc. one month, levels of consumption resulted in a significant reductionpractitioners in total Men’s also has: cholesterol and low-density lipoprotein (LDL) levels (Sowmya 1999). Saw palmetto berry extract 4:1 .............................................................................................125 mg 6. Lethaby AE, et al. Phytoestrogens for vasomotor menopausal symptoms. Estrovera ingredients (per 1 tablet) (dry equiv. 500 mg) Flax lignans Cochrane Database Syst Rev. 2007;(4):CD001395. Medicinal ingredient: Rhapontic Rhubarb 4 mg Flax reduceshas: the amount of DHT produced by reducing cholesterol levels in 7. the Clarkson TB, et al. The role of soy isoflavones in menopausal health: report of Women’s also(rheum rhaponticum root) ERr 731 body.(silicon A meta-analysis of 28 studies between 1990 and 2008 showed that flaxseed ThemgNorth American Menopause Society/Wulf H. Utian Translational Science Silicon dioxide) ........................................................................................................40 Non-Medicina ingredients: in Chicago, IL (October 2010). Menopause. 2011;18:732-753. significantly reduces circulating total andacid LDL-cholesterol concentrations (Pan Symposium Iron (ferric citrate) ................................................................................................................20 mg Microcrystalline cellulose, stearic 8. Heger M, et al. Efficacy and safety of a special extract of Rheum rhaponticum 2009). Flaxseed interventions reducedsodium, total and LDL cholesterol by 0.10 mmol/L (vegetable), croscarmellose silica, (ERr 731) in perimenopausal Recommended one coating capsule(deionized twice (60 capsules perCI: bottle). Bio-Fen® Plus capsules are usually effective women with climacteric complaints: a 12-week (95% CI: -0.20, 0.00 mmol/L) and daily 0.08water, mmol/L (95% -0.16, 0.00 mmol/L), anduse: enteric at respectively. stopping hair loss within the first two were months. Anyonewith experiencing new growth see it withindouble-blind, four months. placebo-controlled trial. Menopause. Significant reductions observed whole flaxseed (-0.21should and randomized, cellulose acetate phthalate, glycerol 2006;13(5):744-759. Once Bio-Fen is stopped, the hairand growth pattern will and slowly return to its original point, however some people may triacetate, ammonium hydroxide, -0.16 mmol/L, respectively) lignan (-0.28 -0.16 mmol/L, respectively) 9. Wober J, et al. Activation of estrogen receptor-beta by a special extract of besupplements able to continue with a lower maintenance hypromellose, maltodextrin, anddose. (Pan 2009). Rheum rhaponticum (ERr 731), its aglycones and structurally related polyethylene glycol). compounds. J Steroid Biochem Mol Biol. 2007;107(3-5):191-201. Bio-Fen has been approved by Health Canada and has received a unique NPN number. In addition to being approved 10.. Hasper I, et al. Long-term efficacy and safety of the special extract ERr 731 of for hair growth applications, Bio-Fen has been approved for additional health benefits Rheum rhaponticum in perimenopausal women with menopausal symptoms. References 2009;16(1):117-131. Angwafor F III, Anderson ML. An open label, dose response study to determine the effect of a Menopause. dietary supplement on dihydrotestosterone, testosterone and estradiol levels in healthy males. J 1. Nutr Nelson HD. Menopause. Lancet. 2008;371(9614):760Int Soc Sports 2008;5:12. 11. Frasorsafe J, etfor al. most Response-specific and ligand dose-dependent modulation of Contraindications: The ingredient combination in Bio-Fen Plus for Men/Women is generally adults. 770. estrogen receptor (ER) alpha activity aspects by ERbeta in the uterus. Endocrinology. Bio-Fen should not be used by patients with diabetes, or known hypersensitivity to any ingredients. Brzezińska-Wcisło L. Evaluation of vitamin B6 and calcium pantothenate effectiveness on hair growth from clinical and trichographic for treatment of diffuse alopecia in women. Wiad 2. Society of Obstetricians and Gynaecologists of Canada. 2003;144(7):3159-3166. Lek 2001;54:11-8. Canadian Consensus Conference on Menopause, 2006 12. Lindberg MK, et al. Estrogen receptor (ER)-beta reduces ERalpha-regulated References J Obstet Gynaecol Can. 2006;28:S1-S112. Chittur S, Parr B,Update. Marcovici G. Inhibition of inflammatory gene expression in keratinocytes using carnitine, and saw between palmetto ERalpha extract. Evid genea composition transcription,containing supporting a "yingthioctic yang" acid relationship andBased Brooks JD, et Am J Clin Nutr. 2004 Feb;79(2):318-25. Complement Alternat MedEM. 2009. 3. al. Umland Treatment strategies for reducing the ERbeta in mice. Mol Endocrinol. 2003;17(2):203-208. Evans BA, et al. 1995 Nov;147(2):295-302. burden of menopause-associated vasomotor symptoms. J effects of13. Kaszkin-Bettag M,blood et al.lipids. Efficacy the special extract ERr 731 from rhapontic Pan A, YuR.D,Clin Demark-Wahnefried W, Franco OH, Lin X. Meta-analysis of the flaxseed interventions on Am of J Clin Nutr 2009;90:288-97. Hoffmann Exp Dermatol. 2002 Jul;27(5):373-82. Manag Care Pharm. 2008;14(3 Suppl):14-19. rhubarb for menopausal complaints: a 6-month open observational study. Altern 2001;39(1):58-65. Hutchins AM,et al. Nutr Cancer. Prager N, Bickett K, French N, Marcovici G. A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the 4. North American Menopause Society. The 2012 hormone Ther Health Med. 2008;14(6):32-38. Prager N, etof al.androgenetic 2002 Apr;8(2):143-52. treatment alopecia.statement J Altern Complement MedAmerican 2002;8:143-52. therapy position of: The North 14. Kaszkin-Bettag M, et al. The special extract ERr 731 of the roots of Rheum Trüeb RM. Exp Gerontol. 2002Society. Aug-Sep;37(8-9):981-90. Menopause 2012;19(3):257-271. Serenoa repens monograph. Alternative Menopause. Medicine Review 1998;3:227-9. rhaponticum decreases anxiety and improves health state and general well-being Wickett RR,5.et al Arch Dermatol Res. 2007 Dec;299(10):499-505. Coon JT, et al. Trifolium pratense isoflavones in the in perimenopausal women. Menopause. 2007;14(2):270-283. Wilt T et al. Database Syst Rev. 2002;(3):CD001423. Sinclair R. Cochrane Male pattern androgenetic alopecia. 1998;317:865-9. treatment of menopausal hotBMJ flushes: a systematic review 15. Kaszkin-Bettag M, et al. Confirmation of the efficacy of ERr 731 in and meta-analysis. Phytomedicine. Sowmya P, Rajyalakshmi P. Hypocholesterolemic effect2007;14(2-3):153of germinated fenugreek seeds in human subjects. Plant Foods Hum 1999;53:359-65. perimenopausal women withNutr menopausal symptoms. Altern Ther Health Med. 159. 2009;15(1):24-34. Stark A, Madar Z. The effect of an ethanol extract derived from fenugreek (Trigonella foenum-graecum) on bile acid absorption and cholesterol levels in rats, Br J Nutr 1993;69:277-87.

