Page 1

IHP SEPTEMBER 2012 | $14.95

CoQ10 and Heart Failure

Galectin-3 and MCP

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By William R Ware, PhD

By Isaac Eliaz, MD, MS, LAc and Heidi Fritz, MA, ND

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Support For the maintenance of good health,1 maintains cardiovascular health2 and helps support cognitive and brain function.3 Also supports the development of the brain, eyes and nerves in children up to 12 years old.4 Help to promote healthy mood balance and reduce serum triglycerides.5

2,800-3,000 mg EPA + DHA per day containing a ratio of EPA:DHA between 0.5:1 and 2:1, in conjunction with conventional therapy, helps to reduce the pain of rheumatoid arthritis in adults.6 Note: Combined EPA + DHA levels should not exceed 3,000 mg/day unless otherwise directed by your healthcare practitioner.

Independently tested Certified for proven quality, purity and label claims. Stable, fresh, less repeat Fish gelatin capsule format offers less repeat. Natural mixed tocopherols protects against oxidation; enhances product freshness and stability; and maintains a great clean taste throughout the entire shelf life of the product. 1. Health Canada. Natural Health Product Monograph - Fish Oil, 2009. [internet] [Accessed February 22, 2012]. Available at: http:// www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/monograph/mono_fish_oil_huile_poisson-eng.php.

2. Health Canada 2009. 3. Health Canada 2009.

4. Health Canada 2009. 5. Health Canada 2009. 6. Health Canada 2009.

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2,800-3,000 mg EPA + DHA per day containing a ratio of EPA:DHA between 0.5:1 and 2:1, in conjunction with conventional therapy, helps to reduce the pain of rheumatoid arthritis in adults.8 Note: Combined EPA + DHA levels should not exceed 3,000 mg/day unless otherwise directed by a healthcare practitioner.

Parts per million (ppm)

PC

Bs

0.00

Note: Includes congeners PCB 28, PCB 52, PCB101, PCB 138 and PCB 180.

Heavy Metal Test Maximum Allowable Limit

0.10 0.08 0.06 0.04

Seroyal Results

0.02

≤0.01

≤0.01

≤0.01

Le ad

Co nt en t

0.00 Co nt en t

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Seroyal Results ≤0.015

0.02

iu m

For the maintenance of good health,3 maintains cardiovascular health4 and helps support cognitive and brain function.5 Also supports the development of the brain, eyes and nerves in children up to 12 years old.6

0.04

Ca dm

1 capsule (800mg EPA + DHA)

0.06

yC on te nt

Support

Maximum Allowable Limit

0.08

er cu r

Amount

0.10

M

Cardiovascular and neurological support

Polychlorinated Biphenyls (PCBs) Test

Parts per million (ppm)

Omega 800 is a unique blend of fish oils from sardine and anchovy to specifically assist in promoting healthy mood balance and to maintain overall cardiovascular health in reducing high serum triglycerides/triacylglycerols levels.2 Omega 800 is naturally flavoured with essential oil of orange and does not have a fishy aftertaste. In addition, the fish gelatin capsule format offers less repeat. Omega 800 also contains naturally mixed tocopherols that protect against oxidation and thus enhance product freshness and stability. A great clean taste is maintained throughout the entire shelf life of the Omega 800. GENESTRA BRANDS™ Omega 800 is involved in stringent quality assurance protocols that independently test and certify products for proven quality, purity and label claims.

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Omega 800

2 capsules (1600 mg EPA + DHA)

Typical Seroyal Sardine & Anchovy Oil Analysis

Maximum Allowable Limit

0.4 0.3 0.2 0.1

Seroyal Results ≤0.01 DD T

0.0

1. NHPD Monograph on Fish Oil. March 2009. 2. NHPD Monograph on Fish Oil. March 2009. 3. Health Canada. Natural Health Product Monograph - Fish Oil, 2009. [internet] [Accessed February 22, 2012]. Available at: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/monograph/mono_fish_oil_huile_poisson-eng.php. 4. Health Canada 2009. 5. Health Canada 2009. 6. Health Canada 2009. 7. Health Canada 2009. 8. Health Canada 2009. This information is for practitioner use only and is not meant to diagnose, treat, cure, prevent any disease or replace traditional treatment, and has not been evaluated by Health Canada.

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PUBLISHER’S LETTER

A Summer Cleanse What a beautiful summer it has been; it has been one of our busiest summers and somehow one of the most relaxing I can recall. I always view the summer as a time to regroup, on all fronts. We purged the garage and basement of things that were just taking up space... what a load off! Our homes end up becoming our offices, warehouse, etc... not a good mix! A good summer cleaning goes a long way; we have our home back! The same can be said for IHP; we had our first Editorial Board meeting from which came some brilliant ideas and direction for future evolution. With this comes purging and realigning. You will be seeing these changes in upcoming issues of IHP. Many of the changes being implemented will further define IHP. I cannot believe how far IHP has advanced over the years. I thank the editorial board and the peer reviewers for being part of its evolution. We strive to help you in your day-to-day practice and keep you in the forefront of scientific advances in integrative medicine.

SJagota­ Sanjiv Jagota Publisher

www.facebook.com/IHPMag

www.twitter.com/IHPMag TM

4 | IHP September 2012 } ihpmagazine.com

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

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ISSN 1920-4302 | SEPTEMBER 2012 Volume 5 • Issue 4

Publisher | Sanjiv Jagota - ext. 6122 Editor-in-Chief | Philip Rouchotas, MSc, ND - ext. 6109 Associate Editor | Angela MacNeil, MSc, ND Art Director | Scott Jordan Design | Sarah Vincett Production | Erin Booth

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Contributors Angela MacNeil, MSc, ND Christopher Habib, ND Heidi Fritz, MA, ND Isaac Eliaz, MD, MS, LAC Gurdev Parmar, ND, FABNO Rishi Mehta, BSc, ND (Cand.) Philip Rouchotas, MSc, ND Heidi Kussman, ND, FABNO William R. Ware, PhD

President | Olivier Felicio - ext. 6107 Vice President Operations | Frank Shoniker - ext. 6109 Controller & Operations | Melanie Seth - ext. 6114 Finance Administrator | Henry Fonseca Advertising Information Sanjiv Jagota Telephone: (416) 203-7900 ext 6125 Email: sanjiv@ihpmagazine.com

Paul Airut Telephone: (416) 203-7900 ext 6103 Email: paul@gorgmgo.com

Jeff Yamaguchi Telephone: (416) 203-7900 ext 6122 Email: jeff@gorgmgo.com

Erin Poredos Telephone: (416) 203-7900 ext 6128 Email: erin@gorgmgo.com

Guaranteed in ratio and stability of pure allicin metabolites using advanced technology: C02 supercritical extraction. Active metabolites are evidence based for a wide range of usage, most notably for cardiovascular health and anti-microbial properties. Superior adherence with just one gelcap per day. Each capsule contains: Garlic (Organic) Supercritical extract .... 282 mg Providing: Vinyldithiines...............0.0855 mg

Circulation Garth Atkinson | Publication Partners 345 Kingston Rd., Suite 101 Pickering, Ontario, L1V 1A1 Telephone: 1-877-547-2246 Fax: 905-509-0735 Email: ihp@publicationpartners.com Subscription Rates Canada $80 (gst included) for six issues | $120 International Published by

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

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EDITOR’S LETTER

Celebrating excellence in integrative medicine The September issue of IHP has been devoted to the topic of cancer since the inception of the publication five years ago... In what has been a relatively short period of time, the application of integrative medicine in oncology has evolved tremendously. Topics covered in this issue of IHP were for the most part unknown a few short years ago. We applaud the champions of integrative oncology in the front lines tirelessly progressing this field. Combining integrative therapies with conventional cancer treatments is proving to be an incredibly valuable strategy. A short list of integrative medical practitioners comes to mind when one discusses integrative oncology; this issues cover story highlights the efforts of Dr Gurdev Parmar, ND, FABNO, among the very best of this short list. Dr Parmar recently launched the Cancer Care Centre, adjacent to the Integrated Health Clinic founded along with his wife, Dr Karen Parmar, over a decade ago. Dr Parmar was eager for us to highlight the newest technological advance to their teams cancer management system, localized hyperthermia. Our clinic profile likewise showcases another member of that short list of worldclass integrative oncology specialists; Dr Holly Fennell, ND. Holly has been practicing integrative oncology for just

under a decade, and delivers a message of incredible importance to all practitioners of integrative medicine; “it is not our patients job to convince MD’s how fantastic ND’s are... that is our job”. Peer- reviewed feature articles include clinical application of low dose naltrexone in cancer management, galectin-3 as a prognostic marker in heart disease, cancer, and the role of MCP in managing galectin-3 levels, and cancer-induced cachexia with emphasis on nutritional strategies for prevention/ treatment. William R. Ware, PhD, adds to his list of contributions to IHP with an incredible discussion of CoQ10 in heart failure. The article is the first I am ever to come across that makes a sound academic argument for preference of the ubiquinol form of CoQ10 relative to the ubiquinone form. Our CE article is coauthored by the issues cover, Dr Parmar, and Chris Habib, ND. The article assimilates available evidence as well as providing clinical pearls regarding the application of dichloroacetate (DCA) in cancer management.

Best regards,

Philip Rouchotas, MSc, ND Editor-in-Chief

hotas

uc P Ro

We invite questions or comments. philip@ihpmagazine.com

8 | IHP September 2012 } ihpmagazine.com

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CONTENTS

40

contents SEP TEMBER 2012 VOLUME 5 – ISSUE 4

ARTICLES 40. Cover Story: Integrated Health Clinic

Cancer Care Centre

48. Clinic Profile: Holly Fennell, ND

InsideOut Health Solutions

FEATURES 52. Galectin-3

An emerging treatment target; role of MCP

60. CoQ10 and Heart Failure

A review of evidence

65. Cancer induced cachexia (CIC) Effective integrative management

73. Low Dose Naltrexone Role as adjunct cancer treatment

48 ihpmagazine.com { September 2012 IHP | 11

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Product MonograPh Bio-Fen Bio-Fen Plus is an oral natural health product used in the treatment of hereditary androgenic alopecia (AGA) for male or female pattern baldness. Without treatment, AGA is progressive, and causes social distress in many affected men and women (Sinclair 1998). Bio-Fen Plus contains extracts NUTRITIONAL SUPPLEMENTS VITAMINS & MINERALS of fenugreekPROGRESSIVE seeds, saw palmetto berries and flax lignans, MULTIPLE as well as specific vitamins. Each ingredient is known to possess inhibitors of the enzyme 5α-reductase. These inhibitors are responsible for relieving symptoms associated with AGA.formula is designed specifically to target The Progressive family offers age, gender, and activity specific vitamin and mineralhereditary formulas. Each One of the the primary of hair loss isthroughout a high level of the male hormone dihydrotestosterone (DHT) within the hair follicle (Vierhapper, 2001). uniquecauses nutritional demands a lifespan. For people with AGA, their follicles have a greater number of androgen receptors to which DHT attaches. 5-α-reductase catalyzes the enzymatic Vitamins Minerals in the Maintenance of Good conversion Multiple of testosterone toand dihydrotestosterone, which binds to theHealth receptor five-fold more avidly than the parent compound (Sinclair 1998). Vazir, et al (2006) evaluated the effect of a micronutrient supplement on mental function in children (aged 6 – 15 years). This double blind, placebo-controlled, matched-pair, cluster, randomized trial assessed a cohort of 608 children for intelligence, attention and concentration,

