IHP Magazine - June/July 2014 by IHP Magazine

clinic profile

PCOS By Christopher Habib, ND and Faryal Luhar, ND

DIET AND INFLAMMATORY BOWEL DISEASE By Jordan Robertson, ND, et al.

SCREENING FOR PREMATURE OVARIAN INSUFFICIENCY

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By Gouri Mukerjee, PhD and Ruslan Dorfman PhD

Dr Alvin Pettle, MD Ruth Pettle Wellness Centre

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JUNE/JULY 2014

Continuing Education Chemotherapy- Induced Peripheral Neuropathy By Rachel M.T. Corradetti, ND and Akbar Khan, MD 1

www.ihpmagazine.com | June/July 2014

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Support cardiovascular health with Statin Care

GENESTRA BRANDS Statin Care combines Coenzyme Q10, L-Carnitine and Vitamin D in a convenient capsule format. A vegetarian formula comprised of gluten-free and dairy-free ingredients, Statin Care supports cardiovascular health and is an antioxidant for the maintenance of good health.1

EGETARIAN

GENESTRA BRANDS. A trusted source of practitioner recommended, scientifically sound formulas for over 30 years. 1. NHPD Monograph on Coenzyme Q10. November 2007.

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GENESTRA BRANDS STATIN CARE PRODUCT MONOGRAPH Statin Care combines Coenzyme Q10, L-Carnitine and Vitamin D in a convenient capsule format. Coenzyme Q10 helps to maintain and support cardiovascular health and is an antioxidant for the maintenance of good health.1 A vegetarian capsule formulated using gluten-free and dairy-free ingredients. Statin therapy: Statins (hydroxymethylglutaryl coenzyme A reductase inhibitors), are first-line agents for lowering cholesterol levels. Statins inhibit the synthesis of cholesterol by reducing the production of mevalonate, a precursor of both cholesterol and coenzyme Q10. Since both cholesterol and coenzyme Q10 are produced by the same pathway, itâ&#x20AC;&#x2122;s not surprising that statins have been reported to reduce serum and muscle coenzyme Q10 levels.2 L-Carnitine: The coadministration of carnitine and simvastatin may represent a new therapeutic option in promoting healthy blood lipids.3 In one study, eighty subjects were randomly assigned to 1 of 2 treatment groups for 3 months. The 2 groups received either simvastatin monotherapy 20 mg (n = 40) or L-carnitine 2 g/d and simvastatin 20 mg (n = 40). After 12 weeks, comparing the 2 groups, combination therapy was reported to support total cholesterol, LDL, small sized LDL proportion, triglycerides, and apoB100.4 Coenzyme Q10: CoQ10 is indispensable in bioenergetics and thus is indispensable to human life itself. The concentration of CoQ10 in the human myocardium is high, and it has been presumed for years that a myocardial deficiency of CoQ10 would be detrimental to cardiac function. A double-blind and double-crossover trial has been conducted by administering CoQ10 (3 x 33.3 mg daily) and a matching placebo orally to two groups of patients. Group A received CoQ10 and then placebo; group B received placebo and then CoQ10. Blood levels of CoQ10 and cardiac function were determined at 0 and 4 weeks (control stabilization period) and at 16 and 28 weeks (after the 12-week CoQ/placebo-treatment periods). For group A, significant increases in CoQ10 blood levels and cardiac function occurred during CoQ10 treatment and then decreased during crossover to placebo. For group B, there was no change in CoQ10 blood levels and cardiac function during placebo treatment, but increases in both parameters occurred in crossover to CoQ10. This clinical improvement could be due to correction of a myocardial deficiency of CoQ10 and to enhanced synthesis of CoQ10-requiring enzymes.5 Vitamin D: Vitamin D is an essential vitamin and is the foundation of many formulas. In a human clinical trial, serum 25 (OH) D was measured in 621 statin-treated patients, which consisted of 128 patients with myalgia at entry and 493 asymptomatic patients. Serum vitamin D was lower in the 128 patients with myalgia than in the 493 asymptomatic patients (28.7 +/- 1.2 vs 34.3 +/- 0.6 ng/mL, P < 0.0001). Serum 25 (OH) D was low in 82 of 128 (64%) patients with myalgia versus 214 of 493 (43%) asymptomatic patients. Of the 82 vitamin-D-deficient, myalgic patients, while continuing statins, 38 were given vitamin D (50,000 units/week for 12 weeks), with a resultant increase in serum vitamin D from 20.4 +/- 7.3 to 48.2 +/- 17.9 ng/mL (P < 0.0001) and resolution of myalgia in 35 (92%).6

REFERENCES 1. NHPD Monograph on Coenzyme Q10. November 2007. 2. Wyman M, Leonard M, Morledge T. Coenzyme Q10: a therapy for hypertension and statin-induced myalgia? Cleve Clin J Med. 2010 Jul;77(7):435-42. 3. Galvano F, Li Volti G, Malaguarnera M, Avitabile T, Antic T, Vacante M, Malaguarnera M. Effects of simvastatin and carnitine versus simvastatin on lipoprotein(a) and apoprotein(a) in type 2 diabetes mellitus. Expert Opin Pharmacother. 2009 Aug;10(12):1875-82. 4. Malaguarnera M, Vacante M, Motta M, Malaguarnera M, Li Volti G, Galvano F. Effect of L-carnitine on the size of low-density lipoprotein particles in type 2 diabetes mellitus patients treated with simvastatin. Metabolism. 2009 Nov;58(11):1618-23. 5. Langsjoen PH, Vadhanavikit S, Folkers K. Response of patients in classes III and IV of cardiomyopathy to therapy in a blind and crossover trial with coenzyme Q10. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4240-4. 6. Ahmed W, Khan N, Glueck CJ, Pandey S, Wang P, Goldenberg N, Uppal M, Khanal S. Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients. Transl Res. 2009 Jan;153(1):11-6.

EACH CAPSULE CONTAINS: Vitamin D (cholecalciferol) . . . . . . . . . . . . . . . . . . . .250 IU / 6.25 mcg L-Carnitine (L-carnitine tartrate). . . . . . . . . . . . . . . . . . . . . . . 500 mg Coenzyme Q10 (bacterial fermentation) . . . . . . . . . . . . . . . . . .50 mg Non-Medicinal Ingredients: Hypromellose, magnesium stearate, silica

Recommended Adult Dose: Take two to four capsules daily or as recommended by your healthcare practitioner. Guaranteed to contain no added wheat, yeast, gluten, soy, artificial colouring or flavouring, antimicrobial preservatives or dairy products. Ideal for vegetarians.

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from the publisher

Bring on the Heat! Fresh off of the annual Primary Care show, I am feeling rejuvenated… I can’t believe how far things have come in just a short few years! Year after year the interest in integrative medicine from conventionally- trained MD’s is exploding! Just around the corner is the annual AANP conference at the beautiful Biltmore resort in Arizona. It always humbles me to see the amazing strides IHP makes, and the AANP shows us that we have reach on an international level.

Sanjiv Jagota Publisher

Connect With Us

www.ihpmagazine.com | June/July 2014

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Premium Tinctures

ON SALE August 1-31

BulkLax® Herbal Fibre Laxative

Product Monograph for IHP, June/July 2014 By Terry Vanderheyden, ND

Prebiotics: Your Gut Bacteria’s Best Friend? What are they? Although probiotic use is very familiar to most IHP readers, the importance of prebiotics may not be as well known. Prebiotics are those indigestible - usually fibrous - food (and supplement) ingredients that are fermented by healthy gut bacteria and thus stimulate and maintain their growth.

Prebiotics: Necessary? Fibre is the primary food for bacteria. Chris Kresser, New York Times bestselling author of Your Personal Paleo Code, emphasizes the importance of prebiotic fibre. He states that, “Prebiotics are much more effective than probiotics at promoting the growth of beneficial bacteria in the gut.”1

Prebiotics and Immunity The composition of bacteria in the gut has a direct effect on the immune system. Several studies confirm this. Take, for example, a 2013 paper which showed that butyrate, an essential gut bacterial metabolite, improves T regulatory cell balance. Specifically, butyrate induces colonic regulatory T (Treg) cells, “which have a central role in the suppression of inflammatory and allergic responses.” 2

Terry Vanderheyden, ND (Research Consultant) Since graduating from the CCNM in 1994, Terry Vanderheyden, ND, has practiced in Ontario, specializing in homeopathic, nutritional, and botanical therapies. Terry lives in Barry’s Bay with his wife Laurie and their 7 children.

References:

Prebiotics and Gut Permeability, aka “Leaky Gut”

1. Kresser C, “You Are What Your Bacteria Eat: The Importance of Feeding Your Microbiome – With Jeff Leach. Revolution Health radio,” Accessed online from http:// goo.gl/u538Ln May 8, 2014.

Healthy colonic microbes change the pH of the colon. i.e. make it more acidic and inhospitable to pathogens. As Bifidobacteria (for example), goes up, pathogens go down. And when pathogens disappear, so does inflammation, which means the intestines become healthier, with tighter junctions.

2. Furusawa Y et al., “Commensal microbederived butyrate induces the differentiation of colonic regulatory T cells,” Nature. 2013 Dec 19;504(7480):446-50.

BulkLax®: Your Premier Source of Prebiotic Fermentable Fibre St. Francis Herb Farm’s BulkLax® contains psyllium (seed and husk), pectin, and Larch Arabinogalactan (AG), all excellent fermentable prebiotics. A significant increase in Lactobacillus spp. was observed, for example, when human subjects consumed Larch AG for a total of 6 weeks. In another study, between 1.5 and 4.5 grams/day increased circulating peripheral blood white blood cells (a typical daily 2-tsp dose of Bulklax contains 2.5g).3 Meanwhile, pectin is 99-percent fermentable by healthy intestinal microbes.4

3. Fitzpatrick A et al., “Larch arabinogalactan: A novel and multifunctional natural product.” AgroFOOD industry hi-tech Jan-Feb 2004: 30-32. 4. MacIntosh, A, “Fiber Supplements: New Thoughts, New Choices,” Alternative & Complementary Therapies, August 1998, pp. 267-275.

In addition, BulkLax® contains herbal ingredients that soothe gut inflammation and act as carminatives. It also includes the rejuvenative Triphala combination, an ancient Ayurvedic Rasayana formula for revitalizing the gastrointestinal system.

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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, 0electronic, 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.

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contents

This Issue: June/July 2014 • Vol. 7 • No. 3

32 Ruth Pettle Wellness Centre Cover Story

Integrative Women’s Health

40 The Root of Health Clinic Profile Putting The Patient First

The Journal of IHP Peer-reviewed articles on clinically revelant topics

Coming Next Issue Green space and patient health

Departments

4 Publisher’s Letter 11 Research News 19 Industry News 24 Calendar 27 Product Profiles 45 Editor’s Letter 47 Peer Review Board 49 Editorial Board 73 Continuing Education:

Supplementation during pregnancy

Chemotherapy- Induced Peripheral Neuropathy

Novel anticancer uses of common Rx meds

By Rachel M.T. Corradetti, ND and Akbar Khan, MD

Cover Photograph by Eric Forget 8

www.ihpmagazine.com | June/July 2014

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Recovery SAP

Science-based intensive probiotic therapy to enhance recovery Probiotics are beneficial bacteria that are normally found in a healthy gastrointestinal system. When someone is experiencing digestive upset—which could range from bloating and indigestion, to conditions such as irritable bowel syndrome (IBS) and inflammatory bowel diseases—, often probiotics can help to reduce or eliminate symptoms by restoring a healthy balance. Different strains of bacteria will serve multiple functions in the intestinal tract, which can include inhibiting pathogenic bacteria, improving digestion, reducing inflammation, and stimulating gastrointestinal immunity by increasing the secretion of IgA and mucin. A higher concentration of probiotics is especially beneficial to help restore balance in the intestinal tract after taking an antibiotic, with conditions such as IBS, or during times of gastrointestinal distress.

ACTIVE INGREDIENTS

Each pH-protected, enteric-coated, NON-GMO vegetable capsule contains:

Total active live probiotic cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 billion Lactobacillus rhamnosus R0011 . . . . . . . . . . . . . . . . . . . . . . . . . 9 billion Lactobacillus helveticus R0052 . . . . . . . . . . . . . . . . . . . . . . . . . . 9 billion Lactobacillus plantarum R1012. . . . . . . . . . . . . . . . . . . . . . . . . . 9 billion Lactobacillus casei R0215 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 billion Bifidobacterium longum R0175 . . . . . . . . . . . . . . . . . . . . . . . . . 9 billion Bifidobacterium infantis R0033 . . . . . . . . . . . . . . . . . . . . . . . . 1 billion Bifidobacterium breve R0070 . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 billion Bifidobacterium bifidum R0071 . . . . . . . . . . . . . . . . . . . . . . . . . 1 billion Lactobacillus delbrueckii ssp. bulgaricus R9001 . . . . . . . . . 1 billion Streptococcus salivarius ssp. thermophilus R0083. . . . . . . 1 billion Plus: Fructooligosaccharides (FOS) and arabinogalactan. Contains no: Preservatives, artificial flavor or color, gluten. Keep refrigerated.

DOSAGE

Adults, adolescents and children ≥1 year old: Take 1–2 capsules daily with water or juice or as directed by your health care practitioner. Follow-up treatment with NFH’s ProBio SAP to maintain intestinal health.

INDICATION

ɶ ɶ ɶ ɶ ɶ

Recovery SAP can be used during antibiotic use to help prevent antibiotic-associated diarrhea as well as subsequent to antibiotic use to quickly reestablish intestinal flora. Recovery SAP assists in preventing pathogenic yeast or bacteria from flourishing in the intestinal tract. Recovery SAP is used to help treat symptoms of IBS including gas, bloating, constipation and diarrhea. Recovery SAP helps treat inflammation by reducing IL8 (proinflammatory) and by increasing IL6 (anti-inflammatory). Recovery SAP can be used to activate immune cells in the intestinal tract and to stimulate the secretion of IgA and mucin.

FEATURES

The high concentration of the 10 probiotic strains found in Recovery SAP allows the gastrointestinal tract to be effectively and quickly repopulated to prevent other bacteria or yeast from being able to populate. The enteric-coated vegetable capsule ensures the delivery of the live probiotics to the intestine because it is resistant to gastric and bile acids.

PURITY, CLEANLINESS AND STABILITY

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

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

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Recovery SAP PRODUCT MONOGRAPH

WHAT ARE PROBIOTICS?

ulcerative colitis, Crohn’s disease and pouchitis.

Probiotics can be defined as living microorganisms which, when ingested in adequate amounts, have beneficial effects on host health by improving intestinal microbial balance, as well as by modulating mucosal and systemic immunity. The most commonly used and studied probiotics are the Lactobacillus, Bifidobacterium and Streptococcus species, which belong to the lactic acid bacteria group. Lactobacilli and Bifidobacteria are normal inhabitants of the human colonic flora, thus giving a rationale for their use as component of functional foods and supplements.(1)

Studies have found the intestinal microflora in IBS patients to be imbalanced, and the frequency of symptoms of IBS to increase after enteric infections.(14) The reestablishment of probiotic bacteria is critical after infection to restore intestinal health. A 2008 meta-analysis showed probiotic use is associated with improvement in global IBS symptoms compared to placebo (pooled relative risk [RRpooled] 0.77, 95% confidence interval [95% CI] 0.62–0.94).(15) Probiotics are also associated with lower frequencies of abdominal pain compared to placebo (RRpooled = 0.78 [0.69–0.88]).(15)

WHAT ARE PREBIOTICS?

EFFECTS ON THE IMMUNE SYSTEM AND INFLAMMATION

A prebiotic is a nondigestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or more bacterial species in the colon, and thus improves host health.(2) Specifically, prebiotics (i.e. fructooligosaccharides [FOS] and arabinogalactan) promote growth of Bifidobacteria and Lactobacilli, decrease intestinal pH, produce short-chain fatty acids, and improve mineral absorption.(2, 3, 4)

PROBIOTICS—GENERAL DOSE AND DURATION

Numerous studies that have evaluated the use of probiotics on physiological effects in humans, such as in the treatment of lactose intolerance, diarrhea, and colon cancer biomarkers, recommend ingesting a daily dose of 109–1010 live bacteria. Most ingested probiotics are transient, pass through the intestinal tract in 3–30 days, and do not permanently adhere to the intestinal wall. These probiotics exert their effects as they proliferate and metabolize while in the small intestine and colon. Different strains of probiotics exert different effects on human health. Thus, proven effects of one strain or species cannot be transferred to others.(4) As a result, it is best to supplement with a high-dose multistrain probiotic to provide an optimal range of health benefits as well as suit the needs of different individuals. Recovery SAP contains a much higher concentration of probiotics compared to many therapeutic probiotic sources. It may be used to restore intestinal balance in cases of acute irritable bowel syndrome (IBS), after experiencing diarrhea, and after taking a course of antibiotics in order to restore optimal ratios of gastrointestinal flora.

PROMOTION OF GUT HEALTH

There are many ways that probiotics may act to improve gut health. Infectious diarrhea and GI disorders, such as irritable bowel syndrome, are conditions associated with altered microbial balance, favoring the development of harmful or pathogenic species. Probiotics may aid in restoring microbial balance through competition with pathogenic microorganisms for nutrients and binding sites on epithelial cells. As well, by producing bacteriocins (antimicrobial substances), organic acids and hydrogen peroxide, probiotics may inhibit the growth of pathogenic bacteria.(1)

ANTIBIOTIC USE

Antibiotics can selectively decrease tissue invasion and eliminate aggressive bacterial species, or globally decrease luminal and mucosal bacterial concentrations, depending on the spectrum of activity.(5) Antibiotic-associated diarrhea (AAD) occurs in 25% of patients receiving antibiotics. A progressive increase in incidence and severity of AAD can be seen over the last decade, and is largely attributed to the common use of broad-spectrum antibiotics.(6)

In addition to improving intestinal microflora, there is now evidence that probiotics have beneficial effects on the immune system. Eighty percent of all immunologically active cells of the body are found in the gut-associated lymphoid tissue (GALT). Normal microfloral balance is necessary for the development of GALT, suggesting the importance of microbe–gut immune system interactions in the development of the immune system. Studies show that probiotics influence the development of both specific and nonspecific cellular and humoral gut mucosal immune responses.(16) Some probiotics enhance the mucosal barrier by increasing the production of innate immune molecules, including goblet-cell-derived mucins and trefoil factors and defensins. Other probiotics mediate their beneficial effects by promoting adaptive immune responses (secretory immunoglobulin A (IgA), regulatory T-cells, interleukin (IL)10).(17) Studies have shown the ability of probiotics to modulate signaling pathways and ultimately resulting in decreased tumor necrosis factor (TNF)-induced IL8 production.(18, 19) Secretory IgA is a very important component of antibody response. Secretory immunoglobulin A is the most important and predominant immunoglobulin in mucosal surfaces. It provides protection against antigens, potential pathogens, toxins, and virulence. IgA-producing B-cells can help prevent overgrowth of unwanted bacterial species. Studies have shown that probiotics can stimulate the production of IgA by plasma cells.(20) An association with specific types of bacterial species (particularly Lactobacilli and Bifidobacteria) helps the host maintain adequate gut barrier and immune mechanisms.(21)

SAFETY OF PROBIOTIC SUPPLEMENTATION

The safety record of probiotics is excellent, with Lactobacilli and Bifidobacteria designated as generally recognized as safe (GRAS).(1) The lack of pathogenicity with probiotic use extends to all age groups and to immunocompromised individuals.(22)

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

Studies showed an overall reduction in the risk of AAD when probiotics were coadministered with antibiotics.(7, 8, 9) In addition to preventing AAD, other studies show the protective effects of probiotics against traveler’s diarrhea and acute pediatric diarrhea.(10, 11, 12) The advantages of probiotic therapy include multiple mechanisms of action against pathogenic bacteria. Ingestion of probiotic bacteria may enhance host flora by lowering intestinal pH, thereby decreasing colonization and invasion by pathogenic organisms; stimulating host immune function; and suppressing pathogenic bacteria colonization.(13) Recovery SAP may be used during antibiotic use to help prevent AAD, used in symptomatic treatment of diarrhea, or used to establish or maintain optimal gastrointestinal ratios of microflora.

TREATING SYMPTOMS OF AN IRRITABLE BOWEL

19.

The imbalance of intestinal microflora can lead to an array of symptoms involving the bowels, which may include intermittent abdominal pain, fluctuation between diarrhea and constipation, bloating and flatulence. Irritable bowel disease may also be associated with chronic and recurring intestinal infections,

For more information visit: www.nfh.ca

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10. 11. 12. 13. 14. 15. 16. 17. 18.

20. 21. 22.

Saarela, M., et al. “Gut bacteria and health foods—the European perspective”. International Journal of Food Microbiology 78, No. 1–2 (2002): 99–117. Gibson, G.R. and M.B. Roberfroid. “Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics”. The Journal of Nutrition 125, No. 6 (1995): 1401–1412. Ronbinson, R.R., J. Feirtag, and J.L. Slavin. “Effects of dietary arabinogalactan on gastrointestinal and blood parameters in healthy human subjects”. Journal of the American College of Nutrition 20, No. 4 (2001): 279–285. Schrezenmeir, J. and M. de Vrese. “Probiotics, prebiotics, and synbiotics—approaching a definition”. The American Journal of Clinical Nutrition 73, No. 2 Suppl (2001): 361S–364S. Balfour, S.R. “Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics”. Gastroenterology 126, No. 6 (2004): 1620–1633. Gao, X.W., et al. “Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients.” The American Journal of Gastroenterology 105, No. 7 (2010): 1636–1641. MacFarland, L.V. “Evidence-based review of probiotics for antibiotic-associated diarrhea and Clostridium difficile infections.” Anaerobe 15, No. 6 (2009): 274–280. Goldin, B.R. and S.L. Gorbach. “Clinical indications for probiotics: an overview”. Clinical Infectious Diseases 46, Suppl. 2 (2008): S96–S100. Dorin, S.I., P.L. Hibberd and S.L. Gorbach. “Probiotics for prevention of antibiotic-associated diarrhea”. Journal of Clinical Gastroenterology 42, Suppl. 2 (2008): S58–S63. Szajewska, H., M. Ruszczyński, and A. Radzikowski. “Probiotics in the prevention of antibiotic-associated diarrhea in children: a meta-analysis of randomized controlled trials”. The Journal of Pediatrics 149, No. 3 (2006): 367–372. McFarland, L.V., G.W. Elmer, and M. McFarland. “Meta-analysis of probiotics for the prevention and treatment of acute pediatric diarrhea”. International Journal of Probiotics and Prebiotics 1, No. 1 (2006): 63–76. McFarland, L.V. “Meta-analysis of probiotics for the prevention of traveler’s diarrhea”. Travel Medicine and Infectious Disease 5, No. 2 (2007): 97–105. Williams, N.T. “Probiotics”. American Journal of Health-System Pharmacy 67, No. 6 (2010): 449–458. Spiller, R.C. “Role of infection in irritable bowel syndrome”. Journal of Gastroenterology 42, Suppl. 17 (2007): 41–47. Nikfar, S., et al. “Efficacy of probiotics in irritable bowel syndrome: a meta-analysis of randomized, controlled trials”. Diseases of the Colon and Rectum 51, No. 12 (2008): 1775–1780. Cebra, J.J. “Influences of microbiota on intestinal immune system development”. The American Journal of Clinical Nutrition 69, No. 5 (1999): 1046S–1051S. Sherman, P.M., J.C. Ossa, and K. Johnson-Henry. “Unraveling mechanisms of action of probiotics”. Nutrition in Clinical Practice 24, No. 1 (2009): 10–14. Bakker-Zierikzee, A.M., et al. “Faecal SIgA secretion in infants fed on pre- or probiotic infant formula”. Pediatric Allergy and Immunology 17, No. 2 (2006): 134–140. Ma, D., P. Forsythe, and J. Bienenstock. “Live Lactobacillus rhamnosus [corrected] is essential for the inhibitory effect on tumor necrosis factor alpha-induced interleukin-8 expression”. Infection and Immunity 72, No. 9 (2004): 5308–5314. Thomas, C.M. and J. Versalovic. “Probiotics-host communication: Modulation of signaling pathways in the intestine”. Gut Microbes 1, No. 3 (2010): 148–163. Saavedra, J.M. “Use of probiotics in pediatrics: rationale, mechanisms of action, and practical aspects”. Nutrition in Clinical Practice 22, No. 3 (2007): 351–365. Borriello, S.P., et al. “Safety of probiotics that contain lactobacilli or bifidobacteria”. Clinical Infectious Diseases 36, No. 6 (2003): 775–780.

2014-05-22 14:13:46

research news

Green tea and vitamin E enhance exercise-induced benefits of several factors

Acupuncture effective as therapy in functional dyspepsia In this study, the effectiveness of acupuncture as a complementary therapy in additional to conventional treatments was evaluated. Functional dyspepsia is a common gastrointestinal complaint in clinical practice. According to the Roma III criteria, it can be classified into two types as the predominant system: epigastric discomfort and postprandial discomfort. The pathophysiology is uncertain, but appears to be related to visceral hypersensitivity, changes in gastroduodenal motility and gastric accommodation and psychological factors. This was a randomized clinical trial where one group was submitted to drug therapy and specific acupuncture (GI) and the other to drug therapy and non-specific acupuncture (GII). The symptoms and quality of life were evaluated at the end of treatment and 3 months afterwards. The results showed that after 4 weeks of treatment there was improvement in gastrointestinal symptoms in Group I and Group II. Quality of life was significantly better in Group I. Anxiety and depression were significantly lower in Group I. 3 months after the treatment, gastrointestinal symptoms remained better only in Group I, when compared to the pre-treatment values. The authors conclude that in patients with functional dyspepsia, the complementary acupuncture treatment is superior to conventional treatment. Arq Gastroenterol. 2013. PMID: 24322192.

In this study, green tea plus vitamin E in addition to exercise were provided to evaluate their effects on body composition, metabolic parameters, and antioxidant parameters in healthy elderly individuals. For 12 weeks, 22 elderly men and women undertook 30 minutes of moderately intense walking for 6 days per week. They were randomly assigned to ingest either green tea plus vitamin E (GTVE) or placebo. Data on anthropometrics, fasting insulin and glucose levels, physical fitness, dietary intake, safety parameters, and biomarkers of oxidation status were recorded and analyzed at the start and end of the study. The results showed that although dietary intake was unchanged, improved exercise capacity followed by a significant reduction in body weight and fasting insulin levels in all participants. Additional consumption of GTVE resulted in a twofold increase in serum vitamin E and a decrease of men's and women's waist circumferences and fasting glucose levels. Plasma protein carbonyls dropped, whereas erythrocyte catalase activities increased in the GTVE group only. Oral peroxidase activities were increased in both groups. The authors conclude that a daily dose of GTVE in healthy elderly men and women may improve exercise-induced benefits in body composition and glucose tolerance and may also lower oxidative burden. J Am Coll Nutr. 2013. PMID: 24015697.

Effects of krill oil on brain function: RCT In this study, the effect of krill oil on cognitive function in elderly subjects using near-infrared spectroscopy and electroencephalography was evaluated. The study design was randomized, double-blind, and parallelgroup comparative. Forty-five healthy elderly males aged 61-72 years were assigned to receive 12 weeks of treatment with: medium-chain triglycerides as placebo, krill oil, which is rich in n-3 PUFAs incorporated in phosphatidylcholine, or sardine oil, which is abundant in n-3 PUFAs incorporated in triglycerides. Changes in oxyhemoglobin concentrations in the cerebral cortex during memory and calculation tasks were measured. The P300 component of event-related potentials was also measured during a working memory task. The results showed that during the working memory task, changes in oxyhemoglobin concentrations in the krill oil and sardine groups were significantly greater than those in the medium-chain triglycerides group at week 12. The differential value for P300 latency in the krill oil group was significantly lower than in the medium-chain triglyceride group at week 12. In the calculation task, changes in the oxyhemoglobin concentrations in the krill oil group were significantly greater than those in the medium-chain triglyceride group at week 12. The authors conclude that n-3 PUFAs activate cognitive function in the elderly, especially with krill oil. Clin Interv Aging. 2013. PMID: 24098072. June/July 2014 | www.ihpmagazine.com

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research news Osteopathic treatment for whiplash injuries In this study, late whiplash syndrome (LWS) was treated with a series of osteopathic treatments to evaluate improvement in symptoms. LWS is the clinical manifestation resulting from whiplash injury. Forty-two patients (mean age 39 years) were evaluated who had LWS due to rear-end car collisions. The intervention was 5 individualized customtailored osteopathic treatments at 1 week intervals. The main outcome measure was the neck-related pain and disability as determined by the Neck pain and Disability Scale (NPAD) and the quality of life assessed on the SF-36. The presence of PTSD was also diagnosed. The results showed that there was clinically relevant and statistically significant improvements in the osteopathic treatment period for the NPAD. In the intervention phase, the NPAD dropped from 41.5 to 26.0 points, which corresponds to an improvement of 37% (95% CI 11.1-19.8). For the SF-36, both the physical and mental component summary showed a significant and substantial improvement during the treatment phase. Prior to treatment, 17 patients were diagnosed with PTSD, this number feel to only 6 during observation. The authors conclude that 5 osteopathic treatments had a beneficial effect on the physical and mental aspects of LWS. J Altern Complement Med. 2013. PMID: 23273259.