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The Journal of IHP – Continuing Education successful completion of the questions at the end of this paper has been approved for continuing education by the bddt-n ; 1.0 credit nutritional medicine and by the cnpbc ; one ce hour.

What not to do Vitamin A and Beta Carotene Philip Rouchotas MSc, ND Integrated Healthcare Practitioners Editor-in-Chief philip@ihpmagazine.com Bolton Naturopathic Clinic 64 King St W, Bolton, Ontario L7E1C7 Heidi Fritz, MA, ND Research Fellow Canadian College of Naturopathic Medicine hfritz@ccnm.edu Bolton Naturopathic Clinic 64 King St W, Bolton, Ontario L7E1C7

Preclinical and observational evidence through the 1970’s, 80’s, and into the 90’s saw beta carotene and vitamin A emerge as agents of tremendous research interest; the two agents in isolation and in combination appeared to be capable of dramatically altering the course of chronic degenerative disease, most notably heart disease and cancer. The stage was set for large, long- term placebo- controlled human intervention trials. Outcomes of these trials however have proven to be among the greatest embarrassments of modern nutritional science. Vitamin A and beta carotene supplementation have been reproducibly demonstrated to deliver an array of detrimental outcomes including but not limited to increased all cause mortality, cancer incidence, and perinatal morbidity. Despite a well- developed evidencebase to this effect, harmful levels of vitamin A and beta carotene remain mainstay components of over- the- counter natural health product formulations, most notably multivitamins. We revisit the vitamin A and beta carotene story in hopes of having integrated healthcare providers become the leaders in a united voice against the widespread inclusion of vitamin A and beta carotene in products offered by the natural health products industry, and to remind our colleagues of the immensely strong evidencebase advocating the complete avoidance of these agents from their clinical practices. November/December 2012 l www.ihpmagazine.com 73

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Introduction Vitamin A (retinol) is a fat-soluble antioxidant and vitamin; and beta carotene is its primary plantderived precursor. Vitamin A has a long history of use as a pharmacologic agent, dating from the 1970s (Fritz 2011, Goodman 2008, Micksche 1977). Over the past 10-15 years, a large and complex body of evidence has accrued, which overwhelmingly indicates a range of specific harmful effects associated with supplementation of this nutrient; these effects range from increased risk of overall mortality, increased risk of lung cancer among high risk populations, poorer perinatal health outcomes among a group of African children, and possible adverse effects on bone (Bjelakovic 2008, Fritz 2011, McGrath 2006, Omenn 1996, Penniston 2006). While it may be difficult for some to conceive of harms associated with a naturally occurring, essential micronutrient, the quite substantial body of research that has reproducibly demonstrated these effects in large; well controlled RCTs among diverse populations increasingly makes this point irrefutable. The evidence can no longer be ignored: vitamin A and beta carotene are two single agents that deserve to be treated with a very high degree of caution with respect to nutrient supplementation. We argue that given the series of seriously harmful effects which have been clearly demonstrated, and considering the range of highly safe agents at our disposal, vitamin A and beta carotene are two substances that should never be utilized as a supplemental intervention in the course of a North American integrative healthcare practice. I. A Global Perspective Historically, vitamin A supplementation has been used in developing countries to prevent blindness due to rampant vitamin A deficiency. Vitamin A deficiency is considered to be a public health problem in 45 of 122 countries in these parts of the world, based on the prevalence of night blindness and biochemical vitamin A deficiency (serum retinol concentration <0.70 Âľmol/l) in preschoolage children (WHO 2009). A recent meta analysis published in the British Medical Journal including 43 trials found that vitamin A supplementation among impoverished children under the age of five significantly reduced the risk of mortality by 24% in 17 trials (rate ratio 0.76, 95% CI 0.69-0.83), and reduced the prevalence of vision problems including night blindness by 68% (RR0.32, 0.210.50) (Mayo-Wilson 2011).

Nonetheless, although this is undoubtedly a crucial therapy regionally, the generalizability of this practice to well nourished North American populations remains minimal. Among Western populations, vitamin A deficiency is virtually nonexistent, with the possible exceptions of select cases among very limited and specific subgroups such as patients who have undergone bariatric surgery or who are severely anorexic (Ballew 2001, Braunstein 2010, Fok 2012). In an excellent review of vitamin Aâ&#x20AC;&#x2122;s safety published in the American Journal of Clinical Nutrition, Penniston argues that hypervitaminosis A is a growing problem in Western populations, in part due to an increasing number of sources containing preformed vitamin A that have become a part of our diet (2006). These include many fortified sources: multivitamins, cod liver oil, and the fortification of common foods such as milk, butter, margarine, breakfast cereals, and some snack foods (Penniston 2006). II. A Historical Perspective In North America during the 1970s and 80s, observational and preclinical research findings sparked an interest in vitamin A as a potential anticancer agent (Kurata 1977, Salonen 1985, Smith 1972, Wald 1980). Studies emerged showing that individuals with higher blood levels of vitamin A and beta carotene (as well as other antioxidants) had a significantly lower risk of developing cancer, including lung cancer (Salonen 1985, Wald 1980). In preclinical models, vitamin A was shown to have antiproliferative effects on epithelial cells, and was able to prevent progression to lung cancer in animals exposed to carcinogens (Kurata 1977, Smith 1972). Early phase I and II trials were initiated investigating vitamin A as an adjunctive treatment for lung cancer, as well as head and neck cancers (Micksche 1977, Thatcher 1980). However, despite the promising early findings, intervention with various forms of vitamin A showed minimal benefits on lung cancer outcomes, based on five RCTS and 26 Phase I and II trials reviewed by Fritz et al (2011). As a result, further research in the area has not been pursued in recent years. In the 1990s, the focus of vitamin A and beta carotene research turned to their use as possible cancer preventive agents. To this end, two large chemoprevention trials were designed, the findings of which are discussed below. Today, vitamin A remains an agent that is sometimes utilized as a single agent or in combination formulas to