Vitaminssupplementation. Results indicated that supplementation Saw palmettomemory, (Serenoaand repens) school achievement, before and after 14 months of micronutrient In a Polish study of 46 women who symptoms alopecia, calcium Standardized with (lipophillic) extract hassignificantly been foundimproved to be a potent inhibitor a range Serenoa of micronutrients attention-concentration over the period of 14 months in had children aged 6of– diffuse 15 years. pantothenate was orally administered twice a day in doses of 100 mg for four to of 5α-reductase, resulting in decreased tissue DHT. An open-label, dose response Increasing mineral content (BMC) during periods of rapid growth (childhood adolescence) prevent osteoporosis andand repeated five months,& and vitamin B6may was effectively injected every day for 20 to 30 days study was conducted on bone 42 healthy males to determine the effect of a combination et al lipid (2006)extract investigated the and effect ofagain a micronutrient supplementation on BMC, bone It area, bone that vitamin after six months (Brzezińska-Wcisło 2001). was and determined of carotenoidage-related astaxanthinbone and loss. saw Shatrugna, palmetto berry on DHT mineral density (BMD) at various sites in children (aged 6 – 16 years). The micronutrient supplement was found to increase tissue growth B6 administered parenterally for a few weeks induces improvement in the hair testosterone levels (Angwafor 2008). The men were divided into two groups: and skeletal shell in apparently normal children over a 14-month period, including site-specific BMD increases at the neck of the femur. condition in a subset of women and reduces hair loss. one group received 800 mg/day of the combination supplement and the other The SHEEP study examined the association the use a multivitamin supplements and the risk of myocardial infarction (MI). Results group received 2000 mg/day of the supplement for 14 days.between ANOVA-RM showed were based on data from a largetotal population-based, study of subjects aged 45 – 70 years. The study included 1296 cases (910 significant within-group increases in serum testeosterone case-control and significant Medicinal dose women) a firstin nonfatal MI and 1685(P=0.05). controls (1143 women) Ingredients frequency-matched to the cases by sex, agePer andcapsule decreases in men, serum386 DHT fromwith baseline both dose groups Theremen, 542 hospital catchments areadose (Holmquist, et al regard 2003). to The from indicate that use of a multivitamin supplements may aid in the was no significant difference between groups with theresults increase ofthis study Fenugreek (Trigonella foenum graecum) primary prevention of MI. 260 mg testeosterone or the decrease of DHT; therefore both doses were effective (Angwafor seed extract 4:1 2008). The elderly are an epidemic of deficiency, and multivitamins and minerals are extremely helpful in reducing risk of a variety of diseases in this population. A study conducted by Girodon, et al (1997) examined theSaw impact of traceberry element and vitamin supplementation in 81 elderly palmetto extract containing 160 mg subjects a 2-yearextract period.ofBefore supplementation elderly were found to have significant deficiencies. Another study tested over liposterolic Serenoa repens (LSESr)more andthan beta-2/3 of the 45% free subjects fatty acids After only 6 months supplementation, significant in these vitamins and minerals were observed. Furthermore, a 200% sitosterol in the treatment of males of (23-64 years of age) with mild toincreases moderate AGA. reduction infectious disease incidence among elderly subjects administered multivitamin was demonstrated. Flax lignans, standardized to 20% Six of 10 (60%) subjectsinwere rated as improved at the final visit, thus establishing 100 mg secoisolariciresinol diglucoside (SDG) the effectiveness of 5α-reductase against in AGA (Prager 2002). Chronic Ageing is associatedinhibitors with a reduction micronutrient intake, making malnutrition an increasing public health problem among the elderly. inflammationGrieger, of the hair is considered beuse a contributing factor for AGA. A for 6 months in 92 elderly subjects. It was found that multivitamin et follicle al (2007) examinedto the of a multivitamin supplement D-calcium pantothenate (Vitamin B5) 10.40 mg supplementation status this vulnerable population, which may reduce the risk of micronutrient-related diseases. study by Chittur et al sought toimproved determinemicronutrient whether blockade of in inflammation using to have a positive effect on bone quality, which may also reduce the risk of osteoporosis. Multivitamin supplementation also appeared LSESr and two anti-inflammatory agents (carnitine and thioctic acid) could alter Niacinamide (Vitamin B3) 10.25 mg the expressionDosage of molecular markers of inflammation (Chittur 2009). It was found Pyridoxine HCl (Vitamin B6) 2 mg that the combination suppressed lipopolysaccharide-activated gene expression of Indication: Aids in the maintenance of good health. chemokines associated with pathways involved in inflammation and apoptosis. Progressive Multiple Age Dosage Riboflavin (Vitamin B2) 1.58 mg The study concluded that 5-alpha reductase inhibitors in combination with Vitamin & Mineral Formula

blockade of inflammatory processes could represent a new two-pronged approach Chew Folic acid with breakfast and ½ tablet with dinner0.095 mg of Children (4 – 8 years) ½ tablet for a total Kids in the treatment of AGA. one tablet daily. Biotin 400 mcg Adolescents (9 – 18 years) Chew one tablet with breakfast and one tablet with dinner for a total Fenugreek Seeds of two tablets daily. non-Medicinal Ingredients Fenugreek seeds contain 5% to 30% protein, steroid sterols, Take one capsule with breakfast, lunch, and dinner, for a total of Activesaponins, Women (19 – 50flavonoids years) Active Women and alkaloidsActive (notably saponins bind and three capsules daily. ActiveSteroid Men (19 – 50 years) Men trigonelline and choline). Inert microcrystalline cellulose and vegetable-based magnesium eliminate extra cholesterol the body; is made from (19 DHT – 50 years) Adult Women and hormones in Women stearate in a veggie-based capsule testosterone, Adult whichMen is in turn is made from cholesterol. Therefore, when excess Men (19 – 50 years) cholesterol isAdult eliminated, DHT can be made (Stark(19 1993). a study of 20 Chew one tablet with breakfast, lunch, and dinner, for a total of three Women – 50In years) Womenless (Chewable) daily. Men (19fenugreek – 50 years) Adult Men12.5g (Chewable) Recommended adult dose: One capsule per day adults who consumed and 18.0g of germinated seed powder for tablets (≥ 50 years) Women 50 of Plus one month, higher levels consumption resultedWomen in a significant reduction in total Take one capsule with breakfast, lunch, and dinner, for a total of three capsules daily. Men (≥ 50 years) Men 50 Plus lipoprotein (LDL) levels cholesterol and low-density (Sowmya 1999). Interactions

Flax lignans daily dose of each vitamin & mineral is included above the minimum dosage value and at or below the maximum dosage value as Flax reduces The the amount of DHT produced by reducing cholesterol levels in the established by the Natural Health Products Directorate (NHPD). The general combinations of vitamins, minerals, and herbal components body. A meta-analysis of 28 studies between 1990 and 2008 showed that flaxseed are safe (NHPD monograph: Multi-Vitamin/Mineral Supplement). significantly reduces circulating total and LDL-cholesterol concentrations (Pan Due to potential toxicity from some of the vitamins, minerals and herbal components, children under 19 years of age are not recommended 2009). Flaxseed interventions reduced total and LDL cholesterol by 0.10 mmol/L to take any of the adult specific formulas (NHPD monograph: Multi-Vitamin/Mineral Supplement). (95% CI: -0.20, 0.00 mmol/L) and 0.08 mmol/L (95% CI: -0.16, 0.00 mmol/L), Due to the potential of toxicity and adverse effects of some of the vitamins, minerals and herbal components, none of the formulas are respectively. Significant reductions were observed with whole flaxseed (-0.21 and recommended for use in pregnant or breastfeeding women (NHPD monograph: Multi-Vitamin/Mineral Supplement). -0.16 mmol/L, respectively) and lignan (-0.28 and -0.16 mmol/L, respectively) of the vitamins, minerals, and herbal components may interact with medication, diseases and conditions, and/or lab test results. It is supplements Some (Pan 2009). recommended that all ingredients be reviewed before use in an individual under medical supervision, taking prescription medication, suffering from a serious and/or pre-existing medical condition (NHPD monograph: Multi-Vitamin/Mineral Supplement).

Quality Assurance References References Angwafor F III,Parameter Anderson ML. An open label, doseTest response studySpecifications to determine the effect of a dietary supplement testosterone supplementation and estradiol levels Girodon F,on et dihydrotestosterone, al (1997). Effect of micronutrient onin healthy males. J Int Soc Sports Nutr 2008;5:12. infection in institutionalized elderly subjects: a controlled trial. Ann Nutr Microbial Metab, 41(2): Brzezińska-Wcisło L. Count Evaluation of vitamin B6 andUSP calcium pantothenate effectiveness on hair growth from clinical and98-107. trichographic aspects for treatment of diffuse alopecia in women. Wiad Total Less than 5,000 cfu/g Grieger JA, et al (2007). Effect of multivitamin on vitamin D status and Lek 2001;54:11-8. Yeast & Mold USP Less than 100 cfu/g heel ultrasound bone density in Australian aged care residents. USP gene expression Negativein keratinocytes using a composition coli International Congress Series,thioctic 1297: 109-119. Chittur S, Parr Escherichia B, Marcovici G. Inhibition of inflammatory containing carnitine, acid and saw palmetto extract. Evid Based Complement Alternat Med 2009. Holmquist C, et al (2003). Multivitamin Supplements Are Inversely USP Negative Salmonella sp Associated with Risk of Myocardial Infraction in Men and Women – Negative Staphylococcus aureus Pan A, Yu D, Demark-Wahnefried W, Franco OH, USP Lin X. Meta-analysis of the effects of flaxseed interventions on blood Am J Clin Nutr 2009;90:288-97. Stockholm Heartlipids. Epidemiology Program (SHEEP). J Nutr, 133: 2650Heavy Metal 2654. Prager N, Bickett K, French N, Marcovici G. A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the Arsenic USEPA < 1.0 ppm NHPD monograph. (2007). Multi-vitamin/mineral supplement, October 22. treatment of androgenetic alopecia. J Altern Complement Med 2002;8:143-52. Shatrugna V, et al (2006). Effect of a micronutrient supplement on health Cadmium USEPA < 0.5 ppm and nutritional status of school children: bone health and body Serenoa repensLead monograph. Alternative Medicine Review 1998;3:227-9. USEPA < 1.0 ppm composition. Nutrition, 22: S33-S39. Total Mercury USEPA < 1.0 ppm Vazir S, et al (2006). Effect of micronutrient supplement on health and Sinclair R. Male pattern androgenetic alopecia. BMJ 1998;317:865-9. Chemical nutritional status of schoolchildren: mental function. Nutrition, 22: S26Sowmya P, Rajyalakshmi fenugreek seeds in human subjects.S32. Plant Foods Hum Nutr 1999;53:359-65. PesticidesP. Hypocholesterolemic effect USPof germinated Absent Conforms to limitsfoenum-graecum) on bile acid absorption and cholesterol levels in rats, Br J Nutr 1993;69:277-87. Stark A, MadarSolvents Z. The effect of an ethanol extractUSP derived from fenugreek (Trigonella

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

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CONTENTS

65

COMING NEXT Issue

• Novel cholesterol markers for predicting CVD risk • Fish oil- resolvins and protectins • Supporting male fertility

60 departments 4. Publisher’s Letter 8. Editor’s Letter 17. Peer Review Board 21. Editorial Board 25. Research News 34. Industry News 37. Product Profiles 80. Continuing Education: Dichloroacetate (DCA)

52

Application in cancer management

14 | IHP September 2012 } ihpmagazine.com

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Hoxsey Formula (Red Clover Combo) ... Healing Degenerative Diseases Cancer Treatment Supports Detoxification Source of Iodine HOXSEY FORMULA INGREDIENTS: Red Clover (Trifolium pratense)

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Burdock Root

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Oregon Grape

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Queen’s Root

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Potassium iodide Our herbs are Certified Organic/ Organic/Wildcrafted.

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• A superb alterative formula that supports detoxification and the treatment of conditions of a degenerative nature • A tonic that in Harry Hoxsey’s words “corrects abnormal blood chemistry and normalizes cell metabolism” by stimulating the elimination of toxins “which are poisoning the system” • Contains red clover, which, as Eclectic physician HW Felter declared, “… unquestionably has a retarding effect upon malignant neoplasms” • Comes in a liquid form and thus has a high degree of bio-availability

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Hoxsey

Hoxsey Formula Formula (Red Clover Combo) ...

(Red Clover Combo)

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

Healing Degenerative Diseases

At 30% of all deaths, cancer now exceeds cardiovascular disease as the number one killer in Canada. From 2000 to 2009, deaths caused by cancer increased in Canada by 13.5% (StatsCan 2009). In the US in 2009, however, cardiovascular disease still exceeded cancer as the leading killer.Cancer Treatment Supports Detoxification

Source of Iodine

Harry Hoxsey

HOXSEY FORMULA INGREDIENTS:

The controversial Harry Hoxsey ran a highly successful cancer clinic in Dallas from the 1920s right through until the late 1950s. He claimed to have received the formula for his tonic from his father. The effect of the tonic formula is to make the body’s physical terrain unfavourable for the survival of cancer cells. Hoxsey further speculated that the treatment “corrects abnormal blood chemistry and normalizes cell metabolism” by stimulating the elimination of toxins “which are poisoning the system” (Hoxsey 1956).

Red Clover (Trifolium pratense)

Astragalus (Astragalus membranaceus)

Terry Vanderheyden, ND Licorice (Glycyrrhiza spp.) Research Consultant Alder Buckthorn

(Rhamnus frangula)

Hoxsey’s treatment was two-fold, involving both a series of escharotic pastes applied externally and an oral tonic to facilitate excretion of toxins.

Terry Vanderheyden, ND, has practiced in Root Burdock Ontario since graduating from the (Arctium CCNM in 1994, lappa) Oregonand Grape specializing in homeopathic, nutritional,

Mildred Nelson

botanical therapies. He also works as a consultant for Phytolacca St. Francis Herb Farm, Inc.(Phytolacca Terry lives in Barry’s Bay americana) with his wife Laurie and their six children. Queen’s Root

In 1963, Hoxsey’s chief nurse, Mildred Nelson, opened the Bio-Medical Center in Tijuana Mexico, the first cancer clinic in the region. In a video testimony, she claims an 80% cure rate with patients using the treatments (from the documentary film, “Hoxsey—How Healing Becomes A Crime”).

(Berberis aquifolium)

(Stillingia sylvatica)

Sarsaparilla

(Smilax spp.)