Curcumin in pediatric inflammatory bowel disease In this study, curcumin therapy was titrated and evaluated in pediatric inflammatory bowel disease (IBD) to evaluate its possible dosage. Prospectively, patients with Crohn's disease or ulcerative colitis in remission or with mild disease (Pediatric Crohn's Disease Activity Index [PCDAI] < 30 or Pediatric Ulcerative Colitis Activity Index [PUCAI] score < 34) were enrolled in a tolerability study. All patients received curcumin in addition to their standard therapy. Patients initially received 500mg twice per day for 3 weeks. Using the forced-dose titration design, doses were increased up to 1g twice per day at week 3 for a total of 3 weeks and then titrated again to 2g twice per day at week 6 for 3 weeks. Validated measures of disease activity, using the PUCAI and PCDAI, and the Monitoring of Side Effect System score were obtained at weeks 3, 6, and 9. The results showed that all patients tolerated curcumin well, with the only symptom that was consistently reported during all 3 visits being an increase in gassiness, which occurred in only 2 patients. Three patients saw improvement in PUCAI/PCDAI score. The authors conclude that curcumin may be used as an adjunctive therapy for individuals seeking a combination of conventional medicine and alternative medicine. J Pediatr Gastroenterol Nutr. 2013. PMID: 23059643. 12

Saw palmetto fruit extract effect on PSA In this study, high doses of saw palmetto as studied in the Complementary and Alternative Medicine for Urologic Symptoms (CAMPUS) trial were evaluated to see if they affect serum prostate specific antigen levels. The CAMPUS trial was a randomized, placebo controlled, double-blind, multicenter, North American trial conducted between 2008 and 2012, in which 369 men older than 45 years with an AUA symptom score of 8 to 24 were randomly assigned to placebo or dose escalation of saw palmetto. It consisted of 320mg for the first 24 weeks, 640mg for the next 24 weeks, and 960mg for the last 24 weeks of this 72-week trial. Serum prostate specific antigen levels were obtained at baseline and at weeks 24, 48, and 72 and were compared between treatment groups. The results showed that serum prostate specific antigen was similar at baseline for the placebo and saw palmetto groups. Changes in prostate specific antigen were similar in both groups. No differential effect on serum prostate specific antigen was observed between treatment arms when the groups were stratified by baseline prostate specific antigen. The authors conclude that saw palmetto extract does not affect serum prostate specific antigen more than placebo, even at high doses. J Urol. 2013. PMID: 23253958.

www.ihpmagazine.com | June/July 2014

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PROGRESSIVE NUTRITIONAL THERAPIES OMEGESSENTIAL® JEWELS Progressive OmegEssential® JEWELS is a high potency blend of cold water, wild caught, purified fish oil along with a family of strategic support nutrients. Fish Oils for the Maintenance of Good Health As a source of omega-3 fatty acids, namely EPA and DHA, fish oils aid in the maintenance of good health, help support cognitive health/brain function and cardiovascular health (NHPD Monograph: Fish Oil). Fontani, et al (2005) conducted a study to evaluate the effect of omega-3 supplementation on cognitive performance in 33 normal healthy men and women (aged 22 – 51 years) during a 35-day period. Tests involving different types of attention were used, along with the Profile of Mood States (POMS). Results showed a mood profile with increased vigour and reduced anger, anxiety and depression states after omega-3. Furthermore, findings indicated that omega-3 supplementation is associated with an improvement of attentional and physiological functions, particularly those involved in complex cortical processing. Higher consumption of fish and omega-3 fatty acids has been associated with a lower risk of coronary heart disease (CHD). Hu, et al (2002) examined the association between fish and omega-3 fatty acid consumption and risk of CHD in women. Dietary consumption and follow-up data from 84,688 female nurses (aged 34 to 59 years) free from cardiovascular disease and cancer were compared from validated questionnaires. The outcomes indicated that women who consumed more fish and fish oil (omega-3 fatty acids) significantly reduced their risk of heart disease (particularly CHD deaths) by 30%, compared to women who rarely ate fish. Similarly, a prospective, nested case-control analysis was performed among apparently healthy men, who had no evidence of prior heart disease by Albert, et al (2002) to address the hypothesis that long-chain omega-3 fatty acids found in fish are associated with a reduced risk of sudden death from cardiac causes. The fatty-acid composition of whole blood in 184 men was compared with the previously collected blood of 94 men, in whom sudden death occurred as the first manifestation of cardiovascular disease. The study reported that men who consumed long-chain omega-3 fatty acids had a significantly reduced risk of sudden death. Dosage Indication: Fish Oil Supplement. Helps support cardiovascular health, brain function and healthy mood balance. Adults (≥ 19 years) Dosage Take 2 softgels with breakfast and 2 softgels with dinner for a total of 4 softgels per day. Interactions Omega-3 fatty acids may increase the risk of bleeding when taken with anticoagulants, aspirin, ginkgo biloba or ginseng (Mason, 2001). Therefore, medical supervision is required. Based on human studies, fish oils may lower blood pressure when taken in certain doses and have additive effects in patients treated with anti-hypertensives (Prisco, et al, 1998). Use with caution. Quality Assurance Parameter Microbial Total Count Yeast & Mold Escherichia coli Salmonella spp Staphylococcus aureus Heavy Metal Arsenic Cadmium Lead Total Mercury

References Test

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Albert C, et al (2002). Blood Levels of Long-Chain n-3 Fatty Acids and the Risk of Sudden Death. The New England Journal of Medicine, Vol. 346 No. 15: 1113-1118, April 11. Fontani G, et al (2005). Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects. European Journal of Clinical Investigation, 35: 691-699. Hu F, et al (2002). Fish and Omega-3 Fatty Acid Intake and Risk of Coronary Heart Disease in Women. The Journal of the American Medical Association, Vol. 287 No. 14, April 10. Jellin JM, et al (2006). Pharmacist’s Letter/Prescriber’s Letter th Natural Medicines Comprehensive Database.8 ed. Stockton, CA: Therapeutic Research Faculty. Mason P. Dietary Supplements. 2nd ed. London: Pharmaceutical Press; 2001. NHPD Monograph. (2006). Fish Oil, August 8. Prisco D, et al (1998). Effect of medium-term supplementation with a moderate dose of n-3 polyunsaturated fatty acids on blood pressure in mild hypertensive patients. Thromb Res. 1:105-12.

research news Valerian and lemon balm use for sleep disorders during menopause

L-carnitine supplementation for fatigue in cancer patients: RCT In this study, the efficacy of L-carnitine supplementation as a treatment for fatigue in patients with cancer was evaluated. It was a double-blind, placebo-controlled trial. Patients with invasive malignancies and fatigue were randomly assigned to either 2g per day of L-carnitine oral supplementation or matching placebo. The primary end point was the change in average daily fatigue from baseline to week 4 using the Brief Fatigue Inventory (BFI). The results showed that three hundred and seventy-six patients were randomly assigned to treatment with L-carnitine supplementation or placebo. L-carnitine supplementation resulted in signficant carninite plasma level increase by week 4. The primary outcome, fatigue, measured using the BFI, improved in both arms compared with baseline. There were no statistically significant differences between arms. Secondary outcomes, including fatigue measured by the Functional Assessment of Chronic Illness Therapy-Fatigue instrument, depression, and pain, did not show significant differences between arms. A separate analysis of patients who were carnitine-deficient at baseline did not show statistically significant improvement in fatigue or other outcomes after L-carnitine supplementation. The authors conclude that four weeks of 2g per day of L-carnitine did not improve fatigue in patients with invasive malignancies and good performance status. J Clin Oncol. 2012. PMID: 22987089.

In this study, the authors wanted to determine whether valerian and lemon balm could assist by enhancing sleep patterns in patients. The start of menopause in women is frequently associated with sleep disruptions with hot flushes intensifying problems. The use of supplementary drugs to ameliorate these symptoms is significant. In this study, 100 women aged 50 to 60 years who complained of sleep disorders were studied. Subjects were selected randomly in a sampling method utilizing two groups of 50 people. The intervention group received valerian and lemon balm, while the placebo group received an inert alternative. The Pittsburgh Sleep Quality Index (PSQI) was administered both before and after the intervention was delivered. The results showed that there was a significant difference observed, with reduced levels of sleep disorders amongst the experimental group when compared to the placebo group. The authors did not elaborate on exactly what benefits were experienced, but likely a reduction in anxiety symptoms and a decrease in sleep onset latency. The authors conclude that valerian and lemon balm may assist menopausal women in reducing their symptoms of sleep disorder. Complement Ther Clin Pract. 2013. PMID: 24199972.

Prenatal SSRI Use and Offspring with Autism In this study, a total of 966 mother-child pairs were evaluated. 492 of the children had autism spectrum disorders (ASD), 154 had developmental delays (DD), and 320 had typical development (TD). The pairs were obtained from the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study, a population-based casecontrol study. Standardized measures confirmed developmental status. Interviews with biological mothers ascertained prenatal SSRI use, maternal mental health history, and sociodemographic information. The results showed that the prevalence of prenatal SSRI exposure was lowest in the TD children (3.4%) but did not differ significantly from ASD (5.9%) or DD (5.2%) children. Among boys, prenatal SSRI exposure was nearly 3 times as likely in children with ASD relative to TD (OR 2.91, 95% CI 1.07-7.93). The strongest association occurred with first-trimester exposure (OR 3.22, 95% CI 1.17-8.84). Exposure was also elevated among boys with DD (OR 3.39, 95% CI 0.98-11.75) and was strongest in the third trimester (OR 4.98, 95% CI 1.20-20.62). Findings were similar among mothers with anxiety or mood disorder histories. The authors conclude that in boys, prenatal exposure to SSRIs may increase susceptibility to ASD or DD. Pediatrics. 2014. PMID: 24733881.

June/July 2014 | www.ihpmagazine.com

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N AT U R A L M E D I C I N E

research news Acupuncture for treatment of arthralgia in women with early breast cancer: pilot study In this pilot study, the safety, efficacy, and feasibility of acupuncture was evaluated in treating aromatase inhibitor-induced arthralgia. Aromatase inhibitors are recommended as adjuvant hormone treatment for postmenopausal women with early breast cancer, but a significant portion experience joint pain and stiffness. A total of 32 patients were randomized to receive either sham or real electroacupuncture twice weekly for 6 weeks. Outcomes of joint pain, stiffness, and physical function were measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), overall pain and severity and interference with the BPI-SF and quality of life with the Functional Assessment of Cancer Therapy-General (FACT-G) instrument. Hand strength was assessed by a grip test, and a serum marker of inflammation (CRP) was also measured. All assessments were performed at baseline, 6 weeks, and 12 weeks, except for blood samples at baseline and 6 weeks only. The results showed that there were no significant differences in outcome measures, however positive trends were observed in stiffness and physical function at week 12 in favour of real electroacupuncture. The authors conclude that acupuncture is feasible and safe in patients with breast cancer with joint pain caused by aromatase inhibitors. Acupunct Med. 2013. PMID: 23722951.

Treating generalized anxiety disorder using CAM In this study, the authors evaluated the effectiveness of a pilot program that used multiple complementary and alternative medicine (CAM) therapies, focusing on self-care behaviours for treatment of generalized anxiety disorder (GAD). The study occurred at a military treatment facility in the Pacific Northwest. Participants were a convenience sample of volunteers seeking treatment, there were 37 enrolled in total who had a documented history of GAD or met screening criteria based on the GAD-7. The participants received acupuncture treatments once a week for 6 weeks and engaged in yogic breathing exercises, self or partner-assisted massage therapy using scented oils, episodic journaling, nutrition counseling, and exercise. The results showed that 68% of the participants completed the program. There were significant reductions in anxiety pre- and posttest using GAD-7 and there were also individual subscale reductions on the Depression Anxiety Stress Scale-21. While not specifically targeted for treatment, secondary exploratory outcomes included reductions in use of anxiolytic medication and in the pain scale. The authors conclude that in this pilot study, a multimodal intervention focusing on self-care behaviours may be feasible for patients seeking adjunctive treatments, and that it may produce anxiolytic effects validated measures. Altern Ther Health Med. 2013. PMID: 23981404. 18

Maternal vitamin D status and small-for-gestational-age offspring In this study, the association between second-trimester maternal serum 25-hydroxyvitamin D concentrations and risk of small for gestational age (SGA) in singleton live births was evaluated. Serum samples at 12-26 weeks of gestation for 25-hydroxyvitamin D were assayed in a sample of participants in a multicenter clinical trial of low-dose aspirin for the prevention of preeclampsia in high-risk women (n=792). The risk of SGA was assessed after adjustment for confounders including maternal prepregnancy obesity, race, treatment allocation, and risk group. The results showed that thirteen percent of neonates were SGA at birth. Mean vitamin D concentrations were lower in women who delivered SGA compared with non-SGA neonates. In adjusted models, vitamin D concentrations of 50-74 nmol/L and 75 nmol/L or greater compared with less than 30 nmol/L were associated with 43% (95% CI 0.33-0.99) and 54% (95% CI 0.24-0.87) reductions in risk of SGA, respectively. Race and maternal obesity each modified this association. White women with vitamin D of 50 nmol/L or greater compared with less than 50 had a 68% reduction in SGA risk and nonobese women with greater than 50 had a 50% reduction in SGA risk. The authors conclude that maternal vitamin D status in the second trimester is associated with risk of SGA. Obstet Gynecol. 2014. PMID: 24463662.

www.ihpmagazine.com | June/July 2014

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industry news Valeant Proposes to Combine With Allergan Valeant Pharmaceuticals International, Inc. announced that it has submitted a merger proposal to the Board of Directors of Allergan, Inc. under which each Allergan share would be exchanged for $48.30 in cash and 0.83 shares of Valeant common stock, based on the fully diluted number of Allergan shares outstanding. Shareholders will be able to elect a mix of cash and shares, subject to proration. The proposal represents a substantial premium based on Allergan’s unaffected price. Allergan shareholders will own 43% of the combined company and thereby continue to participate in the expected value creation of the combined company. Pershing Square, Allergan’s largest shareholder with a 9.7% stake in Allergan, has agreed to elect only stock consideration in the transaction and intends to remain a significant long-term shareholder of the combined company. Valeant and Pershing Square believe that the combination of the two companies is extremely compelling for both Allergan and Valeant shareholders and will create an unrivaled platform for growth and value creation in healthcare.

Non-insecticide treatment kills scalp pest An American study that claims hardto-kill “super lice” account for 97% of head lice cases in Canada for which there is no effective treatment, failed to investigate the availability of effective head-lice treatments in Canada. Contrary to the study’s claim, a safe, effective, noninsecticide treatment to which head lice, including “super lice”, their eggs and larvae cannot develop resistance is available in Canada. The treatment available in Canada is a dimeticone solution, NYDA, with a unique two-step mechanism of action. First, when applied to scalp and hair, NYDA penetrates deeply into the breathing system of lice and eggs, replacing the air. Second, NYDA solution thickens quickly, sealing the breathing system, thus suffocating and killing the parasites. The University of Massachusetts study, published in the March 2014 issue of the Journal of Entomology, examines

the extent and frequency in Canadian and U.S. populations of head lice with a mutation that makes them resistant to the insecticides contained in most head-lice treatments. The study concludes: “Alternative approaches to treatment of head lice infestations are critically needed.” In studies, NYDA has a proven efficacy rate of 97.2%. Most head lice treatments sold in Canada contain insecticide that does not kill all the eggs, leaving them to hatch, causing recurring infestations.

Canada’s Medical Laboratory Professionals Celebrate Awareness The Canadian Society for Medical Laboratory Science (CSMLS) is proud to celebrate awareness. Since 1985, CSMLS has sponsored this special awareness to highlight the vital role of medical laboratory professionals in Canada’s health care system.”Lab professionals are very proud of their role but their work is done behind closed doors so the public does not really understand how valuable it is” says Natalie Campbell, CSMLS President. “The contributions of these often unseen professionals are incredibly important to the health care system.” Over 1.2 million lab tests are performed on a daily basis in Canada and each one tells a story. Lab tests are crucial tools regularly used by medical practitioners to diagnose, monitor and treat patients. Each test provides vital information that guides medical decisions. Without lab tests, and the professionals to conduct them, quality patient care is impossible.

New Vaccines411™ Checklist In support of Immunization Awareness Week 2014, Vaccines411TM has created an immunization brochure for the general public asking: Are your immunizations up-todate? The goal is to encourage patients to talk to their healthcare professionals about which vaccines they may need. The Vaccines411TM immunization brochure contains a checklist that can be downloaded from the Vaccines411TM website and printed. Check off any of the boxes that may apply to you and bring the immunization checklist to your next appointment with your healthcare professional. To book an appointment at a vaccination clinic, visitwww.vaccines411.ca and enter your postal code to find the vaccination clinic nearest to you. The Vaccines411TM immunization brochure is a simple way to get the conversation started about whether your vaccines are up-to-date and for obtaining a healthcare professional’s opinion. “Some people might not know how to initiate the discussion about vaccines with their healthcare professional or don’t know what questions to ask. This checklist not only helps you determine what vaccines you may need or have received, but can also be used as a record. Just like the Clinic Finder, the Checklist was created to help Canadians stay healthy,” explains Francisca Roel, president of FR@SNM and founder of the Vaccines411.ca initiative.

SI Group to Acquire Antioxidants, Ibuprofen and Propofol Businesses from Albemarle SI Group, Inc. announced that it has signed a deal to acquire the Antioxidants, Ibuprofen, and related businesses and assets from Albemarle Corporation. The transaction includes manufacturing sites in Orangeburg, South Carolina, United States and Jinshan, China. This deal expands SI Group’s antioxidants business and will position the company as one of the top three global suppliers of Ibuprofen. “It’s the largest deal in SI Group’s history,” said Frank Bozich, SI Group President & CEO. “This acquisition is a natural fit to our expansion strategy, transforming SI Group into a solutions leader in the global antioxidant and pharmaceutical active ingredients markets.” The acquisition will include Albemarle’s antioxidant product lines, as well as the FDA-regulated Ibuprofen and Propofol businesses. In addition, applications and technical support capabilities in Shanghai and Baton Rouge, Louisiana, United States will be included in the transaction. “This acquisition is a major step in SI Group’s strategy of expanding into complementary, faster growing markets while at the same time continuously improving our core business through business excellence,” said Stephen Haller, Senior Vice President of Strategy and New Business Development. June/July 2014 | www.ihpmagazine.com

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industry news Poverty can make you sick and cost you more, StatsCan study shows The poorer you are the more it costs to stay healthy. That’s the conclusion of a Statistics Canada study released Wednesday and also validation of arguments that poverty is a health issue just as it is an economic one, the Canadian Medical Association (CMA) said. As a percentage of after-tax income, out-of-pocket spending on health care was greater in lower-income households, said the StatsCan study of prices between 1997 and 2009. In 2009, out-of-pocket spending on health care represented 5.7% of total after-tax income in households at the bottom of the income grid, compared with 2.6% at the top of the income scale. “This is further validation of what physicians have been saying for years social determinants like housing, nutrition, education and even literacy have a direct bearing on your health,’’ said Dr. Chris Simpson, Presidentelect of the Canadian Medical Association. “This is why one out of every five dollars spent on the health care system can be attributed to social determinants.’’ In a July 2013 report, the CMA urged the federal, provincial and territorial governments to elimination of poverty in Canada a top priority, and that guaranteed annual income be evaluated and tested through a major pilot project funded by Ottawa. Throughout the study period, StatsCan found the top three components of out-of-pocket health expenditures were dental services, medications and insurance premiums. Almost one in 10 Canadians cannot afford their prescriptions. The CMA believes making drug coverage available to all remains a serious piece of unfinished business in the transformation of the Canadian health care system.

2014 CaRMS R-1 Main Residency Match Results A record number of graduating students and physicians matched to residency training programs in Canada this year, the Canadian Resident Matching Service (CaRMS) announced. A total of 3,255 graduating students and physicians were matched in the 2014 R-1 Main Residency Match and will begin their postgraduate training on July 1, 2014. A total of 2,779 Canadian medical graduates (CMGs) were matched to residency programs, representing 96 per cent of CMGs participating in the match. Of those that matched, the majority (81 per cent) were accepted into one of their top three choices of residency programs, both by discipline and location. Interest in Family Medicine continued to grow, over 38 per cent of our graduates chose a career in Family Medicine – the highest level of interest in this discipline in the past twenty years. There was also a meaningful number of international medical graduates (IMGs) who matched to residency positions this year. A total of 449 IMGs matched a 10 per cent drop from the 2013 R-1 Main Residency Match. The Canadian Resident Matching Service is a not-for-profit organization that works in close cooperation with the medical education community, medical schools and residents/students to provide an electronic application service and a computer match for entry into postgraduate medical training throughout Canada. CaRMS strives to ensure the highest standards of fairness, transparency and neutrality throughout its electronic selection and matching process. It also provides comprehensive data collection, analysis and research that supplies timely intelligence to health policy decision-makers.

Minister Ambrose Continues to Fight Prescription Drug Abuse The Honourable Rona Ambrose, Minister of Health, reaffirmed her commitment to tackle the growing problem of prescription drug abuse head on. The Government of Canada will continue to work with groups like the Canadian Centre on Substance Abuse, different levels of government, doctors, pharmacists, First Nations representatives, law enforcement and addictions specialists to help combat prescription drug abuse, including those associated with oxycontin. Recently, Mr. Ben Lobb, Chair of the House of Commons Standing Committee on Health, tabled the Committee’s report entitled, The Government’s Role in Addressing Prescription Drug Abuse in Canada. The Minister will review the report’s recommendations. As announced in the 2013 Speech from 20

the Throne and Economic Action Plan 2014, the Government has committed to expanding the scope of its National Anti-Drug Strategy to address prescription drug abuse. These actions build on steps we have already taken to limit the illegal diversion of prescription opioids through tighter licensing rules under the Controlled Drugs and Substances Act. Through the Non-Insured Health Benefits Prescription Monitoring Program, we are also addressing the potential misuses of prescription drugs so that First Nations and Inuit clients can get the medications they need without being put at risk.

Metagenics Partners with Vitamin Angels Metagenics, Inc., announced their continued partnership with Vitamin Angels, a non-profit organization dedicated to distributing essential vitamins and minerals to at-risk pregnant women, new mothers, and children under five around the world. “Unfortunately, undernutrition is the underlying cause in 45 percent of deaths in children five and under,” said John Troup, PhD, the chief science officer for Metagenics, Inc. Vitamin Angels maintains that vitamin supplementation is the lowest cost, highest impact investment that can be made in the health of children worldwide. In 2013, contributions from Metagenics funded the efforts in providing a year’s supply of vitamin A for 100,000 children— also establishing the goal for 2014 contributions. Last year Vitamin Angels distributed nearly 200 million vitamins to 30 million children in about 45 countries, including the United States. “Our focus is ensuring that children have the nutritional foundation in place so health is not a barrier to their overall success. With partners such as Metagenics, we are able to help bolster their nutritional status as a step toward removing a hurdle on the path to a healthy future,” said Howard B. Schiffer, president and founder of Vitamin Angels. “With the continued support of our partners, we are one step closer to reaching our goal of serving 40 million children in 2014.” To learn more about how you can support Vitamin Angels, visit www.vitaminangels.org.

www.ihpmagazine.com | June/July 2014

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Curcumin’s Therapeutic Potentials Curcumin is a powerful antioxidant and anti-inflammatory, able to inhibit NF-κB signaling, TNF- α, and joint pain and inflammation. There is also much interest in its therapeutic potential in cancer. Curcumin has been seen as a very promising compound in the treatment and prevention of Alzheimer’s disease based on its ability in in vitro and in vivo research to bind β-amyloid and reduce its build-up in the brain (Frautschy, 2008). But problems of bioavailability, glucuronidation and crossing the blood-brain barrier have prevented clinical success (Baum et al., 2008; Belkacemi et al. 2011). Although many different “high-bioavailability” curcumin products are now available to the natural health industry, many of which have outrageous and unfounded bioavailability claims, the clinical studies behind Longvida® curcumin by far show the most promising results. Bioavailability Although Longvida® curcumin demonstrated a 65-fold increase in bioavailability as determined by its CMax compared to regular curcumin, the AUC (area under the curve) actually showed more than a 100-fold increase due to both better absorption and a longer half-life of 7 hours (Gota et al., 2010). Just one capsule of CurcuMIND delivers a therapeutically effective dose of curcumin, the equivalent of over 13g of a regular 95% curcumin extract. This would require taking 30 capsules of regular 95% curcumin extract, or more than 100 capsules of 750mg turmeric root extract! Longvida® curcumin nano-sized particles have a protective layer that protects them from gastric acid, intestinal fluids andphase II detoxification. Unlike other so-called bioavailable curcumins, Longvida® curcumin exists as free curcumin, not glucuronidated curcumin which does not pass through the blood-brain barrier. Cognitive Benefits of Longvida® Curcumin The incredible increase in bioavailability of Longvida® curcumin compared to normal curcumin has made it possible to study the effect of curcumin on Alzheimer’s disease in vivo, and a human study using the equivalent of 80-120 mg of curcumin from Longvida® curcumin (one capsule of CurcuMIND provides 133 mg) on Alzheimer’s patients is underway (Belkacemi et al., 2011). A new study led by Dr. DiSilvestro (2011) at the University of Ohio found an 8% decrease in serum β -amyloid in healthy subjects after only 1 month at a low dose of 80mg of Longvida® curcumin. Imagine the potential results of longer-term supplementation or in subjects with abnormally high levels of β-amyloid! Other significant findings from DiSilvestro’s study (2011) that relate to cognitive function include decreased salivary amylase, increased plasma catalase, and 14% reductions in both triglycerides and sICAM-1. Salivary amylase is a key marker of physiological stress, and stress is linked to higher β-amyloid levels (Ray et al., 2011). Catalase is an antioxidant enzyme in the body that also binds β-amyloid as well as quenches peroxide free radicals which make β-amyloid more neurotoxic. Reduced catalase levels are linked to increased β-amyloid toxicity and levels and cognitive disorders such as Alzheimer’s disease (Behl et al., 1994; Milton et al., 1999; Torres et al., 2011). Higher triglycerides and sICAM-1 levels are associated with increased levels of β-amyloid and are considered a risk factor for various brain diseases including Alzheimer’s disease (Frohman et al., 1991; Fujiwara et al., 2003; Burgess et al., 2006; Razay et al., 2007; Nielsen et al., 2007; Esmaillzadeh et al., 2008). Why Curcumin with Vitamin D? Vitamin D is also known to be important in immunity and inflammation. Vitamin D receptors are found in the hippocampus, the part of the brain most affected by β-amyloid and Alzheimer’s disease (Taghizadeh et al., 2011). Recent research is showing that vitamin D deficiency is a major factor in Alzheimer’s disease (Grimm et al., 2013), that vitamin D supplementation can help restore synaptic function (Taghizadeh et al., 2011), and that curcumin and vitamin D administered together have additive effects in restoring β-amyloid phagocytosis of some types of macrophages from Alzheimer’s patients (Masoumi et al., 2009; Fiala et al., 2011; Mizwicki et al., 2012). CurcuMIND is Safe & Effective Curcumin is therapeutically beneficial in many degenerative diseases. Longvida® curcumin has a phenomenal safety profile in both healthy individuals as well as in fragile populations such as cancer patients, and regular curcumin has shown no toxicity with up to 12 grams (Cheng et al., 2001; Lao et al., 2006; Gota et al., 2010; DiSilvestro et al., 2012). CurcuMIND by AOR delivers a high dose of Longvida® curcumin, the most bioavailable curcumin on the market that with the greatest potential for regulating inflammation, β-amyloid metabolism and cognitive health. References: Baum L et al. J Clin Psychopharmacol. 2008 Feb;28(1):110-3. Begum AN et al. J Pharmacol Exp Ther. 2008 Jul;326(1):196-208. Behl C et al. Cell. 1994 Jun 17;77(6):817-27. Belkacemi A et al. Expet Rev Mol Med. 2011 Nov; 13(e34):1-15. Buhrmann C et al. J Biol Chem. 2011 Aug 12;286(32):28556-66. Burgess BL et al. Neurobiol Dis. 2006 Oct;24(1):114-27. Cheng AL et al. Anticancer Res. 2001 Jul-Aug;21(4B):2895-900. Dadhaniya P et al. Food Chem Toxicol. 2011 Aug;49(8):1834-42. DiSilvestro RA et al. Nutr J. 2012 Sep 26;11:79. Esmaillzadeh A et al. 2008 Am J Clin Nutr 88(4). Fiala M et al. J Alzheimers Dis. 2011;25(1):135-44.

Frautschy, SA. 38th Annual Meeting of the Society of Neuroscience, Washington DC, November 15, 2008. Frautschy, SA et al. 39th Annual Meeting of the Society of Neuroscience , Chicago, IL October 2009. Frautschy, SA et al. 39th Annual Meeting of the Society of Neuroscience , Chicago, IL October 2009. Frohman EM et al. J Neurol Sci. 1991 Nov;106(1):105-11. Fujiwara Y et al. Gerontology. 2003 Nov-Dec;49(6):374-9. Gota VS et al. J Agric Food Chem. 2010 Feb 24;58(4):2095-9. Grimm MO et al. Neurodegener Dis. 2013 Oct 30. Lao CD et al. BMC Complement Altern Med. 2006 Mar 17;6:10.

Masoumi A et al. J Alzheimers Dis. 2009;17(3):703-17. Milton NG. Biochem. J. (1999) 344, 293-296 Mito S et al. Biol Pharm Bull. 2011 34(7):974-9. Mizwicki MT et al. J Alzheimers Dis. 2012;29(1):51-62. Nielsen HM et al. Neurobiol Dis. 2007 Apr;26(1):27-35. Ray, B et al. Neuroscience. 2011 Jun 16;184:139-50. Razay G et al. Arch Neurol. 2007;64(1):93-96. Taghizadeh M et al. Nutr Neurosci. 2013 Jul 23. Torres LL et al. J Alzheimers Dis. 2011;26(1):59-68.

industry news Safe Bone Healing With Effective New Bone Ingrowth In Osteomyelitis Patients BONESUPPORT, an emerging leader in injectable bone substitutes for orthopedic trauma, bone infections and instrument augmentation related to orthopedic surgery, announced the first patient outcomes data of CERAMENT™|G pertaining to an ongoing clinical trial in patients with osteomyelitis, as presented at The 4th Annual Oxford Bone Infection Conference. In the report, forty-one patients treated with CERAMENT™|G had no recurrence of infection, no late wound leakage, no toxicity and no renal complications at a mean follow-up of 9 months. Additionally, 78% of the patients demonstrated complete bone remodeling at 6 months. CERAMENT™|G is the first injectable antibiotic eluting bone substitute indicated to promote and protect bone healing being jeopardized by infection. “Local antibiotic management of osteomyelitis provides a much needed treatment option for people who suffer from chronic bone infections,” said Mr. Martin McNally, Lead Surgeon of the Bone Infection Unit at the Nuffield Orthopaedic Centre in Oxford, United Kingdom. “We are pleased by early results and are optimistic that CERAMENT™|G offers the potential to improve health outcomes, lower healthcare costs and deliver a higher quality of life for patients suffering from this devastating disease.” Osteomyelitis, or Bone Infection is a $1.7 billion market where prolonged, long-term antibiotic therapy, multiple surgical interventions and the threat of amputation are the current standard of care. Rising prosthetic infections, diabetic ulcers, war injuries, sports injuries, and an increasing resistance to antibiotics contribute to this growing condition.

Walking to support people with kidney disease and promote organ donation The Kidney Foundation is inviting all transplant recipients, living donors and their loved ones to attend one of the fifteen Kidney Walks. Participants may register online or by completing a printed registration form. The Foundation hopes

to welcome a record number of transplant recipients and donors this year in order to celebrate The Kidney Foundation of Canada’s 50th anniversary in the company of patients, families, supporters and health professionals. Since its creation in 1964, The Kidney Foundation of Canada has allocated $110 million to kidney research, enabling thousands of Quebecers to see their quality of life improve significantly and maintain the hope that one day, kidney disease will be beaten. Thanks to research, the kidney has become the most grafted organ, and kidney transplants now have the highest success rate of all transplants. This success is due in part to our researchers’ many accomplishments: the development of antirejection drugs, the discovery of antibodies and improvements in dialysis treatments. Every Kidney Walk is yet another occasion to celebrate achievements and the promising new projects that will help improve the quality of life of people with kidney disease.