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stimulate immune function and as an anticancer agent; the appropriateness of such interventions will emerge from the following discussion of the evidence that has emerged over the past 20 years with respect to vitamin A and beta carotene. Pharmacology Vitamin A is also known as retinol or retinylpalmitate, which is the form that occurs in foods and is used in supplements; however the term is also used to encompass a number of retinoid derivatives, including all-trans-retinoic-acid (ATRA) and 13-cis-retinoic acid (Accutane) (Fritz 2011). Since the focus of this paper is on supplemental use of vitamin A, these pharmaceutical retinoids are not reviewed here. The body obtains vitamin A from two sources: preformed vitamin A, present in cod liver oil, butter, eggs, animal products, and fortified foods (ie. grain products), as well provitamin A carotenoids, most notably beta carotene but also inclusive of alpha carotene and beta cryptoxanthin, which are converted to retinol and retinyl esters in the body (Higdon 2009). It has been estimated that up to 88% of beta carotene is converted to retinyl esters in the intestinal wall, while up to 30% enters lymphatic circulation unchanged (Higdon 2009, Stahl 2005, Tang 2010). Beta carotene possesses singlet oxygen quenching activity, and administration has been shown to increase levels in lung epithelial tissue (Fiedor 2005, Obermueller-Jevic 2002, Patrick 2000). Thus beta carotene’s proposed anticancer effects were thought to be a result of its combined antioxidant activity and known concentration in the lungs. As a fat-soluble nutrient, vitamin A has long been recognized for its potential toxicity at higher dosages. According to Penniston, “daily intakes of >25,000 IU for >6 y and>100,000 IU for >6 mo are considered toxic, but there is wide interindividual variability for the lowest intake required to elicit toxicity” (2006). Classic toxicity symptoms include impaired liver function, with elevated liver enzymes, hypertriglyceridemia, skin rashes, dry eyes, myalgia, and headaches (Fritz 2011). Vitamin A is a recognized teratogen, and can cause congenital malformations such as spina bifida and cleft palate (Ackermans 2011). The Recommended Dietary Allowance for vitamin A in pregnancy is approximately 2500 IU (Higdon 2009). According to the Teratology Society, a balanced North American diet contains between 7000-8000 IU per day, and 8000 IU should be considered the safe upper limit for pregnancy (1987). Currently the upper limit for pregnancy as set by the Food and Nutrition Board

of the Institute of Medicine is 10,000 IU, however this includes both food and supplement sources (NIH 2012).The only known toxicity associated with beta carotene is an orange discoloration of the skin. III. A Scientific Perspective: The Evidence Vitamin A at a Glance: Cochrane Meta Analytic Review A 2008 Cochrane meta analysis combined data from 67 randomized trials assessing antioxidants, including 232,550 participants. Trials investigating any of vitamin A, vitamin C, vitamin E, beta carotene, and selenium were included. Among the studies assessing vitamin A and beta carotene, supplementation was associated with a significant increase in all cause mortality (death from any cause): (RR 1.16, 95% CI 1.10 to 1.24) and (RR 1.07, 95% CI 1.02 to 1.11) respectively (Bjelakovic 2008). Chemoprevention Trials Following upon the early studies of the 1970s and promising animal data, two large chemoprevention trials were conducted in the 90s to investigate the ability of vitamin A and/ or beta carotene to reduce risk of lung cancer among smokers and asbestos workers. The expected outcome was a reduction in risk due to supplementation with these antioxidants, which seemed to have an affinity for the lung epithelial tissue. The Carotene and Retinol Efficacy Trial (CARET) was a multicenter study conducted in the United States. A total of 18,314 smokers and asbestos workers were randomized to receive a combination of 25,000 IU retinyl palmitate plus 30mg beta carotene, or placebo, for four years (Omenn 1996). Instead of a decrease, however, there was a significant increase in the incidence of lung cancer, (RR 1.28; 95% CI 1.04-1.57). Subgroup analysis showed higher risk in asbestos workers (RR 1.40, 95% CI: 0.95–2.07), and current heavy smokers (RR 1.42, 95% CI: 1.07–1.87), while there was a non significant reduction in risk amongst smokers who had already quit at randomization (RR 0.80, 95% CI: 0.48–1.31) (Omenn 1996). Risk of death from all causes was increased 18% (RR 1.18, 95% CI: 1.02–1.37); death from lung cancer was increased 46% (RR 1.46, 95% CI 1.07–2.00); and death from cardiovascular disease was increased by 26% (RR 1.26, 95% CI 0.99–1.61) (Omenn 1996). There was no evidence of increased risk of other cancer types. In addition to the CARET trial, two smaller lung cancer prevention trials exist investigating retinyl palmitate; of these, one showed no significant effects November/December 2012 l www.ihpmagazine.com 75

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(Kamangar 2006), and one shows a reduction in risk of mesothelioma, an asbestos-related lung cancer (de Klerk 1998, Fritz 2011). This last study, the Western Perth Australia study, found a significantly reduced risk of mesothelioma associated with vitamin A supplementation (RR 0.24, 95% CI 0.07-0.86), however, its findings are hampered by an important limitation, namely the lack of a placebo- or inactive- control group (de Klerk 1998). Instead, the beta-carotene arm was used as the comparator. Since beta carotene has in fact been shown to be detrimental, it is quite likely that these apparently supportive findings are in fact falsely inflated. The Alpha Tocopherol Beta Carotene (ATBC) trial was a second large cancer prevention study conducted among Finnish male smokers. A total of 29,133 men were given either 20mg beta carotene, 50mg alpha tocopherol, both, or placebo for between 5-8 years. Investigators found that supplementation of 20mg beta carotene (in this case without vitamin A) increased incidence of lung cancers by 16% compared to those not receiving beta carotene, RR 1.16 (95% CI 1.02 – 1.33) (Albanes 1996). Conditional Pro-oxidant Theory To explain these unanticipated results, the conditional pro-oxidant theory was developed (Omenn 1998). Under certain circumstances, in particular situations of high oxidative stress, an antioxidant may act as a conditional pro-oxidant. It is well established in the field of chemistry that each ion possesses a relative redox potential, which determines whether it is reduced or oxidized in reaction with other substances. Similarly, a weak antioxidant may be oxidized by a stronger prooxidant or vice versa. The resultant new free radical may perpetuate the chain of oxidative damage on other targets. Carotenoids are particularly vulnerable to such oxidation due to their long chains of conjugated double bonds (Omenn 1998), and animal studies have since confirmed that in the presence of cigarette smoke, vitamin A and beta carotene do indeed act as pro-oxidants, with the potential for pro-carcinogenic effects in the body (van Helden 2009, Wang 1999). Although findings of the large CARET and ATBC trials have been the most influential, other chemoprevention trials investigating beta carotene

have also been conducted. A 2008 meta analysis of these confirmed the lack of benefit from beta carotene supplementation (Gallicchio 2008). Among studies comparing beta carotene supplements to placebo, the relative risk of cancer was 1.10 (95% CI 0.89 – 1.36). The six trials included in this review were: 1) the Carotene and Retinol Efficacy Trial (CARET) (Omenn 1996); 2) the Alpha Tocopherol Beta Carotene (ATBC) study (Albanes 1996); 3) the Physicians’ Health Study (PHS) (Cook 2000); 4) the Western Perth, Australia study (de Klerk 1998); 5) the Women’s Health Study (Lee 1999); 6) the Linxian General Population trial (Kamangar 2006). African HIV Studies When evaluating intervention trials with any nutritional agent, the concept of baseline status of the population must be taken into consideration. For example, supplementation among individuals on the brink of scurvy with vitamin C would be expected to deliver an important magnitude of benefit to an array of outcome measures, while the same intervention administered to a population of citrus farmers is far less likely to yield benefit, given the expectation that citrus farmers enjoy a relatively high dietary intake of the vitamin. HIV positive, pregnant women in Tanzania Africa were recruited and assigned to one of four groups; multivitamin, vitamin A (5000IU) and beta carotene (30mg), multivitamin free of vitamin A and beta carotene, and placebo. Outcomes were presented in a series of papers, following the women throughout their pregnancy, as well as following the resulting offspring until age 18 months (Fawzi 2004, McGrath 2006, Merchant 2005, Villamor 2002). The multivitamin free from vitamin A and beta carotene achieved significant benefit to the following outcomes relative to placebo; improved weight gain during pregnancy, reduced risk of low weight gain (<100g/wk) (Villamor 2002), reduced risk of progression to stage IV AIDS or reduced risk of death from AIDS related causes, reduced risk of the following AIDS- related complications (thrush, gingival erythema, angular cheilitis, oral