Bladderwrack

Alterative

References:

(Fucus vesiculosus)

Southern Prickly Ash clava-herculis) 1. Statistics Canada, (Xanthoxylum Leading Causes of Death in Cascara Canada, 2009. Accessed online at http://www. (Rhamnus purshiana) statcan.gc.ca/ Potassium iodide 2. Hoxsey HM. You Don’t Have to Die, New York NY: MilestoneOur Books, 1956. herbs are Certified Organic/ 3. HW Felter. The Eclectic Materia Medica, Organic/Wildcrafted. Pharmacology and Therapeutics, Portland, OR: Eclectic Medical Publications; 1985. Reprinted The Herbs from original 1922 edition, p. 682. A tonic remedy handed down fromtofather to son ingredients,• Eclectic A superb alterative formula4.that supports detoxification K Kemper. “Burdock”, Longwood Herbal Task In•terms of specifi c indications relating the individual physician and the treatment of conditions of a degenerative nature Force. 1999. Accessed from: http://www.mcp. HW Felter, MD asserts, for example, that red clover (Trifolium pratense) “…unquestionably • Made prominent by Harry Hoxsey, a health care practitioner edu/herbal/default.htm has a retarding effect upon malignant neoplasms” (Felter 1922). who treated cancer with an extraordinary degree of success • A tonic that in Harry Hoxsey’s words “corrects 5. Dombradi CA, Foldeak abnormal S. “Screening Report on the Antitumor Activity of Purified Arctium for the better part of the 20th century blood chemistry and normalizes cell metabolism” Meanwhile, medieval German philosopher, herbalist and religious, St. Hildegard of Bingen, Lappa Tumori 52:173, stimulating of Extracts, toxins ”“which are 1966. used burdock (Arctium lappa) to treat cancerous tumours (Kemper 1999).by Burdock is alsothe an elimination 6. Weber D, Wheat JM, Currie GM. Inflammation • A therapeutic legacy inherited by Hoxsey’s chief nurse, poisoningproduct the system” ingredient in the Essiac herbal cancer treatment (St. Francis Herb Farm’s equivalent and cancer: tumor initiation, progression and Mildred Nelson, who claimed an 80% cure rate at her is called The 4-Herb Formula, also available as Four Herb Tea). Taking the history of its use metastasis, and Chinese botanical medicines. clinic in Tijuana, Mexico • Contains red clover, which, as Eclectic physician HW Felter Journal of Chinese Integrative Medicine, as a folk remedy for abnormal growths as their point of departure, scientists Dombradi and declared, “… unquestionablyNovember has a retarding effect upon 2010;8(11):1006–1013. Foldeak (1966) screened burdock for antitumor activity and noted significant properties.

St. Francis Herb Farm’s Hoxsey Formula is an alterative combination designed specifically to support detoxification and the treatment of conditions of a degenerative nature, as well as the general maintenance of good health. Alteratives, it should be noted, are that class of herbal medicines that amend the metabolic processes, enabling the body to deal properly with nutrition and eliminative functions, gradually ridding it of waste tissue.

• Works on the principle of the terrain theory of disease, malignant neoplasms” which holds that disease can be cured when it is denied a Pokeroot (Phytolacca americana) is used in both Western herbalism and traditional hospitable breeding ground in the body • Comes in a liquid form and thus has a high degree Chinese medicine (TCM) for addressing cancer. A review published by Australian scientists of bio-availability highlights that Pokeroot significantly reduced TNF-a and IL-6 levels, both markers of the systemic inflammation that often underlies cancer development (Weber et al. 2010). Products

Note that the combination contains potassium iodide, meaning that, for every ml (~ 30 drops) of the formula, there are 22.5 mg of iodine (as iodide). In my estimation, a dose of up to 50Phone: mg of iodine is appropriate some conditions. Indeed, I recommend a 7-drop daily 866.562.9131 | Fax:for 866.353.0427 dose as a minimal iodine supplement for most healthy non-seaweed eaters.

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In our own day, St. Francis Herb Farm offers Hoxsey’s classic formula to professionals. For more information, visit the website at www.stfrancisherbfarm.com

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PEER REVIEW

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

Elizabeth Cherevaty, BSc, ND Healing Foundations Naturopathic Clinic 111 Norfolk St., 2nd Floor Guelph, Ontario N1H 4J7 drliz@guelphnaturopathic.com

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

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

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

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

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

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

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

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

Daniel Watters, BSc, ND Rosedale Wellness Centre 365 Bloor St East Toronto, Ontario M4W 3L4 wattersdaniel@hotmail.com David Miller, BSc, ND 60 Albert Street Southampton, Ontario NOH 2L0 davidjmillernd@gmail.com

Isaac Eliaz, MD, MS, LAc Amitabha Medical Clinic & Healing Center 7064 Corline Ct # A Sebastopol, CA 95472-4528 ieliaz@sonic.net Jacob Scheer, DC, ND, MHSc 2100 Finch Ave. W. #206 North York, Ontario M3N 2Z9 Jacob.Scheer@utoronto.ca

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PEER REVIEW

Jiselle Griffith, BSc, ND The Health Hub Integrated Clinic 35 Hayden St, Suite 109 Toronto, Ontario M4Y 3C3 info@jisellegriffith.ca

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

Jordan Robertson, BSc, ND Lakeshore Clinic 2159 Lakeshore Road Burlington, Ontario L7R 1A5 jordanrobertsonnd@gmail.com

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

Judah Bunin, BSc, MSc, ND, DrAc Fredericton Naturopathic Clinic 10-150 Cliffe St Fredericton, NB E3A0A1 frednatclin@yahoo.ca Karam Bains, BSc, ND Elixir Health Multiple Clinics karam@elixirhealth.ca Kelly Brown, BSc, ND Healthview Therapy Centre 5118 Roblin Blvd Winnepeg, Manitoba R3R 0G9 drkbrownnd@gmail.com Leigh Arseneau, ND The Naturopathic Institute of Advanced Medicine 122 Simcoe St North Oshawa, Ontario L1G 4S4 docleigh@gmail.com Lindsay Bast, BSc, ND Greenwood Wellness Clinic PO Box 189 1400 Greenwood Hill Rd. Wellesley, ON N0B 2T0 Louise Wilson, BSc, ND 320 Queen St S Bolton, Ontario L7E 4Z9 Dr.louisewilsonnd@gmail.com Mandana Edalati, BA, ND Wellness Naturopathic Centre Suite 213-1940 Lonsdale Ave North Vancouver, British Columbia V7M 2K2 dredalati@gmail.com Melanie DesChatelets, BSc, ND True Health Studio 200-4255 Arbutus St Vancouver, British Columbia V6J 4R1 melanie@drdeschat.com Nicole Egenberger, BSc, ND Remede Naturopathics 214 Sullivan Street Suite 3B New York, New York 10012 info@remedenaturopathics.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, ON L9T 3K8 scoulter@rootsofhealth.ca Sylvi Martin, BScN, ND Fusion Chiropractic and Integrative Health 735 Danforth Avenue Toronto, Ontario M4J 1L2 martin.sylvi@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, NS B3K 5B6 info@theresajahn.com

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AOR Curcumin - Product Monograph Exclusively available in Canada by AOR Curcumin: not turmeric! Curcumin is one of three curcuminoids found in turmeric root. Turmeric root generally contains less than 2% curcumin. While 95% curcumin products are far better therapeutically, curcumin is renowned for being poorly absorbed, and therefore large amounts need to be consumed in order to achieve therapeutic benefits. One three-month study on patients with potentially cancerous lesions attempted to determine a toxicity threshold for curcumin (Cheng et al., 2001). Patients could not tolerate 12g/day of curcumin only because of the bulky dosing, but good compliance, safety and tolerability were observed with up to 8g of regular curcumin. Another dose-escalating study found trace amounts of curcumin in the blood with 10g and 12g with no toxicity symptoms (Lao et al., 2006). A toxicity level for curcumin has still not been defined, but we know that very high doses have been used with few side effects. Although many different “high-bioavailability“ curcumin products are now available to the natural health industry, the clinical studies behind Longvida® curcumin by far show the most promising results. Longvida® curcumin is a patented brand of curcumin developed by the University of California and is available exclusively in Canada from AOR. The clinical studies behind Longvida® are compelling and the results are extraordinary. Longvida® curcumin demonstrated at least a 100-fold increase in bioavailability compared to regular curcumin (Gota et al., 2010). This safety study reported no adverse events to a maximal dose of 1200mg of Longvida® curcumin, the same dose provided in 9 capsules of Curcumin Active, in both healthy volunteers and patients with osteosarcoma. The results of this study were significant relief of pain and inflammation and improved quality of life and sense of well-being. Curcumin has been seen as a very promising compound in the treatment and prevention of Alzheimer’s disease, based on in vitro work, but bioavailability problems have prevented clinical application (extensively reviewed in Belkacemi et al. 2011). 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. A human study using the equivalent of 400-600mg of Longvida® curcumin on Alzheimer“s patients is underway (Belkacemi et al., 2011). A completed study that has not yet been published led by Dr. DiSilvestro at the University of Ohio found increased beta-amyloid clearance in Alzheimer“s patients after only 1 month at a dose of 80mg of Longvida® curcumin! Imagine the potential results of longer-term supplementation! Turmeric vs. Curcumin vs. Curcumin Active Turmeric root supplements absolutely do not offer the same benefits as those containing isolated curcumin. Curcumin is the most potent component of the turmeric root. Unfortunately, turmeric root contains less than 2% of curcumin making it ineffective for any health benefits. In addition, over 95% of all clinical studies have been conducted using isolated curcumin and NOT with turmeric root. Even 750mg of a 10:1 ratio extract of turmeric will deliver no more than 150mg of the active curcumin. One study found only trace amounts of curcumin in the blood in a dose-escalating study of up to 12g of pure curcumin (Lao et al., 2006). This means that in order to achieve trace amounts in the blood which can then transport the curcumin to the target site for therapeutic effect, more than 12g need to be consumed. Curcumin“s benefits have been promising in numerous in vitro studies, but its lack of bioavailability has veiled its efficacy as a nutraceutical. Over the last ten years there has been much research to develop formulations that can deliver more of the active ingredient curcumin without resorting to large doses that patients have difficulty complying with. Curcumin Active is based on the results of this extensive research and delivers the most highly bioavailable curcumin supplement on the market: Longvida® Curcumin – with the latest research showing a greater than 100-fold increase in bioavailability compared to traditional curcumin supplements. Just one capsule of Curcumin Active delivers an effective dose of curcumin, the equivalent of over 13g of 95% extract (Gota et al., 2010). This would require taking 30 capsules of regular 95% curcumin extract, or more than 100 capsules of 750mg turmeric root extract! Bioavailability Mechanism Longvida Curcumin® consists of Solid Lipid Particles™ (SLP) which are tiny nano-sized (1 billionth of a meter) particles that have a protective layer providing a phenomenal increase in stability, potency and effectiveness. Unlike regular curcumin that is easily broken down by the basic pH of the intestines, these solid lipid curcumin particles are resistant to breakdown. What is even more important is the fact that these tiny particles are absorbed very rapidly through the intestinal lining thanks to the protective layer. Once they are absorbed, the particle coating protects the curcumin from phase II detoxification processes, which usually eliminates curcumin and other “foreign” particles quickly from the body; this is the fate of regular curcumin and turmeric supplements. Finally, the tiny size of the nanoparticle allows it to be taken up into the body’s cells quickly to be put to use. This means that they deliver all of the health benefits of curcumin, including pain relief, reduced inflammation, antioxidant properties and other effects much more efficiently than any other curcumin product. In the study that showed a 100-fold increase in absorption compared to regular curcumin, plasma curcumin concentrations did not appear to follow the same dose-dependent curve for all individuals (Gota et al., 2010); this may indicate a range of effective dosing that is dependent on individual biochemistry and physiology. Curcumin Active dosing suggests 9 capsules per day, however this is a maximum, and results can be seen with a much smaller dosage. The Alzheimer’s study mentioned above used less than the equivalent of one capsule of Curcumin Active per day. Therapeutic Potentials Curcumin is well known for its anti-inflammatory and pain relieving properties, which are well supported by clinical studies. These studies have shown that curcumin is highly effective for improving joint mobility and for reducing stiffness, swelling and pain. Inflammation is gaining recognition for being at the root of most degenerative conditions, and NF-κB signaling is becoming notorious for inducing most inflammation-related processes in the human body. Curcumin’s main mechanism of action as an anti-inflammatory is through modulating NFκB signaling. Studies have found positive results when examining curcumin and NF-κB in human tendon cells (Buhrmann et al., 2011), diabetic mice (Yekollu et al., 2011), and rats with autoimmune myocarditis (Mito et al., 2011). Additional recent studies have found that curcumin may be beneficial in inhibiting HIV-1 replication (Gandapu et al., 2011), protecting the liver in chronic liver disease (Bischt et al., 2011), and there is even interest in its therapeutic potential for MS (Xie et al., 2011). As mentioned above, curcumin has an emerging potential in clearing beta-amyloid plaque from the brain in Alzheimer’s patients. Curcumin is also a potent antioxidant and anti-microbial, and is cardioprotective. Still, the abundance of research points towards curcumin’s therapeutic potential in cancer, where it has been found to inhibit TNF-α, angiogenesis, metastasis, encourage cancer cell apoptosis and shrink tumors in some patients, help prevent relapse, and it has been used as adjunct therapy with radiation and certain forms of chemotherapy. Curcumin Active 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. Curcumin Active by AOR delivers a high dose of Longvida® curcumin, the most bioavailable curcumin on the market that is efficient in relieving pain and inflammation and protective against inflammatory-based conditions. References: Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, et al. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J Pharmacol Exp Ther. 2008 Jul;326(1):196-208.

Frautschy, SA et al. Omega 3 DHA and a bioavailable curcumin formulation synergize for Alzheimer prevention. 39th Annual Meeting of the Society of Neuroscience , Chicago, IL October 2009.

Belkacemi, A, Doggui S, Dao L, Ramassamy C. Challenges associated with curcumin therapy in Alzheimer disease. Expet Rev Mol Med. 2011 Nov; 13(e34):1-15.

Frautschy, SA et al. Efficacy of Longvida® in relation to systemic availability in the brain. 39th Annual Meeting of the Society of Neuroscience , Chicago, IL October 2009.