Neurosurgery journal published study reinforces value of highfield iMRI IMRIS Inc. announced that a study published this month in the journa Neurosurgery by the neurosurgical team at Cleveland Clinic adds to growing clinical evidence which validates use of high-field intraoperative MRI (iMRI) as an effective tool for maximizing the amount of surgical resection of gliomas (brain tumors). Conducted using an IMRIS VISIUS® Surgical Theatre, the study retrospectively reviewed use of high-field 1.5T (tesla) iMRI on the extent of resection of enhancing (high-grade) and non-enhancing (low-grade) gliomas in 104 surgical cases. This and past studies have indicated a link between increased or more complete removal of some types of tumors and longer life expectancy and quality of life. Use of iMRI, according to the article, was associated with improvement in the median amount of tumor removal from 94.9 percent before iMRI to a final of 99.6 percent post-surgery after iMRI. Complete resection was possible in 65 percent of patients when iMRI was used compared to 34 percent without iMRI. All resection results were considered statistically significant. The results reinforce previously published evidence that IMRIS systems with highfield iMRI-guided surgery are more effective in achieving complete resection than conventional surgery using neuronavigation and direct visualization alone.

Atrium Innovations announces management transition Atrium Innovations Inc., a globally recognized leader in the development, manufacturing and commercialization of innovative, science-based natural health products, announced that Pierre Fitzgibbon, President and CEO of Atrium, will step down from the Company in 2014, by mutual agreement with the Board of Directors. Mr. Fitzgibbon will remain President and CEO while the Board conducts a search for his replacement and will continue to be one of Atrium’s largest individual shareholders after his departure. On behalf of Atrium’s owners - the Permira Funds, Fonds de solidarité FTQ and Caisse de dépôt et placement du Québec - John Coyle, Partner at Permira, said, “Pierre’s leadership has been critical to developing Atrium and its portfolio of leading global brands into the successful business it is today. We are grateful for his contributions and are pleased that he has agreed to remain in his position to ensure a smooth management transition over the coming months. Atrium has tremendous opportunities ahead and we are confident we will identify a world-class leader to continue the company’s accelerated growth and expansion.” Mr. Fitzgibbon stated, “I am very proud of what our team has achieved and believe that we have established a very strong platform from which the Company can pursue growth and continue to provide outstanding products for our customers. Leading Atrium for the past seven years has been a very rewarding experience in my career and both the Board and I concluded that 2014 is the right time for the Company to find a new leader as I am eager to pursue other interests.” The Board has retained Spencer Stuart, one of the world’s leading executive search consulting firms, to conduct the CEO search. Separately, the Board has also retained J. Robert Swidler & Associates, based in Montreal, to lead the search for a Québec resident Chairman. ■ June/July 2014 | www.ihpmagazine.com

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calendar JUNE June 7 Integrative Medicine for Children's Mental Health Organized by: CSOM Toronto, ON For more information, visit www.csom.ca June 11 Treatment and prevention of adrenal hormone imbalances Organized by: Restorative Medicine Online Teleconference For more information, visit www.restorativemedicine.org/ cme-webinars/ June 11 PCOS and Role of Botanical Medicine Organized by: AANP Format Unspecified For more information, visit www.naturopathic.org June 19-21 Infectious Diseases for Primary Care Organized by: MCE Conferences Smokey Mountains National Park, Tennessee For more information, visit www.mceconferences.com/medicalconferences.php June 21-22 Nutrition for Docs - A Practical, Evidence-based Approach Organized by: CSOM Ottawa, ON For more information, visit www.csom.ca

JULY July 4-6 International Naturopathy Congress ICNM 2014 Organized by: ICNM Paris, France For more information, visit www.icnmnaturopathy.org July 9 Adaptogenic herbs and nutritional treatments for restoring optimal adrenal performance 24

Organized by: Restorative Medicine Online Teleconference For more information, please visit www.restorativemedicine.org/ cme-webinars/

AUGUST August 6-9 AANP Conference Organized by: AANP Keystone, Colorado For more information, visit www.naturopathic.org/aanp2014 August 13 Clinical applications of T4/T3 and the role of T3-containing compounds Organized by: Restorative Medicine Online Teleconference For more information, visit www.restorativemedicine.org/cme-webinars/

SEPTEMBER September Date TBA IVT Therapy Course Organized by: OAND Toronto, ON For more information, visit www.oand.ca September 10 Treatment of postmenopausal hot flashes and sleep disturbances Organized by: Restorative Medicine Online Teleconference For more information, visit www.restorativemedicine.org/ cme-webinars/

September 27-28 Advanced Workshop: Biotherapeutic Drainage Organized by: Seroyal Toronto, ON For more information, visit www.seroyal.com

OCTOBER October 1 A closer look at estrogens, breast health, and other therapeutics Organized by: Restorative Medicine Online Teleconference For more information, visit www.restorativemedicine.org/ cme-webinars/ October 2-3 OAND Business Symposium Organized by: OAND Toronto, ON For more information, visit www.oand.ca October 3-5 Evolution of Disease and Biotherapeutic Drainage for Individualized Medicine Organized by: Seroyal Vancouver, BC For more information, visit www.seroyal.com October 9-12 AARM's Annual Conference Organized by: Restorative Medicine Online Teleconference For more information, visit www.restorativemedicine.org

September 11 Case Management and Treatments for Lyme Disease Organized by: Seroyal Online Teleconference For more information, visit www.seroyal.com

October 11-12 2014 ILANP Conference: Integrative and Nutritional Approaches to GI Health Organized by: AANP Format Unspecified For more information, visit www.naturopathic.org

September 24 Pre and Post Natal Nutrition and Raising "Super Babies" Organized by: Seroyal Online Teleconference For more information, visit www.seroyal.com

October 18 Biotherapeutic Drainage and UNDA Compounds Organized by: Seroyal Seattle, WA For information, visit www.seroyal.com

www.ihpmagazine.com | June/July 2014

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NPN 80012473

Probiotic drops Lactobacillus reuteri DSM 17938 (L. reuteri Protectis ) TM

Digestive Health and Colic Relief

What are BioGaia Probiotic Drops used for? Provide live microorganisms to benefit health and/or to confer a health benefit. Infants: BioGaia helps reduce episodes (duration) of crying in infants suffering from colic. What is the Active Ingredient in BioGaia Probiotic Drops? 5 drops contain a minimum of 100 million live active Lactobacillus reuteri DSM 17938 (L. reuteri Protectis) What is a probiotic? The word “probiotic” means “for life” as opposed to antibiotics which mean “against life”. Probiotics are clinically proven, health fortifying, natural active bacterial cultures. Or as the World Health Organization (WHO) chose to describe it: “Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host.” Not all probiotics are alike. Experts believe that the benefits of probiotics are strain-specific and recommend that all probiotics should be independently tested and evaluated in clinical trials as BioGaia Probiotic Drops have been. What are BioGaia Probiotic Drops? Lactobacillus reuteri Protectis is a patented probiotic bacteria that is in BioGaia Probiotic Drops. Because L. reuteri occurs in the human body it is uniquely adapted to live in humans. With its exceptional and documented health benefits in several areas, L. reuteri is considered a truly superior probiotic. BioGaia Probiotic Drops are a probiotic that helps promote a healthy, balanced digestive system when taken daily. BioGaia Probiotic Drops have demonstrated beneficial effects on common digestive upsets such as diarrhea, constipation, gas and bloating. Are BioGaia Probiotic Drops safe? Safety studies with L. reuteri have been conducted in healthy newborns, small children, adults and immuno-deficient adults over the past decade. In all of these studies, L. reuteri has been proven to be free from side effects, even when given in doses greatly exceeding the levels normally contained in L. reuteri products. Over 3.5 billion daily doses of L. reuteri have been consumed all over the world since 1996, without any reported side effects. How long does it take to feel the effects of taking Biogaia Probiotic Drops? Normally you should notice the effects within a few days. While people who are healthy may not experience any differences, those taking L. reuteri because of a digestive system disturbance may notice an improvement in symptoms after 3-4 days. In some cases it may take longer if the person is, for example, taking a medication affecting the digestive system. Dosage: Adults, Children and Infants: 5 drops once a day or use as directed by your health care practitioner. For use beyond 21 days, consult your health care practitioner. If antibiotics are being taken, take at least 2-3 hours before or after taking antibiotics. Directions: Shake well before using. Warm BioGaia Probiotic Drops slightly by rolling the bottle back and forth in your hands for 1 minute. To get the daily dosage, turn the bottle upside down and the drops will form slowly. The drops may be given on a spoon or added to milk, water or any other suitable drink or food. Do not add to hot food or drink as this may damage the live cultures. The drops do not change the taste of food or drink. Return BioGaia Probiotic Drops to the refrigerator after use. Opened bottle should be used within 3 months.

Non-medicinal Ingredients: Sunflower oil, medium chain triglyceride oil and silicon dioxide. BioGaia Probiotic Drops do not contain preservative or alcohol. Cautions and Warnings: Discontinue use and consult a health care practitioner if symptoms of digestive upset (e.g. diarrhea), occur, worsen, or persist beyond 3 days. Contraindications: Do not use if you are experiencing nausea, fever, bloody diarrhea or severe abdominal pain. Do not use if you have an immune compromised condition (e.g. AIDS, lymphoma, patients undergoing long-term corticosteroid treatment).

200 Yorkland Blvd., Toronto, Ontario M2J 5C1 1-800-263-4057 ® BioGaia is a registered trade mark of BioGaia AB www.biogaia.com

3-340-11-4/5

3028-005

Storage: Keep refrigerated (2-8°C). Do not allow the bottle dropper to come in contact with any liquid, including saliva. Keep the container closed. Opened bottle should be used within 3 months.

product profiles

Legend

g al ine ine thy lth re er tes try ics ics on lth lth tic llin c c a ea ssu anc abe chia iatr riatr triti Hea Hea se ceu edi edi eop u C Di sy d e n r H Pre u a l ra n M l M om Pe G ts N une en’s o P t d u a C u H or m om sc loo et al/N Asia anic p a i m B S V I D W t . n Bo tio Trad tri Nu

Curcummatrix™ Curcummatrix™ offers a patented technology specifically designed to increase the bioavailability. Curcummatrix™ offers a solubility in duodenal conditions 7.5 times greater than the same amount of native curcumin.

NEW Easy-to-Swallow Fish Oil from Progressive

CurcuMIND Delivers vitamin D3 with the equivalent of 13 grams of free curcumin with Longvida® curcumin, the only curcumin known to cross the blood brain barrier.

Each OmegEssential® JEWELS mini softgel has 50% more EPA than most regular strength softgels and it’s only half the size!

NAC SAP NAC SAP from NFH provides 500mg per capsule of this important glutathione precursor. N-Acetylcysteine (NAC) is a precursor to glutathione synthesis and also acts on its own to reduce the effects of reactive oxygen species. NAC has been demonstrated to have antifibrotic activity and may be a useful treatment in disease processes that involve fibrosis. NAC also has mycolytic properties and decreases viscosity of lung secretions.

Metagenics Launches NutraGems Omega Forte™ NutraGems Omega Forte features health-promoting omega-3s with vitamins A, D, E, and K in great-tasting, citrus-flavored gels that melt in the mouth— perfect for children and adults who prefer not to swallow pills. Nutritional Support That’s Easy to Take. Metagenics.com • 800.268.6200 June/July 2014 | www.ihpmagazine.com

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product profiles

Legend

Mag-Matrix Liquid™ Mag-Matrix Liquid™ is a unique blend of highly absorbable magnesium sources-magnesium glycinate, malate and citrate. Sweetened with xylitol and a subtle but pleasing natural lemon flavour.

Ferring VSL#3®is a high potency blend of 8 different probiotics. It contains the highest concentration of probiotic bacteria (450 billion CFU per sachet) available in Canada.

St Francis Herb Farm Red Clover Plus Salve Red Clover Plus is an unrivalled general purpose and first aid salve for a range of skin conditions. In addition, this salve makes for a powerful alternative to cortisone cream.

Genestra Brands Al-gen Al-gen (formerly ALLER-GEN) is a phyto-gen comprised of synergistic ingredients including black currant, rosemary and juniper that have been carefully selected. Al-gen is a symbiotic preparation with phytonutrient properties. This plant based extract is available in 15ml liquid and is recommended for adults and children over 12 years of age. Simply drop 10 drops directly in the mouth or mix with a drink.

proteins+Natural Chocolate Peanut Butter Introducing a NEW flavour: proteins+Natural Chocolate Peanut Butter • Great tasting! • Provides 28g of high quality alpha+TM whey protein isolate per serving • Blends easily with no clumping • Builds lean muscle* • Supplies a balance of all amino acids which helps build and repair body tissues • Builds antibodies

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product profiles

Legend

L-Glutamine SAP L-Glutamine SAP provides the amino acid L-glutamine is an easy to dose palatable powder form at 5g per scoop. l-Glutamine is the most abundant amino acid in the human body .L- Glutamine is metabolized in the small intestine and serves as an important fuel source for intestinal mucosa. Glutamine plays an important protective role in the intestinal tract, and is crucial for patients with increased permeability of the intestinal system, which can be seen in patients with inflammatory bowel diseases including for example Crohn’s disease or ulcerative colitis, as well as in irritable bowel syndrome and allergies. This amino acid plays an important role in nutrient metabolism, the immune system, protein turnover and acid-base balance.

Metagenics Launches BenesomTM

Vegan greens+ O natural vanilla flavour Now everyone can enjoy greens+ - the original and only RESEARCH-PROVEN green food supplement. We have specially formulated Vegan greens+ O for consumers who have allergies and sensitivities to certain foods and environmental chemicals.

Benesom is used as a sleep aid and to relieve nervousness. It contains melatonin, which helps to reduce the time it takes to fall asleep in people with delayed sleep phase disorder. This exciting formulation also contains Chinese Skullcap, Passionflower, Lemon Balm, Magnesium, Valerian and other ingredients. Sixty tablets per bottle. Metagenics.com • 800.268.6200

Genestra Brands HMF Forte is a moderate-level, long term maintenance probiotic with 10 billion CFU per dose. Ideal for vegans, it supports a healthy normal digestive flora and comes in a convenient vegetable capsule format. Great for adults and children (6 years and older), the formula is glutenfree and dairy-free making it perfectly suitable for those with allergies and sensitivities.

BASENTABS pH-balance PASCOE® The Basis of Health Are your patients suffering from persistent stress, chronic fatigue or nutritional imbalance? If they are experiencing any of these, they might need support to regulate their acid-base balance. For all important metabolic functions to work optimally, the body’s acid-base balance must be in equilibrium. BASENTABS pH-balance PASCOE® is a revolutionary formula with a balanced mixture of bicarbonates, now with Zinc. Proven high alkalinizing capacity, a key basic therapy for chronic illnesses, free of sugar, gluten and lactose For more information, visit: www.pascoe.ca. June/July 2014 | www.ihpmagazine.com

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A Breakthrough in Healthy Aging

PhytoMulti The Smart Multi

“

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foundation supplementation designed to help defy aging. It’s the only multi providing a research-based, broad spectrum of phytonutrients and plant extracts scientifically tested for antioxidant protection and DNA stability potential.† With PhytoMulti, provide your patients a solution that supports healthy aging unlike any other daily PhytoMulti tablets are available with or without iron.

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Validated by Total ORACFN (oxygen radical absorbance capacity) and Comet assays. Capsules are composed of plant-derived ingredients. Not all contents inside the capsule are vegetarian.

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METAGENICS PHYTOMULTI PhytoMulti by Metagenics is a robust multivitamin fortified with over 20 phytonutrient extracts, including lutein, greet tea extract, and resveratrol. As such, PhytoMulti is an ideal product for use in adults in order to optimize vitamin and mineral status, in lieu of poor dietary intake or increased physiological requirements, but also provides a broad spectrum of plant nutrients in order to mimic the many health effects of a plant-based diet. The USDA MyPlate recommendations include between 9-10 servings of fruits and vegetables per day, but less than 10% of adults achieve this target (Murphy 2011). The Mediterranean dietary pattern is an example of a well-researched diet that is very high in phytonutrients. The Mediterranean diet is associated with markedly lower risk of several chronic diseases, including cardiovascular disease and diabetes (Eustruch 2006, Interact Consortium 2011, Nordmann 2011), and a high fruit and vegetable diet has been shown to reduce risk of cancer (Block 1992), in large part due to high amounts of combined phytonutrients. Phytonutrients have been shown to confer beneficial health effects through numerous mechanisms, including modulation of signal transduction pathways, antioxidant properties, and through hormonal effects. PhytoMulti contains over 20 of these plant substances, including: lutein, zeaxanthin, acacia nilotica, and extracts of artichoke leaf, grape seed extract, green coffee, green tea, citrus bioflavonoids, resveratrol, prune skin, watercress, rosemary, pomegranate, lycopene, cinnamon, bitter melon, and blueberry. Multivitamin supplementation has been shown to benefit a variety of physical and cognitive parameters particularly in children, pregnant women or women who may become pregnant, individuals under increased stress, individuals with poor absorption, and the elderly. In pregnancy, supplementation with a folic acid containing multivitamin has been shown to reduce risk of complications such as placental abruption, preeclampsia, in addition to decreasing risk of congenital defects including neural tube defects, anencephaly, myelomeningocele, meningocele, oral facial cleft, structural heart defects, limb defects, urinary tract anomaly, and hydrocephalus when used prior to conception and during the first trimester (Wilson 2007). Periconceptional multivitamin use in lean women has been shown to decrease the risk of small-for-gestational-age (SGA) under the 5th percentile by up to 46% compared to non-users (OR=0.54, 95% CI), and has been associated with a 71% reduction in preeclampsia risk (OR=0.29, 95% CI) in lean women, users versus non-users (Catov 2007; Bodnar 2006). Periconceptional multivitamin use has also been associated with reduced risk of several pediatric cancers, including leukemia (OR=0.61) (39% reduced risk); pediatric brain tumors (OR=0.73) (27% reduced risk); and neuroblastoma (OR=0.53) (47% reduced risk) in a recent metaanalysis (Goh 2007). In patients under high levels of psychological stress, use of a multivitamin has been shown improve perceived levels of stress and psychometric parameters. Gruenwald et al (2002) found that use of a multivitamin for 6 months resulted in a 40.7% overall improvement in self rated stress levels using a psychologicalneurological questionnaire to assess “psycho-organic, central vegetative, and somatic discomforts.” Other outcomes included a 29% decrease in frequency of infections and 91% decrease in gastrointestinal discomfort. Schlebusch et al (2000) found similar benefit on various psychometric parameters in a 30 day trial (1997), and Harris found that multivitamin supplementation can improve measures of mood, stress, and alertness in older men (2011). Importantly, supplementation with a spectrum of B vitamins has also been shown to reduce ratings of workplace stress (Stough 2011). Several trials have shown increased cognitive performance in children taking a multivitamin supplement. Benton et al (1988) found a significant increase in nonverbal intelligence in children taking a multi versus those taking placebo after 8 months’ intervention. In a 14 month study of 608 children, Vazir et al (2006) found a significant increase in attention-concentration increment scores in those supplemented with a micronutrient-fortified beverage versus those receiving placebo. Additional benefits demonstrated in children include a reduced mean duration (5.0 versus 7.5 days, supplement versus placebo) of several common childhood illnesses including such as fever, cough and cold, diarrhea, and ear infections (Sarma 2006). In the elderly, multivitamin supplementation has been shown to significantly improve status of such nutrients as vitamin D, vitamin B6, vitamin B12, folate, vitamin C, vitamin E, zinc, and selenium (McKay 2000; Girodon 1997). In addition, supplementation has also been found to significantly reduce rates of infection in the elderly, as found a trial in 81 subjects given various supplemental combinations of micronutrients and followed over a 2 year period (Girodon 1997).

PhytoMulti: Active Ingredients* (per 1 tablet) Ingredient Vitamin A as retinyl acetate Vitamin A as carotenoids Vitamin E d-alpha tocopherol Vitamin C ascorbic acid Vitamin D3 cholecalciferol Vitamin K phytonadione Thiamine mononitrate

Dose 2500 2500 50 60 500 60 12.50

Unit IU IU IU mg IU mcg mg

Riboflavin 7.50 mg Niacin 6.25 mg Niacinamide 18.75 mg Pantothenic acid 37.5 mg Vitamin B6 pyridoxine HCl 12.50 mg Calcium L-Mefolinate 400 mcg Vitamin B12 cyanocobalamin 120 mcg Biotin 250 mg Magnesium citrate 20 mg Chromium polynicotinate 100 mcg Copper citrate 500 mcg Iodine potassium iodide 75 mcg Manganese citrate 250 mcg Molybdenum aspartate 25 mcg Selenium aspartate 50 mcg Zinc citrate 7.50 mg * In addition to extracts of over 20 phytonutrients.

References Benton D, Roberts G. Lancet. 1988 Jan 23;1(8578):140-3. Block G, et al. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutrition and cancer 1992;18(1):1-29. Bodnar LM, Tang G, Ness RB, Harger G, Roberts JM. Am J Epidemiol. 2006 Sep 1;164(5):470-7. Epub 2006 Jun 13. Catov JM, Bodnar LM, Ness RB, Markovic N, Roberts JM. Am J Epidemiol. 2007 Aug 1;166(3):296-303. Epub 2007 May 11. Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Fertil Steril. 2008 Mar;89(3):668-76. Epub 2007 Jul 10. Eustruch R, Martínez-González MA, Corella D, et al. Ann Intern Med. 2006 Jul 4;145(1):1-11 Girodon F, Lombard M, Galan P, Brunet-Lecomte P, Monget AL, Arnaud J, Preziosi P, Hercberg S. Ann Nutr Metab. 1997;41(2):98-107. Goh YI, Bollano E, Einarson TR, Koren G. Clin Pharmacol Ther. 2007 May;81(5):685-91. Epub 2007 Feb 21. Grieger JA, Nowson CA, Jarman HF, Malon R, Ackland LM. Eur J Clin Nutr. 2007 Nov 28. Gruenwald J, Graubaum HJ, Harde A. Adv Ther. 2002 May-Jun;19(3):141-50. Harris E, Kirk J, Rowsell R, Vitetta L, Sali A, Scholey AB, Pipingas A. Hum Psychopharmacol. 2011 Dec;26(8):560-7. InterAct Consortium. Diabetes Care. 2011 Sep;34(9):1913-8. McKay DL, Perrone G, Rasmussen H, Dallal G, Hartman W, Cao G, Prior RL, Roubenoff R, Blumberg JB. J Am Coll Nutr. 2000 Oct;19(5):613-21. Murphy MM, et al. Journal of the American Dietetic Association 2011:in press. Nilsen RM, Vollset SE, Rasmussen SA, Ueland PM, Daltveit AK. Am J Epidemiol. 2008 Apr 1;167(7):867-74. Epub 2008 Jan 10. Nordmann AJ, Suter-Zimmermann K, Bucher HC, et al. Am J Med. 2011 Sep;124(9):841-51.e2. Ribeiro ML, Arçari DP, Squassoni AC, Pedrazzoli J Jr. Mech Ageing Dev. 2007 Oct;128(10):577-80. Epub 2007 Aug 15. Sarma KV, Udaykumar P, Balakrishna N, Vijayaraghavan K, Sivakumar B. Nutrition. 2006 Jan;22(1 Suppl):S8-14. Schlebusch L, Bosch BA, Polglase G, Kleinschmidt I, Pillay BJ, Cassimjee MH. S Afr Med J. 2000 Dec;90(12):1216-23. Stough C, Scholey A, Lloyd J, Spong J, Myers S, Downey LA. Hum Psychopharmacol. 2011 Oct;26(7):470-6. Tanvetyanon T, Bepler G. Cancer. 2008 Jul 1;113(1):150-7. Vazir S, Nagalla B, Thangiah V, Kamasamudram V, Bhattiprolu S. Nutrition. 2006 Jan;22(1 Suppl):S2632. Wilson RD, et al. J Obstet Gynaecol Can. 2007 Dec;29(12):1003.

cover story

RUTH PETTLE WELLNESS CENTRE Integrative Womenâ&#x20AC;&#x2122;s Health By Christopher Habib, ND Photography by Eric Forget

We at IHP Magazine are excited to share the story of Dr. Alvin Pettle, MD and his team. Dr. Pettle is a pioneer Canadian gynecologist who practices integrative medicine. He has published a number of articles on natural hormones and has had numerous television and radio appearances. He graduated from the University of Toronto medical school in 1969 and received his fellowship on obstetrics and gynecology in 1974.

Ruth Pettle Wellness Centre 3910 Bathurst Street Toronto, ON M3H 5Z7 Phone: (416)-633-4101 Website: www.drpettle.com

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cover story

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Dr. Pettle practiced obstetrics and gynecology for 25 years at The Etobicoke General Hospital, where for a period of 4 years he was the Chief of Obstetrics and Gynecology. Dr. Pettle was the Canadian pioneer in the Leboyer Gentle Birth Technique, which incorporates a soothing and joyous atmosphere and using dim lights and warm baths to promote a gentle birthing process. Dr. Pettle delivered one hundred babies as an intern in 1969 at Mount Sinai Hospital and has since assisted in an impressive 10,000 deliveries. Since the start of his career in medicine, Dr. Pettle had a strong interest in Womenâ&#x20AC;&#x2122;s Health. In 1994, he took 6 months off to figure out what to do with his life. At this point, he transitioned away from allopathic medicine towards integrative medicine, realizing he wanted to work with bioidentical hormones. He covered a maternity leave for Dr. Sonja Kustka, MD and worked in an office on St-Clair Avenue for 5 years. He then opened The Ruth Pettle Wellness Center, named in memory of his mother who passed away of breast cancer. The clinic spans 4 separate levels and is approximately 3500 square feet in total. The clinic incorporates numerous practitioners and offers a variety of health services. Dr. Pettle works closely with his wife, Carol Pettle, who is a registered nurse and formally the Head Nurse of the Labor and Delivery Department at The Etobicoke 34

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General Hospital. In addition to some administrative management, Carol also interviews patients, draws blood for lab testing, and counsels patients on various aspects of their health including nutrition. The clinic also features Raisa Weisspapir who practices homeopathy and Dr. Gregory Pugen, MD who does IV therapy, chelation, and bioidentical hormone therapy for men; Dr. Benjamin Merzel, DC, ND, who is an integrative chiropractor and board certified acupuncturist who treats painful joints and muscles without drugs; Walter Orlowski, a homeopathic doctor specializing in hypnotherapy. Finally, the clinic also provides thermography, which is managed by board certified thermographer, Dr. Alexander Mostovoy, MD. The majority of the patients at the clinic have an interest in bioidentical hormone therapy, which Dr. Pettle believes is the way of the future. In his practice, he sees a large number of women who are experiencing perimenopause and have estrogen dominance. In general, his main treatment outcomes are achieving hormonal balance and mitigating any symptoms of PMS. Dr. Pettle teaches women how to deal with unopposed estrogen and a large part of his practice is on breast cancer prevention. He believes prevention is of paramount importance. In this regard, he feels one of the biggest mistakes

that physicians have made is to prescribe oral hormones (such as estrone and DHEA). He explains that the consequences of prescribing hormones orally may create a higher degree of risk and can become problematic due to the way the body processes them. By providing hormones through other routes of administration such as transdermally, the first pass of the liver can be avoided and the end-result is usually a safer and more effective treatment for the patient. Dr. Pettle also believes the importance of progesterone has been understated, especially for those between the ages of 40 and 50. Dr. Pettle routinely measures hormone levels. He believes it is useful to show patients the actual objective changes that occur as a result of their treatment. Although there is a cost associated with it, Dr. Pettle believes one of the most accurate ways to assess someoneâ&#x20AC;&#x2122;s hormone levels is to do a 24-hour urine collection test. The clinic utilizes the laboratory services of Rocky Mountain Analytical and Meridian Valley Labs. Using these tests among others, Dr. Pettle is able to achieve successful treatment outcomes using the smallest doses possible. Prescribing hormones is not a cookie-cutter approach and everything must be individualized. As a result of Dr. Pettleâ&#x20AC;&#x2122;s experience, he is extremely knowledgeable in terms of what mix of hormones might work well for individual patients. June/July 2014 | www.ihpmagazine.com

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Dr. Pettle believes the allopathic community is uncomfortable with bioidentical hormones, in part because the topic has not been largely explored during the medical education process. However, he feels the future of medicine depends on integrating the strengths of various practitioners. In particular, he is a big fan of naturopathic medicine, botanical medicine, and homeopathy. He’s previously taught at the Canadian College of Naturopathic Medicine and believes that the education process in medical schools needs to incorporate bioidentical hormones. He believes that all health care practitioners should respect one another and seek to collaborate with each other for the best interest of the patient. His ideal model of health puts the patient at the centre of a wheel, with each spoke corresponding to the different practitioners or services that that patient can access. With this type of system, he believes the patients are the winners. He also feels that doctors should learn from their patients as he does, and similarly that they should learn from each other. To this end, he has several physicians come into his office to train them in the use of hormones. Dr. Pettle currently manages up to 150 patient visits per week. He wakes up at 4:30am on a daily basis and begins with phone consultations at 6:30am, sometimes communicating with people across the globe. He has been involved with co-authoring a number of books and has also written his own book, titled ‘My Prescriptions for Life’. He is currently working on a breast cancer prevention book. Eventually, he is hoping to write a book with his wife about their entire story and all that their experiences in Women’s Health has taught them. Although many doctors do not want to put themselves on the radar when it comes to bioidentical hormones, Dr. Pettle has been a strong leader in this field. We at IHP wish him continued success. ■

Dr. Alvin Pettle, MD, FRCP Carol Pettle, RN Raisa Weisspapir, Homeopath Dr. Gregory Pugen, MD Dr. Alexander Mostovoy, MD Dr. Benjamin Merzel, DC, ND Walter Orlowski, Homeopath, Hypnotherapist

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For Details, write #114 on Free Info Page, page 96.

ihpSept10_NAHS_Ad.indd 1

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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

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clinic profile

The root of Health Putting The Patient First By Christopher Habib, ND Photography by Robyn Russell

his issue IHP is pleased to share the story of an integrative clinic in the Oakville community. Dr. Jodie Peacock, ND, has been managing her clinic, The Root of Health, for over 5 years. She initially wanted to open her own clinic after being exposed to a number of clinics through her work with NFH (Dr. Peacock is a Medical Consultant and Territory Manager). Her vision was to create a space where likeminded practitioners could work together, while still maintaining their own independent practices. She wanted to provide many healthcare alternatives in one physical location, and that way patients could reasonably obtain all services in one place with a strong continuity of care. Dr. Peacock believes inter-referrals among different practitioners is what really allows for the best patient experience. Within her clinic model practitioners pay rent, but itâ&#x20AC;&#x2122;s not intended to be a financial burden. For example, a practitioner may start working one day a week and have low overhead, and then scale up as time goes on. Part of the goal is to ensure the clinic team feels supported and works in interest of the clinic as a whole. When Dr. Peacock first opened her doors, it was just her and Sarah Ritchie, BA, B.Ed, RMT, RAc, Reiki Master. Today she works with a full team of diverse practitioners and collectively they see upwards of 100 patient visits per week.