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The Journal of IHP – Continuing Education

ulcer, reported mouth and throat ulcer, painful tongue and mouth, difficult or painful swallowing, nausea and vomiting, dysentery, fatigue, rash, and acute URTI), increased CD4+ counts, reduced viral load (Fawzi 2004), reduced risk of development of hypertension during pregnancy (Merchant 2005), improved psychomotor development index score in resulting offspring, and reduced risk of developmental delay on the motor scale (McGrath 2006). The multivitamin containing vitamin A and beta carotene achieved significant benefit to the following outcomes relative to placebo; improved weight gain during pregnancy, reduced risk of low weight gain (<100g/wk) (Villamor 2002), reduced risk of the following AIDS- related complications (thrush, angular cheilitis, rash) (Fawzi 2004), reduced risk of development of hypertension during pregnancy (Merchant 2005), and improved the psychomotor development index score in resulting offspring (McGrath 2006). Vitamin A and beta carotene supplementation on their own produced no outcomes significantly different from placebo. The authors highlight that the relative magnitude of benefit for outcomes impacted by multivitamins with or without vitamin A and beta carotene was greater across the board for the group receiving the multi free from vitamin A and beta carotene. Also, as described above, the multi free from vitamin A and beta carotene achieved benefit to a far broader and clinically relevant range of outcomes relative to the group receiving a multi containing vitamin A and beta carotene. Although not indicated by the data of the trial, one may make the stretch to suggest that it is as though the inclusion of vitamin A and beta carotene in the multi reversed the benefit expected from delivery of a multi to this malnourished population. The team followed this trial up with a trial among 8468 pregnant, HIV- negative women in Tanzania, Africa. In this follow- up trial, subjects were assigned to one of two groups; placebo or multi free of vitamin A and beta carotene. It was deemed unethical to include a group that received vitamin A and beta carotene (Fawzi 2007). If vitamin A and beta carotene are incapable of materially benefiting this obviously malnourished population, what benefit can possibly be hoped for when supplementing relatively well- nourished, freeliving North American populations? Potential Bone Toxicity Penniston has outlined the somewhat weaker but still important evidence suggesting that high intake

of preformed vitamin A may be associated with poorer bone health, in particular osteoporosis (2006). In human observational studies, higher intake of preformed vitamin A has been associated with increased risk of osteoporosis, up to three fold greater compared to those with the lowest levels of serum retinol (MataGranados 2010). Increased vitamin A intake has also been associated with increased risk of hip and wrist fracture (Opotowsky2004, White 2006). In animal studies, feeding a retinoic acid enriched diet compared to a standard diet resulted in significantly lower bone mineral content and bone mineral density after two and four weeks (Hotchkiss 2006, Xue 2011). Yet other studies have found no significant effects in animals or humans (Ambrosini 2012, Wray 2011). Although the evidence in this area is not yet conclusive, it is an important topic to follow and be aware of. Biomarker Hypothesis Intervention trials have established a very strong case against supplementation with vitamin A and/ or beta carotene. However, a very large body of observational evidence has, and continues to show that determination of dietary beta carotene intake, through food frequency questionnaire or through determination of plasma beta carotene levels, positively and powerfully predicts reduced risk of heart disease and cancer. What explains the apparent discrepancy between expected benefit from elevating plasma beta carotene levels as demonstrated through observational evidence to the detriment witnessed from supplementation with beta carotene? One must take into account the concept of biomarker. The very nature of observational evidence is that it does not include an intervention. When beta carotene intake is estimated, or better yet, when plasma beta carotene levels are determined, where is the beta carotene coming from? It is most certainly not coming from supplementation. Hindsight has taught us that plasma beta carotene is the single best available biomarker of exposure to fruit and vegetables. It is erroneous to conclude “plasma beta carotene of X reduced risk of chronic disease”. It is far more appropriate to conclude “fruit and vegetable consumption of X, objectively confirmed by assessment of plasma beta carotene, protected against risk of chronic degenerative disease”. A landmark investigation, the BASEL study, prospectively followed 4858 men for 12 years. Participants were divided into quintiles based on baseline determination of plasma beta carotene. November/December 2012 l www.ihpmagazine.com 77

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Individuals in the lowest quintile of plasma beta carotene were found to be at a 49% elevated risk of developing cancer (Stahelin 1991). Similarly, 1720 men were divided into quartiles based on baseline determination of plasma beta carotene. Individuals in the highest quartile were found to be at a 48% reduced risk of all cause mortality and a 43% reduced risk of death from cardiovascular disease (Greenberg 1996). The above observational study also included an intervention arm; across each quartile, subjects were randomized to receive a beta carotene supplement or placebo. As could be anticipated, individuals in the highest quartile of baseline plasma beta carotene received no benefit from the intervention. Surprisingly, yet completely in- line with the biomarker hypothesis of plasma beta carotene status, subjects in the lowest quartile of baseline plasma beta carotene also achieved no benefit from intervention with a beta carotene supplement (Greenberg 1996). Hindsight has indeed proven 20/20. The community of nutritional scientists as a whole has recognized the importance of plasma beta carotene as an accurate marker of fruit and vegetable consumption, and likewise recognized its lack of importance as a “nutrient unto itself” for impact to risk of chronic degenerative

disease. Modern observational trials demonstrating beta carotene as protective against chronic degenerative disease conclude that their outcomes strengthen recommendations for the public to consume more fruit and vegetables (Hak 2004). Modern intervention trials that include dietary modification as part of the intervention utilize determination of plasma beta carotene to assess compliance; if participants comply with recommendations for increased consumption of fruit and vegetables, plasma beta carotene of the intervention group is elevated relative to the control group (Pierce 2007, vanBreda 2004).

References

de Klerk NH, Musk AW, Ambrosini GL, Eccles JL, Hansen J, Olsen N, Watts VL, Lund HG, Pang SC, Beilby J, Hobbs MS. Vitamin A and cancer prevention II:comparison of the effects of retinol and betacarotene. Int J Cancer. 1998 Jan30;75(3):362-7.