Bisht S, Khan MA, Bekhit M, Bai H, Cornish T, Mizuma M, et al. A polymeric nanoparticle formulation of curcumin (NanoCurc™) ameliorates CCl4-induced hepatic injury and fibrosis through reduction of pro-inflammatory cytokines and stellate cell activation. Lab Invest. 2011 Sep;91(9):1383-95.

Gandapu U, Chaitanya RK, Kishore G, Reddy RC, Kondapi AK. Curcumin-loaded apotransferrin nanoparticles provide efficient cellular uptake and effectively inhibit HIV-1 replication in vitro. PLoS One. 2011 6(8):e23388.

Buhrmann C, Mobasheri A, Busch F, Aldinger C, Stahlmann R, Montaseri A, Shakibaei M. Curcumin modulates nuclear factor kappaB (NF-kappaB)-mediated inflammation in human tenocytes in vitro: role of the phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem. 2011 Aug 12;286(32):28556-66. Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001 Jul-Aug;21(4B):2895-900. Dadhaniya P, Patel C, Muchhara J, Bhadja N, Mathuria N, Vachhani K, Soni MG. Safety assessment of a solid lipid curcumin particle preparation: acute and subchronic toxicity studies. Food Chem Toxicol. 2011 Aug;49(8):1834-42. Frautschy, SA. Bioavailability, brain concentrations, activity and dose-response of Longvida® SLCP. 38th Annual Meeting of the Society of Neuroscience , Washington DC, November 15, 2008.

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Gota VS, Maru GB, Soni TG, Gandhi TR, Kochar N, Agarwal MG. Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. J Agric Food Chem. 2010 Feb 24;58(4):2095-9. Lao CD, Ruffin MT, Normolle D, Heath DD, Murray SI, Bailey JM et al. Dose escalation of a curcuminoid formulation. BMC Complement Altern Med. 2006 Mar 17;6:10. Mito S, Watanabe K, Harima M, Thandavarayan RA, Veeraveedu PT, Sukumaran V, et al. Curcumin ameliorates cardiac inflammation in rats with autoimmune myocarditis. Biol Pharm Bull. 2011 34(7):974-9. Xie L, Li XK, Takahara S. Curcumin has bright prospects for the treatment of multiple sclerosis. Int Immunopharmacol. 2011 Mar;11(3):323-30. Yekollu SK, Thomas R, O’Sullivan B. Targeting curcusomes to inflammatory dendritic cells inhibits NF-κB and improves insulin resistance in obese mice. Diabetes. 2011 Nov;60(11):2928-38.

4/2/12 12-08-14 12:49:20 2:31PM PM


EDITORIAL BOARD

Welcome to the IHP Editorial Board In our continued efforts to elevate the academic quality of IHP, we are pleased to announce the formation of our Editorial Board. The purpose of the Editorial Board is to help guide the direction of the publication, in a manner that A) improves academic quality and rigor, B) exerts a positive impact on patient outcomes, C) contributes to knowledge of integrative healthcare, and D) showcases evolving trends in the healthcare industry. We have appointed a dynamic mix of individuals representing integrative MD’s, profession-leading ND’s, and members of

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

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

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

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

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EDITORIAL BOARD

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

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

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

Dugald Seely, ND, MSc Dr Seely is a naturopathic doctor and director of research at the Canadian College of Naturopathic Medicine (CCNM). Dugald completed his masters of science in cancer research from the University of Toronto with a focus on interactions between chemotherapy and natural health products. In his current role as director of research, Dugald is the principal investigator for a number of clinical trials, and is actively pursuing relevant synthesis research in the production of systematic reviews and metaanalyses. 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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Product MonograPh Bio-Fen Bio-Fen Plus is an oral natural health product used in the treatment of hereditary androgenic alopecia (AGA) for male or female pattern baldness. Without treatment, AGA is progressive, and causes social distress in many affected men and™women (Sinclair 1998). Bio-Fen Plus contains extracts METAGENICS STROVERA of fenugreek seeds, saw palmetto berries and flax lignans, as well as specificEvitamins. Each ingredient is known to possess inhibitors of the enzyme 5α-reductase. These inhibitors are responsible for relieving symptoms associated with hereditary AGA. One of the primary causes of hair loss is a high level of the male hormone dihydrotestosterone (DHT) within the hair follicle (Vierhapper, 2001). For people with AGA, their follicles have a greater number of androgen receptors to which DHT attaches. 5-α-reductase catalyzes the enzymatic conversion of testosterone to dihydrotestosterone, which binds to 80026945 the receptor five-fold more avidly than the parent compound (Sinclair 1998). Vitamins designed to reduce hot flashes and other menopausal symptoms SawEstrovera palmettoby(Serenoa repens) Metagenics features a special extract of Siberian rhubarb root (Rheum rhaponticum) In a (HT). Polish study of 46 women who had symptoms of diffuse alopecia, calcium Standardized (lipophillic) Serenoa been found be a potenthormone inhibitortherapies without potential serious adverseextract eventshas associated with to conventional pantothenate was orally administered twice a day in doses of 100 mg for four to of 5α-reductase, resulting in decreased tissue DHT. An open-label, dose response months, and B6 was injected every[1]. dayInfor to 30 days andthe repeated study was conducted on 42 healthy males to menstruation determine thehas effect of afor combination Menopause is the clinical term used after ceased one year, afterfive which women arevitamin considered postmenopausal the20 Western world, again after six months It was determined of carotenoid astaxanthin and sawispalmetto berry with lipid51extract on median DHT and age range for natural menopause 40 to 58 years, being the age for menopause. The average(Brzezińska-Wcisło age of menopause 2001). in Canada is also 51, and it that is vitamin estimated levels that women over age 50 will almost one quarter (22%) of the population by the yearparenterally 2026 [2]. Of symptoms, hot flashes B6 administered forallathe fewmenopausal weeks induces improvement in the hair testosterone (Angwafor 2008). Thecomprise men were divided into two groups: referred to as800 hot mg/day flushes) of arethe the combination most commonsupplement and potentially 80% of suffer condition in women a subsetinofWestern women countries and reduces hairfrom loss.hot flashes, with 30% one(also group received anddebilitating. the other Nearly reporting hot2000 flashes severeofand enough to seriously affect quality of life [3]. group received mg/day the frequent supplement for 14 days. ANOVA-RM showed significant within-group increases in serum total testeosterone and significant Medicinal Ingredients Perrecommended capsule HT is considered the most effective medical treatment relief of hot flashes and other menopausal symptoms [4]. However, HT isdose currently decreases in serum DHT from baseline in both dose option groupsfor(P=0.05). There for moderate to severebetween vasomotor symptoms due to potential increased cancer, cardiovascular events and other unwanted side effects [1]. The wasonly no significant difference dose groups with regard to the increaserisk of of breast Fenugreek (Trigonella foenum graecum) North American Menopause Society recommends using the lowest possible dose for the shortest duration possible [3]. The Society for Obstetricians 260 mg and testeosterone or the decrease of DHT; therefore both doses were effective (Angwafor extract Gynaegologists of Canada also recommends using the lowest effective dose for HT [2].seed Women with 4:1 a history of cardiovascular events, venous thromboembolism, 2008). breast or uterine cancer, or liver disease, should not use estrogen to alleviate vasomotor symptoms [1]. Saw palmetto berry extract containing 160 mg Another study tested non-pharmalogical liposterolic extracttherapies, of Serenoa repens (LSESr) and beta45% acids Among the natural phytoestrogens are the most popular and thefree mostfatty studied category. Phytoestrogens are plant substances found in sitosterol in clover, the treatment of males (23-64 that yearspossess of age) weak with mild to moderate soy, red flax, hops, and others, estrogenic activityAGA. by binding to estrogen receptors (ER). However, systematic review of literature found Flax lignans, standardized to 20% Six that of 10phytoestrogens (60%) subjects were as improved at the visit, thus establishing such as rated isoflavones, lignans, andfinal 8-prenylnaringenin have, at best, only modest effect in ameliorating menopausal symptoms [5-7]. 100 mg secoisolariciresinol diglucoside (SDG) the effectiveness of 5α-reductase inhibitors against AGA (Prager 2002). Chronic inflammation hair follicle is considered be a contributing factor for AGA.(Rheum A Since 1993,ofathe special phytoestrogen extracttofrom the root of Siberian rhubarb rhaponticum) known in scientific literature as ERr 731™ has been D-calcium pantothenate (Vitamin B5) 10.40 mg recommended practitioners in Germany for of menopausal hot flashes study by Chittur etbyalhealthcare sought to determine whether blockade inflammation using and related complaints [8]. Unlike Chinese rhubarb (e.g., R. palmatum, R. officinale) other medicinal rhubarb that and contain strongacid) laxatives the main constituents of ERr 731 are hydroxystilbenes, including LSESr and twooranti-inflammatory agentsspecies (carnitine thioctic couldanthraquinones, alter Niacinamide (Vitamin B3) 10.25 mg and(Chittur desoxyrhapontigenin They are found to be agonists of estrogen receptor β (ERβ) and do not display ERα the rhaponticin, expression ofdesoxyrhaponticin, molecular markersrhapontigenin, of inflammation 2009). It was[8]. found in endometrial tissue inlipopolysaccharide-activated laboratory studies [9]. ERβ activation is involved estradiol-mediated reduction HCl (Vitamin B6)of hot flashes [10]. In2tissues mg that express both thatactivity the combination suppressed gene expression of in thePyridoxine ERα and associated ERβ, ERβ with acts as a negative regulator of ERα and offers chemokines pathways involved in inflammation and protection apoptosis. against ERα-mediated effects in the breast and endometrium [11, 12]. Riboflavin (Vitamin B2) 1.58 mg The study concluded that 5-alpha reductase inhibitors in combination with Clinical have demonstrated 1 tablet (4 mg) daily of ERr 731 offers effective relief for common menopausal symptoms, including hot flashes [8, 10, 13blockade of trials inflammatory processes that could represent a new two-pronged approach Folic 0.095 mg 15]. For example, in a multicenter, randomized, placebo-controlled clinical trial in which 112acid perimenopausal women with menopausal symptoms received either 1 in the treatment of AGA. tablet of ERr 731 (n=56) or placebo (n=56) for 12 weeks, ERr 731 treatment compared with placebo treatment resulted in [15]: Biotin 400 mcg • A significant reduction of the Menopause Rating Scale (MRS) total score and in each individual MRS item score Fenugreek• SeedsA significant reduction in the number of hot flashes, from an average of 12 per day at baseline to 2.8 ±2.8 (mean ± SE) per day at 12 weeks non-Medicinal Ingredients Fenugreek•seeds A contain 5% to 30% protein, steroid sterols, flavonoids significant reduction in the hot flashsaponins, weekly weighted score and alkaloids (notably trigonelline and choline). Steroid saponins bind and Inert microcrystalline cellulose and vegetable-based magnesium eliminate extra cholesterol andwith hormones in theERr body; is 24 made fromwomen reported continued symptom reduction to help improve quality of life In a long-term clinical study subjects taking 731 DHT for up to months, stearate in a veggie-based capsule testosterone, which is in turn is made from cholesterol. Therefore, when excess through reduced anxiety, negative mood, and sleep disturbances [10]. cholesterol is eliminated, less DHT can be made (Stark 1993). In a study of 20 Data from these clinical show ERr 731fenugreek is well tolerated; no ERrfor731-related adverse events observed. [8, 10, per 13-15] Recommended adultare dose: One capsule day adults who consumed 12.5gtrials andalso 18.0g of that germinated seed powder one month, higher levels of consumption resulted in a significant reduction in total ERr 731,and thelow-density active ingredient in Estrovera, available to healthcare cholesterol lipoprotein (LDL) islevels (Sowmya 1999). practitioners in North America, exclusively from Metagenics, Inc.

Flax lignans Lethaby AE, et al. Phytoestrogens for vasomotor menopausal symptoms. Estrovera tablet) by reducing cholesterol levels6. in the Flax reduces theingredients amount of (per DHT1 produced Cochrane Database Syst Rev. 2007;(4):CD001395. ingredient: Rhubarb 4 mg body.Medicinal A meta-analysis of 28 Rhapontic studies between 1990 and 2008 showed that flaxseed 7. Clarkson TB, et al. The role of soy isoflavones in menopausal health: report of (rheum rhaponticum root) ERr 731 significantly reduces circulating total and LDL-cholesterol concentrations (Pan The North American Menopause Society/Wulf H. Utian Translational Science Non-Medicina ingredients: 2009). Flaxseed interventions reduced total and LDL cholesterol by 0.10 mmol/L Symposium in Chicago, IL (October 2010). Menopause. 2011;18:732-753. cellulose, and stearic acid (95%Microcrystalline CI: -0.20, 0.00 mmol/L) 0.08 mmol/L (95% CI: -0.16, 0.00 mmol/L), 8. Heger M, et al. Efficacy and safety of a special extract of Rheum rhaponticum (vegetable), croscarmellose sodium, silica, with whole flaxseed (-0.21 and respectively. Significant reductions were observed (ERr 731) in perimenopausal women with climacteric complaints: a 12-week and enteric coating (deionized water, -0.16 mmol/L, respectively) and lignan (-0.28 and -0.16 mmol/L, respectively) randomized, double-blind, placebo-controlled trial. Menopause. cellulose acetate phthalate, glycerol supplements (Pan 2009). 2006;13(5):744-759. triacetate, ammonium hydroxide, hypromellose, maltodextrin, and polyethylene glycol).