The Root of Health 1525 Cornwall Road, Unit #6 Oakville, Ontario Phone: 905-845-ROOT (7668) Email: rootofhealthinfo@gmail.com Website: http://www.rootofhealth.ca

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The clinic is approximately 1400 square feet and consists of six treatment rooms, a common kitchen area with laundry and labs, and a common waiting area. Three of the treatment rooms are larger and accommodate for more treatment space and desk space. The other rooms are used for bodywork and counseling work. In general, the services offered at the clinic include naturopathic medicine, osteopathy, massage, acupuncture, reiki, craniosacral therapy, homeopathy, nutritionist services, ayurvedic services, and reflexology. The practitioners at the clinic have a variety of specialties. Dr. Peacock's practice is a general family practice, with a focus in fertility and pain management. She uses acupuncture a significant amount, as well as botanicals or nutrients depending on specific patient deficiencies. Sarah Ritchie is very intuitive with her treatments. Sheâ&#x20AC;&#x2122;s a unique practitioner because of her focus in eastern medical modalities including TCM, Shiatsu and energy work and she gets great results with her patients. Dr. Ann Nakajima, ND, has a larger focus on homeopathy, UNDA drainage, Bowen therapy, and TCM. She focuses on women's and childrenâ&#x20AC;&#x2122;s health. Mark Aquino, Osteopath, uses manual osteopathic techniques and focuses on infants, children and adults and deals with conditions like colic, digestive concerns, and various pain issues. Tanya Hamlet RMT has a focus on treating lymphatic conditions and pregnancy. Carol Anne Rayson DCHM has a practice founded on Classical Hahnemannian Homeopathy for all Life Stages, using LM potencies: she is also proficient in Inspiring Homeopathy, CEASE therapy & detoxification with Isopathic Remedies. Ismat Nathani Doctorate in Natural Medicine, has over 20 years of practice in Natural medicine specializing ayurveda & yoga care for neurology and endocrinology imbalances. Linda Taylor, DCHM (Hons.) practises Classical Homeopathy and has a special interest in aging, children and womenâ&#x20AC;&#x2122;s issues. Dr. Laura Crawford ND has a clinical focus on mood disorders and the endocrine system. The clinic's marketing consists of their website, a monthly newsletter, and they also attend numerous external events or wellness fairs within the Oakville and Burlington areas. The rest is word of mouth or referrals from other practitioners. The clinic has relationships and refers to a pelvic health physiotherapist, a chiropractic clinic that does a lot of rehabilitation work, physiotherapists, and even a plastic surgeon for select dermatological procedures. Most of the time, prospective patients contact the clinic looking for a particular service. If they are calling for a specific complaint like back pain, they could potentially see any of the practitioners. In these situations, reception will discuss the options with them and direct them accordingly. 42

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clinic profile

Dr. Jodie Peacock, BSc, ND, RAc Dr. Laura Crawford, BBA, ND Dr. Ann Nakajima, BSc(Hons), ND Mark Aquino, RMT Osteopath (Thesis writer) Sarah Ritchie, BA, BEd, RMT, RAc, Reiki Master Tanya Hamlet, RMT Over time and as is inevitable with any clinic, practitioners have left for various reasons. One of the things that makes The Root of Health unique is that many of the practitioners that have left have opened their own clinics. Dr. Peacock has fostered good relationships with all the practitioners such that inter-referrals continue to occur, despite changing circumstances. None of the practitioners at the clinic have any ego with regards to their individual practices. The clinic is happy to accommodate different circumstances because at the end of the day they all believe it’s about the quality of the patient care that is provided. The Root of Health also sometimes allows practitioners to build their practices by providing free space to a practitioner while they are in training in the process of accumulating a specific amount of client hours (currently Maria Fiordialisi is offering complimentary treatment to patients while finishing up specialized training in reflexology). One of the challenges Dr. Peacock has faced is replacing practitioners who have built successful practices, but for some reason need to move on. It becomes challenging because all of the team members are so integrated. She also says that managing 10 people in the same space also brings its own challenges. The clinic has an on-site dispensary and they carry a variety of high-quality brands including NFH, Douglas Labs, Thorne, Seroyal, Biomed, Heel, Pascoe, and Guna. They also carry teas

Carol Anne Rayson, DCHM, HD, RHN Linda Taylor, DCHM (Hons) Ismat Nathani, Ayurvedic Practitioner Maria Fiordialisi reflexologist (Current Study) Wendy Budisavljevic, Administrator

from Clef-des-Champ. The main lab services are provided by Rocky Mountain Analytical, Doctor’s Data, Great Plains Lab, and Metametrix. Due to the practitioners available, the clinic also carries an impressive homeopathic dispensary that consists of over 200 individual remedies (largely from Boiron). They will also custom order from Helios if required. This year The Root of Health got nominated for the 2013 Oakville business award in the professional service provider’s category. Dr. Peacock shares some advice to newer practitioners. She suggests that when they start their practice, they should pick somewhere they want to stay and put a lot of effort into it. From her vast experience with NFH and personally with her clinic, she has seen that the harder you work, the more success you will have. When Dr. Peacock was asked if she has any messages for her patients, she said, "We want you to have an excellent experience. We’re happy to communicate with each other at the clinic to serve you, and we will communicate externally on your behalf as well. We're happy to work with your medical doctor. Patient care is our highest priority!" Some of Dr. Peacock's future plans are to expand on IV therapy services offered at the clinic as well as offering more services that would provide natural alternatives to botox and surgeries for cosmetic purposes. IHP would like to thank Dr. Peacock for sharing her inspiring story with us. ■ June/July 2014 | www.ihpmagazine.com

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The Journal Of

p51

Diet in inflammatory bowel disease prevention and management A Review

By Karen Chen, Justina Ellery, Jordan Robertson, ND, Johanna Sildam, Chelsea Soares, Tina Wang

p58

High genetic heterogeneity of Premature Ovarian Insufficiency From DNA replication and repair to hormonal regulation By Gouri Mukerjee, PhD and Ruslan Dorfman, PhD

p66

PCOS

Natural Alternatives

By Christopher Habib, ND and Faryal Luhar, ND

p73

Chemotherapy- Induced Peripheral Neuropathy Natural therapies

By Rachel M.T. Corradetti, ND and Akbar Khan, MD

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editor’s letter

In Memoriam Dr Anthony Godfrey 1940-2014 The naturopathic profession lost a most dear and treasured member of its family… Dr Godfrey touched the life of every ND in the country… Gentle demeanor, intense love of plants and all things spiritual, gifted speaker and educator, and an incredibly talented clinician. Dr Godfrey will be sorely missed.

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 | Christopher Habib, ND Art Director | Scott Jordan (416) 203-7900 ext. 6106 Production Manager | Erin Booth (416) 203-7900 ext. 6110 Junior Designer | Tamara Kelly Contributors Philip Rouchotas, MSc, ND Christopher Habib, ND Akbar Khan, MD Rachel M.T. Corradetti, ND Gouri Mukerjee, PhD Ruslan Dorfman, PhD Faryal Luhar, ND Karen Chen Justina Ellery Jordan Robertson Johanna Sildam Chelsea Soares Tina Wang President | Olivier Felicio (416) 203-7900 ext. 6107 Controller & Operations | Melanie Seth Advertising Information Sanjiv Jagota | Tel: (416) 203-7900 ext 6125 Email: sanjiv@ihpmagazine.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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Published by IHP Magazine

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 publisherâ&#x20AC;&#x2122;s liability shall not exceed the amount of the publisherâ&#x20AC;&#x2122;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.

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peer review

Peer Review Board Members Andrea Maxim, ND Healing Journey Naturopathic Clinic 25 Caithness St. W. Caledonia, Ontario N3W 1B7 andreamaximnd@gmail.com

Claire Girgis, ND Zawada Health 201 City Centre Drive, Suite 404 Mississauga, Ontario L5B 2G6 claire@zawadahealth.com

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

Anthony Moscar, ND Mahaya Forest Hill 73 Warren Road, Suite 102 Toronto, Ontario M4V 2R9 anthonymoscar@gmail.com

Colin MacLeod, ND Alderney Chiropractic 164 Ochterloney St. Dartmouth, Nova Scotia B2Y 1E1 info@drcolinmacleod.com

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

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

Daniel Watters, BSc, ND Rosedale Wellness Centre 365 Bloor St East Toronto, Ontario M4W 3L4 dwatters@rosedalewellness.com

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

David W Lescheid, BSc, PhD, ND Lichtentaler Strasse 48 76530 Baden-Baden, Germany 20davidl20@gmail.com

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

Ashley Weber, HBSc, ND Upper Beach Health and Wellness 1937 Gerrard St E. Toronto, Ontario ashleywebernd@gmail.com Berchman Wong, ND Adjust Your Health 5809 Macleod Tr SW, Suite 218 Calgary, Alberta T2H 0J9 berchman.nd@gmail.com Betty Rozendaal, BES, MA, ND Thornhill Naturopathic Health Clinic 12A Centre Street Thornhill, Ontario L4J 1E9 drbetty@thornhillnaturopathic.ca Brock McGregor, ND McGregor Naturopathic 220 St Clair Street Chatham, Ontario N7L 3J7 drbrock@mcgregornd.com Carol Morley, ND Zawada Health 201 City Centre Drive, Suite 404 Mississauga, Ontario L5B 2G6 info@zawadahealth.com Christopher Knee, ND, MSc The Dempster Clinic â&#x20AC;&#x201C; Center for Integrated Medicine 97 Scollard Street Toronto, Ontario knee.christopher@gmail.com

David Miller, BSc, ND 662 Gustavus Street Port Elgin, Ontario N0H2C0 drdavend@yahoo.ca Denisa Maruyama, ND Kona Wellness Center for Integrative Medicine 74-5565 Luhia Street Suite C-2 Kailua-Kona, Hawaii drmaruyama@konawellness.com Elaine Lewis, HBSc, ND Back to Play Chiropractic 592 Rathburn Road West Mississauga, Ontario L5B 3A4 elewis@ccnm.edu Elena Rossi, MSc, ND Mahaya Health Services 105-2 College Street Toronto, Ontario M5G 1K3 info@mahayahealth.com Elizabeth Cherevaty, BSc, ND Norfolk Chiropractic Wellness Centre 86 Norfolk Street, Suite 101 Guelph, Ontario N1H 4J2 elizabeth.cherevaty@gmail.com

Isaac Eliaz, MD, MS, LAc Amitabha Medical Clinic & Healing Center 7064 Corline Ct #A Sebastopol, California 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 12 Irwin Ave, Suite 200 Toronto, Ontario jiselle@healthhubclinic.com John David Millar, BSc, ND Jacksoncreek Natural Health Centre 187 Sherbrooke St. Peterborough, Ontario naturo@jacksoncreek.ca Jordan Robertson, BSc, ND Lakeshore Clinic 2159 Lakeshore Road Burlington, Ontario L7R 1A5 jordanrobertsonnd@gmail.com

June/July 2014 | www.ihpmagazine.com

peer review Judah Bunin, BSc, MSc, ND, DrAc Fredericton Naturopathic Clinic 10-150 Cliffe St Fredericton, New Brunswick E3A0A1 frednatclin@yahoo.ca

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

Judith Ancheta, ND FertilityCare Toronto 688 Coxwell Avenue, Suite 100 Toronto, ON M4C 3B7 judy@drjudynd.com

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

Karam Bains, BSc, ND Inside Out Wellness 3650 Langstaff Road, Unit 12 Woodbridge, Ontario karam@elixirhealth.ca Kate Whimster, ND Kew Beach Naturopathic Clinic 2010 Queen Street East, 2nd floor Toronto, Ontario kwhimster@wavelengthwellness.com Kendra Smith, ND Toronto, Ontario drkendra.nd@gmail.com Kelly Brown, BSc, ND Clinic One 286 McDermont Avenue Winnipeg, Manitoba R3B 1H6 drkbrownnd@gmail.com Leigh Arseneau, ND Centre for Advanced Medicine 670 Taunton Rd East Whitby, Ontario L1R 0K6 info@advancedmedicine.ca Lindsay Bast, BSc, ND Greenwood Wellness Clinic PO Box 189 1400 Greenwood Hill Rd. Wellesley, Ontario N0B 2T0 lindsay.bast@greenwoodclinic.ca Louise Wilson, BSc, ND 320 Queen St S Bolton, Ontario L7E 4Z9 dr.louisewilsonnd@gmail.com Maria Shapoval, ND Canadian College of Naturopathic Medicine 1255 Sheppard Ave East Toronto, Ontario M2K 1E2 mshapoval@ccnm.edu

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Meghan MacKinnon, ND Armata Health Centre 126 Welling St. W, Unit 201B Aurora, Ontario L4G 2N9 drmeg.nd@gmail.com Melanie DesChatelets, BSc, ND True Health Studio 200-4255 Arbutus St Vancouver, British Columbia V6J 4R1 melanie@drdeschat.com Misa Kawasaki, BSc, ND Meridian Wellness 13085 Yonge Street, Suite 205 Richmond Hill, Ontario L4E 3S8 drkawasaki@meridianwellness.ca Nicole Egenberger, BSc, ND Remede Naturopathics 214 Sullivan Street Suite 3B New York, New York 10012 info@remedenaturopathics.com Nicole Sandilands, ND Durham Natural Health Centre 1550 Kingston Rd, Suite 318 Pickering, Ontario L1V 1C3 info@dnhc.ca Rajesh Ragbir, ND Scarborough Naturopathic Clinic 1585 Markham Road, Suite 211 Scarborough, Ontario M1B 2W1 ragbir.nd@gmail.com Raza Shah, BSc, ND St. Jacobs Naturopathic 1-9 Parkside Drive St. Jacobs, Ontario N0B 2NO stjacobs.nd@gmail.com Rochelle Wilcox, BA, ND Living Well Integrative Health Centre

2176 Windsor Street Halifax, Nova Scotia B3K 5B6 drwilcox@balancehealthcentre.ca Sarah Vadeboncoeur, ND Ottawa Integrative Health Centre 1129 Carling Ave Ottawa, Ontario K1Y 4G6 sarahmvadeboncoeur@gmail.com Scott Clack, ND Touchstone Naturopathic Centre 950 Southdown Rd, Unit B5 Mississauga, Ontario L5J 2Y4 sclack.nd@touchstonecentre.com Shawna Clark, ND Forces of Nature Naturopathic Clinic 2447 1/2 Yonge St Toronto, Ontario M4P 2E7 info@shawnaclarknd.com Stephanie Swinkles, DDS Elmsdale Dental Clinic 4-269 Highway 214 Elmsdale, Nova Scotia N2S 1K1 steph_moroze@hotmail.com Susan Coulter, BSc, ND Roots of Health 2-497 Laurier Ave Milton, Ontario L9T 3K8 scoulter@rootsofhealth.ca Sylvi Martin, BScN, ND Fusion Chiropractic and Integrative Health 735 Danforth Avenue Toronto, Ontario M4J 1L2 sylvi.martin@gmail.com Tanya Lee, BSc, ND The Health Centre of Milton 400 Main St East Suite 210 Milton, Ontario L9T 1P7 tanyalee.nd@gmail.com Terry Vanderheyden, ND Bayside Naturopathic Medicine 118 Bay Street Barryâ&#x20AC;&#x2122;s Bay, Ontario KOJ 1B0 doctrv@gmail.com Theresa Jahn, BSc, ND Living Well Integrative Health Centre 2176 Windsor Street Halifax, Nova Scotia B3K 5B6 info@theresajahn.com

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.

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.

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.

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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 was the first Canadian Naturopathic Physician to qualify with a fellowship from the American Board of Naturopathic Oncology in 2007. 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 integrated health care facilities in Canada. Dr. Parmar was a consulting naturopathic physician at the Lions Gate Hospital cancer clinic from 2008 to 2012. He has established collaborative relationships with many oncologists and other practitioners, ensuring patients are provided a truly integrative and evidence-guided treatment. Dr. Parmar is also active in writing and lecturing in the fields of clinical hyperthermia, the tumour microenvironment, and integrative oncology. He continues to serve as a board member for the Oncology Association of Naturopathic Physicians, a position he has held since 2008. He is licensed by the College of Naturopathic Physicians of B.C.

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 multi-centred 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.

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The Journal of IHP

1 | Bachelor of Health Sciences (Honours) Candidate, McMaster University 2 | Bachelor of Health Sciences (Honours), McMaster University 3 | Bachelor of Health Sciences, McMaster University, Naturopathic Doctor, Canadian College of Naturopathic Medicine 4 | Bachelor of Health Sciences, McMaster University

Diet in inflammatory bowel disease prevention and management A review

By: Karen Chen1, Justina Ellery2, Jordan Robertson3, Johanna Sildam4, Chelsea Soares2, Tina Wang1 June/July 2014 | www.ihpmagazine.com

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Abstract As a result of inconsistent health improvement and severe adverse effects associated with the use of current drug therapies, inflammatory bowel disease (IBD) patients have turned to alternative treatments such as diet modification to help alleviate IBD disease symptoms. This review discusses the role of diet in preventing and managing IBD symptoms. Specifically, the influences of dietary intake of gluten, fiber, Fermentable Olio-, Di-, and Mono-saccharides and Polyols (FODMAPs), dairy, meat, and polyunsaturated fats are elucidated. This review concludes that though substantial evidence exists for each of these topics and their role in IBD, more research should be conducted in order to further delineate the role of diet in IBD symptom development and control. Recommendations include careful monitoring and coordination of diet on a case-per-case basis in patients with IBD in order to decrease adverse IBD-associated symptoms. This can be achieved through elimination and reintroduction diets, which may allow practitioners to identify dietary sources of IBD flare-ups. Introduction Inflammatory bowel disease (IBD) is a chronic disorder characterized by inflammation within the gastrointestinal (GI) tract as a result of dysregulated interactions between the mucosal immune system and intestinal microorganisms in genetically predisposed individuals (Hyun 2006, Neuman 2007). IBD manifests itself as either ulcerative colitis (UC), with localized inflammation and ulcerative lesions occurring in superficial layers of the colon, or Crohn’s disease (CD), with inflammation and lesions occurring transmurally and sporadically along the entire length of the GI tract (Hyun 2006, Neuman 2007). Chronic inflammation leads to clinical symptoms such as weight loss, abdominal pain, and bloody diarrhea, all of which can negatively impact patients’ quality of life (Hendrickson 2002). IBD can affect individuals of all ages, but is most commonly diagnosed in the second or third decade of life. In 2012, the prevalence of individuals with IBD was 233,000 in Canada, with an approximate incidence rate of 10,200 cases per year. The economic cost of IBD in Canada has been estimated at $2.8 billion per year, considering both the direct and indirect costs of healthcare (Rocchi 2012). There is currently no cure for IBD (Mulder 2013). Instead, treatment approaches focus on symptom management, with the predominant therapy being 5-aminosalicyclic acid, a mild anti-inflammatory, in combination with steroids (Panaccione 2008). Following the failure of this therapy option, stronger immunosuppressive 52

therapies such as thiopurine analogues, methotrexate, and calcineurin inhibitors are prescribed in order to ameliorate disease symptoms (Panaccione 2008). However, data on these immunosuppressive therapies has either been inconclusive or has demonstrated the drugs’ lack of ability to induce and maintain remission (Khan 2011). Although there is evidence that one thiopurine analogue, azathioprine, is moderately effective at preventing relapse, this effect disappears after four years of use (Bouhnik 1996, Khan 2011). The numerous side effects of these drugs prevent this class of treatment from being an ideal option for long-term management (de Boer 2007, Haslam 2000, Loftus 2004, Mason 2013). For example, severe adverse effects such as hypertension, lethargy, and lower respiratory tract infection have been found in 51% of participants taking the immunosuppressant cyclosporin for long term treatment of IBD (Haslam 2000). As a result of inconsistent health improvement and the aforementioned severe adverse effects of current drug therapies, IBD patients have turned to alternative treatments, such as diet modification, to help alleviate disease symptoms (Hendrickson 2002). These altered diets can include or exclude many items, such as gluten, fiber, FODMAP carbohydrates, dairy, meat, and polyunsaturated fats. Though no one diet has been proven to help treat all cases of IBD, the focus of this literature review will be to collect and summarize current research on diet-based approaches to IBD prevention and treatment.

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Gluten Though celiac disease is not an IBD, studies have shown an increased incidence of non-celiac gluten sensitivity (NCGS) (Watanabe 2013) and celiac disease (Oxford 2013, Tavakkoli 2012) in IBD patients compared to non-IBD patients (13% vs. 1% and 9% vs. 1%, respectively). NCGS and celiac disease often present with similar symptoms, which can be ameliorated by the adoption of a gluten-free diet; however, the two are differentiated by distinct clinical features (Kabbani 2014). Celiac disease is often characterized by the presence of three elements: 1) a genetic predisposition to the disease, determined by the expression of HLA-DQ2 or HLA-DQ8 proteins, 2) gluten as the precipitating factor to symptoms, and 3) autoantibodies against tissue transglutaminase (tTG) (Schuppan 2013). The presence of tTG leads to structural changes to a-gliadin, a protein component of gluten, which is then presented on HLA-DQ2 or HLA-DQ8 to cytotoxic CD8+ T cells in the lamina propria of the gut (Schuppan 2013). Additionally, helper CD4+ T cells in the lamina propria release pro-inflammatory cytokines, which leads to intestinal inflammation, similar to that observed in IBD (Schuppan 2013). Gluten-containing foods have been linked to worsened symptoms in IBD patients (Asakura 2008, Brown 2010, Mishkin 1997, Riordan 1993, Triggs 2010). In cases of IBD patients with NCGS, one study found that eliminating gluten from the diet significantly reduced liquid stools per day (from 6.2 to 1.5) compared to gluten-eating controls (from 4.0 to 4.7) (Watanabe 2013). Though this evidence pertains to NCGS IBD patients, research has shown that gluten consumption is linked to increased intestinal permeability and inflammation. Due to the association between intestinal permeability and diseases such as rheumatoid arthritis, multiple sclerosis, and depression (de Punder 2013), it may be beneficial for non-gluten-sensitive IBD patients to also exclude gluten from their diets to reduce the risk of developing the aforementioned comorbidities.

Dietary Fiber The efficacy of fiber intake as a dietary intervention for IBD has been of interest due to prospective studies showing decreased CD risk in patients with high vs. low (24.3g/d, 11.6g/d) fibre consumption (Ashwin 2013). One study following 170,000 women over 26 years found a 40% CD risk decrease in those with high fibre intake, especially fiber derived from fruits (6.4g/d) (Ashwin 2013). These results are supported by additional studies (Hou 2011). Although dietary fiber has been associated with decreased UC incidence in some studies, few trials have yielded statistically significant results (Ashwin 2013, Hou 2011). A retrospective study conducted on patients with CD demonstrated that individuals treated with a fiber-rich (32.6g/d), unrefined-carbohydrate diet and conventional medication experienced a reduction in hospital visits (total 111 vs. 533) and surgeries required (1 vs. 5) when compared to patients in a drug-only treatment group (Heaton 1979). More recently, a study administering 20g of fiber per day through oat bran in bread

to quiescent UC patients displayed improvement in abdominal pain and gastroesophageal reflux with no adverse effects or relapse activity observed (Hallert 2003). Open label studies where patients with mild to moderate UC consumed 20g/d of germinated barley foodstuff (GBF) in conjunction with standard drug treatments resulted in various clinical activity improvements including decreased diarrhea, less blood in stool, and lower cumulative recurrence rates (Bamba 2002, Hanai 2004). Though the mechanisms through which these foods benefit IBD is not fully elucidated, possible explanations suggest that fiber can indirectly affect IBD through interacting with the intestinal microbiome and increasing production of butyrate (Flint 2008). Fiber intake results in residential bacteria fermentation, which increase short chain fatty acid (SCFA) production in the colon (Viladomiu 2013). SCFAs, such as butyrate, down-regulate and modulate intestinal inflammatory factors, cytokines interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α (TNF-α), all of which play a role in intensifying inflammation and aggravating intestinal tissue; SCFAs therefore indirectly prevent damage to colonic mucosa (Galvez 2005, Rodríguez-Cabezas 2002, Viladomiu 2013). Dietary fiber intake is also associated with promoting anti-inflammatory actions, as it increases the percentage of Treg immune cells in the gut and decreases interferon-y (IFNy) production (Galvez 2005, Viladomiu 2013). The therapeutic effects of dietary fiber may also be due to shifting microbiota profiles through favouring the survival of bacteria capable of SCFA fermentation. This is suggested by research reporting that vegans and vegetarians, who may consume more fibre through fruits and vegetables, have lowered bifidobacterium compared to omnivores (Zimmer 2012). In contrast, ulcerative colitis patients have increased bifidobacterium, as well as increased bacteriodes, enterococcus, and clostridium species in the gut compared to controls (Wang 2014, Zhang 2013).

FODMAPs A diet with decreased amounts of highly fermentable, but poorly absorbed short chain carbohydrates and polyols consumed, known as the FODMAPs diet (Fermentable Olio-, Di-, and Mono-saccharides and Polyols) is a relatively new method of treating IBD (Gibson 2005). FODMAPs include fructooligosaccharides (wheat, legumes), lactose (milk), fructose (fruits, honey), galactans (legumes) and sorbitol (artificial sweetener) (Gearry 2009, Gibson 2005). It has been found that a diet rich in FODMAPs causes elevated intestinal permeability, which is a biomarker of susceptibility for CD (Gibson 2005). FODMAPs in the small intestine are poorly absorbed, and exert an osmotic effect by drawing water into the large intestine due to their small molecular size (Barrett 2010, Gearry 2009). The FODMAPs are then fermented by the colonic microflora in the large intestine, producing hydrogen and/or methane gas (Barrett 2010, Gearry 2009). The increase in fluid and gas in the intestines results in diarrhea, bloating, gas, abdominal pain, and distention (Barrett 2010). A diet low in FODMAPs can lead June/July 2014 | www.ihpmagazine.com

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to a decrease in these gastrointestinal symptoms in individuals with CD and UC (Gearry 2009). However, this diet has been shown to have no or a negative effect on constipation in study subjects (Gearry 2009, Gibson 2005). This diet requires time and dedication to achieve desirable outcomes, and is more favorable for individuals with higher education and who have more time to spend on food shopping (Gearry 2009). In addition to FODMAPs, an older diet popularized by Elaine Gottschall’s book Breaking the Vicious Cycle: Intestinal Health Through Diet, called the Specific Carbohydrate Diet (SCD), has been used in the treatment of IBD. Like FODMAPs, the SCD limits the use of certain complex carbohydrates such as disaccharides and polysaccharides, on the basis that these may not be completely digested by the body, and may serve as fuel for overgrowth of bacteria and yeast instead. Although most evidence is anecdotal, and there is limited scientific evaluation of the SCD, a recent study assessed the effectiveness of the SCD in children with Crohn’s disease (Suskind 2014). A retrospective chart analysis, this study included seven children aged seven to 16 years of age with Crohn’s disease receiving the SCD for an average of 14.6 months, and no immunosuppressive medications. Disease severity ranged from mild to severe. The authors stated that “Although the exact time of symptom resolution could not be determined through chart review, all symptoms were notably resolved at a routine clinic visit three months after initiating the diet. Each patient’s laboratory indices, including serum albumin, C-reactive protein, hematocrit, and stool calprotectin, either normalized or significantly, improved during follow-up clinic visits” (Suskind 2014).

Jowett 2004, Mishkin 1997, Triggs 2010). One prospective study comprised of 67,581 female participants showed that high animal protein consumption including meat and fish was associated with a significantly increased risk of being diagnosed with IBD (HR 3.31 and 3.03 for total and animal protein, respectively) (Jantchou 2010). Regarding clinical activity, a study conducted on UC patients demonstrated that high intake of meat (OR compared with low intake 3.74), particularly red and processed meat (OR 6.88), was associated with IBD relapse (Jowett 2004). Additionally, many studies point to a link between red meat and worsened symptoms (Cohen 2013, Hou 2011, Jantchou 2010, Jowett 2004, Triggs 2010). Current research does not provide conclusive evidence on the effects of fish. Some note that fish is beneficial to many patients (Hou 2011, Triggs 2010) while others claim it is not (Hou 2011, Mishkin 1997).

Polyunsaturated Fats

In countries adopting “Western-style” diets, which include more high-fat dairy consumption, the prevalence of IBD has also increased (Asakura 2008). This suggests that increased dairy consumption can lead to greater IBD incidence, though this relationship is not observed in all countries (Jantchou 2010). As with other self-reported food intolerances in IBD, dairy has not been shown to have consistent effects in all IBD patients. Some studies (Brown 2010, Cohen 2013, Mishkin 1997, Riordan 1993, Triggs 2010, Wright 1965) have reported that dairy milk is associated with worsened diarrhea, bloating, and gas in many patients. Conversely, dairy yoghurt has been seen to ameliorate these symptoms in many patients (Cohen 2013, Triggs 2010), highlighting the possibility that the positive effects of introducing beneficial gut bacteria surpass the negative effects of dairy. Dairy should be avoided with caution, as it has been shown that patients who perceive dairy to be harmful for them do not meet their recommended daily allowance (RDA) for calcium intake as frequently as dairy-consumers (87.6% vs. 105.8% RDA) (Vernia 2013).

Epidemiological evidence has illustrated a link between dietary fat intake and the incidence of IBD. Studies have shown a lowered incidence of IBD in the Eskimo population, whose diet is rich in omega-3 n-3 polyunsaturated fats (PUFA) (Kromann 1980), and an increased risk of IBD in Western populations with a diet characterized by high n-6 PUFA and a decreased ratio of n-3:n-6 fat consumption (Hou 2011, Lupien 1994, Simopoulos 1994). In addition, higher intake of linoleic acid (n-6 PUFA) is associated with increased UC risk, while oleic (n-9 MonoUFA) and docosahexaenoic acids (DHA n-3 PUFA) have been associated with a decreased UC risk (Tjonneland 2009). A 2010 study by Uchiyama et al. investigated the impact of dietary omega-3 and -6 intake ratios on maintaining remission in individuals with IBD. These fats were of particular interest as N-6 PUFAs are considered to be pro-inflammatory given that linoleic acid, the major n-6 PUFA, increases inflammatory mediators, including prostaglandin E2 and leukotriene B4 (Rachmilewitz 1982, Sharon 1984). In addition, animal studies have shown that n-3 PUFAs, which include a-linolenic acid, DHA, and eicosapentaenoic acid, are generally antiinflammatory (Hassan 2010, Ibrahim 2011). The study used 230 individuals with UC and CD who had achieved remission from drug therapy and prescribed them a dietary regimen that provided a n-3:n-6 fat intake ratio of 1:1. All steroids and immunosuppressants were gradually removed after achievement of remission, except for 5-ASA and thiopurines. The results showed that the dietary regimen resulted in changes of n-3:n-6 ratios in the patients’ erythrocyte membranes. Consequently, remission rates after 12-18 months were 79.7% and 54.3% in patients who maintained a n-3:n-6 membrane ratio of greater than 0.65, and less than 0.65, respectively (Uchiyama 2010).