Ackermans MM, Zhou H, Carels CE, Wagener FA, Von den Hoff JW. Vitamin A and clefting: putative biological mechanisms. Nutr Rev. 2011 Oct;69(10):613-24. Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti M, Hartman AM, Palmgren J, Freedman LS, Haapakoski J, Barrett MJ, Pietinen P, Malila N, Tala E, Liippo K, Salomaa ER, Tangrea JA, Teppo L, Askin FB, Taskinen E, Erozan Y, Greenwald P, Huttunen JK. Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, betacarotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst. 1996 Nov 6;88(21):1560-70. Ambrosini GL, Bremner AP, Reid A, Mackerras D, Alfonso H, Olsen NJ, Musk AW, de Klerk NH. No dose-dependent increase in fracture risk after long-term exposure to high doses of retinol or beta-carotene. Osteoporos Int. 2012 Sep 18. [Epub ahead of print] Ballew C, Bowman BA, Sowell AL, Gillespie C. Serum retinol distributions in residents of the United States: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. 2001 Mar;73(3):586-93.

Conclusion Over the past 20 years, an eloquent and well developed body of research has emerged that clearly delineates the detrimental effects associated with the use of supplemental vitamin A and beta carotene. Concrete harm has been reproducibly documented with respect to a number of important clinical outcomes, including all cause mortality, cancer incidence, perinatal morbidity, and potentially bone density. Given the range of safe and effective interventions available, we recommend against the routine use of vitamin A and beta carotene in North American integrative healthcare practice. ■

Fawzi WW, Msamanga GI, Spiegelman D, Wei R, Kapiga S, Villamor E, Mwakagile D, Mugusi F, Hertzmark E, Essex M, Hunter DJ. A randomized trial of multivitamin supplements and HIV disease progression and mortality. N Engl J Med. 2004 Jul 1;351(1):23-32. Fawzi WW, Msamanga GI, Urassa W, Hertzmark E, Petraro P, Willett WC, Spiegelman D. Vitamins and perinatal outcomes among HIV-negative women in Tanzania. N Engl J Med. 2007 Apr 5;356(14):1423-31. Fiedor J, Fiedor L, Haessner R, Scheer H. Cyclic endoperoxides of beta-carotene, potential pro-oxidants, as products of chemical quenching of singlet oxygen. BiochimBiophysActa. 2005 Aug 15;1709(1):1-4. Fok JS, Li JY, Yong TY. Visual deterioration caused by vitamin A deficiency in patients after bariatric surgery. Eat Weight Disord. 2012 Jun;17(2):e144-6.

Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2012 Mar 14;3:CD007176.

Fritz H, Kennedy D, Fergusson D, Fernandes R, Doucette S, Cooley K, Seely A, Sagar S, Wong R, Seely D. Vitamin A and retinoid derivatives for lung cancer: a systematic review and meta analysis. PLoS One. 2011;6(6):e21107.

Braunstein A, Trief D, Wang NK, Chang S, Tsang SH. Vitamin A deficiency in New York City. Lancet. 2010 Jul 24;376(9737):267.

Goodman GE, Alberts DS, Meyskens FL. Retinol, vitamins, and cancer prevention:25 years of learning and relearning. J ClinOncol. 2008 Dec 1;26(34):5495-6.

Cook NR, Le IM, Manson JE, Buring JE, Hennekens CH. Effects of beta-carotene supplementation on cancer incidence by baseline characteristics in the Physicians’ Health Study (United States). Cancer Causes Control. 2000 Aug;11(7):617-26.

Greenberg ER, Baron JA, Karagas MR, Stukel TA, Nierenberg DW, Stevens MM, Mandel JS, Haile RW. Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation. JAMA. 1996;275(9):699-703.

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Questions 1. Which of the following is true about vitamin A or beta carotene? a) Vitamin A has a long history of use as a pharmacologic agent, dating from the 1970s b) Vitamin A can cause congenital malformations such as spina bifida and cleft palate c) Beta carotene is particularly vulnerable to oxidation damage due to its long chains of conjugated double bonds d) All of the above 2. The RDA for vitamin A in pregnancy can easily be obtained from food. It is: 1) 1000 IU 2) 2500 IU 3) 10,000 IU 4) 25,000 IU 3. Penniston (2006) writes that daily intakes of vitamin A greater than 25,000 IU for six years and greater than 100,000 IU for six months are considered toxic, but that â&#x20AC;&#x153;there is wide interindividual variability for the lowest intake required to elicit toxicity.â&#x20AC;? This means for some individuals, toxicity is elicited at even lower dosages and this threshold would be difficult to predict. a) True b) False 4. Vitamin A deficiency is a problem for pre-school children in impoverished nations. In this population, vitamin A deficiency contributes to vision problems and night blindness. In Western populations however, vitamin A and beta carotene supplementation have been associated with which of the following: a) increased risk of all cause mortality b) decreased risk of lung cancer c) decreased risk of cardiovascular disease d) all of the above 5. The CARET study administered vitamin A and beta carotene to male smokers and asbestos workers. After 4 years, investigators found which of the following: a) 16% increased risk of lung cancer b) 28% increased risk of lung cancer c) 16% increased risk of a fatal heart attack d) 28% increased risk of a fatal heart attack

6. In retrospect, scientists have proposed vitamin A/ beta carotene as conditional pro-oxidants. This means that in the presence of a strong oxidizing agent such as cigarette smoke, vitamin A and beta carotene may react andbecome themselves pro-oxidants, with the potential to act as carcinogens. a) True b) False 7. In a large study of HIV positive pregnant women and their children conducted in Africa, a multivitamin free of vitamin A and beta carotene outperformed both placebo and the regular multivitamin containing vitamin A/ beta carotene. In a followup trial by the same researchers, subjects were assigned to one of two groups only; placebo or multi free of vitamin A and beta carotene. It was deemed unethical to include a group that received vitamin A and beta carotene. a) True b) False 8. Observational human evidence has suggested that which of the following may be associated with higher vitamin A intake? a) Synergy with vitamin D b) Risk of bone fracture and osteoporosis c) Lower risk of acne d) All of the above 9. In the early studies, blood levels of beta carotene were associated with dramatically reduced risk of which of the following chronic diseases? a) cancer b) cardiovascular disease c) a and b d) none of the above 10. One of the most important roles of beta carotene today in nutritional sciences is its use as a biomarker. Beta carotene levels in the blood are representative of total dietary fruit and vegetable intake, and serum beta carotene is used as a marker of compliance with such a prescribed diet. a) True b) False

Fax or email answers to: 416.703.6392 or philip@ihpmagazine.com Name: Address: City: Province: Postal Code: Phone: Email: Fax: Practice Registration #:

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PRODUCT MONOGRAPH

fast joint care+

Introduction fast joint care+ by Genuine Health is a novel, rapidly acting formulation designed to help alleviate joint pain and stiffness. fast joint care+ is a patented ingredient containing naturally occurring combination of molecules derived from natural eggshell membrane (NEM), Gallus gallus. These molecules include fibrous proteins such as collagen type I, glycosaminoglycans (GAGs) such as chondroitin sulfate and dermatan sulfate, sulftated glycoproteins such as glucosamine, hyaluronic acid, and a host of other related proteins (Ruff 2009a). fast joint care+ is unique as a joint care product. Unlike the most commonly used medications for the condition, such as NSAIDs, NEM is a disease-modifying agent, meaning that it not only improves the symptoms of arthritis but also helps repair damaged tissue. NSAIDs carry significant risks, such as development of peptic ulcer disease, renal failure, and hemorrhage; this underscores the importance of developing safe treatment alternatives (Vangsness 2009). Unlike the natural alternatives glucosamine and chondroitin sulfate that can take several weeks to act, NEM works within 7-10 days. New research now indicates that fast joint care+ is also an effective treatment for non arthritic joint pain and fibromyalgia. Osteoarthritis Osteoarthritis (OA) is the most common musculoskeletal condition in Westernized countries; approximately 27 million Americans are estimated to be clinically diagnosed with OA, while upwards of 46 million are thought to be affected by arthritis as a non-specific category (Vangsness 2009, Lawrence 2008, Theis 2007). The impact of OA includes pain, loss of function and mobility, physical and psychosocial disability, complications of NSAID therapy, and financial costs to the healthcare system. Direct average annual per person medical expenditures due to arthritis ranged from $1454- 2206 (Theis 2007). Two initial pilot studies involving 11 and 26 subjects respectively with pre-existing joint disorders found significant reductions in joint pain, joint stiffness, and pain on range of motion (ROM) compared to baseline (Ruff 2009a). After 7 days there was a 25% reduction in pain, while at 30 days there was a 51% reduction. At 30 days, there was a 43% improvement in flexibility. Nearly 50% of the patients reported being pain free after 1 month. A more rigorous, double blinded RCT involving 67 subjects with osteoarthritis found similar effects. NEM was given at 500 mg per day for 2 months. Researchers found significant improvements in pain and stiffness as graded by WOMAC (a clinically relevant OA assessment tool) both at 10 days and at 60 days. After 10 days, 54% of subjects in the treatment group had a 20-30% reduction in pain, compared to 24% in the placebo group; at 60 days, 32% vs 12% had ≥50% reduction in pain. Similar findings were demonstrated for stiffness, with 25% reduction at 10 days, and 53% at 60 days. (Ruff 2009b) Non Arthritic Joint Pain In addition to studies on NEM, fast joint care+ as a whole has been specifically assessed in subjects with non arthritic joint pain. In a randomized study, 60 unmedicated subjects with chronic (but non-arthritic) joint pain were given either 500mg of fast joint care+ or placebo for one month. Those in the fast joint care+ group reported a reduction in post-exercise pain ratings, with four times less pain than the placebo group (Berardi, unpublished data). This exciting finding shows that fast joint care+ is an effective therapy for those “weekend warriors” suffering from joint pain, and not exclusively for those suffering from osteoarthritis. Fibromyalgia An open-label pilot study supervised by Toronto area fibromyalgia specialist Alison Bested, MD investigated the effects of 500mg of fast joint care+ among 15 patients when given daily for eight weeks. Outcomes were measured using the Fibromyalgia Impact Questionnaire (FIQ) and Brief Pain Inventory (BPI) scales before and at the conclusion of the study. Results showed that fast joint care+ significantly improved sleep, pain while working (i.e. performing activities), and overall pain ratings in FM. “Enjoyment of Life”, “Everyday Work” and “Missed Work” scales also trended towards improvement (Bested, unpublished data) Recommended Use 500 mg or one capsule per day. Contraindicated in persons with allergy to egg or egg products. No known adverse effects. References Berardi J. Egg Shell Membrane Reduces Joint Pain. Unpublished data. Bested A. Summary of a pilot, open-label, study of eggshell membrane (fast joint care+) in fibromyalgia patients. Completed April 2012. Unpublished data. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, Gabriel S, Hirsch R, Hochberg MC, Hunder GG, Jordan JM, Katz JN, Kremers HM, Wolfe F; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008 Jan;58(1):26-35. Ruff KJ, Winkler A, Jackson RW, DeVore DP, Ritz BW. Eggshell membrane in the treatment of pain and stiffness from osteoarthritis of the knee: a randomized, multicenter, double-blind, placebo-controlled clinical study. Clin Rheumatol. 2009 Aug;28(8):907-14. Ruff KJ, DeVore DP, Leu MD, Robinson MA. Eggshell membrane: a possible new natural therapeutic for joint and connective tissue disorders. Results from two open-label human clinical studies. Clin Interv Aging. 2009;4:235-40. Theis KA, Helmick CG, Hootman JM.Arthritis burden and impact are greater among U.S. women than men: intervention opportunities.J Womens Health (Larchmt). 2007 May;16(4):441-53. Vangsness CT Jr, Spiker W, Erickson J. A review of evidence-based medicine for glucosamine and chondroitin sulfate use in knee osteoarthritis. Arthroscopy. 2009 Jan;25(1):86-94.

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Adrenal SAP PRODUCT MONOGRAPH

THE ADRENAL GLAND AND ITS ROLE IN THE BODY

The adrenal glands produce hormones involved in mediating the stress response (epinephrine, norepinephrine, and cortisol), immunity (cortisol), reproduction (including estrogen and testosterone), and blood pressure control (aldosterone).(2) They are a key component of the hypothalamic-pituitary-adrenal (HPA) axis, a complex hormone feedback system between the brain and the adrenal glands that controls the stress response and regulates many body processes including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure.(3) The adrenal glands are also involved in the sympatho-adrenal axis, secreting acetylcholine in response to acute stressors to initiate the sympathetic “fight or flight response”.

ADAPTOGENIC HERBS INCREASE THE BODY’S ABILITY TO WITHSTAND ACUTE AND CHRONIC STRESS

An adaptogen is defined as a substance that increases bodily resistance to noxious agents or factors, has a normalizing influence on a pathological state, and increases the ability of an organism to adapt to and avoid damage from environmental factors.(3) The beneficial effects of multidose administration of adaptogens are mainly associated with their effects on the HPA axis via balancing the releases of adrenaline, corticosteroids, and nitric oxide.(3) Conversely, a single dose can mediate the sympatho-adrenal system, providing a rapid response to control the acute reaction to a stressor by dampening the spike in catecholamines, neuropeptides, ATP, nitric oxide, and eicosanoids.(3)

ADRENAL FATIGUE

that it possesses antioxidant, antimicrobial, anti-inflammatory, anthelmintic and radioprotective activities.(12) It has also been shown to lower serum cortisol concentrations and diminish the negative effects of noise stress in a rat model.(13)

Licorice (Glycyrrhiza glabra)