Wober J, et al. Activation of estrogen receptor-beta by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds. J Steroid Biochem Mol Biol. 2007;107(3-5):191-201. References 10. ofHasper I, supplement et al. Long-term efficacy and safety of the special extractlevels ERrin731 of males. J Angwafor F III, Anderson ML. An open label, dose response study to determine the effect a dietary on dihydrotestosterone, testosterone and estradiol healthy Int Soc Sports Nutr 2008;5:12. Rheum rhaponticum in perimenopausal women with menopausal symptoms. References Menopause. 2009;16(1):117-131. Brzezińska-Wcisło L. Evaluation of vitamin B6 and calcium pantothenate effectiveness on hair growth from clinical and trichographic aspects for treatment of diffuse alopecia in women. Wiad 1. Nelson HD. Menopause. Lancet. 2008;371(9614):76011. Frasor J, et al. Response-specific and ligand dose-dependent modulation of Lek 2001;54:11-8. 770. estrogen receptor (ER) alpha activity by ERbeta in the uterus. Endocrinology. Chittur B, Marcovici G. Inhibition inflammatory gene expression in keratinocytes using a composition containing carnitine, thioctic acid and saw palmetto extract. Evid Based 2. S, Parr Society of Obstetricians andofGynaecologists of Canada. 2003;144(7):3159-3166. Complement Alternat Med 2009. Canadian Consensus Conference on Menopause, 2006 12. Lindberg MK, et al. Estrogen receptor (ER)-beta reduces ERalpha-regulated Update. J Obstet Gynaecol Can. 2006;28:S1-S112. Pan A, Yu D, Demark-Wahnefried W, Franco OH, Lin X. Meta-analysis of the effects of flaxseed onsupporting blood lipids.a Am J Clin Nutrrelationship 2009;90:288-97. gene interventions transcription, "ying yang" between ERalpha and 3. Umland EM. Treatment strategies for reducing the ERbeta mice. Mol 2003;17(2):203-208. Prager N, Bickett K, French N, Marcovici G. A randomized, double-blind, placebo-controlled trial toindetermine the Endocrinol. effectiveness of botanically derived inhibitors of 5-alpha-reductase in the of menopause-associated vasomotor symptoms. J treatment ofburden androgenetic alopecia. J Altern Complement Med 2002;8:143-52. 13. Kaszkin-Bettag M, et al. Efficacy of the special extract ERr 731 from rhapontic Manag Care Pharm. 2008;14(3 Suppl):14-19. rhubarb for menopausal complaints: a 6-month open observational study. Altern Serenoa monograph. Medicine Review 4. repens North AmericanAlternative Menopause Society. The 1998;3:227-9. 2012 hormone Ther Health Med. 2008;14(6):32-38. therapy position statement of: The North American Sinclair R. Male pattern androgenetic alopecia. BMJ 1998;317:865-9. 14. Kaszkin-Bettag M, et al. The special extract ERr 731 of the roots of Rheum Menopause Society. Menopause. 2012;19(3):257-271. rhaponticum decreases anxiety and improves health state and general well-being Sowmya Rajyalakshmi P. Hypocholesterolemic of germinated subjects. Plant Foods Hum Nutr 1999;53:359-65. 5. P, Coon JT, et al. Trifolium pratense effect isoflavones in the fenugreek seeds in human in perimenopausal women. Menopause. 2007;14(2):270-283. treatment of menopausal hot flushes: a systematic review Stark A, Madar Z. The effect of an ethanol extract derived from fenugreek (Trigonella on bile absorption and cholesterol levels inof rats, Br731 J Nutr 15.foenum-graecum) Kaszkin-Bettag M,acid et al. Confirmation of the efficacy ERr in 1993;69:277-87. and meta-analysis. Phytomedicine. 2007;14(2-3):153perimenopausal women with menopausal symptoms. Altern Ther Health Med. Vierpper H,159. Nowotny P, Maier H, Waldhausl W. Production rates of dihydrotestosterone in healthy men and women and in men with male pattern baldness: determination by stable isotope/ 2009;15(1):24-34. dilution and mass spectrometry. J Clin Endocrinol Metab 2001;86:5762-4.

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12-08-15 10:56 AM


RESEARCH NEWS

Moderate dietary weight loss reduces myocardial steatosis in obese and overweight women.

Internet-based cognitive behavioral treatment is effective for adolescents with chronic fatigue syndrome

Excessive myocardial triglyceride (MTG) content in obesity and type 2 diabetes is associated with impaired cardiac function. This study was conducted to assess influences of moderate dietary weight loss in non-diabetic obese and overweight women on MTG content and cardiac function. A subgroup of 38 women was selected from the B-SMART study population that compared weight loss and associated metabolic and cardiovascular markers with reduced-carbohydrate and reducedfat hypocaloric diets. An average weight reduction of 5.4Âą4.3kg at six months was associated with a relative decrease of MTG of 25% and the response was similar with carbohydrate and fat restriction. Diastolic function expressed as ratio of peak filling rate in E- and A-Phase (PFR(E)/PFR(A)) was unchanged. Reductions of left atrial size (P = 0.002), the normalized ratio of PFR(E) and early diastolic lengthening velocity PLV (P < 0.001), and fat free mass (P = 0.007) reflected altered cardiac volume loading after diet, but did not correlate to MTG content. Therefore, moderate dietary weight loss reduced MTG content in women with uncomplicated overweight or obesity but dietary macronutrient composition did not affect the extent of MTG reduction. Int J Cardiol. 2012 Apr 9. PMID: 22494864

Cognitive behavioral therapy is a promising treatment for chronic fatigue syndrome (CFS), but its availability is restricted. This open label study investigated the effectiveness of the first dedicated internet-based therapeutic program for adolescents with CFS [Fatigue In Teenagers on the interNET (FITNET)]. Adolescents aged 12-18 years with CFS were randomly assigned to FITNET or usual care in a 1:1 ratio at one tertiary treatment centre in the Netherlands. Primary outcomes of school attendance, fatigue severity, and physical functioning were assessed at six months of full school attendance. Sixty-eight of 135 adolescents were assigned to FITNET and 67 to usual care, and 67 and 64, respectively, were analyzed. FITNET was significantly more effective than usual care for all dichotomized primary outcomes (75% vs 16%; RR 4.8; 95% CI 2.7-8.9; p<0.0001), absence of severe fatigue (85% vs 27%; RR 3.2; 95% CI 2.1-4.9; p<0.0001), and normal physical functioning (78% vs 20%; RR 3.8; 95% CI 2.3-6.3; p<0.0001). No serious adverse events were reported. The authors concluded that FITNET offers a readily accessible and highly effective treatment for adolescents with CFS and that these results justify its implementation on a broader scale. Lancet. 2012 Feb 29. PMID: 22385683

Loneliness increases stress-related inflammatory and neuroendocrine responses in women Loneliness is a predictor of mortality and increased cardiovascular morbidity. Since inflammation is a potential pathway through which loneliness might impact health, this study was conducted to investigate the relationship between loneliness and inflammatory interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and monocyte chemotactic protein-1 (MCP-1) responses to standardized mental stress. A secondary purpose was to evaluate whether individual variations in cortisol responses influenced the hypothesized relationship between loneliness and inflammation. Saliva samples and blood were taken from 524 healthy middle-aged men and women from the Whitehall II cohort at baseline, immediately after stress tasks, and 45 min later. Greater loneliness (measured with the revised UCLA loneliness scale) was associated with larger IL-6 (P = 0.044) and IL-1Ra (P = 0.006) responses to psychological stress and higher MCP-1 (P < 0.001) levels in women (but not men), independently of age, grade of employment, body mass index, and smoking status. Cortisol responsiveness was inversely related to loneliness in women; the odds of being a cortisol responder decreased with increasing loneliness (P = 0.008). Therefore, the impact of loneliness on health in women may be mediated in part through dysregulation of inflammatory and neuroendocrine systems. Psychoneuroendocrinology. 2012 Apr 11. PMID: 22503139 ihpmagazine.com { September 2012 IHP | 25

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RESEARCH NEWS

Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson’s disease

Lower cortisol levels predict recurrence in remitted patients with recurrent depression

Type 2 diabetes (T2DM) may increase the risk of Parkinson’s disease (PD). This cohort study evaluated the role of oral anti-hyperglycemic agents (OAA) in any diabetes-PD linkage. A representative cohort of 800,000 was obtained from the Taiwan National Health Insurance database. Those with T2DM were matched with those diabetes-free by birth-date and gender for the comparison of PD incidence. Related to diabetes-free, the hazard ratio (HR) was 2.18 (95% CI 1.27-3.73) for T2DM without OAAs and 1.30 (95% CI 0.77-2.19) with OAAs. For sulfonylurea alone, the PD incidence densities (PID, per 10,000 person-years) increased from 58.3 (95% CI 46.6-70.1) to 83.2 (95% CI 68.6-97.7), with similar findings by gender, but little difference if metformin was used. The metformin-alone HR was 0.95 (95% CI 0.53-1.71), sulfonylurea-alone 1.57 (95% CI 1.15-2.13), and combined therapy 0.78 (95% CI 0.61-1.01) and these differences persisted when incident PD was excluded for four years after T2DM diagnosis. The use of metformin first, in those without insulin, provided an HR of 0.40 (0.17-0.94). The authors concluded that incident PD risk in T2DM increases 2.2-fold and sulfonylureas further increase risk by 57%, which is avoided by combination with metformin. Parkinsonism Relat Disord. 2012 Apr 10. PMID: 22498320

Major Depressive Disorder (MDD) is a highly recurrent disease and stress-responsive system dysfunction seems to persist after remission. In patients with chronic and recurrent depressive episodes, state related hypothalamic-pituitary-adrenal (HPA)axis dysregulation might be a risk factor for prospective recurrence. This study examined the predictive effect of cortisol on consecutive episodes in remitted recurrently depressed patients. Cortisol was assessed in the saliva of 55 remitted recurrently depressed patients who were followed prospectively for 5.5 years after remission. Lower mean morning cortisol levels predicted earlier time to recurrence over 5.5 years after correction for residual symptoms (P = 0.015); residual symptoms and childhood trauma slightly confounded this association. Lower cortisol levels were associated with having experienced traumatic childhood life events (42.3% in patients with lower cortisol versus 19.2% in patients with higher cortisol). The authors concluded that these data provide further support for the predictive role of HPA axis dysregulation (i.e. lower morning cortisol levels) on recurrence in recurrently depressed patients. They also suggested that childhood trauma is associated with having lower cortisol levels and that it might have long-term consequences for dealing with stress and the HPA-axis. Psychiatry Res. 2012 Apr 11. PMID: 22503382

Exposure to violence during childhood is associated with telomere erosion Telomere erosion has been suggested as a potential mechanism linking stress to cellular aging, disease, and mortality in humans. This prospective longitudinal study was conducted to examine telomere erosion in relation to children’s exposure to violence. Repeated telomere measurements were conducted in children while they experienced stress and violence was assessed as exposure to maternal domestic violence, frequent bullying victimization, and physical maltreatment by an adult. Participants were 236 children with one or more violence exposures recruited from the Environmental-Risk Longitudinal Twin Study, a nationally representative 1994-1995 birth cohort. Each child’s mean relative telomere length was measured in baseline and follow-up DNA samples using the quantitative PCR method for T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). Compared with their counterparts, the children who experienced two or more kinds of violence exposure showed significantly more telomere erosion between age-five baseline and age-ten follow-up measurements, even after adjusting for sex, socioeconomic status, and body mass index (P=0.015). The authors concluded that this finding supports a mechanism linking childhood stress with telomere maintenance, which is observed at a young age and has potential impact for life-long health. Mol Psychiatry. 2012 Apr 24. PMID: 22525489 26 | IHP September 2012 } ihpmagazine.com

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How to Read a Fish Oil Label

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

NPN#80005548

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

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

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

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

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

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

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

✓ Serving Size

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

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

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

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

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

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

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

®

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

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12-08-14 2:36 PM


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

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

amount per teaspoon

Calories

45

Vitamin A

850 IU

Vitamin D

400 IU

Vitamin E

10 IU

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

1100 mg 500 mg 400 mg 40 mg

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

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RESEARCH NEWS

Inflammatory ocular adverse events might be increased with the use of oral bisphosphonates

Omega-3 fatty acid supplementation improves citalopram efficacy in depression

This retrospective cohort study involving 934 147 residents of British Columbia (10 827 first-time users of bisphosphonates and 923 320 nonusers) was conducted to examine the risk of inflammatory ocular adverse events in a pharmacoepidemiologic cohort study. The incidence rate among first-time users was 29/10 000 person-years for uveitis and 63/10 000 person-years for scleritis. In contrast, the incidence among people who did not use oral bisphosphonates was 20/10 000 person-years for uveitis and 36/10 000 for scleritis (number needed to harm: 1100 and 370, respectively). First-time users had an elevated risk of uveitis (adjusted RR 1.45; 95% CI 1.25-1.68) and scleritis (adjusted RR 1.51; 95% CI 1.34-1.68). The rate ratio for the propensity-scoreadjusted analysis did not change the results (uveitis RR 1.50 and 95% CI 1.29-1.73; scleritis RR1.53 and 95% CI 1.39-1.70). The authors concluded that people using oral bisphosphonates for the first time might be at a higher risk of scleritis and uveitis compared to people with no bisphosphonate use. Therefore, patients taking bisphosphonates should be familiar with the signs and symptoms of these conditions so that they can immediately seek assessment by an ophthalmologist if necessary. CMAJ. 2012 Apr 2. PMID: 22470169