Meat

Discussion

Animal protein has been shown to have an effect on both IBD incidence and IBD health outcomes (Hou 2011, Jantchou 2010,

This review highlights the implications gluten, fiber, FODMAP carbohydrates, dairy, meat, and polyunsaturated fats have on

Dairy

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IBD (Appendix I). Effective dietary strategies for IBD seem to decrease existing GI inflammation (high fiber, GBF and n-3 PUFA, or low FODMAPs), or decrease food-induced immune activation (low gluten, dairy, or meat). Conclusions for clinical consideration are difficult to draw due to various limitations present in the research. For instance, though studies on dietary fibre indicate fruits as a preferred source of fibre in controlling IBD symptoms, the FODMAPs diet calls for the exclusion of certain fruits, given their potential for adverse IBD-related outcomes. The emerging evidence in these two areas suggest that the therapeutic effect of high-fiber diets may be limited by the inclusion of high FODMAP containing foods. Thus, further studies on the effect of high-fiber, lowFODMAP diets are needed. Another limitation of dietary studies lies in the inherent difficulty of adherence to dietary interventions; patients may introduce bias into observed results

if diet regimens are not properly followed. Although there are challenges to the use of dietary interventions to treat IBD, there is compelling evidence for the use of these treatments in practice. The use of diet alone has been shown to reduce the incidence of flare-ups (Wild 2007), increase remission time (7.5 vs. 3.8 months) and decrease relapse rates at 2 years (62% vs. 79%) when compared to 40 mg doses of prednisone daily (Riordan 1993). Administration of diet in conjunction with standard anti-inflammatory treatment can also lead to greater symptom alleviation. Ultimately, dietary modulation in the prevention and control of IBD should be tailored to individual patients. This may be accomplished through the use of elimination and reintroduction diets, which allow practitioners to identify the food sources causing IBD flare-ups (Candy 1995). This review provides a starting point for such interventions.

Appendix I. Clinical Implications of Diet on IBD Gluten

Fiber

Prevention

Symptom Management

- I ncreases intestinal permeability, which is linked to several inflammatory and autoimmune conditions

-G luten-free diets shown to reduce liquid stools in gluten-sensitive patients

-F iber intake of 24.3g/d, especially derived from fruit (6.4g/d) decreases CD incidence - Inconclusive results for UC development

-D ue to links to inflammatory and autoimmune conditions, excluding gluten from non-sensitive patients may prove beneficial for symptom management -H igh-fiber, oats bran, and GBF-incorporated diets improve clinical activities and lower rates of relapse in CD and UC -B eneficial effects linked to increased butyrate production and potential shifts in microbiota

FODMAPs

- Diet rich in FODMAPs causes elevated intestinal permeability

-D iet low in FODMAPs leads to decreased gastrointestinal symptoms in individuals with CD and UC including diarrhea, bloating, gas, abdominal pain, and distention

Dairy

-C ountries adopting Western-style diets with increased dairy consumption display higher prevalence of IBD

-D airy associated with worsening or ameliorating IBD symptoms in different patients

-F emale participants showed that high animal protein consumption (meat and fish) was associated with increased risk of IBD

-H igh intake of meat (particularly red and processed meat) was associated with IBD relapse in UC patients and worsened symptoms

Meat

-P ositive effects linked to introducing beneficial gut bacteria

-C urrent research does not provide conclusive evidence on the effects of fish Polyunsaturated Fats (PUFAs)

-E pidemiology studies demonstrated lowered incidence of IBD in high omega3 (fish) consumption countries, and increased IBD risk with spread of western diet, which is low in n-3, high in n-6

- I ntervention of 1:1 dietary intake ratio of n-3:n-6 fats helps to maintain remission at 12-18 months - Greater ratios of n-3:n-6 intake is correlated with increased proportion of patients in remission

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Conclusion This review has discussed the role of diet in managing IBD symptoms, specifically, the influences of gluten, fiber, FODMAP carbohydrates, dairy, meat, and polyunsaturated fat consumption. Though much evidence exists for each of the topics discussed herein, more research should be conducted in order to further delineate the role of diet in IBD symptom development and control. Given the studies explored in this review, it is evident that ingestion of these foods should be carefully monitored and coordinated in patients with IBD in order to decrease and modulate adverse IBD-associated symptoms. ■

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High genetic heterogeneity of Premature Ovarian Insufficiency From DNA replication and repair to hormonal regulation Gouri Mukerjee, PhD and Ruslan Dorfman PhD Disclosure Statement: Gouri Mukerjee and Ruslan Dorfman are employed by Geneyouin, a company that offers genetic screening testing.

Geneyouin Inc. 250 Yonge St, Suite 2201 Toronto, ON, Canada M5B 2L7 gouri @geneyouin.ca

Abstract Primary ovarian insufficiency greatly influences a womanâ&#x20AC;&#x2122;s fertility potential and her overall health. The condition affects about 1â&#x20AC;&#x201C;2 % of women and in most cases, the cause is undefined. Primary ovarian insufficiency (POI) may be caused by any process that results in dysfunction or depletion of ovarian follicles, reducing the number of oocytes within the ovary. The tendency for POI to run in families implies a strong genetic component underlying the condition. The most common single gene mutation to cause POI is the premutation of the fragile-X mental retardation gene 1 (FMR1), located on Xq27.3. Many other candidate genes have been suggested to play a role in the POI etiology, with mutations identified in genes involving follicle function and oogenesis, such as FOXL2, BMP15, NR5A1, Inhibin A, LHR, FSHR and the phenotype. In addition, variations in genes involved in meiosis and DNA repair have been hypothesized to affect the normal process of follicle formation and diminish ovarian reserve resulting in infertility. An alternative approach to identify novel POI candidate genes is the genome-wide analysis and we also report on a few studies that might have identified novel susceptibility genes for POI.

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The Journal of IHP Introduction A woman’s ovary has several million potential oocytes at around five months of gestational age. These are held in a quiescent state until required for ovulation, years later. Most of these potential oocytes are destroyed by the body before birth presumably as part of a quality control mechanism. Between infancy and the age of 40 years, the potential oocytes are gradually reduced from approximately one million to 10,000 in each ovary and around the age of 40, the process of egg destruction accelerates with normal aging. Unfortunately, some women can experience irregular menstrual cycles and stop producing oocytes in their early 30’s leading to the condition called Premature Ovarian Insufficiency (POI). Genetic analysis has identified aberrations in several biological pathways that can result in this condition. This review summarizes the evidence for involvement of multiple developmental genes, as well as highlights the role of known oncogenes in POI.

Disease Definition A woman, through her reproductive life, uses fewer than 500 eggs, a tiny proportion of the original millions (Hsueh 1994, Tilly 2001). Primary Ovarian Insufficiency (POI) or Premature Ovarian Failure (POF) may be caused by any process that results in dysfunction or depletion of ovarian follicles, reducing the number of oocytes within the ovary. It is defined as early menopause with elevated levels of serum gonadotrophins before the age of 40 (Coulam 1982). Various terms have been used to describe this deviation from healthy ovarian function, including ‘premature menopause’. Albright (1942) coined the term ‘primary ovarian insufficiency’ to emphasise that the primary defect was within, rather than outside the ovary. Other conditions involving endocrine disturbances outside the ovary can also result in abnormal ovulation including pituitary disorders, adrenal dysfunction, or polycystic ovary syndrome. The term ‘ovarian insufficiency’ is regarded as more scientifically accurate than ‘ovarian failure’ (De Vos 2010) as insufficiency indicates impaired ovarian function suggesting that follicular activity of the ovary might intermittently recover, years after diagnosis leading to pregnancy in some women (Nelson 2005).

Disease Diagnosis Primary ovarian insufficiency (POI) affects about 1–2 % of women (Vegetti 2000) and in most cases, the cause is undefined. Destruction of primordial follicles by toxic agents, autoimmune response, activation of proapoptotic pathways, or accelerated

follicular recruitment might result in premature depletion of the pool of primordial follicles. Accurate and timely diagnosis of POI poses challenges as hormonal and biochemical tests do not show the monthly follicle loss and thus do not indicate the true biological age of ovaries. Direct evidence of depletion of the resting pool of follicles can be reliably provided only through assessment of the total number of follicles in whole ovaries. Testing of biopsy samples of ovaries has been suggested as a diagnostic method to measure ovarian follicular reserve (Massin 2008), with other investigators concluding that analysis of laparoscopic biopsy samples cannot be used to predict follicular distribution in ovarian cortex (Lambalk 2004).

Genetics of POI Chromosomal abnormalities account for 12% of cases (Jiao 2012), and the familial aggregation often associated with POI indicating a significant genetic contribution. Incidence of familial cases among women with POI has been reported to be as low as 4% (Conway, 1996), but it might be an underestimation and epidemiological studies have indicated incidence of familial POI as high as 30% (Cramer 1995, Torgerson 1997). In a large Italian study, Vegetti et al. (1998) found that the condition was inherited in one-third of the idiopathic POI patients. Pedigree studies on affected families showed a mode of inheritance suggestive of autosomal dominant sex-limited transmission or X-linked inheritance with incomplete penetrance (van Kasteren 1999). Using family history can help distinguish between familial or sporadic primary ovarian insufficiency as the risk of female relatives developing this condition may be as high as 100% in familial primary ovarian insufficiency, or as low as 1% in sporadic cases (van Kasteren 1999). In rare cases, sufficient ovarian follicles are present but they do not function i.e. oocytes do not mature in regular cycles. However, in a large proportion of cases no cause is found and they are classified as idiopathic or karyotypically normal spontaneous ovarian failure (Laml 2000).

Unraveling the genetic causes of POI Several methods have been used to elucidate the role of genetic contributors in the pathogenesis of POI — transgenic ‘knockout’ animals, mutation screening in affected women, analysing pedigree data in linkage analysis. Genetic association studies aim to identify candidate genes or genome regions that contribute to a specific trait or disease by identifying a correlation between disease status and genetic variation (Cordell 2005) and we report on several candidate genes that are believed to contribute to POI. June/July 2014 | www.ihpmagazine.com

POI genes on the X-chromosome Premature ovarian senescence is many times associated with abnormalities in the X chromosome. Women with structural and numerical abnormalities in the X chromosome make up the largest subgroup with POI. During early embryonic development, one of the X chromosomes is randomly inactivated by methylation in female somatic cells (Sato 2004). In some women with X chromosome structural abnormalities, such as large deletions and unbalanced translocations, skewed patterns of X chromosome inactivation (SXCI) may result with the abnormal inactive X chromosome in most of the cells. Other women may inherit only one X chromosome (45,X) leading to congenital Turner’s syndrome (Sybert 2004). Although one X chromosome is sufficient to allow the normal development of most organs and initial differentiation of ovaries, oocytes need two active X chromosomes. Defective X chromosome leads to insufficient gene dosage of many genes, and haploinsufficiency of the X chromosome results in depletion of the oocyte pool in the first 10 years of life.

Link between Fragile X and POI Mutations in the FMR1 gene can also lead to the expansion of a CGG trinucleotide repeat located at the 5’ UTR region of the gene. Long repeats of 200 CGG trineucleotides lead to reduced gene expression and Fragile X mental retardation syndrome. Repeat lengths between 59 and 199 of the CGG repeat confer an unstable premutation state. Women with the premutation allele have a substantially increased risk of POI. Besides Turner’s syndrome, premutation in the FMR1 gene is the most common known congenital cause of POI. Cryptic deletions in FMR2 gene, located near the FMR1, have also been suggested as an X chromosome-linked cause of primary ovarian insufficiency (Murray 1999).

Multiple rare mutations in oocyte development and hormone regulation genes contribute to the risk of POI FOXL2 is a member of the forkhead /hepatocyte nuclear factor 3 gene family of transcription factors that plays a role in sex determination. Mutations in FOXL2 cause congenital blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) that is characterized by premature death of egg cells (Crisponi 2001). Foxl2 knockout mice were shown to replicate the findings in humans (Schmidt 2004). Reduced Foxl2 expression resulted in the characteristic cranio-facial alterations and infertility with folliculogenesis being blocked at the early stages. A functional study supporting the role of FOXL2 mutations in nonsyndromic POI was reported by Laissue et al. (2009). A novel FOXL2 missense mutation p.G187N was found in a case of POI without BPES. The subcellular localization of the mutant protein was normal, but its functional activity was significantly lower than that of normal FOXL2 protein.

NR5A1 NR5A1 gene, also called steroidogenic factor 1, plays a key role in 60

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ovarian development and function. Mutations in the gene were detected in members of four families with a history of POI but not in the 700 control alleles (Lourenco 2009). Mutations were associated with a range of ovarian anomalies, with functional analysis revealing that mutant proteins had altered transcriptional activity that is important for follicle growth and maturation.

Members of the TGF superfamily Hetrozygous mutations in BMP15 (Bone Morphogenetic Protein 15), an oocyte-specific growth/differentiation factor that stimulates folliculogenesis and is expressed in oocytes during early folliculogenesis, has been implicated in POI (Di Pasquale 2004). It is presumably expressed from both X chromosomes in oocytes, and could potentially show a gene dosage effect. BMP15 maps to a locus on the short arm of X chromosome (Xp11.2), within a ‘POI critical region’ (Persani 2009). In humans, mutations in BMP15 gene have been found in POI cohorts. Rossetti et. al. (2009) demonstrated that BMP15 protein coding variations resulted in reduced production of bioactive BMP15 proteins in comparison with wild type, thus functional effects of these mutation is consistent with a mechanism of haploinsufficiency. Mature BMP15 proteins with missense variations also showed significant reduction in their biological effects in human cell-lines (Rossetti 2009). Besides BMP15, other TGFβ family members have a relevant role in the progression of folliculogenesis. GDF9 is also expressed in the oocyte. Several studies reported that variations in GDF9 gene (p.K67E; p.V216M; p.S186Y; p.P103S; and p.T238A) were found in women with POI but were not detected in the control samples (Laissue 2006, Kovanci 2007).

Inhibin A, NOBOX Inhibin A plays an important role in regulating ovarian function either as a negative modulator of pituitary FSH synthesis. Inhibin A (INHA) gene knockout mice have raised FSH levels, are infertile and develop tumors in the gonads at an early age with nearly 100% penetrance (Matzuk 1992). Therefore, Inhibin A was regarded as a candidate gene for mutational studies. One missense variation of INHA gene (p.A257T) was found to be associated with POI in several populations: the INHA variant was identified in Indian, New Zealand and Slovenian patients (Shelling 2000, Dixit 2004). An Italian study also reported a significant association between the p.A257T allele in INHA and sporadic (4.5%) and familial (7.7%) POI cases (Marozzi 2002). However, other studies have found no differences in variant frequency between POI cases and controls (Corre 2009). NOBOX and FIGLA are oocyte-specific transcription factors, and deletion of either of these genes could accelerate post-natal oocyte loss. Mutations in NOBOX seem to occur more frequently in the Caucasian POI population. The NOBOX missense variant, p.R355H, first identified in 1 of 96 Caucasian POI subjects, could disrupt the binding of the NOBOX homeodomain to DNA (Qin 2007). Bouilly et al. (2011) subsequently demonstrated that lossof-function NOBOX mutations accounted for 6.2% of POI cases in a Caucasian cohort of 178 participants.

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Gonadotropin Receptors

Genome Wide Association Studies in POI

FSHR and LHR are glycoprotein hormone receptors which together with their binding hormones, LH and FSH, are essential for normal reproductive function. A linkage analysis in a Finnish population revealed a significant association between a locus containing both FSHR and LHR genes and ovarian developmental disorder. Sequencing of the entire FSHR gene revealed a homozygous missense mutation, p.A189V (Aittomaki 1995) that has been observed only in the Finnish population suggesting a founder effect. From in vitro studies it was observed that the p.A189V mutation had altered receptor folding and it failed to reach the plasma membrane, causing complete FSH resistance.

Genes mentioned above were chosen as candidates in the context of POI because they are known to be associated with folliculogenesis or other related biological pathways. Genome Wide Association Studies (GWAS), on the other hand, is unbiased and discovery-driven, providing a comprehensive approach that is based on a case-control design.

STAG3 Using a combination of genome wide linkage analysis and exome sequencing in a consanguineous (people descended from the same ancestor) family with POI, Caburet et al. (2014) identified a homozygous 1-bp deletion in the gene encoding stromal antigen 3 (STAG3). All affected family members analyzed were homozygous for the mutation. This finding was supported by the phenotype of female mice with a homozygous disruption in Stag3. These mice were sterile and their fetal oocytes were arrested at early prophase I, leading to oocyte depletion at one week of age.

Genes involved in meiosis and DNA repair It has been proposed that genetic defects in meiotic genes are involved in POI as several meiotic-gene knockout mice have phenotypes resembling human POI. Wang et al (2014) identified a heterozygous mutation in a meiotic gene, HFM1, which encodes a protein necessary for homologous recombination of chromosomes, in two sisters suffering from POI. Variants in genes that affect the normal processes of primordial germ-cell proliferation, oocyte meiosis, and follicle formation are plausible candidates in the pathogenesis of POI. Also, Hfm1-deficient mice are infertile (Guiraldelli 2013).

BRCA1 mutations, fertility treatments and POI As infertility is associated with breast and ovarian cancer risks, Oktay et al (2010) hypothesized that mutations in the BRCA1 and BRCA2 genes may be associated with low response to fertility treatments. Low response to ovarian stimulation is a strong indication of diminished ovarian reserve and infertility. As DNA repair is deficient in patients with BRCA mutations, their oocytes may be more prone to DNA damage, and when DNA damage cannot be repaired, apoptotic pathways are activated. Thus, oocytes with deficient BRCA function may be prematurely eliminated, resulting in early depletion of oocyte pool and, as a consequence, POI. Oktay et al (2010) found that in BRCA mutation-positive patients, the incidence of low ovarian response was significantly higher compared to BRCA mutation-negative patients. Of note, all BRCA mutation-positive low responders to fertility treatment had BRCA1 mutations, but not BRCA2 mutations. These finding can explain, in part, the link between infertility and breast/ovarian cancer risks.

PTHB1 and ADAMTS19 In a two-stage association study in a Korean population (101 cases and 87 controls), Kang et al. (2008) showed a strong association of POI with the PTHB1 gene. PTHB1 was first identified in osteoblastic cells and then in other tissues, but not the ovary, and its physiological function remains unknown. PTHB1 variants have been described in a subset of patients with Bardetâ&#x20AC;&#x201C;Biedl syndrome who sometimes exhibit POI. It is possible that the study has identified PTHB1 as a novel susceptibility gene for POI. Knauff et al. (2009) conducted a GWAS involving 309 158 SNPs in 99 unrelated idiopathic Caucasian POI patients and 235 unrelated controls, focusing on chromosomal areas and candidate genes previously implicated in POI. A genome-wide significant association was observed for a SNP (rs246246) which maps to an intron of ADAMTS19, a gene encoding a zinc-dependent metalloprotease, known to be up-regulated in the female mouse gonads during sexual differentiation. Although limited by sample size, this proof-of-principle studyâ&#x20AC;&#x2122;s findings did reveal ADAMTS19 as a biologically plausible candidate gene for POI.

Early Menopause and Primary Ovarian Insufficiency Early menopause (EM) affects up to 10% of the female population. Perry et al (2013) undertook a meta-analysis of GWAS in 3493 EM cases and 13 598 controls from 10 independent studies. Although no novel genetic variants were discovered, 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT), were found to be associated with both EM and POI. This included genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG, PRIM1) and immune function (IL11, NLRP11, BAT2) suggesting common biological and genetic mechanism for these two related phenotypes. The 17 alleles associated with younger menopause age were also associated with increased risk of EM and POI. Their data supported the hypothesis that EM and POI have overlapping polygenic aetiology, with individuals who carry more risk variants for lower-age-at-menopause having an increased risk of EM and POI. In GWAS, genetic variations are investigated in unrelated affected individuals compared to matched controls by means of single nucleotide polymorphisms (SNPs). The drawback is that the SNPs are not chosen on the basis of their possible functional effect. The approach follows the common diseasecommon variant hypothesis and would fail to identify rare and novel variations in genes involved in oocyte development and maturation. June/July 2014 | www.ihpmagazine.com

A rapid decline in the cost of sequencing is enabling effective mutational analysis for rare and common variations along with chromosomal deletions and copy number analysis. Application of genome or exome sequencing to identify variants can confirm and validate the role of candidate genes described in this overview and reveal the function of new genes which have a role in the etiology of POI.

Genetic heterogeneity The genetic studies described above demonstrate the high genetic heterogeneity of POI. It is likely that most severe familial cases of early onset (before age of 30) are caused by rare, highly penetrant mutations, while POI of later onset are caused by a large number of less penetrant alleles. It is also possible that different genes play a role in the development of familial and sporadic POI. The condition should be regarded as a complex genetic disease and as with other complex genetic disorders; it is characterized by familial clustering without an obvious Mendelian pattern of inheritance because several genes, their mutations and environmental factors contribute to the etiology of the disease.

Can genetic testing impact on POI management? Considering that 1% of women suffer from primary ovarian insufficiency, the underlying mechanism is unknown in 90% of the cases, and that an even a larger fraction of infertile women may be suffering from occult primary ovarian insufficiency, discovery of susceptibility genes for POI will have positive implications for understanding the link between infertility and the pathogenic mechanism. However, as the pathogenic mechanism remains unknown in most cases of POI, should women with idiopathic POI be screened for genetic alterations? Screening for the most prevalent alterations i.e. X chromosome abnormalities, FMR1 premutations and the BRCA1 alleles would not only identify the cause of disease but also help affected women make more informed reproductive decisions. Also, when a genetic alteration is observed in one of the POI candidate genes in a woman suffering from idiopathic POI, it can be useful for family counselling, and to help predict other female relatives who might be at higher risk for POI and fertility loss at a young age. This information is particularly important now, as many women choose to conceive in their late thirties and early forties, when the risk of POI is highest. Women who experience irregular menstrual cycles should be concerned and consider not deferring child bearing to a later age due to an increasing risk of POI. Genome sequencing can identify potential cause of both female and male infertility, as well as carrier status for multiple genetic disorders, helping couples make more informed reproductive decisions. Important limitations of genomic sequencing to predict disease risk include its potential use in genetic selection. While for a condition such as POI, information gathered from genetic screening may allow those at risk to start trying to conceive at a younger age, and increase chances of a healthy pregnancy; screening for genetic diseases may influence the decision to carry pregnancies to term. For example, there is robust data indicating that well over 50% of Down’s syndrome 62

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pregnancies detected by antenatal screening are selectively terminated (Natoli 2012, Wu 2013). For healthcare providers, the ethical consequences of applying genetic screening should be evaluated on a case-by-case basis. ■

References

Aittomäki K, Lucena J, Pakarinen P, et al. Mutation in the follicle stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995;82:959–68. Albright F, Smith P, Fraser R. A syndrome characterized by primary ovarian insufficiency and decreased stature. Am J Med Sci. 1942;204:625–48. Bouilly J, Bachelot A, Broutin I, Touraine P, Binart N. Novel NOBOX lossof-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort. Hum Mutat. 2011 Oct;32(10):1108-1113. Caburet S1, Arboleda VA, Llano E, Overbeek PA, Barbero JL, Oka K, Harrison W, Vaiman D, Ben-Neriah Z, García-Tuñón I, Fellous M, Pendás AM, Veitia RA, Vilain E. Mutant cohesin in premature ovarian failure. N Engl J Med. 2014 Mar;370(10):943-949. Conway GS. Clinical manifestations of genetic defects affecting gonadotrophins and their receptors. Clin Endocrinol (Oxf).1996;45:657–663. Cordell HJ, Clayton DG. Genetic association studies. Lancet. 2005; 366:1121–1131. Corre T, Schuettler J, Bione S, Marozzi A, Persani L, Rossetti R, Torricelli F, Giotti I, Vogt P, Toniolo D et al. A large-scale association study to assess the impact of known variants of the human INHA gene on premature ovarian failure. Hum Reprod. 2009;24:2023–2028. Coulam CB. Premature gonadal failure. Fertil Steril. 1982;38:645–655. Cramer DW, Xu H and Harlow BL. Family history as a predictor of early menopause. Fertil Steril. 1995; 64:740–745. Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, Bisceglia L, Zelante L, Nagaraja R, Porcu S et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ ptosis/epicanthus inversus syndrome. Nat Genet. 2001;27:159–166. De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet. 2010 Sep 11;376(9744):911-921. Di Pasquale E, Beck-Peccoz P & Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet. 2004;75:106–111. Dixit H, Deendayal M & Singh L. Mutational analysis of the mature peptide region of inhibin genes in Indian women with ovarian failure. Hum Reprod. 2004;19:1760–1764. Guiraldelli MF, Eyster C, Wilkerson JL, Dresser ME, Pezza RJ. Mouse HFM1/ Mer3 is required for crossover formation and complete synapsis of homologous chromosomes during meiosis. PLoS Genet. 2013;9(3):e1003383. Hsueh AJ, Bellig H, Tsafrin A. Ovanan follicle atresia: hormonally controlled apoptotic process. Endocrine Rev. 1994; IS 707-724. Jiao X, Qin C, Li J, Qin Y, Gao X, et al. Cytogenetic analysis of 531 Chinese

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women with premature ovarian failure. Hum Reprod. 2012;27:2201–2207. Kang H1, Lee SK, Kim MH, Song J, Bae SJ, Kim NK, Lee SH, Kwack K. Parathyroid hormone-responsive B1 gene is associated with premature ovarian failure. Hum Reprod. 2008 Jun;23(6):1457-65. Knauff EA, Franke L, van Es MA, van den Berg LH, van der Schouw YT, Laven JS, Lambalk CB, Hoek A, Goverde AJ, Christin-Maitre S et al. Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene. Hum Reprod. 2009;24:2372–2378. Kovanci E, Rohozinski J, Simpson JL, Heard MJ, Bishop CE & Carson SA. Growth differentiating factor-9 mutations may be associated with premature ovarian failure. Fertil Steril. 2007; 87:143–146. Laissue P, Christin-Maitre S, Touraine P, Kuttenn F, Ritvos O, Aittomaki K, Bourcigaux N, Jacquesson L, Bouchard P, Frydman R et al. Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. Eur J Endocrinol. 2006;154:739–744. Laissue P, Lakhal B, Benayoun BA, Dipietromaria A, Braham R, Elghezal H, Philibert P, Saad A, Sultan C, Fellous M et al. Functional evidence implicating FOXL2 in non-syndromic premature ovarian failure and in the regulation of the transcription factor OSR2. J Med Genet. 2009;46:455–457. Lambalk C, de Koning C, Flett A, van Kasteren Y, Gosden R, Homburg R. Assessment of ovarian reserve. Ovarian biopsy is not a valid method for the prediction of ovarian reserve. Hum Reprod. 2004; 19: 1055–59. Laml T, Schulz-Lobmeyr I, Obruca A, Huber JC, Hartmann BW. Premature ovarian failure: etiology and prospects. Gynecol Endocrinol. 2000 Aug;14(4):292-302. Lourenco D, Brauner R, Lin L, De Perdigo A, Weryha G, Muresan M, Boudjenah R, Guerra-Junior G, Maciel-Guerra AT, Achermann JC et al. Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med. 2009;360:1200–1210. Marozzi A, Porta C, Vegetti W, Crosignani PG, Tibiletti MG, Dalpra L & Ginelli E. Mutation analysis of the inhibin alpha gene in a cohort of Italian women affected by ovarian failure. Hum Reprod. 2002;17:1741–1745. Massin N, Méduri G, Bachelot A, Misrahi M, Kuttenn F, Touraine P. Evaluation of different markers of the ovarian reserve in patients presenting with premature ovarian failure. Mol Cell Endocrinol. 2008;282: 95–100. Matzuk MM, Finegold MJ, Su JG, Hsueh AJ & Bradley A. Alphainhibin is a tumour-suppressor gene with gonadal specificity in mice. Nature. 1992;360:313–319.

Perry JR, Stolk L, Franceschini N, Lunetta KL, Zhai G, McArdle PF, Smith AV, Aspelund T, Bandinelli S, Boerwinkle E. Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat Genet. 2009;41:648–650. Persani L, Rossetti R, Cacciatore C & Bonomi M. Primary ovarian insufficiency: X chromosome defects and autoimmunity. J Autoimmun. 2009;33:35–41 Qin Y, Choi Y, Zhao H, Simpson JL, Chen ZJ & Rajkovic A. NOBOX homeobox mutation causes premature ovarian failure. Am J Hum Genet. 2007;81:576–581. Rossetti R, Di Pasquale E, Marozzi A, Bione S, Toniolo D, Grammatico P, Nelson LM, Beck-Peccoz P & Persani L. BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein. Human Mutation. 2009;30:804–810. Sato K, Uehara S, Hashiyada M, Nabeshima H, Sugawara J, Terada Y, et al. Genetic significance of skewed X-chromosome inactivation in premature ovarian failure. Am J Med Genet. 2004;130(3): 240-244. Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier AC, Treier M. The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development. 2004 Feb;131(4):933-42

Shelling AN, Burton KA, Chand AL, van Ee CC, France JT, Farquhar CM, Milsom SR, Love DR, Gersak K, Aittomäki K et al. Inhibin: a candidate gene for premature ovarian failure. Hum Reprod. 2000;15:2644–2649. Sybert V, McCauley E. Turner’s syndrome. N Engl J Med. 2004;351:1227–1238. Tilly JL. Commuting the death sentence: how oocytes strive to survive. Nat Rev Mol Cell Biol. 2001;2(11):838-848. Torgerson DJ, Thomas RE and Reid DM. Mothers and daughters menopausal ages: is there a link? Eur J Obstet Gynecol Reprod Biol. 1997;74:63–66. Uda M, Ottolenghi C, Crisponi L, Garcia JE, Deiana M, Kimber W, Forabosco A, Cao A, Schlessinger D & Pilia G. Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development. Hum Mol Genet. 2004;13:1171–1181. van Kasteren YM1, Hundscheid RD, Smits AP, Cremers FP, van Zonneveld P, Braat DD. Familial idiopathic premature ovarian failure: an overrated and underestimated genetic disease? Hum Reprod. 1999 Oct;14(10):2455-2459.