Licorice has been valued for its antimicrobial, anti-inflammatory, lipid-lowering, and antiulcerogenic effects. Seven-day supplementation at a dose of 150 mg/kg in mice was shown to enhance memory and learning capacity and significantly reverse pharmaceutically induced amnesia.(14) This herb has also demonstrated antidepressant effects in mice, comparable to treatment with imipramine (15 mg/kg i.p.) and fluoxetine (20 mg/kg i.p.) via an increase in norepinephrine and dopamine.(15) In addition, Glycirrhiza acts on the adrenal-pituitary-kidney axis to stimulate the release of renin and raise blood pressure.(16)

Schizandra (Schizandra chinensis)

Schizandra is an important herb in traditional Chinese medicine, and has been used as a kidney tonifier to relieve mental strain.(17) In a double-blind, placebo-controlled study of athletes, an extract of schizandra supplemented prior to heavy physical exercise significantly increased performance, and prevented the rise in salivary nitric oxide and cortisol that was observed in the placebo group.(18) This herb has also been shown to be hepatoprotective in mice via enhancement of mitochondrial glutathione status and induction of heat shock proteins which protects against TNF-α-induced apoptosis of liver cells.(19)

Trace Minerals: Magnesium and Zinc

Dysfunction of the HPA axis has been shown to produce clinical symptoms of profound fatigue, unrefreshing sleep, postexertional malaise, headaches, and impaired memory and concentration.(4) A study demonstrated that chronic unpredictable stress (CUS) results in significant depletion of dopamine (DA), noradrenaline (NA), and 5-hydroxytryptophan (5-HTP) in the hippocampus, in contrast to the sharp increase of these monoamines that occurs when subjected to an acute stressor.(5) The paradoxical decrease in monoamine level in CUS can partly be explained on the basis of increased stress sensitization and their preferential and higher utilization during severe stressful conditions,(6) and supports the theory that long-term stress causes eventual “burnout” of the adrenal gland.

Magnesium is an especially important cofactor in energy production, and has important roles in pH balance and body temperature homeostasis.(20) Supplementation of this mineral in pigs improves ability to handle long-term stress.(21)

BOTANICAL AND NUTRITIONAL SUPPORT FOR ADRENAL FUNCTION

Vitamin B6 is involved in more bodily functions than almost any other single nutrient. It is required for normal nervous system function, in the synthesis of RNA and DNA, and aids in maintaining sodium and potassium balance.(18)

Siberian ginseng (Eleutherococcus senticosus)

Eleutherococcus has historically been used as a tonic during periods of recovery from surgery and convalescence, and recent research has demonstrated that it increases aerobic metabolism of tissues to facilitate tissue repair.(6) A study of 50 volunteers of both sexes was conducted to examine the effects of an Eleutherococcus extract on immune function and physical fitness. After 30 days of supplementation, researchers documented an increased rate of blastic transformation of lymphocytes, greater maximal oxygen uptake (VO2 max, an indicator of cardiorespiratory endurance), and reduced serum total cholesterol, LDL cholesterol, and triglyceride levels.(7) Even a single dose of this herb results in increased mental performance and physical working capacity, without any of the side effects commonly associated with pharmacological stimulants including addiction, tolerance, abuse potential, disordered sleep, and rebound hypersomnolence.(3)

Panax ginseng (Panax quinquefolium)

Panax species have had widespread use as a general tonic in Southern Asia for more than 5000 years, and are believed to promote health and longevity. Recent research shows that the ginsenosides in this herb are effective in normalizing the negative effects seen with chronic stress in mice: elevated plasma cortisol, increased levels of the proinflammatory cytokines IL2 and IL6, and depletion of noradrenaline, dopamine, and 5-hydroxytryptophan in the hippocampus.(5)

Astragalus (Astragalus membranaceous)

Astragalus is a well-known herb in traditional Chinese medicine, and the saponins from this plant demonstrate significant lymphocyte proliferation and immunostimulatory activities.(8) In a study on diabetic mice, the polysaccharides were shown to enhance the adaptive capacity of the hepatic endoplasmic reticulum, improving insulin sensitivity, and lowering blood glucose.(9)

Ashwaghanda (Withania somnifera)

Ashwanghanda is an adaptogen that has been used in Ayurvedic practice for more than 2500 years.(10) One of the main detrimental effects of chronic stress is immunosuppression.(11) Withania administered orally to chronically stressed mice significantly reversed T-cell depletion and increased the expression of Th1 cytokines.(11) In a rat model of long-term stress, an extract of this herb attenuated symptoms of glucose intolerance, gastric ulcerations, male sexual dysfunction, cognitive deficits, immunosuppression, and mental depression that were seen in control animals.(10)

Holy Basil (Ocimum sanctum)

Holy basil is another important herb in Ayurvedic medicine, and research has shown

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Zinc is highly concentrated in the adrenal glands and has structural, enzymatic and regulatory actions. It is required for adrenal hormone production and is depleted during periods of stress.(22)

B Vitamins

Vitamin B5, known as the “antistress vitamin,” plays a role in the production of adrenal gland hormones and is required for their proper functioning.(20)

Vitamin C (Ascorbic Acid)

Vitamin C is highly concentrated in the adrenal gland, where it functions as an antioxidant.(23) It is released in response to adrenocorticotropic hormone (ACTH), which is then followed by a decrease in adrenal cholesterol levels, suggesting the role of ascorbate in steroidogenesis.(24) It has been elucidated that vitamin C acts as an auxiliary electron donor in the aldosterone formation system.(23) In a swine model, vitamin C supplementation improved coping ability in response to chronic stress.(21)