The current randomized, masked, placebo-controlled study was performed to explore the efficacy of combination therapy with omega-3 fatty acids plus citalopram versus citalopram plus placebo (olive oil). Forty-two subjects participated in this nine-week study of combination therapy (two 1 g capsules containing a blend of 900 mg eicosapentaenoic acid, 200 mg docosahexaenoic acid, and 100 mg of other omega-3 fatty acids twice daily plus citalopram) versus monotherapy (two 1 g capsules of olive oil per day plus citalopram) in the initial treatment of individuals with major depressive disorder (MDD). Results revealed that the combination therapy demonstrated significantly greater improvement in Hamilton Depression Rating scale scores over time (P = 0.008) beginning at week four (P = 0.014). The authors concluded that combination therapy was more effective than monotherapy in decreasing signs and symptoms of MDD during the eight weeks of active treatment; however, combination therapy did not seem to enhance the speed of the initial antidepressant response. These results suggest that there may be an advantage to combining omega-3 fatty acids with a selective serotonin uptake inhibitor in the initial treatment of individuals with MDD. J Clin Psychopharmacol. 2012 Feb;32(1):61-4. PMID: 22198441

A meta-analysis of alternative smoking cessation aids Acupuncture, hypnotherapy, and aversive smoking are the most frequently studied alternative smoking cessation aids. Although these aids are often used as alternatives to pharmacotherapies for smoking cessation, their efficacy is unclear. The current random effect meta-analysis was conducted on randomized controlled trials to determine the efficacy of alternative smoking cessation aids. The Cochrane Library, EMBASE, Medline, and PsycINFO databases were systematically searched through December 2010 and only trials that reported cessation outcomes as point prevalence or continuous abstinence at six or 12 months were included. Overall, 14 trials were identified, six that investigated acupuncture (N = 823), four that investigated hypnotherapy (N = 273), and four that investigated aversive smoking (N = 99). The estimated mean treatment effects were as follows: acupuncture (OR 3.53; 95% CI 1.03-12.07), hypnotherapy (OR 4.55; 95% CI 0.98-21.01), and aversive smoking (OR 4.26; 95% CI 1.26-14.38). The authors concluded that these results suggest that acupuncture and hypnotherapy may help smokers quit. While aversive smoking may help smokers quit, it is important to note that no recent trials have investigated this intervention. Further, more evidence is needed to determine whether alternative interventions are as efficacious as pharmacotherapies. Am J Med. 2012 Apr 11. PMID: 22502956

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RESEARCH NEWS

Zinc for the treatment of the common cold: systematic review and meta-analysis

The Obesity Paradox, Cardiorespiratory Fitness, and Coronary Heart Disease.

This systematic review and meta-analysis was conducted to evaluate the efficacy and safety of zinc for the treatment of the common cold. Electronic databases and other sources for studies published through to September 2011 were searched and 17 randomized controlled trials comparing orally administered zinc with placebo or no treatment were included (N = 2,121). Compared to placebo, subjects receiving zinc had a shorter duration of cold symptoms (mean difference -1.65 days; 95% CI -2.50 to -0.81); however, heterogeneity was high (I2 = 95%). Zinc shortened the duration of cold symptoms in adults (mean difference -2.63; 95% CI -3.69 to -1.58), but no significant effect was seen among children (mean difference -0.26; 95% CI -0.78 to 0.25). Heterogeneity remained high in all subgroup analyses, including by age, dose of ionized zinc, and zinc formulation. The occurrence of adverse events (RR 1.24; 95% CI 1.05-1.46), bad taste (RR 1.65; 95% CI 1.27-2.16), and nausea (RR 1.64; 95% CI 1.19-2.27) were more common in the zinc group than in the placebo group. Therefore, oral zinc formulations may shorten the duration of common cold symptoms but large high-quality trials are needed before definitive recommendations can be made. CMAJ. 2012 May 7. PMID: 22566526

This study investigated the associations of cardiorespiratory fitness (CRF) and different measures of adiposity with cardiovascular disease (CVD) and all-cause mortality in men. Data from men with documented or suspected coronary heart disease (CHD) in the Aerobics Center Longitudinal Study (N = 9,563) were analyzed using baseline body mass index (BMI), CRF (quantified as the duration of a symptom-limited maximal treadmill exercise test), waist circumference (WC), and percent body fat (BF). After adjustment for age, examination year, and multiple baseline risk factors, men with low fitness had a higher risk of all-cause mortality in the BMI categories of normal weight (hazard ratio [HR] 1.60; 95% CI 1.24-2.05), obese class I (HR 1.38; 95% CI 1.04-1.82), and obese class II/III (HR 2.43; 95% CI 1.55-3.80) but not overweight compared with the normal-weight and high-fitness reference group. A similar pattern was noted for WC and percent BF tertiles and for CVD mortality. Among men with high fitness, there were no significant differences in CVD and all-cause mortality risk across BMI, WC, and percent BF categories. Therefore, using adiposity to assess mortality risk in patients with CHD may be misleading unless fitness is considered. Mayo Clin Proc. 2012 Apr 11. PMID: 22503065

N-acetylcysteine supplementation for the prevention of atrial fibrillation after cardiac surgery: meta-analysis Oxidative stress may play a pivotal role in the pathophysiology of atrial fibrillation, the most common type of arrhythmia after cardiac surgery. Since N-acetylcysteine (NAC) is a free radical scavenger, it may attenuate this pathophysiologic response and reduce the incidence of postoperative atrial fibrillation (POAF). This meta-analysis was conducted to assess the efficacy of NAC supplementation on the prevention of POAF. Medline and Embase were systematically reviewed for studies published up to November 2011, in which NAC was compared with controls for adult patients undergoing cardiac surgery. Eight randomized trials (n = 578) were included and outcome measures included the incidence of POAF and hospital length of stay (LOS). NAC supplementation was found to significantly reduce the incidence of POAF (OR 0.62; 95% CI 0.41-0.93; P = 0.021) compared with controls, but had no effect on LOS (weighted mean difference 0.07; 95% CI 0.42-0.28; P = 0.703). The authors concluded that prophylactic NAC supplementation might effectively reduce the incidence of POAF but note that the overall quality of current studies is poor. Adequately powered randomized controlled trials with POAF incidence as a primary outcome measure are necessary before concrete conclusions can be made. BMC Cardiovasc Disord. 2012 Feb 24;12(1):10. PMID: 22364379

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Product MonograPh Bio-Fen SBT SeaBuckThorn Single Source capSuleS Bio-Fen Plus is an oral natural health product used in the treatment of hereditary androgenic alopecia (AGA) for male or female pattern baldness. increasing concentrations of seabuckthorn seed oil. Seabuckthorn oil Seabuckthorn oil has a long history of use for the treatment of Without treatment, AGA is progressive, and causes social distress in many affected men and women (Sinclair 1998). Bio-Fen Plus contains seed extracts was also able to significantly increase activity of the antioxidant enzymes inflammatory conditions of the skin, respiratory, gastrointenstinal, and of fenugreek seeds, saw palmetto berries and flax lignans, as well as specific vitamins. Each ingredient is known to possess inhibitors of the enzyme superoxide dismutase,AGA. catalase, glutathione peroxidase and glutathione reproductive systems, amongst others (Suryakumar 2011). Seabuckthorn 5α-reductase. These inhibitors are responsible for relieving symptoms associated with hereditary reductase. Liver glutathione contentthe washair alsofollicle increased, whereas hepatic oil is a rich source of omega-3 alpha linolenic acid (ALA), which provides One of the primary causes of hair loss is a high level of the male hormone dihydrotestosterone (DHT) within (Vierhapper, 2001). malondialdehyde (a marker of lipid peroxidation) was reduced (Ting a basis for its application in the treatment chronicnumber inflammatory For people with AGA, their follicles haveofa greater of androgen receptors to which DHT attaches. 5-α-reductase catalyzes the enzymatic 2011). Figure 1 shows a summary of the mechanisms of action 1998). attributed conditions as as the maintenance of good health,which including conversion of well testosterone to dihydrotestosterone, bindshealthy to the receptor five-fold more avidly than the parent compound (Sinclair to Seabuckthorn oil (adapted from Suryakumar 2011). skin and mucus membranes (Suryakumar 2011, Ting 2011). Saw palmetto (Serenoa repens) Standardized (lipophillic) Serenoa extract has been found to be a potent inhibitor phytochemistry of 5α-reductase, resulting in decreased tissue DHT. An open-label, dose response Seabuckthorn, also known as Hippophae rhamnoides, is a shrub study on 42 healthy males and to determine the effect of2011). a combination nativewas toconducted cold arid regions of Europe Asia (Suryakumar A of carotenoid astaxanthin and saw palmetto berry lipid extract on DHT and wide spectrum of pharmacological effects have been reported for SBT, testosterone levels (Angwafor 2008). The men were divided into two groups: including antioxidant, immunomodulatory, anti-atherogenic, anti-stress, one group received 800 mg/day of the combination supplement and the other hepatoprotective, and tissuefor repair effects (Suryakumar group received 2000radioprotective mg/day of the supplement 14 days. ANOVA-RM showed significant within-group increases serum testeosteronealland 2011). Chemical analyses of the in plant havetotal demonstrated partssignificant to be decreases in serumsubstances DHT from baseline vitamins in both dose (P=0.05). There rich in bioactive including A, C,groups E, K, riboflavin, was significant difference betweenlycopene); dose groups with regard(ergosterol, to the increase of folicnoacid; carotenoids (carotene, phytosterols testeosterone or the decrease of DHT; therefore both doses were effective (Angwafor stigmasterol, lansterol, amyrins); organic acids (malic acid, oxalic acid); 2008).

polyunsaturated fatty acids including omega-3s; and some essential amino

acids (Listudy 2007,tested Suryakumar 2011). Oiloffrom the seed is particularly Another liposterolic extract Serenoa repens (LSESr) andhigh betasitosterol in the treatment of males (23-64 years age) ALA) with mild to moderate in linoleic (18:2 n-6) and α-linolenic (18:3ofn-3, acids, while theAGA. Six of 10 (60%) subjects wereacid rated(16:1 as improved final (Ting visit, thus establishing pulp is rich in palmitoleic n-7, upattothe50%) 2011). the effectiveness of 5α-reductase inhibitors against AGA (Prager 2002). Chronic inflammation of the hair follicle is considered to be a contributing factor for AGA. A antioxidant study by Chitturcapacity et al sought to determine whether blockade of inflammation using Studiesand in two animals have shown that seabuckthorn oil has significant LSESr anti-inflammatory agents (carnitine andseed thioctic acid) could alter antioxidant In models of of carbon tetrachloride (CCl4)-induced the expressioneffects. of molecular markers inflammation (Chittur 2009). It was found that the combination suppressed oil lipopolysaccharide-activated gene radical expression of oxidative stress, seabuckthorn was able to improve DPPH chemokines with pathways involvedactivity, in inflammation apoptosis. scavengingassociated activity, ferrous ion chelating reducingand power and The study concluded that 5-alpha reductase inhibitors in combination with inhibition of lipid peroxidation activity, in a dose-dependent manner with blockade of inflammatory processes could represent a new two-pronged approach in the treatment of AGA.

Vitamins In a PolishTrials study of 46 women who had symptoms of diffuse alopecia, calcium clinical pantothenate was orally administered twice acontrolled day in doses of administration 100 mg for four to In a randomized, double blind, placebo trial, five months, and vitamin B6 was injected every day for 20 to 30 days and repeated of seabuckthorn oil was able to improve mucus membrane function, as again after six months (Brzezińska-Wcisło 2001). It was determined that vitamin demonstrated a significant in symptoms of dry eyes,inasthewell B6 administeredby parenterally for reduction a few weeks induces improvement hairas effects onintear film of hyperosmolarity, a key factor condition a subset women and reduces hair loss. in dry eye. One hundred

subjects between the ages of 20 and 75 years who were experiencing dry eye symptoms were given 2g (2 capsules) of seabuckthorn oil or a placebo Medicinal Ingredients dose Per capsule oil daily for 3 months from fall to winter. Over the course of the study, Fenugreek (Trigonella foenum graecum) there was a general increase in tear film osmolarity. with the 260Compared mg seed extract placebo group,4:1 this increase was significantly less in the seabuckthorn oil group (P = 0.04).berry Theextract maximum intensities of redness Saw palmetto containing 160 mgand burning also tended to be lower in the seabuckthorn oil group: P = 0.04 for redness, 45% free fatty acids and P = 0.05 for burning. Researchers concluded that seabuckthorn oil oil Flax lignans, standardized to 20% “attenuated the increase in tear film osmolarity 100 during mgthe cold season and secoisolariciresinol diglucoside (SDG) positively affected the dry eye symptoms” (Larmo 2010). D-calcium pantothenate (Vitamin B5)

10.40 mg

Dosage Niacinamide (Vitamin B3) 10.25 mg Seabuckthorn oil should be supplemented at a dose of 2g (equivalent to HClday. (Vitamin B6) 2 mg 2Pyridoxine capsules) per Seabuckthorn oil is generally well tolerated, with no known adverse effects. Riboflavin (Vitamin B2) 1.58 mg Folic acid

0.095 mg

Biotin 400 mcg Figure 1. Seabuckthorn Mechanisms of Action Fenugreek Seeds non-Medicinal Ingredients Fenugreek seeds contain 5% to 30% protein, steroid saponins, sterols, flavonoids INCREASED and alkaloids (notably trigonelline and choline). Steroid saponins bind and ANGIOGENESIS Inert microcrystalline cellulose and vegetable-based magnesium eliminate extra cholesterol and hormones in the body; DHT is made from stearate in a veggie-based capsule testosterone, which is in turn is made from cholesterol. Therefore, when excess cholesterol is eliminated, less DHT can beUPREGULATED made (Stark 1993). In a study of 20 ENDOBENOUSANTIOXIDANTS Recommended adult AMPLIFIED dose: One capsule per day adults who consumed 12.5g and 18.0g of germinated fenugreek seed powder for COLLAGEN SYNTHESIS one month, higher levels of consumption resulted in a significant reduction in total cholesterol and low-density lipoprotein (LDL) levels (Sowmya 1999). Flax lignans Flax reduces the amount of DHT produced by reducing cholesterol levels in the body. A meta-analysis of 28 studies between 1990 and 2008 showed that flaxseed significantly reduces circulating total and LDL-cholesterol concentrations (Pan REDUCED 2009). Flaxseed interventions reduced total and LDL cholesterol by 0.10SBT mmol/L LEAF AQUEOUS (95% CI: -0.20, 0.00 mmol/L)ROSMEDIATED and 0.08 mmol/L (95% CI: -0.16, 0.00 mmol/L), LYOPHILIZED EXTRACT respectively. Significant reductionsINJURY were observed with whole flaxseed (-0.21 and -0.16 mmol/L, respectively) and lignan (-0.28 and -0.16 mmol/L, respectively) supplements (Pan 2009).