Murray A, Webb J, Dennis N, Conway G, Morton N. Microdeletions in FMR2 may be a significant cause of premature ovarian failure. J Med Genet. 1999;36:767–770.

Vegetti W, Grazia TM, Testa G, de Lauretis Yankowski, Alagna F, Castoldi E, Taborelli M, Motta T, Bolis PF, Dalpra L et al. Inheritance in idiopathic premature ovarian failure: analysis of 71 cases. Hum Reprod. 1998;13:1796–1800.

Natoli JL, Ackerman DL, McDermott S, Edwards JG. Prenatal diagnosis of Down syndrome: a systematic review of termination rates (1995-2011). Prenat Diagn. 2012 Feb;32(2):142-53.

Vegetti W1, Marozzi A, Manfredini E, Testa G, Alagna F, Nicolosi A, Caliari I, Taborelli M, Tibiletti MG, Dalprà L, Crosignani PG. Premature ovarian failure. Mol Cell Endocrinol. 2000 Mar;161(1-2):53-57.

Nelson L, Covington S, Rebar R. An update: spontaneous premature ovarian failure is not an early menopause. Fertil Steril. 2005;83:1327–1332.

Wang J1, Zhang W, Jiang H, Wu BL; Primary Ovarian Insufficiency Collaboration. Mutations in HFM1 in recessive primary ovarian insufficiency. N Engl J Med. 2014 Mar 6;370(10):972-4.

Oktay K, Kim JY, Barad D, Babayev SN. Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks. J Clin Oncol. 2010 Jan;10;28(2):240-244.

Wu J, Morris JK. Trends in maternal age distribution and the live birth prevalence of Down’s syndrome in England and Wales: 1938-2010. Eur J Hum Genet. 2013 Sep;21(9):943-7.

June/July 2014 | www.ihpmagazine.com

The PROBIOTIC most recommended by pharmacists in Canada* Helps to REDUCE the RISK of Clostridium difficile-Associated Diarrhea in hospitalized patients

Helps to REDUCE the RISK of Antibiotic-Associated Diarrhea

* Gao et al. 2010. Dose-response Efficacy of a Probiotic Formula in Reducing Clostridium difficile-associated Diarrhea. AM J Gastroenterology. 105(7); 1636-1641.

Pharmacy Practice+ & L’actualité pharmaceutique 2014 Survey on OTC Counselling & Recommendations

Bio-K+ 50 Billion CFU Probiotic Capsule ®

• NPN: 80015104 (Helps to reduce the risk of Antibiotic Associated Diarrhea) • NPN: 80038453 (Helps to reduce the risk of C. Difficile Associated Diarrhea in hospitalized patients)

Pharmacology

Hospital Protocol Administration

Potential Mechanisms of Action It was shown that L. acidophilus CL1285®, L. casei LBC80R® and L. rhamnosus CLR2® strains have an excellent gastrointestinal survival rate. In fact, starter cultures resist to a pH of 2.5 and, when the strains are encapsulated with enteric coating, they can resist a pH of 1.5 for 2 hours1. Both strains survived to a high concentration of bile salt. This resistance allows a safe delivery of the probiotics to the GI tract and results in a production of antimicrobial molecules such as organic acids or bacteriocins. These molecules have been shown to directly eliminate various pathogenic bacteria such as C. difficile, E. faecium, E. faecalis, E. coli O157:H7, L. monocytogenes and methicillin-resistant S. aureus (MRSA)2,3. The secretion of an unknown metabolite was shown to reduce the cytotoxicity of toxin A/B secreted by C. difficile. Finally, administration of the CL1285® starter culture modulates the fecal microbiota by increasing the total lactic acid bacteria and total anaerobe count and reducing the Staphylococcus sp. Count4.

Bio-K+® is an effective solution to add to an existing hospital protocol to help reduce Clostridium (C.) difficile infections. This recommendation is based on clinical studies done with the 50 billion CFU probiotic capsule. Bio-K+® is effective when given in prophylaxis to adult patients (18+) under antibiotic treatment. Protocol administration: 2 capsules of Bio-K+® 50 Billion after the first dose of the prescribed antibiotic therapy, and continue daily usage of Bio-K+® for 5 additional days after completion of the antibiotic therapy. Bio-K+® should be administered within 2 hours after consuming the first antibiotic dose. The procedure is different for patients with a nasogastric tube. A nasogastric tube (NGT) or Levin tube is a flexible probe inserted via the nose or the mouth in order to reach the stomach. The tube can also reach the small intestine (nasoduodenal tube). This intervention requires a medical prescription and can have multiple purposes:

Health Claim5 • Helps to reduce the risk of Clostridium diffcile associated diarrhea (CDAD) in hospitalized patients. • Helps to reduce the risk of Antibiotic Associated Diarrhea (AAD). • Probiotic that forms part of a natural healthy gut flora. • Provides live microorganisms that form part of a natural healthy gut flora. • Probiotic that contributes to a natural healthy gut flora. • Probiotic to benefit health and/or confer a health benefit. • Provides live microorganisms to benefit health and/or to confer a health benefit.

Supplied Bio-K+® guaranties a minimum of 50×109 L. acidophilus CL1285®, L. casei LBC80R® and L. rhamnosus CLR2® per capsule at expiration date. These bacteria are live and protected with an enteric coating. Lyophilized bacteria are the result of fermentation, concentration and freeze-dry processes. A mixture containing a predetermined concentration of lyophilized bacteria, cellulose, ascorbic acid, and magnesium stearate is prepared. This mixture is then added in a vegetable cellulose capsule pigmented with colloidal silicone dioxide. Then, the capsule is enteric coated. Each capsule contains: ≥50×109 live strains of L. acidophilus CL1285®, L. casei LBC80R® and L. rhamnosus CLR2®. Non medicinal ingredients: ascorbic acid, cellulose, ethylcellulose, hypromellose, magnesium stearate, medium chain triglycerides, silicone dioxide, sodium alginate and titanium dioxide. Packaging options are: • 15 capsules: one bottle contains 15 capsules • 100 capsules: one box includes 10 sheets of 10 blister packed capsules • 250 capsules: one bottle contains 250 capsules • 1,000 capsules: one shipper includes 10 boxes of 10 sheets of 10 blister packed capsules Refrigerate at 4°C for maximum activity.

• Ensure the emptying of the stomach, eliminate gas (air and gastric secretions). • Before an intestinal surgery. • Liquid administration. • Allows stomach washing. • Allows to feed the patient on a short time period (force-feeding administration). • Analysis of gastric liquid. Millette et al.1 demonstrated that the Bio-K+® enteric coated capsules confer an excellent gastrointestinal (GI) survival to the probiotic strains. Millette et al.4 demonstrated the GI survival of the same strains under a pH ≥ 2.5 (without an enteric coating). It is not recommended to open the capsules, to rehydrate the lyophilized bacteria in a liquid and to consume the obtained suspension. The lyophilized bacteria are more sensitive to the acidity. If there are no other options available (i.e. patients with NGT receiving intravenous antibiotics), follow these steps to optimize the effectiveness of the Bio-K+® formula and to assure the safety of the patients: 1. Do not open the Bio-K+® capsules in the patient’s room. 2. Open and add the powder of one or two Bio-K+® capsules to 30mL of physiologic sterile water. 3. Stir the mixture with the tip of a 50 CC syringe. 4. With the 50 CC syringe, take the bacterial mixture. 5. Disinfect the external side of the syringe before bringing it in a patient’s environment. 6. Inject the suspension in the NGT, 15 minutes after the administration of a meal if possible. 7. Rinse the force-feed tube with 30 mL of physiologic water.

PCOS Natural Alternatives

Christopher Habib, ND and Faryal Luhar, ND

Christopher Habib, ND Clinic Director Mahaya Forest Hill 102-73 Warren Road Toronto, ON M4V 2R9 info@chrishabibnd.com Faryal Luhar, ND Oakville Naturopathic Wellness Centre 2172 Wyecroft Road, Unit 22 Oakville, ON L6L 6R1 ndluhar@hotmail.com

Abstract Polycystic ovarian syndrome (PCOS) affects 5-10% of women across all ethnicities and its clinical manifestation varies widely among individuals. The presence of insulin resistance, hyperinsulinemia, and obesity are associated with reproductive symptoms, and these metabolic disturbances place those affected at greater risk for developing cardiovascular disease and diabetes. Women with PCOS often seek care for menstrual disturbances, androgen excess, and infertility. Conventional treatment of PCOS is largely symptom-based with therapies aimed at these categories. While conventional pharmaceutical treatments may offer benefit in PCOS, they present risks for adverse effects such as hepatotoxicity, renal toxicity, teratogenicity, and multiple pregnancies. Numerous natural treatments exist that are commonly used as alternatives to prescription medications, such as inositol, cinnamon, chromium, and N-acetyl-cysteine (NAC). The evidence primarily indicates that natural alternatives may be used to address the insulin resistance and hyperinsulinemia seen in many patients with PCOS. Inositol has shown to be effective in improving the hormonal and metabolic profiles in PCOS. Cinnamon and chromium have shown to have benefit by improving insulin signalling and glucose control. NAC has been shown to significantly increase both ovulation rate and pregnancy rate.

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Polycystic ovarian syndrome (PCOS) was first reported in 1935, when Stein and Leventhal described a series of seven women who presented with oligo/amenorrhea, hirsutism, obesity (BMI > 25), infertility, and enlarged ovaries with multiple cysts (Madnani 2013, Sirmans 2013). This condition is now recognized as a common heterogeneous disorder affecting women of reproductive age and can be hereditary (Ebejer 2013, Sirmans 2013). It affects 5-10% of women across all ethnicities and its clinical manifestation varies widely among individuals (Madnani 2013). Stein and Leventhal originally observed a primary ovarian defect in the women studied, classifying this disorder as polycystic ovarian disease (Madnani 2013). It has become clear in recent years that the disorder is associated with major metabolic and reproductive morbidities and as such is now known as PCOS (Gerli 2007). The presence of insulin resistance, hyperinsulinemia, and obesity are associated with the reproductive symptoms, and recent data provide evidence that these metabolic disturbances place those affected at greater risk for developing cardiovascular disease and diabetes (Fulghesu 2002, Sirmans 2013). Women with PCOS often seek care for menstrual disturbances, androgen excess, and infertility (Sirmans 2013). Although 30% of women with PCOS have normal menses, the majority report oligomenorrhea, amenorrhea, and prolonged erratic menstrual bleeding (Sirmans 2013). Hirsutism is a common symptom of androgen excess prevalent in up to 70% of women with PCOS. A modified FerrimanGallwey scoring system is used to evaluate hair growth at seven sites with a total score of eight or more being indicative of hirsutism (Sirmans 2013). More than 90% of normally menstruating women with hirsutism present with polycystic ovaries through ultrasound. Other markers of hyperandrogenism are acne, oily skin, and certain virilisation patterns such as a deep voice or alopecia (Ciotta 2011, Madnani 2013). Acne is less prevalent than hirsutism, possibly due to higher dihydrotestosterone levels resulting from the expression activity of 5Îą-reductase in the sebaceous glands and hair follicles (Madnani 2013).

PCOS is the most common cause of anovulatory infertility where follicular growth is halted due to disturbances in normal follicular development (Sirmans 2013). A normal ovulatory cycle comprises a complex interplay of hormones from the pituitary, hypothalamus, adrenals, and ovaries where eventually the secretion of FSH and LH target the follicles in the ovary, allowing only one to undergo maturation to become the dominant or graffian follicle (Madnani 2013). The LH surge that takes place mid-cycle then stimulates ovulation. In PCOS however, a dominant follicle does not develop and ovulation does not ensue (Sirmans 2013). Obesity is a common feature of PCOS with 70% of these women exhibiting exaggerated insulin secretion (Fulghesu 2002). There is a decreased sensitivity to circulating insulin (possibly due to a defect in phosphorylation of tyrosine kinase in the insulin receptor), resulting in hyperinsulinemia which in turn increases androgen production (Madnani 2013). Hepatic production of sex hormone binding globulins (SHBG) is reduced thereby increasing concentrations of free androgens (Sirmans 2013). Insulin resistance occurs independently of obesity, however it is consistent with metabolic syndrome common in women with PCOS (Sirmans 2013). Impaired glucose tolerance and type 2 diabetes are also highly prevalent in these women, who are also at risk for developing dyslipidemia (Latha 2012). Studies reveal that elevated plasma insulin levels enhance VLDL synthesis and triglyceride levels, resulting in atherogenic effects in arteries (Latha 2012, Sirmans 2013). A relationship between oxidative stress and PCOS has been shown to influence the cardiovascular system as a result of lipid peroxidation, as well as the reproductive system through its effects on oocyte maturation, ovarian steroidogenesis, corpus luteum functions and other fertilization processes (De Leo 2012, Latha 2012). Equally interesting is the finding that women with PCOS have significantly higher levels of C-reactive protein (CRP) when compared to healthy weight controls, suggesting that this is an inflammatory condition (Ebejer 2013). CRP levels can predict risk of coronary June/July 2014 | www.ihpmagazine.com

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heart disease and other elevated cytokines suggesting an immune component in the pathogenesis of PCOS (Ebejer 2013). Conventional treatment of PCOS is largely symptombased with therapies aimed at three categories: menstruationrelated disorders, androgen-related symptoms, and infertility (Madnani 2013, Sirmans 2013). Low dose combined hormonal contraceptives are the primary treatment choice for PCOSrelated menstrual disorders, as well as hirsutism and acne for patients avoiding pregnancy (Sirmans 2013). Anti-androgens such as spironolactone and finesteride are also prescribed, but with great caution due to their ability to feminize a male fetus if pregnancy occurs, and so are typically combined with oral contraceptive pills (Sirmans 2013). The oral contraceptives do not correct the underlying ovulatory defect and also possibly worsen insulin sensitivity. Agents for improving insulin sensitivity include metformin and thiazolidinediones (eg. Rosiglitazone) which may also aid in restoring ovulation and improving metabolic disturbances (Ebejer 2013). Clomiphene citrate is the drug of first choice for anovulatory infertility and acts as an anti-estrogen to stimulate FSH (Ciotta 2011). Although clomiphene citrate is the gold-standard drug for ovulation induction in those with PCOS, resistance is seen in as much as 40% of women (Saha 2013). While these treatments may offer benefit in PCOS, they present risks for adverse effects such as hepatotoxicity, renal toxicity, teratogenicity, and multiple pregnancies (Madnani 2013). Numerous natural treatments exist that are commonly used as alternatives to prescription medications. These treatments include inositol, cinnamon, chromium, and N-acetyl-cysteine (NAC). The evidence for these natural therapies is reviewed.

Inositol Mounting evidence points to the central role of insulin resistance (IR) and compensatory hyperinsulinemia in the pathogenesis of PCOS (Dona 2012, Nordio 2012). These conditions predispose patients towards the development of dyslipidemia, impaired glucose tolerance, type 2 diabetes mellitus, and cardiovascular disease (Dona 2012). Several studies show that an altered insulin transduction induces abnormal ovarian steroidogenesis (Nordio 2012). Reducing serum insulin and androgen levels and restoring ovulation are typically treated with insulin-sensitizing drugs such as metformin (Nordio 2012). Metformin is generally well tolerated, however common side effects of metformin may include reduced vitamin B12 levels and gastrointestinal upset (Sato 2013). There is a good body of evidence to suggest that inositol functions as a natural insulin sensitizer, and may improve the effectiveness of metformin. Inositol is a six carbon polyalcohol which has also been characterized as an insulin-sensitizer, with reported improvements in glucose tolerance, ovulation and androgen concentration (Galletta 2011). It exists as nine different stereoisomers, two of which have been shown to be insulin mediators; namely myo-inositol (MI) and D-chiro-inositol (DCI) (Galletta 2011, Nordio 2012). The history of inositol 68

treatment stems from studies performed by Larner et al. in 1993, who originally sought to unravel the causes of type 2 diabetes mellitus (Galletta 2011). Larner undeniably showed that administration of these two inositol phosphoglycans (IPG), MI and DCI reduced hyperglycemia in a dose-dependent manner (Galletta 2011). Subsequent studies suggested that a deficiency in tissue availability, or an altered metabolism of IPG mediators may contribute to insulin resistance (Dona 2012, Nordio 2012). In 1999, Nestler et al. reported the efficacy of DCI in treating 22 obese PCOS women where 50% of subjects ovulated after four weeks of treatment (Nestler 1999). An increase in insulin sensitivity and a reduction in serum androgen levels were also reported and similar effects were produced in later studies (Galletta 2011). Inspired by the results obtained by Nestler, a research group at the AGUNCO Obstetrics and Gynecology Center in Italy began to study the effects of MI in PCOS patients and results showed a similarity in effectiveness between MI and DCI in treating metabolic disturbances and ovarian dysfunction. The study, conducted over 16 weeks, demonstrated regular menstrual cycles and a 40% pregnancy rate (Papaleo 2007). Another 16-week randomized placebo-controlled trial by Gerli et al. of 92 women with oligomenorrhea and PCOS showed a significant reduction in the mean time until the first ovulation in the myo-inositol-treated group (Gerli 2007). During the first week of treatment, a significant increase in E2 concentrations was also observed, indicating a relatively rapid effect of treatment. Considerable reductions in weight were also noted, along with lower circulating leptin and higher HDL levels (Gerli 2007). Although MI and DCI exert similar effects on insulin resistance, a direct comparison between the two molecules has been elucidated with respect to oocyte quality and maturation (Galletta 2011, Nordio 2012). It appears that elevated concentrations of MI in follicular fluid play a specific role in follicular maturation, while DCI may be more involved with enhancing insulin response (Dona 2012). MI is converted into DCI via â&#x20AC;&#x153;epimerizationâ&#x20AC;?, a process that is dependent on insulin. The MI/DCI physiological ratio is specific in each tissue (Nordio 2012). In particular, DCI concentrations are present in insulin sensitive tissues that are responsible for glycogen synthesis and storage such as the liver, muscles, and fat (Galletta 2011). The ovaries however, never become insulin resistant leading to hyperinsulinemia in these organs (Nordio 2012, Galletta 2011). During insulin resistance, the MI/DCI conversion rate is affected resulting in an overproduction of DCI and a reduction of MI and this ensuing MI depletion in tissues is a possible cause for poor oocyte quality (Galletta 2011). On this basis, a combination treatment due to synergistic effects, has shown efficacy in improving the hormonal and metabolic profiles in PCOS (Nordio 2012). Oxidative stress is another factor involved in PCOS, where reactive oxygen species are produced faster than the endogenous antioxidant systems can neutralize (Dona 2012). Hyperglycemia increases the generation of reactive oxygen species, which eventually attack certain proteins creating an inflammatory

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state (De Leo 2012). This in turn induces insulin resistance, hyperandrogenism and increases the risk of cardiovascular disease in women with this disorder. A dosage of 1200 mg/day of inositol has yielded therapeutic effects in lowering inflammation, serum androgens, and insulin levels (Dona 2012). Inositol belongs to the B-Complex group of vitamins and is present in phospholipids in human cells (Ciotta 2011). Increasing evidence supports its effectiveness in reducing hormonal, metabolic and oxidative abnormalities in patients with PCOS (Dona 2012). Inositol is promising as a safe and beneficial first-line and adjunctive treatment for women with this disorder.

Cinnamon and Chromium Cinnamon (Cinnamomon cassia) and chromium are two supplemental therapies that have been studied and shown to have benefit in the treatment of PCOS (Anderson 2007). Both appear to have similar effects on insulin signalling and glucose control. In an eight-week pilot study, fifteen women with PCOS were randomized to a daily 500mg cinnamon extract or placebo (Wang 2007). The results of this study showed significant reductions in insulin resistance as measured by fasting and two-hour oral glucose tolerance tests (OGTT) in the cinnamon group as compared to the placebo group. The proposed mechanism of action is that cinnamon extract may potentiate insulin action by enhancing the insulin signaling pathways, leading to increased phosphatidylinositol 3-kinase activity, which in turn regulates insulin-stimulated glucose uptake and glycogen synthesis, as seen in in vivo rat studies (Qin 2003). In particular, the polyphenol type-A polymer procyanidin (which can be extracted from cinnamon), appears to be particularly helpful in enhancing the insulin signalling pathways. In addition, cinnamon has been demonstrated to have antioxidant effects in people with impaired fasting glucose who are overweight or obese, which may also partially explain how it benefits those with PCOS (Roussel 2009). In a pilot study of chromium supplementation in women with PCOS, 200mcg daily of chromium picolinate improved glucose tolerance compared with placebo, but did not improve ovulatory frequency or other hormonal parameters (Lucidi 2005). In a separate trial with five obese subjects who had PCOS, trivalent chromium (also as chromium picolinate) was supplemented at a dose of 1000mcg and given without change in diet or activity level. The results showed that the chromium caused a 38% mean improvement in glucose disposal rate (as tested with a euglycemic hyperinsulinemic clamp technique) (Lydic 2006). Finally, there was a double-blind randomized clinical trial comparing 200mcg daily of chromium picolinate versus metformin for three months (Amooee 2013). The results showed that chromium significantly decreased fasting blood sugar and serum levels of fasting insulin. There were no significant differences in ovulation and pregnancy rates. In this study, only metformin was associated with decreased hyperandrogenism, but overall chromium was better tolerated. Together these studies represent the totality of recently published trials on these two supplements in the treatment of PCOS.

N-acetyl-cysteine (NAC) There is research showing that NAC can play a role in insulin secretion in pancreatic beta-cells (Santini 1997). NAC also increases cellular levels of the antioxidant glutathione, which can itself influence insulin receptor activity (Ammon 1992). One trial used this information as justification for seeing if NAC would improve insulin sensitivity in women with PCOS (Fulghesu 2002). In this trial, 37 women with PCOS were assessed. Insulin sensitivity was measured by using the hyperinsulinemic euglycemic clamp technique and other measurements were also obtained at baseline and after treatment (including oral glucose tolerance test, lipid blood profile, and hormonal assay). Trial participants were administered 1.8g of NAC orally for five to six weeks. The results showed that although many parameters were unchanged (fasting glucose, fasting insulin, and glucose area under the curve), insulin area under the curve after the OGTT was significantly reduced and the peripheral insulin sensitivity increased. A significant improvement was observed in hyperinsulinemic subjects. A set of trials has also examined NAC supplementation in PCOS patients who were clomiphene citrate resistant. In the earliest of these studies, 150 women undergoing therapy for infertility were assigned randomly to receive either 1.2g daily of NAC or placebo with 100mg daily of clomiphene citrate for five days starting at day 3 of the cycle (Rizk 2005). The results showed that the combination of NAC and clomiphene citrate significantly increased both ovulation rate and pregnancy rate (49.3% vs 1.3% and 21.3% vs 0%, respectively). A more recent study that included 180 PCOS infertile patients showed that NAC was safe and well-tolerated as an adjuvant therapy to clomiphene citrate (Salehpour 2012). NAC improved ovulation and pregnancy rates and may have had some beneficial impacts on endometrial thickness. A recent review of the evidence on the topic showed that three separate studies (a 2006 prospective controlled pilot study, a 2007 prospective randomized controlled study, and a 2010 randomized controlled trial) were all unable to replicate the results found by the first study (Saha 2013). In the most recent of these studies, 192 women were similarly randomized to receive either clomiphene citrate combined with either 1.8g NAC or metformin for three treatment cycles (Abu Hashim 2010). The results of this study showed that over a three-month follow-up period, the women who received the metformin combination had higher ovulation and pregnancy rates compared to the NAC group (69.1% vs 20.0% and 22.7% vs 5.3%). The authors concluded that the efficacy of the metformin combination therapy is higher than that of NAC combination for inducing ovulation and achieving pregnancy. The evidence on NAC remains mixed, which means it may or may not help women with PCOS, but at the very least is well-tolerated.

Conclusion PCOS is characterized by the presence of hyperandrogenism, insulin resistance, hyperinsulinemia, and obesity and is associated with an increased risk for developing cardiovascular June/July 2014 | www.ihpmagazine.com

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disease and diabetes. Conventional approaches to management of PCOS often involve used of the oral contraceptive pill, which can regulate menstrual bleeding but fails to correct ovulatory defects and may worsen insulin sensitivity, and metformin, which is generally well tolerated although it may deplete vitamin B12 levels. Natural medicines such as inositol, cinnamon, chromium, and NAC have been studied as natural alternatives or adjunctive treatments. Inositol has shown efficacy

in improving the hormonal and metabolic profiles in PCOS, as well as possibly providing anti-inflammatory and anti-oxidant actions. Cinnamon and chromium have shown to have benefit by purportedly improving insulin signalling and glucose control. The data on NAC is mixed but may help with ovulation and pregnancy rates. Overall, the safety profile of natural supplements is excellent and together, they provide patients with additional viable treatment options. ■

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;19(11):2043-8.

menstrual cyclicity in women with polycystic ovary syndrome. Fertil Steril. 2005;84(6):1755-7.

Ammon HP, Muller PH, Eggstein M, Wintermantel C, Aigner B, Safayhi H, Stutzle M, Renn W. Increase in glucose consumption by acetylcysteine during hyperglycemic clamp. A study with healthy volunteers. Drug Res. 1992;42(5):642-5.

Lydic ML, McNurlan M, Bembo S, Mitchell L, Komaroff E, Gelato M. Chromium picolinate improves insulin sensitivity in obese subjects with polycystic ovary syndrome. Fertil Steril. 2006;86(1):243-6. Madnani N, Khan K, Chauhan P, Parmar P. Polycystic ovarian syndrome. Indian Journal of Dermatology, Venereology and Leprology. May-June 2013;79.3:310

Amooee S, Parsanezhad ME, Ravanbod Shirazi M, Alborzi S, Samsami A. Metformin versus chromium picolinate in clomiphene citrate-resistant patients PCOS: A double-blind randomized clinical trial. Iran J Reprod Med. 2013;11(8):611-8.

Nordio M, Proietti D. The Combined therapy with myo-inositol and D-Chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. European Review for Medical and Pharmacological Sciences. 2012; 16: 575-581

Ciotta L, Stracquadanio M, Pagano I, Carbonaro A, Palumbo M, Gulino F. Effects of Myo-Inositol supplementation on oocyte’s quality in PCOS patients: a double blind trial. European Review for Medical and Pharmacological Sciences. 2011; 15: 509-514

Papaleo E, Unfer V, Baillargeon JP, De Santis L, Fusi F, Brigante C, Marelli G, Cino I, Redaelli A, Ferrari A. Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction. Gynecol Endocrinol 2007;23(12):700-3.

De Leo V, La Marca A, Cappelli V, Stendardi A, Focarelli R, Musacchio MC, Piomboni P. Evaluation of the treatment with D-chiro-inositol on levels of oxidative stress in PCOS patients. Minerva Ginecologica. Dec 2012;64(6): 531-8.

Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y. Cinnamon extract (traditional herb) potentiates in vivo insulin-regulated glucose utilization via enhancing insulin signaling in rats. Diabetes Res Clin Pract. 2003;62(3):139-48.

Dona G, Sabbadin C, Fiorel C, Bragadin M, Giorgino FL,Ragazzi E, Clari G, Bordin L, Armanini D. Inositol administration reduces oxidative stress in erythrocytes of patients with polycystic ovary syndrome. European Journal of Endocrinology. 2012; 166:703–710 Ebejer K, Calleja-Agius J. The role of cytokines in polycystic ovarian syndrome. Gynecol Endocrinol. 2013; 29(6): 536–540 Fulghesu AM, Ciampelli M, Muzj G, Belosi C, Selvaggi L, Ayala GF, Lanzone A. N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome. Fertil Steril. 2002;77(6):1128-35. Galletta M, Grasso S, Vaiarelli A, Roseff S. Bye-bye Chiro-inositol – Myoinositol: true progress in the treatment of polycystic ovary syndrome and ovulation induction. European Review for Medical and Pharmacological Sciences. 2011; 15: 1212-1214 Gerli S, Papaleo E, Ferrari A, Di Renzo GC. Randomized, double blind placebo-controlled trial: effects of Myo-inositol on ovarian function and metabolic factors in women with PCOS. European Review for Medical and Pharmacological Sciences. 2007;11: 347-354 Latha M, Bhaskar MV, Sharma SSB, Sumapreethi A. Evaluation of Dyslipidemia and Oxidative Stress in patients with Polycystic Ovarian Syndrome. Journal of Evolution of Medical and Dental Sciences. Nov 2012; 1(5): 769-775 Lucidi RS, Thyer AC, Easten CA, Holden AE, Schenken RS, Brzyski RG. Effect of chromium supplementation on insulin resistance and ovarian and

Rizk AY, Bedaiwy MA, Al-Inany HG. N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate-resistant patients with polycystic ovary syndrome. Fertil Steril. 2005;83(2):367-70. Roussel AM, Hininger I, Benaraba R, Ziegenfuss TN, Anderson RA. Antioxidant effects of cinnamon extract in people with impaires fasting glucose that are overweight or obese. J Am Coll Nutr. 2009;28(1):16-21. Saha L, Kaur S, Saha PK. N-acetyl cysteine in clomiphene citrate resistant polycystic ovary syndrome: A review of reported outcomes. J Pharmacol Pharmacother. 2013;4(3):187-91. Salehpour S, Sene AA, Saharkhiz N, Sohrabi MR, Moghimian F. N-Acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. J Obstet Gynaecol Res. 2012;38(9):1182-6. Santini MT, Cametti C, Indovina PL, Peterson SW. Menadione induces changes in the membrane electrical properties associated with downregulation of insulin receptors in human erythrocytes. Exp Hematol. 1998;26(6):466-71. Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clinical Epidemiology. 2014:6 1–13 Wang JG, Anderson RA, Graham GM 3rd, Chu MC, Sauer MV, Guarnaccia MM, Lobo RA. The effect of cinnamon extract on insulin resistance parameters in polycystic ovary syndrome: a pilot study. Fertil Steril. 2007;88(1):240-3.

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PRODUCT MONOGRAPH

OIL OF OREGANO

PRODUCT MONOGRAPH activrecover+ and Vegan activrecover+

activrecover+ is a sportsisnutrition supplementextract designedof specifically for postexercise Thisconstituents new formula from genuine health complements activfuel+, Oil of Oregano a hydrophobic Origanum vulgare leaf.consumption. Major active include the monoterpene its sister formula, which supplies nutrients required before and during exercise to maximize energy production and improve performance. activrecover+ on the other phenolic compounds carvacrol and thymol. Carvacrol and thymol are potent antimicrobials with synergistic bactericidal, hand provides nutrients to support the third stage of performance – recovery – and assist with repairing and building muscle. The formula activrecover+ is designed fungicidal, and antihelminthic activity. to provide high quality protein and include branched chain amino acids post-workout, help replace glycogen stores, improve recovery time, and support optimal immune function, all with the end result of ultimately elevating performance. activrecover+ is effective in conjunction with exercise of any intensity.