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

Sigurjonsdottir, H.A., et al. “Is blood pressure commonly raised by moderate consumption of liquorice?”. Journal of Human Hypertension 9, No. 5 (1995): 345–348. Meletis, C.D. and W.A. Centrone. “Adrenal fatigue: Enhancing quality of life for patients with a functional disorder”. Alternative and Complementary Therapies 8, No. 5 (2002): 267–272. Panossian, A. and H. Wagner. “Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose administration”. Phytotherapy Research 19, No. 10 (2005): 819–838. Van Den Eede, F., et al. “Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome”. Neuropsychobiology 55, No. 2 (2007): 112–120. Rasheed, N., et al. “Involvement of monoamines and proinflammatory cytokines in mediating the anti‑stress effects of Panax quinquefolium”. Journal of Ethnopharmacology 117, No. 2 (2008): 257–262. Bleakney, T.L. “Deconstructing an adaptogen: Eleutherococcus senticosus”. Holistic Nursing Practice 22, No. 4 (2008): 220–224. Szołomicki, J., et al. “The influence of active components of Eleutherococcus senticosus on cellular defence and physical fitness in man”. Phytotherapy Research 14, No. 1 (2000): 30–35. Ragupathi, G., et al. “Evaluation of widely consumed botanicals as immunological adjuvants”. Vaccine 26, No. 37 (2008): 4860–4865. Mao, X., et al. “Astragalus polysaccharide reduces hepatic endoplasmic reticulum stress and restores glucose homeostasis in a diabetic KKAy mouse model”. Acta Pharmacologica Sinica 28, No. 12 (2007): 1947–1956. Bhattacharya, S. and A. Muruganandam. “Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress”. Pharmacology, Biochemistry, and Behavior 75, No. 3 (2003): 547–555. Khan, B., et al. “Augmentation and proliferation of T lymphocytes and Th‑1 cytokines by Withania somnifera in stressed mice”. International Immunopharmacology 6, No. 9 (2006): 1394–1403. Gupta, P., et al. “Constituents of Ocimum sanctum with antistress activity”. Journal of Natural Products 70, No. 9 (2007): 1410–1416. Archana, R. and A. Namasivayam. “A comparative study of different crude extracts of Ocimum sanctum on noise stress”. Phytotherapy Research 16, No. 6 (2002): 579–580. Dhingra, D., M. Parle, and S. Kulkarni. “Memory enhancing activity of Glycyrrhiza glabra in mice”. Journal of Ethnopharmacology 91, No. 2–3 (2004): 361–365. Dhingra, D. and A. Sharma. “Antidepressant‑like activity of Glycyrrhiza glabra L. in mouse models of immobility tests”. Progress in Neuro-Psychopharmacol & Biological Psychiatry 30, No. 3 (2006): 449–454. Al‑Qarawi, A.A., et al. “Liquorice (Glycyrrhiza glabra) and the adrenal‑kidney‑pituitary axis in rats”. Food Chemical Toxicology 40, No. 10 (2002): 1525–1527. Lu, Y., and D.F. Chen. “Analysis of Schisandra chinensis and Schisandra sphenanthera”. Journal of Chromatography A 1216, No. 11 (2009): 1980–1990. Panossian, A., et al. “Effects of heavy physical exercise and adaptogens on nitric oxide content in human saliva”. Phytomedicine 6, No. 1 (1999): 17–126. Tang, M., P. Chiu, and K. Ko. “Hepatoprotective action of schisandrin B against carbon tetrachloride toxicity was mediated by both enhancement of mitochondrial glutathione status and induction of heat shock proteins in mice”. Biofactors 19, No. 1–2 (2003): 33–42. Balch, P. Prescription for nutritional healing, Fourth Ed. New York, NY, USA: Penguin Group, 2006. Peeters, E., et al. “Influence of supplemental magnesium, tryptophan, vitamin C, and vitamin E on stress responses of pigs to vibration”. Journal of Animal Science 83, No. 7 (2005): 1568–1580. King, J.C. and C.L. Keen. “Zinc” in Modern Nutrition in Health and Disease, Ninth Ed. Shils, M.E., J.A. Olson, M. Shikne, and A.C. Ross, eds. Baltimore, MD, USA: Williams & Wilkins, (1999): pp. 223–240. Mitani, F., et al. “Ascorbate stimulates monooxygenase-dependent steroidogenesis in adrenal zona glomerulosa”. Biochemical and Biophysical Research Communications 338, No. 1 (2005): 483–490. Padayatty, S., et al. “Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone”. The American Journal of Clinical Nutrition 86, No. 1 (2007): 145–149.

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IHP 2012

Adrenal SAP Science-based nutrients for adrenal gland support

Stress is an unavoidable force to which the human organism is constantly exposed in both shortterm bursts and over extended periods of time. The body’s ability to withstand the damaging effects of stress is mediated primarily by the adrenal (aka suprarenal) glands: small, triangular glands located on top of the kidneys, that secrete hormones involved in blood-pressure regulation, reproduction, and the stress response. Excessive and prolonged mental and physical stress can lead to adrenal insufficiency and associated symptomatic manifestations including fatigue, immunosuppression, and impaired blood-sugar and blood-pressure control. Adrenal SAP is a combination of vitamins, minerals and adaptogenic herbs that support and strengthen the adrenal glands to improve adrenal function.

ACTIVE INGREDIENTS

Two (2) NON-GMO vegetable capsules contain: regular licorice-free Vitamin C (ascorbic acid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500 mg. . . . . . . . . . 500 mg Vitamin B5 (calcium pantothenate) . . . . . . . . . . . . . . . . . . . . . . . . 100 mg. . . . . . . . . . 100 mg Ashwagandha (Withania somnifera) 3.5% withanolides. . . . 100 mg. . . . . . . . . . 100 mg Holy basil (Ocimum sanctum) 10% ursolic acids . . . . . . . . . . . . 100 mg. . . . . . . . . . 100 mg Panax ginseng (Panax quinquefolium) 20% ginsenosides . . 100 mg. . . . . . . . . . 100 mg Licorice (Glycirrhiza glabra) 10% glycyrrhizin . . . . . . . . . . . . . . . 100 mg. . . . . . . . . . . . . . . . — Schizandra (Schizandra chinensis) 9% schizandrins . . . . . . . . . 50 mg. . . . . . . . . . . . 50 mg Astragalus (Astragalus membranaceus) 3% astragalosides . . 50 mg. . . . . . . . . . . . 50 mg Vitamin B6 (pyridoxal-5’-phosphate) . . . . . . . . . . . . . . . . . . . . . . . . 50 mg. . . . . . . . . . . . 50 mg Magnesium (from magnesium bisglycinate). . . . . . . . . . . . . . . . 20 mg. . . . . . . . . . . . 38 mg Zinc (from zinc picolinate) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 mg. . . . . . . . . . . . 10 mg Siberian ginseng (Eleutherococcus senticosus) 0.8% eleutherosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 mg. . . . . . . . . . . . 10 mg Contains no: Preservatives, artificial flavor or color, yeast, soy, wheat, gluten, dairy, sugar or starch. Adrenal SAP contains 90 capsules per bottle.

DOSAGE

Adults: 1 to 3 capsules daily with meals or as directed by your health care practitioner. WARNING: Adrenal SAP contains licorice (Glycirrhiza glabra), therefore patients with hypertension should only use this product under the care of a health care practitioner.(1)

LICO R NOW ICE-FREE AVAI LABL E

WARNING: If you are pregnant or breast-feeding, consult your health care practitioner before taking this product.

INDICATION

Adrenal SAP provides nutritive and botanical support for adrenal function to improve energy levels, mental and physical performance, memory, mood, immune function, and increase the ability to withstand the effects of acute and chronic stress.

INCREASED BIOAVAILABILITY

The botanicals in Adrenal SAP are ethanol-extracted for standardized isolation of active constituents. Adrenal SAP is supplied in a vegetable capsule for easy digestion.

PURITY, CLEANLINESS AND STABILITY

Third-party testing is performed on finished product to ensure Adrenal SAP is free of heavy metals, pesticides, volatile organics and other impurities.

Scientific Advisory Panel (SAP): adding nutraceutical research to achieve optimum health

Nutritional Fundamentals for Health • 3405 F.-X.-Tessier, Vaudreuil, QC J7V 5V5 • Tel. 1 866 510 3123 • Fax. 1 866 510 3130 • www.nfh.ca

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