ENHANCED EXPRESSION OF MMP-2 & MMP-9

References Angwafor F III, Anderson ML. An open label, dose response study to determine the effect of a dietary supplement on dihydrotestosterone, testosterone and estradiol levels in healthy males. J Int Soc Sports Nutr 2008;5:12.

ACCELERATED WOUND CONTRACTION

AUGMENTED ECM-STABILIZATION

Brzezińska-Wcisło L. Evaluation of vitamin B6 and calcium pantothenate effectiveness on hair growth from clinical and trichographic aspects for treatment of diffuse alopecia in women. Wiad Lek 2001;54:11-8. Chittur S, Parr B, Marcovici G. Inhibition of inflammatory gene expression in keratinocytes using a composition containing carnitine, thioctic acid and saw palmetto extract. Evid Based Complement Alternat Med 2009.

IMPROVED RE-EPITHELIALIZATION

Pan A, Yu D, Demark-Wahnefried W, Franco OH, Lin X. Meta-analysis of the effects of flaxseed interventions on blood lipids. Am J Clin Nutr 2009;90:288-97. Prager N, Bickett K, French N, Marcovici G. A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia. J Altern Complement Med 2002;8:143-52.

References Serenoa repens monograph. Alternative Medicine Review 1998;3:227-9. Ting HC, Hsu YW, Tsai CF, Lu FJ, Chou MC, Chen WK. The in vitro and in vivo antioxidant properties of seabuckthorn (Hippophae rhamnoides L.) seed oil. Food Chemistry 125 (2011) 652–659.

Sinclair R. Male pattern androgenetic alopecia. BMJ 1998;317:865-9.

Sowmya P, Rajyalakshmi P. Hypocholesterolemic effect of germinated fenugreek seeds in human subjects. Plant Foods Hum Nutr 1999;53:359-65.

Larmo PS, Järvinen RL, Setälä NL, Yang B, Viitanen MH, Engblom JR, Tahvonen RL, Kallio HP. Oral sea buckthorn oil attenuates tear film osmolarity and symptoms in individuals with dry

Stark Madar Z.Aug;140(8):1462-8. The effect of an ethanol extract derived from fenugreek (Trigonella foenum-graecum) on bile acid absorption and cholesterol levels in rats, Br J Nutr 1993;69:277-87. eye. JA, Nutr. 2010

Li T, Beveridge T, Drover J. Phytosterol content sea buckthorn rhamnoidesinL.) seed oil: andand identification. Chemistry 101 (2007) 1633–1639. Vierpper H, Nowotny P, Maier H, Waldhausl W. of Production rates (Hippophae of dihydrotestosterone healthy menExtraction and women in men with Food male pattern baldness: determination by stable isotope/ dilution and mass spectrometry. J Clin Endocrinol Metab 2001;86:5762-4. Suryakumar G, Gupta A. Medicinal and therapeutic potential of Sea buckthorn (Hippophae rhamnoides L.). J Ethnopharmacol. 2011 Nov 18;138(2):268-78.

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RESEARCH NEWS

Beetroot juice and novel beetrootenriched bread products have blood pressure-lowering effects Two separate randomly controlled, single-blind, cross-over, postprandial studies were performed in normotensive volunteers to investigate ambulatory blood pressure (BP) following consumption of either four doses of beetroot juice (BJ) (N = 18; 0, 100, 250, and 500 g), or three bread products (control bread, red beetroot- and white beetroot-enriched breads (N = 14; 0, 100, and 100 g beetroot, respectively). Total urinary nitrate/nitrite (NOx) was measured at baseline, and at two, four, and 24 h post-ingestion. Over a 24 h period, BJ consumption significantly, and in a near dose-dependent manner, lowered systolic BP (SBP; P < 0.01) and diastolic BP (DBP; P < 0.001) compared to control and the beetroot-enriched bread products lowered SBP and DBP (red beetroot-enriched bread, P < 0.05), with no statistical differences between the varieties. Total urinary NOx significantly increased following the consumption of 100 g (P < 0.01), 250 g (P < 0.001) and 500 g BJ (P < 0.001) and after red beetroot-enriched bread ingestion (P < 0.05). These data demonstrated the BP-lowering cardioprotective effects of a low dose of beetroot, which seem to be unaffected by processing. Br J Nutr. 2012 Mar 14:1-9. PMID: 22414688

Use of antidiabetic agents increase the risk of pancreatic cancer This case-control study was conducted to explore the association between the use of antidiabetic drugs, diabetes, and the risk of pancreatic cancer. Using the UK-based General Practice Research Database (GPRD), cases included patients with a first-time diagnosis of pancreatic cancer (N = 2,763, mean age 69.5±11.0 years). Six controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the GPRD before the index date. Long-term use (≥30 prescriptions) of metformin was not associated with an altered risk of pancreatic cancer (OR 0.87; 95% CI 0.59-1.29), but there was a suggestion of effect modification by gender, as long-term use of metformin was linked to a decreased risk in women (OR 0.43; 95% CI 0.23-0.80). Long-term use of sulfonylureas (≥30 prescriptions; OR: 1.90; 95% CI 1.32-2.74) and insulin (≥40 prescriptions; OR 2.29; 95% CI 1.34-3.92) were both associated with an increased risk of pancreatic cancer. The authors concluded that use of sulfonylureas and insulin was associated with an increased risk of pancreatic cancer and use of metformin was associated with a decreased risk of pancreatic cancer in women only. Am J Gastroenterol. 2012 Apr;107(4):620-6. PMID: 22290402

Amoxicillin for the treatment of acute rhinosinusitis Although evidence to support antibiotic treatment for acute rhinosinusitis is limited, antibiotics are commonly used. This randomized, placebo-controlled study was conducted to determine the incremental effect of amoxicillin treatment over symptomatic treatments for 166 adults with uncomplicated, clinically diagnosed acute rhinosinusitis. A ten-day course of either amoxicillin (1,500 mg/d) or placebo was administered in three doses per day. All patients received a 5- to 7-day supply of symptomatic treatments for pain, fever, cough, and nasal congestion to use as needed. The mean change in Sinonasal Outcome Test-16 scores was not significantly different between groups on days three or ten but differed at day seven favoring amoxicillin (mean difference between groups of 0.19; 95% CI, 0.024 to 0.35). There was no statistically significant difference in reported symptom improvement at days three or ten, whereas at day seven more participants treated with amoxicillin reported symptom improvement (P = 0.02). No between-group differences were found for any other secondary outcomes and no serious adverse events occurred. The authors concluded that among patients with acute rhinosinusitis, a ten-day course of amoxicillin compared with placebo did not reduce symptoms at day three of treatment. JAMA. 2012 Feb 15;307(7):685-92. PMID: 22337680

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INDUSTRY NEWS Japanese bluefin tuna is carrying radioactive contamination Massive bluefin tuna have carried radioactive contamination across 6,000 miles of the Pacific Ocean to the California shores. The Pacific bluefin tuna that can grow to 10 feet and weigh more than 1,000 pounds, spawn off the Japan coast and swim east at breakneck speed to school in waters off California and the tip of Baja California, Mexico. This is the first time a large migrating fish has been shown to carry radioactivity such a long distance. The levels of radioactive cesium were 10 times higher than the amount measured in tuna off the California coast in previous years. It is important to note that these levels are still far below safe-to-eat limits set by the U.S. and Japanese governments. Previously, smaller fish and plankton were found with elevated levels of radiation in Japanese waters after the March 2011 magnitude-9 earthquake that triggered a tsunami that damaged the Fukushima Dai-ichi reactors. Scientists report that bluefin tuna absorbed radioactive cesium from swimming in contaminated waters and feeding on contaminated prey such as krill and squid.

Canadian College of Naturopathic Medicine opens first integrative cancer centre in Eastern Canada The Ottawa Integrative Cancer Centre (OICC), which is both a treatment clinic and an integrative oncology research centre, has opened its doors to provide multidisciplinary complementary medicine and whole-person care for people with cancer. It is the first integrative oncology and research centre in Eastern Canada to provide whole-person cancer care that includes complementary medicine. The Centre’s clinical practice and visionary research agenda is led by Dugald Seely, ND, MSc, FABNO, the executive director and founder of the OICC who also serves as the Director of Research and Clinical Epidemiology at the Canadian College of Naturopathic Medicine (CCNM).

“Providing complementary therapies in an evidence-based manner, supporting conventional medicine, is both desired by patients and is much needed in the cancer community,” says Seely. “Well over half of all cancer patients embrace complementary therapies alongside conventional treatments during their cancer journey and this proportion is growing. Often patients do not communicate their complementary care choices with conventional oncologists. A common concern among oncologists is the potential for complementary medicine to interfere with conventional therapies such as chemotherapy and radiation therapy. The OICC is committed to working with patients, their families and their health-care providers to develop a complementary, non-interfering therapeutic program to optimize overall wellness,” adds Seely.

Home-based dialysis is more popular in developing versus developed countries Researchers at Lawson Health Research Institute at London Health Sciences Centre have discovered that developing countries have faster growing rates of home-based peritoneal dialysis for kidney failure than the developed world. This is noteworthy since peritoneal dialysis is more cost effective than hospital-based hemodialysis. Records from 1997 to 2008 in 130 countries were analyzed and results revealed that 59% of peritoneal patients were treated in developing countries as opposed to 41% in developed countries. Throughout the 12 years of the study, peritoneal dialysis patients in developing countries increased by 24.9 patients per million populations versus 21.8 per million populations in developed countries. Despite this increase, the overall proportion of all dialysis patients treated with peritoneal dialysis in developed countries has actually declined by 5.3%, while developing countries have seen no change. The researchers believe that these findings may impact future business and research innovations.

Researchers discover the gene for a rare disorder Using next-generation sequencing technology, researchers at Alberta Children’s Hospital Research Institute (ACHRI) have identified the gene that causes Nager Syndrome, a condition that causes deformation in a child’s face and limbs, as well as deafness. This gene has eluded scientists for more than 60 years. “Genetic disorders of children are individually rare but collectively common, affecting the lives of hundreds of thousands of children in Canada. And most of the genes that cause these conditions have yet to be found,” says Dr. Francois Bernier. “While Nager Syndrome may be rare, it doesn’t feel like it when it’s your child whose future health is unknown.” This discovery was the result of an international collaboration between FORGE Canada and the University of Washington.

Canadian cancer death rate is decreasing Canadian Cancer Statistics 2012 released by the Canadian Cancer Society in collaboration with the Public Health Agency of Canada and Statistics Canada has revealed that the cancer death rate in Canada is decreasing. Between 1988 and 2007, overall death rates dropped by 21% in men and 9% in women, resulting in nearly 100,000 lives saved over the last 20 years. Declines in death rates were seen in all four major cancers: lung, colorectal, breast, and prostate. Although the death rate is dropping, cancer is still the leading cause of death in Canada. “A large body of evidence has accumulated over the last 30 years showing that about half of cancers can be prevented,” says Gillian Bromfield, Director, Cancer Control Policy, Canadian Cancer Society. “Even greater gains can be made in reducing cancer rates if more is done to help Canadians embrace healthy lifestyles and if governments do more to create policies that encourage people to make these changes.” For more information about Canadian Cancer Statistics 2012, visit the Society’s website at cancer.ca/ statistics

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INDUSTRY NEWS Researchers develop rapid test strips for bacterial contamination in swimming water Researchers at McMaster University have developed a rapid testing method using a simple paper strip that can detect E. coli in recreational water within minutes with much greater accuracy than existing portable technology. This new tool can contribute to improved global public safety. The work is described in a paper published in the journal Analytical and Bioanalytical Chemistry. “Coliforms are always a big problem,” says the paper’s lead author John Brennan, a McMaster chemistry professor who holds the Canada Research Chair in Bioanalytical Chemistry. “The methods used to detect outbreaks are slow, and tend not to be portable, as they often need a lab-based amplification step prior to testing, causing a time lag between an outbreak and a beach closure.” These new strips are coated with chemicals that react to the bacteria, and are printed using inkjet technology. Within 30 minutes of sampling, the paper changes colour to indicate the presence of E. coli, with colours coded to represent different forms and concentrations of the bacteria. Commercialization of a final product could take as little as two to three years.