Human studies

Rebuild Oil of Mediterranean Oregano had antihelminthic effects when given at 600 mg emulsified oil per day in 14 adults who had Whey protein isolate is a complete protein source delivering all nine essential amino acids and helps meet the higher protein demands associated with physical tested positive enteric parasites Blastocystis Entamoeba Endolimax Aftermuscle 6 weeks activity (Fulgoni 2008).for Exercise increases protein requirementshominis, 1) up to 25% to maintain hartmanni, existing muscleand mass, and 2) up tonana. 50% to gain massof (Lemon treatment, thereincreases was complete resolution ofregulate parasitic infection in 8 cases, while Blastocystis hominis scores(from decreased inasthree 1997). Dietary protein thermogenesis and helps blood glucose. According to one study, even a 3% increase in protein 15 to 18% a percent of total calories) was associatedsymptoms with greater fat loss and the to keep it off after who 6 months Joneswith 2008).Blastocystis Vegan activrecover+ contains more cases; gastrointestinal improved inability 7 of the 11 subjects had(Paddon presented hominis plant- based protein derived from yellow peas and potatoes.

infection. (Force 2000)

Branched chain amino acids (leucine, isoleucine, valine) are anabolic and promote muscle synthesis. In addition, research has shown that BCAAs decrease muscle Animal and In vitroduring studies protein breakdown (catabolism) exercise; improve motivation and performance by decreasing the mental perception of fatigue; improve reaction time during performance; lower the stress hormone cortisol during recovery; reduce the typical onset muscle soreness (DOMS) associated with exercise; reduce Carvacrol forlevels oralofcandidiasis in immunocompromised rats was founddelayed to be as effective as treatment with Nystatin, reducing muscle fatigue associated with exercise (Howatson 2012, Shimomura 2010). the number of colony forming units (CFU’s) and completely clearing hyphae from oral surfaces when given for 8 days

(Chami In its vitro, carvacrol determined exert an inhibitory effect against 6 different strains2012). of Candida species Creatine is well2004). known for ability to increasewas strength and fat freeto mass especially in conjunction with resistance training (Cooper Creatine acts as a primarily due to extensive lesion of the plasma membrane (Salgueiro 2003). phosphorus donor in the regeneration of ATP from ADP via the ATP- phosphocreatine energy system, a crucial anaerobic energy source during high intensity (Cooperseveral 2012). In addition, a species, recent study demonstrated creatine’s abilityaureus, to reduceBacillus markers of muscle activity as well ashas in between of high intensity activity Carvacrol potentbouts antimicrobial activity against microbial including Staphylococcus damage (serumEscherichia creatinine kinase, as well as improve joint rangeCandida of motion and muscle and soreness following repeated boutsofofthese, resistance training albicans (Veggi 2013). subtilis, coli,CK), Psuedomonas aeruginosa, albicans, Aspergillus niger; out Candida

has been most susceptible (Santoyo 2006). Carvacrol thymol thought to exert additive effect by disrupting Glutamine is an found important fuel for immune cells, particularly neutrophils, storedand within skeletalare muscle (Lagranha 2008).an Glutamine helps optimize immune function bacterial membrane (Lambert(Cury-Boaventura 2001). Oregano hasInbeen shown to inhibit Methicillin resistant strains Staph. 2012). addition, glutamine may help offset loss of lean muscle mass of during acute illness: to prevent overtraining inducedintegrity immune suppression during infection, the body mobilizes muscle stores of glutamine in order to feed the immune system, thereby catabolizing muscle mass (Lightfoot 2009). Administering supplemental glutamine during this time may help offset this effect and maintain lean body mass.

Re-Energize activrecover+ provides approximately 20g carbohydrates from corn, brown rice, and orange. Depletion of glycogen stores is a key factor in determining the amount of time required for exercise recovery, and the post-exercise consumption of carbohydrates is the most important factor in replenishing glycogen (Beelen 2010). Consumption of protein/ amino acids in addition to carbohydrates post exercise causes insulin release and boosts the glycogen replacement rate (Beelen 2010). Restore Lemon verbena extract possesses antioxidant effects and has been shown to reduce muscle damage and offset neutrophil damage in athletes in response to chronic running eccentric exercise (Funes 2011). Tart cherry juice has been shown to reduce muscle pain following running exercise (Kuehl 2010) and attenuate the reduction in muscle strength following exercise, with a 22% loss of strength in the placebo group compared to only 4% in the tart cherry juice group (Connolly 2006). Figure 1: Structure of Carvacrol (left) and Thymol (right)

aureustoand epidermis, andrestoring attenuates biofilm formation (Nostrain2004; Directions: rebuild muscles while energy, mix one scoop (40g)inofvitro activrecover+ one to 2007). one and a half cups (250-375mL to taste) water. For best results, take 1 serving immediately after exercising. 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 Table 1. activrecover+ and Vegan activrecover+ formula, per 40g (1 scoop) relative safety of Oregano oil. Action Ingredient Dose Carvacrol was shown to be hepatoprotective against ischemia and reperfusion injury in rats; both carvacrol and silymarin Rebuild Whey protein isolate (bovine milk) 6.6g had similar beneficial effectspea onprotein AST isolate and ALT levels (Canbek 2007). Carvacrol also increased liver regeneration rate in rats Pisum sativum: Yellow activrecover+ after partial hepatectomy (Uyanoglu 2008). Pisumstudies sativum: of Yellow pea protein isolate Mutagenicity carvacrol show only weak activity; carvacrol is excreted in urine after 24 hours in large quantities, Solanum tuberosum: Potato tuber protein isolate Vegan unchanged or as glucoronide and sulphate conjugates (De Vincenzi 2004). activrecover+ Pisumsativum: yellow pea protein isolate

5.7g 2.0g L-leucine Canbek M, Uyanoglu M, Bayramoglu G, Senturk H, Erkasap1.0g N, Koken T, Uslu S, Demirustu C, Aral E, Husnu Can Baser 500mg Effects ofL-isoleucine carvacrol on defects of ischemia-reperfusion in the rat liver. Phytomedicine. 2008 Jan. L-valine 500mg Fitoterapia 2004; 75(7-8): 801-804. De Vincenzia M et al. Constituents of aromatic plants: carvacrol. L-glutamine 500mg Force M Zea et al. Inhibition of enteric parasites by emulsified oil of oregano in vivo. Phytother Res. 2000 May;14(3):213-4. Re-Energize mays fruit: D-glucose 9.5g

References Creatine monohydrate

Lambert Oryza RJ, Skandamis PN, Coote PJ, Nychas GJ. A study of7.9g the minimum inhibitory concentration and mode of action of sativa: whole grain sprouted brown rice dry syrup oregano essential oil, thymol and carvacrol. J Appl Microbiol. 2001 Sep;91(3):453-62. Citrus sinensis: sweet orange fruit powder 4.0g Nostro A,Aloysiacitrodora: Roccaro AS, Bisignano G,leaf Marino A, Cannatelli MA, Pizzimenti FC, Cioni PL, Procopio F, Blanco AR. Effects of Restore lemon verbena 600mg oregano, Prunuscerasus: carvacrol andtartthymol on Staphylococcus aureus and Staphylococcus epidermidis biofilms. J Med Microbiol. cherry fruit skin 100mg 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. References May 7;7:17. et al. J IntSocSports Nutr. 2010 Salgueiro LR et al. Chemical composition and antifungal activity Kuehl of theKS, essential oil of Origanum virens on Candida species. Beelen M, et Med. al. Int J2003 Sport Sep;69(9):871-4. NutrExercMetab. 2010 Dec;20(6):515-32. Lagranha CJ, et al. Amino Acids. 2008 Apr;34(3):337-46. Planta Connolly DA, et al. Br J Sports Med. 2006 Aug;40(8):679-83. Lemon PW, et al. Can J ApplPhysiol. 1997 Oct;22(5):494-503. Santoyo Cavero S, Jaime L, Ibañez E, Señoráns FJ, Reglero G. Supercritical dioxide extraction ofSuppl):S384-90. compounds with Cooper R, et al.S,J IntSoc Sports Nutr. 2012 Jul 20;9(1):33. Lightfoot A, et carbon al. Crit Care Med. 2009 Oct;37(10 antimicrobial L.: determination of optimal extraction J Food Prot. Cury-Boaventura MF,activity et al. Eur from J ApplOriganum Physiol. 2008vulgare Jun;103(3):289-94. Paddon-Jones D, et al. Amparameters. J ClinNutr. 2008 May;87(5):1558S-1561S. Fulgoni VL, et al. Am J ClinNutr. 2008 May;87(5):1554S-1557S. Shimomura Y, et al. Int J Sport NutrExercMetab. 2010 Jun;20(3):236-44. 2006;69(2):369-75. Funes L, et al. EurM, J Appl Physiol. Veggi K FT,upon et al. Int 23. [Epub ahead of Uyanoglu Canbed M,2011 AralApr;111(4):695-705. E, Husnu Can Baser K. Effects of carvacrol theJ Sport liver NutrExercMetab.2013 of rats undergoingJan partial Howatson G, et al. J IntSoc Sports Nutr. 2012 May 8;9(1):20. print] hepatectomy. Phytomedicine 2008; 15(3): 226-9.

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.

ChemotherapyInduced Peripheral Neuropathy Natural therapies

By Rachel M.T. Corradetti, ND and Akbar Khan, MD

Medicor Cancer Centres 4576 Yonge St, Suite 301, Toronto, ON, Canada, M2N 6N4 akhan@medicorcancer.com rachel@rachelcorradetti.com

Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is characterized by a variety of symptoms including paresthesia, numbness, burning pain, allodynia and hyperalgesia, typically in a “stocking and glove” distribution. It affects a large percentage of chemotherapy recipients often leading to delay or cessation of treatment, which can be detrimental to their cancer recovery. Sadly, patients are often left with the symptoms of this debilitating condition long after treatment has stopped. Little is understood of CIPN, despite the research that has been conducted into pharmaceutical and natural therapies. Currently there is no consistent standard of care to manage this condition. This review serves to highlight the current state of evidence regarding the theorized pathophysiology of CIPN, the chemotherapeutic agents most responsible, the pharmaceutical agents commonly used to manage it, and the natural therapies offering new hope to reduce neurological symptoms in this patient population.

Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a severe, dose-limiting toxicity condition causing a variety of sensorimotor deficits including paresthesia, numbness, burning pain, allodynia and hyperalgesia, typically appearing in a “stocking and glove” distribution (Areti 2014, Han 2013). CIPN is most often a sensory neuropathy as described, but motor neuropathy is also possible. This may manifest as weakness of distal muscles or reduced deep tendon reflexes (Bristol-Myers Squibb 2011, GlaxoSmithKline

2002, Sanofi-aventis 2010). It is experienced by 30-40% of chemotherapy patients on average with reports of up to 70% depending on the chemotherapeutic agent used (Areti 2014, Beijers 2012). Often, the experience of CIPN does not resolve after treatment has stopped (Han 2013). Its pervasiveness amongst chemotherapy patients has led the National Cancer Institute to deem it a major cause of treatment cessation. Therein lies the potential for decreased chemotherapeutic efficacy and higher relapses of cancer (Areti 2014). June/July 2014 | www.ihpmagazine.com

A variety of chemotherapeutic agents are associated with CIPN: platinum compounds (cisplatin, oxaliplatin), taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine), epothilones (ixabepilone), proteasome inhibitors (bortezomib) and thalidomide. While the exact mechanisms of nerve damage are not completely clear, theories abound including: microtubule disruption, oxidative stress and subsequent mitochondrial damage, altered ion channel activity, myelin sheath damage, DNA damage and neuro-inflammation (Areti 2014). Nerves have a higher amount of phospholipids, mitochondria-rich axoplasms and weak cellular oxidative defenses making them more susceptible to damage. Furthermore, anti-cancer drugs cause free-radical production leading to greater physical neuron damage by demyelination, mitochondrial dysfunction, microtubular damage and apoptosis. Overall, oxidative stress seems to be the biggest issue. This is also known to be a factor in CharcotMarie-Tooth disease and diabetic neuropathy â&#x20AC;&#x201C; two of the most common neuropathic disorders (Areti 2014). Oxidative damage is compounded by a number of other factors: polychemotherapy in cancer treatment (Areti 2014), use of other non-chemotherapeutic drugs, patient age, preexisting conditions such as pernicious anemia, diabetes, HIV/AIDs, alcoholism, and/ or vitamin B12 deficiency (Armstrong 2005). With such diverse effects on the nerves, a number of strategies have been investigated for prevention and treatment of CIPN. There are few clear winners amongst the pack, and there is currently no widely-accepted primary prevention or treatment regimen for CIPN (Hershman 2014). This paper will review current practice with respect to pharmaceutical interventions and discuss the evidence on naturopathic nutraceutical and acupuncture strategies for prevention and treatment of CIPN.

Allopathic Treatment Options There are many publications exploring allopathic management of CIPN. Medical researchers have reached into their toolboxes to determine if well-known symptomatic treatments for non-chemotherapy-induced neuropathic conditions (e.g. diabetic neuropathy) will benefit those suffering from CIPN. These include NSAIDS, opioids (oxycodone and tramadol), gabapentin, recombinant human leukemia inhibitory factor, SSNRIs (venlafaxine, duloxetine), 74

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tricyclic antidepressants (TCAs) (nortriptylline and amitriptylline), anticonvulsants (carbamazepine, pregabalin, lamotrigine), and erythropoietin. Unfortunately, all of these allopathic therapies are utilized in an attempt to control the unpleasant symptoms of neuropathy rather than preventing or actually treating it. Such symptomatic therapies are not specific to the underlying cause of the neuropathy and often provide little to no effect when formally studied in clinical trials (Kaley 2009). Overall, allopathic treatment of CIPN has proven to be wrought with difficulties. As such, there is great interest in a naturopathic approach to CIPN management.

Naturopathic Treatment There are a number of naturopathic therapies that have been investigated for management of CIPN. These include both nutraceuticals and acupuncture. A notable difference with the naturopathic approach to neuropathy is that various natural agents have actual neuroprotective and neuroregnerative potential. This is a large improvement over a purely conventional approach, which only masks neuropathic pain. When used for CIPN prevention, nutraceuticals must also show that they are able to reduce the neurotoxic effects of the chemotherapeutic agents, while not interfering with its anti-tumour activity. Wellaccepted nutraceutical options include calcium and magnesium infusions with multiple studies also focused on acetyl-L-carnitine (ALC). Acupuncture is also an up-and-coming field of research for CIPN management, especially because it can be used in conjunction with chemotherapy without risk of interaction. This review will cover evidence pertaining to a range of natural therapies including ALC, N-acetylcysteine (NAC), glutathione, alpha-lipoic acid (ALA), vitamins B6, B12 & E, calcium, magnesium, glutamine, omega-3 fatty acids, melatonin and acupuncture will be reviewed.

Acetyl-L-carnitine The mechanism of action of ALC is unclear. It is theorized that ALC may modulate nerve growth factor expression and promote nerve regeneration to increase nerve conduction and velocity (Kaley 2009), while also blocking A-fiber and C-fiber nociceptor firing (Bianchi 2005). It acts as an antioxidant to move acetyl groups across mitochondrial membranes, while also playing a role in catabolic and anabolic

The Journal of IHP – Continuing Education

mechanisms (Pachman 2011). Pisano (2003) investigated the potential role of ALC in the treatment of paclitaxel- and cisplatininduced peripheral neuropathy in rat models revealing a significant difference in CIPN with no effect on anti-tumour activity. However, a recent phase III trial failed to show significant prevention of CIPN when ALC was administered concurrently with taxane chemotherapy (Hershman 2012). That being said, it has still shown benefit in the treatment of CIPN post-chemotherapy with cisplatin and paclitaxel (Areti 2014, Bianchi 2005, Maestri 2005, Schloss 2014). While it is highly tolerable, nausea and insomnia have occasionally been reported with its use (Bianchi 2005, Maestri 2005). Patients with a history of seizures must use ALC cautiously, since it can increase seizure frequency (De Grandis 1995, Hendler 2001, Juvenon Inc 2003, Zdanowicz 2001).

N-acetyl-cysteine (NAC) NAC acts to increase glutathione concentration, while decreasing the cytotoxic effects of platinum adducts in the dorsal root ganglia (Kaley 2009, Schloss 2013). In a recent randomized pilot study conducted by Lin (2006), fourteen stage-three colon cancer patients receiving oxaliplatin were treated with oral NAC. Fewer patients in the treatment group developed CIPN, however, the small sample size meant the results did not reach statistical significance. It would be beneficial to conduct a larger study of this potentially effective preventative agent.

Glutathione Glutathione supplementation has shown good effect in treating CIPN patients (Pachman 2011, Piccolo 2014). It has a high affinity for heavy metals, thereby reducing platinum adducts causing oxidative damage in the dorsal root ganglia (Piccolo 2014). A number of clinical trials have also reported that glutathione does not affect chemotherapeutic activity while reducing neurotoxic effects, especially when treating oxaliplatininduced peripheral neuropathy (Cascinu 2002, Cascinu 1995). An RCT conducted in 52 patients with colorectal cancer treated with oxaliplatin with or without the addition of glutathione reported significantly reduced incidence of grade two to four neuropathy based on National Cancer Institute common toxicity criteria (p=0.003) assessed after 12 cycles of chemotherapy, as well as better sensory nerve condition on electrophysiological testing associated with glutathione treatment (Cascinu 2002). The chemotherapy response rate was 26.9% in the glutathione arm and 23.1% in the placebo arm, indicating no reduction in the effectiveness of oxaliplatin (Cascinu 2002). Glutathione has also been investigated with cisplatin therapy. There is a phase II trial suggesting lack of negative interaction between glutathione and cisplatin in patients with ovarian cancer when glutathione was given at 2500mg IV before cisplatin infusion (Locatelli 1993). Another early prospective study assessed administration of IV glutathione prior to cisplatin infusion in ovarian cancer patients, and while there was no comparator group, authors judged that “use of GSH is a safe new method for high-dose cisplatin administration. This regimen is well-tolerated and very effective in ovarian cancer patients with bulky disease

and warrants further evaluation” (Di Re 1990). Finally, an RCT conducted in patients with ovarian cancer demonstrated that use of glutathione led to decreased toxicity, resulting in a significantly greater percentage of patients able to receive treatment with six rounds of cisplatin compared with patients not co-treated with glutathione, 58% versus 39%, (p = 0.04) (Smyth 1997). Importantly, the group treated with glutathione plus cisplatin demonstrated a non-significant trend to better treatment response as assessed clinically, 73% versus 62% (p=0.25). A 2014 Cochrane review assessing the role of agents including glutathione for the prevention of neuropathy induced by platinum drugs concluded that there is insufficient evidence to conclude efficacy in preventing CIPN, but noted “modest but promising (borderline statistically significant) results favouring [its] ability to reduce the neurotoxicity of cisplatin and related chemotherapies” (Albers 2014).

Alpha-Lipoic Acid (ALA) Gedlicka (2003) has investigated ALA use in CIPN patients caused by docetaxel/cisplatin showing beneficial results with no side effects. ALA is a potent lipophilic antioxidant that is suspected to decrease oxidative stress (Gedlicka 2003, Pachman 2011). It also has proven benefits in the treatment of diabetic neuropathy (Bertolotto 2012). Guo et al (2014) studied 243 cancer patients in a randomized, double-blind placebocontrolled trial where ALA (or placebo) was dosed orally at 600mg three times daily. Only 70 patients completed the trial due to compliance issues. As such, clinical significance could not be determined. The authors suggest that intravenous therapy may allow for greater patient compliance, and more studies are needed to properly investigate ALA.

Vitamins B6 and B12 Diagnostic evaluation of CIPN often involves testing vitamin B6 and B12 levels, since deficiencies of these agents are known to cause peripheral neuropathy. An early double-blind, randomized, placebo-controlled trial found vitamin B6 significantly reduced CIPN from cisplatin and hexamethylmelamin administration (Wiernik 1992). This study also observed a reduced response duration associated with B6 use, however, with a median of 6.4 months until progression in the B6 group, compared to 10.1 months it the group without B6 treatment (Wiernik 1992). However, there was no impact from use of B6 on time to treatment failure or overall survival (Wiernik 1992). Other studies of B6 suggest an opposite effect, protecting against capecitabine (5-fluorouracil prodrug, Xeloda) induced hand-foot syndrome, but showing no deleterious effect on anti-tumour effects (Corrie 2012). In this study, administration of pyridoxine resulted in “an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15-1.6, P=0.26)” (Corrie 1992). Further research is needed to better elucidate the effects of B6 on specific chemotherapy regimens. June/July 2014 | www.ihpmagazine.com

Vitamins B6 and B12 have also been wellevaluated in diabetic neuropathy since they are key cofactors for a number of metabolic processes including DNA synthesis and regulation (Miranda-Massari 2011, Xu 2013), which increases the biological plausibility that they may prove useful in CIPN as well.

Calcium and Magnesium Calcium and magnesium infusions have been shown to be especially beneficial for oxaliplatininduced peripheral neuropathy. Oxalate (a metabolite of oxaliplatin) is toxic to voltagegated sodium channels, and chelation of oxalate with calcium and magnesium appears to prevent neuropathy (Kaley 2009, Pachman 2011). While trials to date have investigated small sample sizes and have produced limited data, the evidence is supportive in general (Gamelin 2004, Grothey 2011). Gamelin demonstrated benefit on neuropathy without affecting tumor response rate: 20% of patients in the treatment group developed neuropathy compared to 45% in the control group (2004). In the Combined Oxaliplatin Neurotoxicity Prevention Trial (CONCEPT), Grothey showed that calcium magnesium infusion reduced grade two or greater sensory neuropathy as well as oxaliplatin induced sensory neuropathy in patients with colorectal cancer on infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) (2011). Interim results of this study reported possible decreased response rates associated with calcium magnesium therapy, however upon analysis of the final data, a null effect on response rates was found (Grothey 2011). Finally, a retrospective analysis of 755 patients with colorectal cancer found that the incidence of all grade neurotoxicity in the Ca/Mg(+) group and the Ca/Mg(-) group was 85% and 92%, respectively (p = 0.02), and the response rate was 43.1% versus 50%, respectively (p = 0.11), respectively, indicating benefit on incidence of neuropathy without reduction in anticancer effects (Knijn 2011). Calcium gluconate and magnesium sulfate have been proposed to increase the concentration of extracellular calcium and decrease the hyperexcitability of neurons exposed to oxaliplatin (Wolf 2008).

Glutamine Glutamine is a non-essential amino acid stored in skeletal muscle and the liver, which can decline during long periods of stress, such 76

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as malignancy (Beijers 2012). Glutamine is known to up-regulate nerve growth factors in animal models (Gwag 1997, Vandat 2001, Wolf 2008) and is thought to be best used as a neuroprotective agent (Stubblefield 2005, Vahdat 2001, Visovsky 2007). Wang (2007) initially reported a study using glutamine for prevention of oxaliplatin-induced neuropathy that showed a significantly lower incidence of neuropathy in the glutamine group after four cycles. However, other studies have not shown clinical significance (Vahdat 2001). Glutamine may have a role in neuroprotection, but data from larger, double-blinded, randomized, placebo-controlled trials is still needed.

Omega-3 Fatty Acids Omega-3 fatty acids (eicosapentanoic acid, EPA and docosahexanoic acid, DHA) are polyunsaturated fats, integrated into the phospholipid membrane of peripheral nerves. They help to regulate signal transduction, while also inhibiting pro-inflammatory cytokines causing neuropathy, and reducing the production of further pro-inflammatory mediators (Coste 2003, Shapiro 2003). Researchers believe omega-3 fatty acids require further studies using larger sample sizes, but current results show promise for both CIPN prophylaxis and treatment (Areti 2014, Schloss 2013). A couple of recent RCTs show benefit from omega-3 fatty acids on CIPN. Ghoreishi et al found that treatment with approximately 1800mg combined EPA+DHA (10% EPA component) significantly reduced the incidence of paclitaxel-induced peripheral neuropathy in breast cancer patients (2012). The number of patients not developing neuropathy was 21 (70%) in the omega-3 fatty acid group, compared to 11 (40.7%) in the placebo group,odds ratio OR = 0.3, .95% CI 0.10-0.88, p = 0.029). Another RCT in patients with non small cell lung cancer (NSCLC) on paclitaxel and cisplatin/carboplatin treatment found that supplementation with an EPA-enriched supplement (100% EPA component) resulted in improvements in several parameters including fatigue, appetite, and neuropathy: while the control group had significant increases in nausea and vomiting (p=0.02) and neuropathy (p=0.004) associated with chemotherapy, the EPA-treated group showed no change (p>0.05) (Sรกnchez-Lara 2014). Importantly, omega-3 fatty acids have

The Journal of IHP – Continuing Education

not only been shown to not interfere with the effectiveness of chemotherapy, but in select patient populations they may even improve anticancer effectiveness, adding further benefit to their use in these situations. Notably, in patients with non-small cell lung cancer undergoing first-line treatment with carboplatin with vinorelbine or gemcitabine, use of 2.5g omega-3s containing 2.2g EPA + 240-500mg DHA resulted in significantly higher response rates (60.0% vs 25.8%, p = .008) and a trend toward longer overall survival (60.0% vs 38.7%; p = .15) (Murphy 2011).

Melatonin Melatonin is a pineal hormone that naturally enhances neuroprotection by inhibiting the production of free radicals. Research conducted by Nahleh showed the connection between taxane-induced peripheral neuropathy and concurrent oral supplementation with melatonin (2010). Twenty-two breast cancer patients were dosed 21mg of melatonin at bedtime daily for 28 days. Results revealed a reduction in CIPN symptoms whereby 45% of patients experienced only mild neuropathy and 55% of patients experienced no neuropathy at all. Furthermore, there was no reduction of chemotherapeutic effect. Technically, the results are not considered statistically significant due to the sample size of 22 patients. Since positive results were elucidated by this trial, and since melatonin has been useful in treating other cancer symptoms including cachexia, stomatitis, and asthenia, it would be ideal to further investigate melatonin’s effect on CIPN with larger clinical trials. Furthermore, two meta analysis of RCTs investigating melatonin in combination with chemotherapy have shown lack of negative interactions on anticancer effects, with improved survival at one year, and a reduction of other side effects of chemotherapy, respectively (Mills 2005, Seely 2012).

Vitamin E According to Areti, the evidence supporting vitamin E is controversial (2014). While a large trial conducted by Kottschade showed no significant difference in patients treated with all varieties of CIPN (2011), smaller studies by Pace (2003) and Argyriou (2012) found a significant benefit. Vitamin E is useful for protection against microtubule dysfunction caused especially by cisplatin. Larger studies are needed to show proof of efficacy (Kaley 2009, Pachman 2011, Piccolo 2014, Schloss 2013).

Capsaicin There are currently no clinical trials studying the use of capsaicin in CIPN specifically, but other neuropathic conditions show benefit from treatment with capsaicin due to its depletion of substance P in distal nerve endings (Kaley 2009). Topical symptom control strategies offer benefit over oral medications simply because they have reduced absorption and therefore less risk of systemic toxicity and interference with chemotherapeutic agents (Pachman 2011).

Acupuncture While its physiological mechanism is not fully understood, acupuncture has been studied for its energetic ability to ease the

symptoms of CIPN. Acupuncture has been previously studied for peripheral neuropathy experienced in HIV and diabetic patients with positive results (Abuaisha 1998, Phillips 2004). Wong conducted a pilot prospective case series of 5 patients, which treated Traditional Chinese Medicine elements of Qi and Blood (2006). It revealed a reduction in CIPN across all patients while maintaining remission. A later trial conducted by Schroeder provided similar results suggesting larger, randomized trials are needed, especially since acupuncture has no known interaction with chemotherapy drugs (2012).

Recommendations While there is an abundance of natural therapies with a theoretical basis for managing CIPN, there are a number of limitations that affect their study. Each chemotherapeutic agent has a different effect on neurons, as does each natural therapy, meaning it is difficult to find a single comprehensive treatment for CIPN. Furthermore, appropriate measures for assessing CIPN severity are as varied as the symptoms themselves, resulting in difficulty in comparing the results of different studies. Finally, while many studies have been conducted in total, the research base on individual agents and use of adequate sample size to produce definitive results is sometimes lacking as a result of limited available funding for research on non-proprietary agents. Another serious limitation of the current body of literature is lack of trials examining the role of combination naturopathic therapy. Due to the multiple mechanisms of nerve injury induced by chemotherapy, it would be reasonable to theorize that a combination of natural medications with a diverse range of neuroregnerative properties may be more efficacious than single agent therapy. For example, in the authors’ experience, a combination of high doses of B vitamins with high dose ALA and ALC can have a profound and lasting effect on debilitating, intractable CIPN (post-chemotherapy), with minimal side effects. Where possible, use of the activated forms of vitamins is recommended, for example methylcobalamin (B12), pyridoxal5-phosphate (P5P, B6) and benfotiamine (B1), in order to circumvent any factors notably genetic polymorphisms that may impede adequate in vivo conversion by individuals. With respect to individual nutraceuticals, current studies demonstrate limited evidence for their administration in conjunction with chemotherapeutic agents. The most wellestablished CIPN therapies include: • oral vitamin E with cisplatin (Argyriou 2012, Pace 2003) • oral vitamin B6 with cisplatin (Corrie 2012, Wiernik 1992) • omega-3 fatty acids with paclitaxel (Ghoreishi 2012, SánchezLara 2014) • intravenous glutathione with oxaliplatin (Cascinu 2002, Cascinu 1995) • intravenous calcium magnesium with oxaloplatin (Gamelin 2004, Grothey 2011) Further research is needed before these nutraceuticals are established as routine CIPN prophylactics. Therapies like melatonin, calcium and magnesium injections, glutathione and ALA deserve larger investigations. Finally, acupuncture June/July 2014 | www.ihpmagazine.com

should also be considered for larger scale trials since it is welltolerated and effective without interfering with the efficacy of chemotherapeutic agents. Since CIPN is a severe side effect of neurotoxic chemotherapy, treatments aimed at prevention, treatment or alleviating the symptoms are in high demand. Naturopathic treatments with neuroprotective and neuroregenerative potential have a particularly important role in this area. With continued research it is likely that natural therapies will come to the forefront as leading treatments for this crippling condition. ■ References Abuaisha BB, Costanzi JB, and Boulton AJ. Acupuncture for the treatment of chronic painful peripheral diabetic neuropathy: a long-term study. Diabetes Research in Clinical Practice. 1998; 39 (2): 115-21. Albers JW, Chaudhry V, Cavaletti G, Donehower RC. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2014;3:CD005228. Areti, A., Ganesh, V, Naidu, VGM, and Kumar, A. Oxdative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox Biology. 2014; 2; 289–295. Argyriou, AA, Bruna, J, Marmiroli, P, and Cavaletti, G. Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Critical Reviews in Oncology/ Hematology. 2012; 82; 51-77. Armstrong T, Almadrones L, Gilbert MR. Chemotherapy-induced peripheral neuropathy. Oncol Nurs Forum. 2005 Mar 5;32(2):305-11. Beijers, AJM, Jongren, JLM, and Vreugdenhil, G. Chemotherapy-induced neurotoxicity: the value of neuroprotective strategies. Netherlands Journal of Medicine. 2012; 70 (1): 18-25. Bertolotto F, Massone A. Combination of alpha lipoic acid and superoxide dismutase leads to physiological and symptomatic improvements in diabetic neuropathy. Drugs R D. 2012 Mar 1;12(1):29-34. Bianchi, G, Vitali, G, Caraceni, A, et al. Symptomatic and neurophysiological responses of paclitaxel or cisplatin-induced neuropathy to oral acetyl-L-carnitine. European Journal of Cancer. 2005; 41: 1746-1750. Bristol-Myers Squibb. (2011 April). Taxol (paclitaxel) injection prescribing information. Princeton, NJ. Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM, Beretta GD, Ubiali E, Catalano G. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002 Aug 15;20(16):3478-83. Cascinu S, Cordella L, Del Ferro E, Fronzoni M, Catalano G. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. J Clin Oncol. 1995 Jan;13(1):26-32. Corrie PG, Bulusu R, Wilson CB, Armstrong G, Bond S, Hardy R, Lao-Sirieix S, Parashar D, Ahmad A, Daniel F, Hill M, Wilson G, Blesing C, Moody AM, McAdam K, Osborne M. A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications. Br J Cancer. 2012 Aug 7;107(4):585-7. Coste TC, Gerbi A, Vague P, Pieroni G, Raccah D. Neuroprotective effect of docosahexaenoic acid-enriched phospholipids in experimental diabetic neuropathy. Diabetes. 2003 Oct;52(10):2578-85. 78

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De Grandis, D. Acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy. CNS Drugs. 2007; Suppl 1: 39-43. De Grandis D, Santoro L, Di Benedetto P. L-Acetyl carnitine in the treatment of patients with peripheral neuropathies. A short term, double-blind clinical study of 426 patients. Clin. Drug Invest. 1995; 10 (6): 317-322. Di Re F, Bohm S, Oriana S, Spatti GB, Zunino F. Efficacy and safety of high-dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer. Cancer Chemother Pharmacol. 1990;25(5):355-60. Gamelin, L, Boisdron-Celle, M, Delva, R, et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for advanced colorectal cancer. Clinical Cancer Research. 2004; 10: 4055-4061. Gedlicka, C, Korneck, GV, Schmid, K and Scheithauer, W. Amelioration of docetaxel/cisplatin induced polyneuropathy by α-lipoic acid. Annals of Oncology. 2003; 14: 339-340. Ghoreishi, Z, Esfahani, A, Djazayeri, A, et al. Omega-3 fatty acids are protective against paclitaxel-induced peripheraly neuropathy: a randomized double-blind placebo controlled trial. BMC Cancer. 2012; 12: 335-342. GlaxoSmithKline. (2002 November). Navelbine (vinorelbine tartrate) injection prescribing information. Research Triangle Park, NC. Grothey A, Nikcevich DA, Sloan JA, Kugler JW, Silberstein PT, Dentchev T, Wender DB, Novotny PJ, Chitaley U, Alberts SR, Loprinzi CL. Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol. 2011 Feb 1;29(4):421-7. Guo, Y, Jones, D, Palmer, JL, et al. Oral alpha-lipoic acid to prevent chemotherapyinduced peripheral neuropathy: a randomized, double-blind, placebo-controlled trial. Support Care Cancer. 2014; 22 (5): 1223-1231. Gwag BJ, Sessler FM, Robine V, Springer JE. Endogenous glutamate levels regulate nerve growth factor mRNA expression in the rat dentate gyrus. Mol Cells. 1997 Jun 30;7(3):425-30. Han, Y, and Smith, MT. Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN). Frontiers in Pharmacology. 2013; 4: 1-16. Hendler S.S, Rorvik D, eds. Acetyl-L-carnitine, L-carnitine. PDR for Nutritional Supplements. 2001. Montvale, Medical Economics Company, Inc. p 9-11, 255-259. Hershman DL, Unger JM, Crew KD, Minasian LM, Awad D, Moinpour CM, Hansen L, Lew DL, Greenlee H, Fehrenbacher L, Wade JL 3rd, Wong SF, Hortobagyi GN, Meyskens FL, Albain KS. Randomized double-blind placebocontrolled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol. 2013 Jul 10;31(20):2627-33. Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, Chauhan C, Gavin P, Lavino A, Lustberg MB, Paice J, Schneider B, Smith ML, Smith T, Terstriep S, Wagner-Johnston N, Bak K, Loprinzi CL. Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014 Apr 14. Juvenon, Inc. (2003a) Questions & Answers. Juvenon™. [http://www.juvenon. com/qa.html].

The Journal of IHP – Continuing Education Kaley, T, and DeAngelis, LM. Therapy of chemotherapy-induced peripheral neuropathy. British Journal of Haematology. 2009; 145: 3-14. Knijn N, Tol J, Koopman M, Werter MJ, Imholz AL, Valster FA, Mol L, Vincent AD, Teerenstra S, Punt CJ. The effect of prophylactic calcium and magnesium infusions on the incidence of neurotoxicity and clinical outcome of oxaliplatinbased systemic treatment in advanced colorectal cancer patients. Eur J Cancer. 2011 Feb;47(3):369-74. Kottschade, LA, Sloan, JA, Mazurczak, MA, et al. The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase III clinical trial. Support Cancer Care. 2011; 19: 1769-1777. Lin, PC, Lee, MY, Wang, WS, et al. N-acetylcysteine has neuroprotective effects against oxaliplatin-based adjuvant chemotherapy in colon cancer patients: preliminary data. Support Cancer Care. 2006. 14: 484-487. Locatelli MC, D'Antona A, Labianca R, Vinci M, Tedeschi M, Carcione R, Corbo A, Venturino P, Luporini G. A phase II study of combination chemotherapy in advanced ovarian carcinoma with cisplatin and cyclophosphamide plus reduced glutathione as potential protective agent against cisplatin toxicity. Tumori. 1993 Feb 28;79(1):37-9. Maestri, A, De Pasquale-Ceratti, A, Cundari, et al. A pilot study on the effect of acetyl-L-carnitine in paclitaxel- and cisplatin-induced peripheral neuropathy. Tumori. 2005; 91 (2): 135-138. [Abstr] Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005 Nov;39(4):360-6. Miranda-Massari, JR, Gonzalez, MJ, Jimenez, FJ, et al. Metabolic correction in the management of diabetic peripheral neuropathy: improving clinical results beyond symptom control. Current Clinical Pharmacology. 2011; 6 (4): 260-273. Murphy RA, Mourtzakis M, Chu QS, Baracos VE, Reiman T, Mazurak VC. Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. Cancer. 2011 Aug 15;117(16):3774-80. Nahleh, Z, Pruemer, J, Lafollette, J, and Sweany, S. Melatonin, a promising role in taxane-related neuropathy. Clinical Medicine Insights: Oncology. 2010; 4: 35-41. Pace, A, Savarese, A, Picardo, M, et al. Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. Journal of Clinical Oncology. 2003; 21: 927–31. Pachman, DR, Barton, DL, Watson, JC and Loprinzi, CL. Chemotherapyinduced peripheral neuropathy: prevention and treatment. Clinical Pharmacology and Therapeutics. 2011; 90 (3): 377-387. Phillips, KD, Skeiton, WD, and Hand, GA. Effect of acupuncture administered in a group setting on pain and subjective peripheral neuropathy in persons with human immunodeficiency virus disease. Journal of Alternative Complementary Medicine. 2004; l0 (3): 449-55. Piccolo, J and Kolesar, JM. Prevention and treatment of chemotherapy-induced peripheral neuropathy. American Journal of Health-System Pharmacy. 2014; 71: 19-25. Pisano, C, Pratesi, G, Laccabue, D, et al. Paclitaxel and cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine. Clinical Cancer Research. 2003; 9: 5756-5767. Sánchez-Lara K, Turcott JG, Juárez-Hernández E, Nuñez-Valencia C, Villanueva G, Guevara P, De la Torre-Vallejo M, Mohar A, Arrieta O. Effects of an oral nutritional supplement containing eicosapentaenoic acid on nutritional

and clinical outcomes in patients with advanced non-small cell lung cancer: Randomised trial. Clin Nutr. 2014 Apr 4. pii: S0261-5614(14)00081-8. Sanofi-Aventis. (2010). Taxotere (docetaxel) prescribing information. Bridgewater, NJ. Updated December 2013. URL: http://products.sanofi.us/Taxotere/taxotere. html Accessed May 2014. Schloss, JM, Colosimo, M, Airey, C, et al. Nutraceuticals and chemotherapy induced peripheral neuropathy (CIPN): a systematic review. Clinical Nutrition. 2013; 32: 888-893. Schroeder, S, Meyer-Hamme, G, and Epplee, S. Acupuncture for chemotherapyinduced peripheral neuropathy (CIPN): a pilot study using neurography. Acupuncture in Medicine. 2012; 30: 4-7. Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, Mills E. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther. 2012 Dec;11(4):293-303. Shapiro H. Could n-3 polyunsaturated fatty acids reduce pathological pain by direct actions on the nervous system? Prostaglandins Leukot Essent Fatty Acids. 2003 Mar;68(3):219-24. Sima, A, Calvani, M, Mehra, M, and Amato, A. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy. Diabetes Care. 2005; 28 (1): 89-94. Smyth, JF, Bowman, A, Perren, T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial. Annals of Oncology. 1997; 8 (6): 569-73. Stubblefield MD, Vahdat LT, Balmaceda CM, Troxel AB, Hesdorffer CS, Gooch CL. Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study. Clin Oncol (R Coll Radiol). 2005 Jun;17(4):271-6. Vahdat, L, Papadopoulos, K, Lange, D, et al. Reduction of paclitaxel-induced peripheral neuropathy with glutamine. Clinical Cancer Research. 2001; 7: 1192-1197. Visovsky, C, Collins, M, Abbott, L, Aschenbrenner, J and Hart, C. Putting evidence into practice: evidence-based interventions for chemotherapy-induced peripheral neuropathy. Clinical Journal of Oncology Nursing. 2007; 11 (6): 901-913. Wang, WS, Lin, JK, Lin, TC, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist. 2007;12 (3): 312-319. Wiernik, PH, Yeap, B, Vogl, SE, et al. Hexamethylmelamine and low or moderate dose cisplatin with or without pyridoxine for treatment of advanced ovarian carcinoma: a study of the Eastern Cooperative Oncology Group. Clinical Cancer Investigation Journal. 1992; 10 (1): 1-9. Wolf, S, Barton, D, Kottschade, L, et al. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. European Journal of Cancer. 2008; 44: 1507-1515. Wong, R and Sagar, S. Acupuncture treatment for chemotherapy-induced peripheral neuropathy – a case series. Acupuncture in Medicine. 2006; 24 (2): 87-91. Xu, Q, Pan, J, Yu, J, et al. Meta-analysis of methylcobalamin alone and in combination with lipoic acid in patients with diabetic peripheral neuropathy. Diabetes Research and Clinical Practice. 2013; 101: 99-105. Zdanowicz M.M. Acetyl-L-carnitine’s healing potential. Natural Healing Track. 2001; [http://www.nhir.com/tests/oct_2001.pdf].

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Questions 1. Which of the following accurately describe chemotherapy induced peripheral neuropathy (CIPN)? a) characterized by a stocking and glove distribution b) affects sensory nerves only c) affects quality of life but rarely results in chemotherapy treatment breaks d) all of the above 2. Which of the following chemotherapies are typically associated with CIPN? a) platinum compounds (cisplatin, oxaliplatin) b) taxanes (paclitaxel, docetaxel) c) vinca alkaloids (vincristine) d) all of the above 3. Treatment with which of the following currently constitutes the standard of care for CIPN? a) gabapentin b) tricyclic antidepressants such as amitriptyline c) opioids such as oxycodone d) none of the above 4. Acetylcholine is thought to promote nerve regeneration through promotion of mitochondrial function and transfer of acetyl groups across mitochondrial membranes. a) true b) false 5. A recent phase III trial failed to show significant prevention of CIPN when ALC was administered concurrently with taxane chemotherapy, however, benefit has been demonstrated for CIPN related to cisplatin and paclitaxel. a) true b) false

7. There is strong evidence suggesting that glutathione may interfere with the effectiveness of the chemotherapies referred to by question 6. a) true b) false 8. Two RCTs have demonstrated benefit for fish derived omega-3 fatty acids in the treatment of CIPN secondary to paclitaxel based chemotherapy. In addition to CIPN, EPA has been shown to reduce nausea and vomiting and may improve treatment response to carboplatin based chemo. a) true b) false 9. One study has suggested that ~20mg melatonin may reduce taxane related CIPN in breast cancer patients, but the study lack sufficient sample size to demonstrate statistical significance. a) true b) false 10. Calcium magnesium intravenous infusions are useful for oxaliplatin-induced CIPN. Which of the following is true about this treatment? a) Is thought to chelate oxalate, a metabolite of oxaliplatin which is toxic to voltage gated sodium channels on neurons. b) the CONCEPT study initially showed decrease in grade 2 or greater neuropathy in colorectal cancer patients treated with FOLFOX c) interim results of the CONCEPT study suggested decreased treatment efficacy of FOLFOX associated with calcium magnesium treatment, however final results showed no effect on anticancer efficacy. d) all of the above

6. Glutathione has been studied for the treatment of CIPN related to which chemotherapies? a) oxaloplatin and cisplatin b) capecitabine and 5-fluorouracil c) paclitaxel and docetaxel d) all of the above

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fast joint care+

Introduction greens+ whole body NUTRITION 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), whole Gallusbody gallus. These molecules includefrom fibrous proteins suchisasa superfood collagen type I, glycosaminoglycans (GAGs)nutritional such as chondroitin greens+ NUTRITION, a new offering Genuine Health, concentrate designed as an all-in-one formula for sulfate andsupport. dermatan sulfate, sulftated glycoproteins such as glucosamine, hyaluronic acid, and a host to ofsupport other related proteins (Ruff health total body This convenient, great-tasting, and allergen-free product helps rebalance body systems immune and digestive 2009a). ingredients, and support mood cognitive function.Unlike the most commonly used medications for the condition, such as NSAIDs, NEM is fast joint care+ is unique as and a joint care product. 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 sea fermented whole foods (carrot, tomato, kale, cocoa, and rice bran); fermented plant based protein fromthat brown fermented safebuckthorn); treatment alternatives (Vangsness 2009). Unlike theolive, natural alternatives glucosamine and chondroitin sulfate can rice; takeand 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 (Chen 2013); introduces healthy bacteria to the gut, aiding digestion and immune function. Fermentation also improves the tolerability of foods joint pain andand fibromyalgia. that otherwise trigger immune reactions, such as gluten (Calasso 2012).

Osteoarthritis The formula base is Vegan greens+ OTM, a combination of colorful plant-based antioxidants and alkalinizing nutrients that provides the equivalent of Osteoarthritis (OA)and is the most common musculoskeletal condition in Westernized approximately 27 million Americans are TM six servings of fruits vegetables. A University of Toronto study has shown that greens+countries; estimated to to placebo be clinically diagnosed with OA, while 46 millionhave are thought to bebeen affected bytoarthritis as a non-specific category compared (Berardi 2008). Plant-based foods upwards and their of antioxidants reproducibly shown be inversely associated with a host (Vangsness 2009, Lawrence 2008, Theis 2007). The impact of OA includes pain, loss of function and mobility, physical and psychosocial of chronic diseases including cancer, cardiovascular disease, osteoporosis, and cognitive impairment (Bao 2012, Estruch 2013, Leenders 2013, Loef disability, of NSAID therapy, and financial costs to the healthcare system. Direct average annual per person medical 2012, Rivascomplications 2013). expenditures due to arthritis ranged from $1454- 2206 (Theis 2007).

® (a proprietary blend of wild Two initial pilot studies involving 11extract, and 26NeuroFactor subjects respectively with pre-existing joint disorders found in joint TM blueberries), a proprietary coffee bean that stimulates Brain-Derived Neurotrophic Factor significant (BDNF) andreductions protects against neuropain, joint stiffness, anda proprietary pain on range of motion (ROM) compared (Ruff After 7 days there wasDismutase a 25% reduction in that degeneration, as well as cantaloupe extract, Extramel®, thattoisbaseline particularly rich2009a). in the antioxidant Superoxide (SOD) and pain, while at health. 30 days there was a 51% reduction. At 30 days, there was a 43% improvement in flexibility. Nearly 50% of the patients supports brain

reported being pain free after 1 month.

Adult dosage: Mixdouble 1-2 scoops (16.2-32.4g) of greens+ body NUTRITION in 1-1 ½ cup (250-375mL) purewas water or juice. Shake If you A more rigorous, blinded RCT involving 67 whole subjects with osteoarthritis found similar effects. of NEM given at 500 mg well. per day are a new user of greens+, begin with 1 scoop daily and gradually increase to 2 scoops daily over a 3 week period. Take 2 hours before or after taking for 2 months. Researchers found significant improvements in pain and stiffness as graded by WOMAC (a clinically relevant OA assessment other medications.

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 Caution 25% liver reduction at 10 days, and 53% at of 60liver days.trouble (Ruff(abdominal 2009b) pain, dark urine, jaundice) or are taking medications for diabetes, blood pressure, sion, disorder or develop symptoms or seizures. Do not use if you are taking health products that affect blood coagulation (eg. blood thinners, clotting factor replacements, acetylsalicylic

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 Non medicinal ingredients: Stevia rebaudiana: organic steviacare+ leaf or placebo1.for one month.per Those in the fast joint care+ group reported a reduction in post-exercise pain ratings, with four times less pain than Table Ingredients 34.2g (2 scoops) Vegan greens+group O TM base formula unpublished data). This the placebo (Berardi, exciting finding shows that fast joint silicon care+ dioxide. is an effective therapy for those “weekend ~7.5g palmitate, maltodextrin, warriors” suffering from joint pain, and not exclusively for those suffering from osteoarthritis. Oryza sativa: fermented, sprounted whole grain brown rice protein concentrate Fibromyalgia (non-GMO; 80% protein)

12.5g

References:

Bao PP, et al. Fruit, vegetable, and animal food intake and breast cancer risk

hormone Alison receptor Bested, status. Nutr Cancer. 2012 Aug;64(6):806-19. An open-label pilot study supervised by Toronto area fibromyalgiaby specialist MD investigated the effects of 500mg of Fermented fast jointblend: care+ among 15 patients when given daily for eight weeks. Outcomes were measured using the Fibromyalgia Impact 2308mg Berardi JM, Logan AC, Rao AV. Plant based dietary supplement increases Questionnaire (FIQ) and Brief Pain Inventory (BPI) scales before and at the of Nutr. the study. Results 1154mg urinary pH. conclusion J Int Soc Sports 2008 Nov 6;5:20.showed that Oryza sativa (Rice bran); 692mg fast jointoleracea care+(Purslane significantly while working (i.e. performing activities), and overall pain ratings in FM. Portulaca plant); improved sleep, pain 231mg M, et al.towards The sourdough fermentation may enhance the recovery “Enjoyment of Life”, “Everyday Work” and “Missed Work” scalesCalasso also trended improvement (Bested, unpublished data) Daucus corota (Purple carrot root);

231mg Olea europaea (Olive fruit); 231mg gluten-free diet. Eur J Nutr. 2012 Jun;51(4):507-12. Solanum lycopersicum Recommended Use(Tomato fruit); 231mg Brassica (Organic kaleContraindicated plant); 500 mgoleracea or one viridis capsule per day. in persons with allergy to egg or egg products. No known adverse effects. 231mg Hippophae rhamnoides (Sea buckthorn fruit); 231mg stage temperature-induced Aspergillus oryzae solid-state fermentation. J Sci Nigella sativa (Black cumin seed); References 231mg Food Agric. 2013 Apr 30. doi: 10.1002/jsfa.6209. Phyllanthus emblica (Organic amla fruit); Berardi J. Egg Shell Membrane Reduces Joint Pain. Unpublished data. 231mg Theobroma cacao (Organic cocoa seed) 6g Estruch et al; in PREDIMED Study Investigators. Primary prevention of Bested A. Summary of aVitaFibreTM pilot, open-label, study of eggshell membrane (fast joint R, care+) fibromyalgia patients. Completed April 2012. Unpublished Isomaltooligosaccharides: cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013 Apr data. (fermented; non-GMO) 4;368(14):1279-90. Lawrence RC,DFelson DT, Helmick H, Deyo RA, Gabriel S, Hirsch R, Hochberg MC, Hunder GG, Jordan JM, Katz JN, Kremers Vegan Vitamin (ergocalciferol from CG, Arnold LM, Choi 800 IU/ HM, Wolfe F; National Arthritis Data Workgroup. Estimates of arthritis other conditions in United States. Part II. Agaricus bisporus; non-GMO, organic) 20mcg of the prevalence Leenders M, et al.and Fruit and rheumatic vegetable consumption andthe mortality: European Arthritis Rheum. 2008 Jan;58(1):26-35. prospective investigation into cancer and nutrition. Am J Epidemiol. 2013 120mg Aug 15;178(4):590-602.

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.

100mg Coffea arabica (NeuroFactor TM whole coffee fruit Loef M, et al. Fruit, vegetables and prevention of cognitive decline or concentrate) dementia: a systematic review of J Nutr Health Aging. 2012 Results Ruff KJ, DeVore DP, Leu MD, Robinson MA. Eggshell membrane: a possible new natural therapeutic forcohort joint studies. and connective tissue disorders. Jul;16(7):626-30. from two open-label human clinical studies. Clin Interv Aging. 2009;4:235-40. Vaccinium ovalifolium & uliginosum 100mg TM Theis KA, Helmick CG, Hootman burden and impact are greater U.S. women than men: opportunities.J Womens Health wild Alaskan blueberryJM.Arthritis fruit) (AuroraBlue Rivasamong A, et al. Mediterranean diet and intervention bone mineral density in two age (Larchmt). 2007 May;16(4):441-53. groups of women. Int J Food Sci Nutr. 2013 Mar;64(2):155-61. 10mg Cucumis melo (Extramel® cantaloupe fruit juice Vangsness CT Jr, Spiker W, Erickson J. A review of evidence-based medicine for glucosamine and chondroitin sulfate use in knee osteoarthritis. concentrate)

Arthroscopy. 2009 Jan;25(1):86-94.

Inositol SAP PRODUCT MONOGRAPH

POLYCYSTIC OVARY SYNDROME (PCOS)

HIRSUTISM, ACNE AND SKIN DISORDERS

Comorbidities, signs and symptoms of PCOS commonly include features of metabolic syndrome—including insulin resistance, obesity, and dyslipidemia—, in addition to hyperandrogenemia, reflected in hirsutism, alopecia, and acne. Insulin resistance appears in both obese and nonobese women diagnosed with PCOS.(3, 7)

FERTILITY

Polycystic ovary syndrome (PCOS) is the most common cause of ovulatory disorders and female infertility. It is estimated that this syndrome affects 6–10% of women of childbearing age. Increased insulin levels and impaired glucose tolerance may play causative roles in the development of hyperandrogenemia, the metabolic and reproductive changes in PCOS, through their synergism with luteinizing hormone (LH) to enhance androgen production.(1, 2, 3, 4, 5, 6)

Since the association of hyperinsulinemia, impaired glucose tolerance and insulin sensitivity with PCOS was realized, conventional treatments of this disorder have included pharmaceutical insulin-sensitizing drugs such as metformin, oral contraceptives for the regulation of menstruation, antiandrogenic agents such as spironolactone to address hirsutism, and clomiphene to induce ovulation if desired. Inositol-containing phosphoglycans (IPGs) have been discovered to play a role in activating enzymes that control glucose metabolism.(1, 2, 7) It is speculated that a decrease in the availability or utilization of IPG mediators may contribute to insulin resistance in the pathogenesis of PCOS. Up to 50–70% of women diagnosed with PCOS demonstrate insulin resistance and impaired glucose tolerance.(2, 3, 8)

METABOLIC, LIPID AND HORMONAL EFFECTS OF MYO-INOSITOL

myo-Inositol has been shown in multiple prospective studies to significantly reduce plasma LH, testosterone, free testosterone, HOMA index, and insulin levels within 3 months.(4, 9) Constantino et al. performed a randomized, double-blind, placebo-controlled trial using myo-inositol and found that myo-inositol supplementation at 4 g/d significantly reduced blood pressure, cholesterol, triglyceride, testosterone, and SHBG levels.(5) Minozzi et al. compared the effects of 4 g/d myo-inositol in combination with oral contraceptives versus oral contraceptives alone and found that combination therapy may be more effective than oral contraceptives alone at modulating pertinent hormone levels in PCOS.(10) For more information visit: www.nfh.ca

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myo-Inositol has been shown to reduce symptoms of hirsutism and acne associated with PCOS after 3 months. The decrease in the number of cases exhibiting hirsutism of all severities in this study was statistically significant at 3-month and 6-month follow-ups. 30 % of cases exhibited complete remission of hirsutism symptoms by the 6-month follow-up. The number of cases exhibiting acne also significantly decreased over the 6-month trial, with complete disappearance being reported in 53% of cases.(6) In a study by Genazzani et al., 2 g/d myo-inositol supplementation over 6 months restored menstrual cyclicity in all amenorrheic and oligomennorheic subjects.(9) 88% of amenorrheic subjects supplemented with 4 g/d myo-inositol in a study by Papaleo et al. achieved at least one spontaneous menstrual cycle within 6 months. 40% of subjects in the same study achieved clinical pregnancy, with no incidence of multiple pregnancy.(6) Raffone et al. compared the efficacy of 4 g/d myo-inositol and metformin in combination and alone and concluded that myo-inositol alone is more effective than metformin alone as first-line treatments for the restoration of normal menstrual cycles and in the treatment of infertility.(2) Furthermore, Morgante et al. establish that metformin alone, or in combination with clomiphene, has no advantage in inducing ovulation in patients with PCOS, and should be reserved for patients exhibiting glucose intolerance.(7) It is believed that myo-inositol may improve oocyte quality and ovarian function via modification of calcium signaling, required especially in the final stages of oocyte maturation.(2, 11, 12)

REFERENCES 1. Unfer, V. “Polycystic ovary syndrome: a vitamin deficiency? Floating a new pathogenesis hypothesis”. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

European Review for Medical and Pharmacological Sciences 14, No. 12 (2010): 1101–1105. Raffone, E., P. Rizzo, and V. Benedetto. “Insulin sensitiser agents alone and in co-treatment with r-FSH for ovulation induction in PCOS women”. Gynecological Endocrinology 26, No. 4 (2010): 275–280. Fritz, H. “Polycystic ovary syndrome: Role of inositol in PCOS management”. Integrated Healthcare Practitioners Oct. 2009: 83–87. Zacchè, M.M., et al. “Efficacy of myo-inositol in the treatment of cutaneous disorders in young women with polycystic ovarian syndrome”. Gynecological Endocrinology 25, No. 8 (2009): 508–513. Costantino, D., et al. “Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial”. European Review for Medical and Pharmacological Sciences 13, No. 2 (2009): 105–110. Papaleo, E., et al. “myo-Inositol in patients with polycystic ovary syndrome: A novel method for ovulation induction”. Gynecological Endocrinology 23, No. 12 (2007): 700–703. Morgante, G., et al. “The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen”. Fertility and Sterility 9, Issue 8, 2011: 2642–2644. Azziz, R., et al. “The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report”. Fertility and Sterility 91, Issue 2 (2009): 456–488. Genazzani, A.D., et al. “myo-Inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome”. Gynecological Endocrinology 24, No. 3 (2008): 139–144. Minozzi, M., et al. “The effect of a combination therapy with myo-inositol and a combined oral contraceptive pill versus a combined oral contraceptive pill alone on metabolic, endocrine, and clinical parameters in polycystic ovary syndrome”. Gynecological Endocrinology 27, No. 11 (2011): 920–924. Papaleo, E., et al. “Contribution of myo-inositol to reproduction”. European Journal of Obstetrics & Gynecology and Reproductive Biology 147, No. 2 (2009): 120–123. Gerli, S., et al. “Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS”. European Review for Medical and Pharmacological Sciences 11, No. 5 (2007): 347–354.

2014-05-22 14:09:47

Inositol SAP

myo-Inositol powder for the treatment of polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is the most common cause of ovulatory disorders and female infertility. Signs and symptoms of PCOS may include anovulation or menstrual irregularities; ovarian cysts on ultrasound; hyperandrogenism including hirsutism, acne and alopecia; insulin resistance; and obesity. Insulin resistance and secondary hyperinsulinemia appear to play a causative role in the development of PCOS. myo-Inositol has been suggested as a first-line therapy in the treatment of PCOS, and has been shown to be effective in mitigating the symptoms of this syndrome and its associated comorbidities.

Each scoop contains:

ACTIVE INGREDIENTS

Inositol (myo-inositol). . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 g

Contains no: Preservatives, allergens, artificial flavor or color, sweeteners, wheat, gluten, soy, starch, yeast, citrus, egg or dairy.

DOSAGE

Adults: Mix 1 scoop to 8 oz. (250 ml) of water or juice one to three times daily mixed into juice or water or as directed by your health care practitioner. Consult a health care practitioner for use beyond 6 weeks.

INDICATIONS

Inositol SAP may be effective in the treatment of PCOS and its related morbidities—including hypercholesterolemia, hyperandrogenemia, hyperinsulinemia, hirsutism, acne, and menstrual irregularity—, and in the restoration of ovarian activity and infertility.

SAFETY

myo-Inositol is generally well-tolerated. At therapeutic doses up to 4 g/d, no significant adverse events have been reported for the oral supplementation of myo-inositol in studies for up to 6 months.

PURITY AND CLEANLINESS

Third-party testing is performed on finished product to ensure Inositol SAP is free of heavy metals, pesticides, solvents 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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2014-05-22 14:09:47

NEW!

Fermented NUTRITION FOR YOUR WHOLE BODY All your daily nourishment. One convenient product.

Beyond an all-in-one Complete, Nourishing Superfood drink. 100% vegan, gluten free, & dairy free.

Look for our new greens+ whole body nutrition at genuinehealth.com or in a store near you.

Total body system support from carefully selected ingredients to support mood, brain, eye, d igestive health and more. Over 70% fermented ingredients to speed up digestion and enable more efficient absorption of essential nutrients & antioxidants, restoring intestinal balance.

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