New treatment is now available for patients with Non-Hodgkins Lymphoma and Multiple Myeloma Mozobil™ (plerixafor), a new treatment for the mobilization of stem cells in patients with non-Hodgkin’s Lymphoma (NHL) and multiple myeloma (MM), is now available in Canada. Mozobil™ is designed to mobilize hematopoietic stem cells from the bone marrow into the bloodstream where they can be collected, making it more likely for patients with certain types of cancer to proceed to transplant. Currently, before a transplant takes place, patients receive growth factors and possibly chemotherapy to mobilize hematopoietic stem cells into the bloodstream, allowing them to be

collected. A minimum number of 2 million stem cells per kilogram of body weight must be collected; for many patients this process can take three of four hours over multiple days to complete and ~15 to 20% of patients fail to mobilize enough cells. This new treatment option enhances the probability of a successful stem cell collection and subsequent transplant provides hope for those patients who otherwise would not have had this option.

claimant ($761 in 2011 vs $757 in 2010); 2) increased utilization by ~2.5% every year (average number of prescriptions per claimant in 2011 was 12.6 vs 12.3 in 2010); 3) decreased cost per prescription ($60.45 in 2011 vs $61.55 in 2010); 4) increased average dispensing fee ($10.74 in 2011 vs $10.64 in 2010); 5) decreased generic prices from approximately 60% of brand price to between 30%-45%; and 6) increased average price per brand prescription.

mihealth introduces mihealthView ™ app to the app store

New diagnostic tool for Tuberculosis in the North

mihealth Global Systems has announced the launch of a revolution in personalized healthcare communications with the mihealthView ™ app, which is available on the App Store for iPhone, iPad, and iPod touch. Patients can now manage and store their personal medical information and histories on their iPhone, iPad, and iPod touch and have safe, secure, and global access to their personal health records. Patients can track their own health information, including current prescriptions and medications, allergies, test results, and vaccination histories. The mihealthView ™ app is available for $9.99 at www.itunes.ca/appstore. For more information visit: www.mihealth.com

Express Scripts Canada releases findings of 2011 Drug Trend Report Express Scripts Canada has announced the findings of the Express Scripts Canada 2011 Drug Trend Report, an annual report that provides one of the country’s most comprehensive analyses into the use of prescription drugs and related trends in the private sector throughout Canada. Among the primary findings of the report is that while drug spend remained flat in 2011, private drug plans in Canada wasted approximately $5 billion in drug spend for the 2011 calendar year. The report defines waste as “spending that does not result in improvements to health outcomes”. Other key findings included: 1) increased average annual drug spend per

A new diagnostic device that will help fight the spread of tuberculosis (TB) in the North has been unveiled. The portable and automated device, Xpert MTB/RIF has recently been approved by Health Canada to diagnose TB. It can identify TB and also drug resistant TB from a sputum sample in only 90 minutes, which is much faster than current laboratory methods. The technology is based on a new molecular method that identifies the TB bacteria’s specific DNA in the sample and is thought to be more accurate and specific than current diagnostic methods.

Cytochroma announces positive Phase 2b results for CTAP101 Capsules Cytochroma has announced positive Phase 2b clinical trial results for its CTAP101 Capsules that effectively and safely lowered elevated plasma intact parathyroid hormone (iPTH) in patients with Stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency. “CTAP101 Capsules performed well above our expectations in the Phase 2b study,” stated Dr. Charles W. Bishop, President and CEO of Cytochroma. “No marketed therapy both effectively controls elevated serum parathyroid hormone levels and corrects the underlying vitamin D insufficiency in CKD patients. These strong data indicate that CTAP101 Capsules is a highly differentiated product compared to current treatment options. We look forward to initiating Phase 3 trials later this year.” ihpmagazine.com { September 2012 IHP | 35

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INDUSTRY NEWS Tongue analysis software has been developed at Missouri University University of Missouri (MU) researchers have developed computer software that combines the ancient practices of Traditional Chinese Medicine tongue diagnosis and modern medicine by providing an automated system for analyzing images of the tongue. “Knowing your zheng classification can serve as a pre-screening tool and help with preventive medicine,” said Dong Xu, chair of MU’s computer science department in the College of Engineering. “Our software helps bridge Eastern and Western medicine, since an imbalance in zheng could serve as a warning to go see a doctor. Within a year, our ultimate goal is to create an application for smart phones that will allow anyone to take a photo of their tongue and learn the status of their zheng.” More information will be accessible in the journal article entitled “Automated Tongue Feature Extraction for ZHENG Classification in Traditional Chinese Medicine”, which has been accepted for publication in Evidence Based Complementary and Alternative Medicine.

Experts say that physicians should be paid to report adverse drug reactions Experts say that mandatory physician reporting of adverse drug reactions could strengthen post market surveillance of pharmaceuticals in Canada. It has been estimated that one in nine emergency department visits in Canada are due to drug-related adverse events. However, it is difficult to obtain absolute data on adverse drug reactions in Canada since physician reporting is entirely voluntary and therefore conditional on doctors having the time and inclination to do the additional paperwork. Linda Wilhelm, an independent member of the Best Medicines Coalition, an alliance of organizations and individuals for the promotion of drug safety says that increased reporting by health professionals could fill some of the gaps in current data. She explains, “There’s been a lot of

push-back from the physician community on mandatory reporting because the time it would take for them to do it is quite labour intensive”. She goes on to say, “If it’s valuable for the physician to complete that form, then they should be compensated for completing it.”

Status quo wait times The Canadian Institute for Health Information (CIHI) says that improvements in wait times for priority procedures have leveled off across Canada. Some provinces have failed to maintain previous gains in providing timely access to targeted surgeries, such as joint replacements. In the report Wait Times in Canada — A Summary, 2012, CIHI notes that roughly four out of five Canadians received priority-area procedures, including hip and knee replacements, cataract surgery, hip fracture repairs, and radiation therapy, within clinically recommended time frames for the second year in a row. The majority (97%) of patients received radiation therapy within the suggested 28-day time frame but in comparison, some 82% of patients received timely access to hip replacement and cataract surgery, while 79% underwent hip fracture repairs, and 75% knee replacement surgery. The report shows patients wait the longest, and increasingly longer, for knee replacements. In British Columbia, Prince Edward Island (PEI), and New Brunswick, for example, the proportions of knee replacements performed within the recommended 182-day time frame have dropped by at least 10 percentage points since 2009 to 67%, 55%, and 53%, respectively.

Ottawa Integrative Cancer Centre and Ottawa Regional Cancer Foundation launch a whole-person cancer-care program The Ottawa Integrative Cancer Centre (OICC) has launched an innovative whole-person cancer-care education program in partnership with the Ottawa Regional Cancer Foundation’s Maplesoft

Centre. The “Integral Healing Program: Empowerment on the Cancer Journey” provides a set of educational modules designed to share evidence-based complementary care options with cancer patients, survivors, and their support network, providing them with knowledge and tools to take better control of their disease management. The program consists of four, weekly half-day workshops. Each session incorporates hands-on interactive learning, audio-visual teaching aids, and lively group discussions with topics including: 1) cancer and complementary therapies; 2) cancer and nutrition; 3) relationships and family dynamics; and 4) prevention of recurrence. All sessions are free of charge. For more information on workshop content and the instructors, please visit OICC events at www.oicc.ca.

University of Maryland completes most extensive full-face transplant to date The University of Maryland released details of the most extensive full-face transplant completed to date, including both jaws, teeth, and tongue. The 36-hour operation occurred on March 19-20, 2012 at the R Adams Cowley Shock Trauma Center at the University of Maryland Medical Center and involved a multi-disciplinary team of faculty physicians from the University of Maryland School of Medicine and a team of over 150 nurses and professional staff. The face transplant recipient, 37-year-old Richard Lee Norris of Hillsville, Virginia, was injured in 1997 in a gun accident. Since that time, he has undergone multiple life-saving and reconstructive surgeries. Due to the accident, Mr. Norris lost his lips and nose and had limited movement of his mouth. “The resources and talent that made this complex organizational effort a reality was months in the making and touched all areas of the hospital,” says Jeffrey A. Rivest, president and chief executive officer of the University of Maryland Medical Center. “The Medical Center staff is honored to care for patients and families facing such tremendously complex medical challenges.” •

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PRODUCT PROFILES Biotherapeutic Drainage™ Liver & Kidney PLUS Adrenal Support Convenient 3 week program designed to facilitate the emunctories through deep intra and extracellular elimination while respecting natural physiology. This global drainage protocol targets the primary emunctories of the liver and kidney plus provides adrenal support.

GENESTRA BRANDS™ • Carnitine (Acetyl L-carnitine 500 mg) Carnitine provides neurological support and pain relief. It helps to reduce fatigue, 1, 2 helps to enhance cognitive function in the elderly 3 and helps to relieve muscle pain and pain associated with neuropathy.4 Carnitine is also critical in energy production.5 It transports long-chain fatty acids into the mitochondria so they can be oxidized to produce energy.6 It is concentrated in tissues (skeletal and cardiac muscle etc.) that utilize fatty acids as dietary fuel.7

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

CurcuMIND Inflammation and low vitamin D levels are associated with auto-immune diseases like IBD, Alzheimer’s and even cancer. Curcumin is a powerful anti-inflammatory, limited by poor bioavailability. Longvida® curcumin, available exclusively from AOR, is the most bioavailable curcumin on the market, up to 100 times more bioavailable than traditional curcumin. CurcuMIND, by AOR, combines Longvida® curcumin with vitamin D3 for synergistic effectiveness against inflammatory conditions. Recent pre-clinical research has demonstrated that the combination of vitamin D3 and curcumin may be a powerful combination to prevent and reduce amyloid plaques, which are associated with Alzheimer’s disease.

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PRODUCT PROFILES

The Whole Body Antioxidant PhytoBerry® is a highly concentrated antioxidant that features over 40 ingredients and provides the equivalent of 6 to 8 servings of fresh fruit. It has been designed to increase energy, support immune function and protect your entire body from head to toe by targeting every organ and body system. Plus, it tastes great!

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

XanthiTrim XanthiTrim reduces fatty liver, supports thermogenesis and the body’s natural ability to metabolize fat. What is XanthiTrim? A clinically researched patented combination of brown seaweed extract, fucoxanthin, pomegranate seed oil and GreenSelect® Phytosome.

QÜELL – Not just another fish oil. QÜELL FISH OIL is a Supercritical CO2 triglyceride fish oil. Unique among other fish oils for its critical extraction, purity, bioavailability and concentrations. Critical Concentration: The Supercritical CO2 process is able to create highly concentrated levels of EPA and DHA in triglyceride form. The result is a product that can deliver significant amounts of EPA and DHA in easy to swallow softgels.

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PRODUCT PROFILES

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

ViraClear EPs 7630™ Viraclear EPs 7630™ contains a proprietary extract, obtained from the roots of the Pelargonium sidoides plant, an herb long used to treat cough and respiratory ailments. It works differently, unlike conventional remedies that simply mask symptoms, Viraclear EPs 7630™ addresses the cause to help speed recovery and shorten the duration of upper respiratory tract infections.

o3mega triple strength + D3 Just one capsule provides the recommended daily dose of 900mg of EPA/DHA for cardiovascular support, and 1,000 IU of vitamin D3. Our Omega-3 is independently tested to be pure, fresh and free of all toxins and PCBs. Pure, Wild, Fresh, Toxin & Phthalate-Free; id System™ enteric coated; 5 Star IFOS Rating & USP Certified.

Sereniten Plus Unregulated elevated levels of cortisol impair stage four delta wave sleep, destabilize mast cells, inhibit digestive enzyme production and increases endothelin and LDL levels. All of these effects contribute to increased cardiovascular disease, allergies, IBS and IBD. Balancing the hypothalamicpituitary axis by re-establishing appropriate sensitivity within the feedback loop assists in mitigating these effects and normalizing cortisol levels.

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COVER STORY

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Integrated

COVER STORY

Health

Clinic Cancer Care Centre By Philip Rouchotas MSc, ND Photography by Katie Huisman

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COVER STORY

W

e showcased the Integrated Health Clinic in the September 2009 issue of IHP. Dr’s Karen and Gurdev Parmar have been busy for the past three years.

Karen and Gurdev founded the clinic in 2000, with the mission statement of the facility serving as a guiding force governing all patient interactions; “at Integrated Health Clinic, we strive to treat all of our patients with compassion and respect, providing treatment options that are individualized for healing and quality of life”. The facilities golden rule is to ensure “every patient receives five- star service”. Word has spread across the country and the continent as to the cutting- edge treatments offered at the facility. Patients come to Fort Langley from near and far seeking the exceptional standard of care, reputation, and commitment to the best available medicine the facility has been delivering for over a decade. Not a week ago while meeting with a highly reputable naturopathic oncologist in the Toronto area was I informed of several patients the ND had personally referred to visit the Fort Langley facility for treatments not available anywhere else in Canada.

Dr. Gurdev Parmar has entrenched himself in the Canadian and North American landscape as an elite level practitioner of integrative oncology. Something the Parmar’s had been planning for several years has recently come to fruition; the establishment of the Cancer Care Centre adjacent to the Integrated Health Clinic. The Cancer Care Centre is an 1800 sqft facility dedicated to the ever- growing patient base seeking the oncology expertise of Gurdev, his associate Dr. Johan Ghazali, and the other essential team members. Of similar timing was a major clinical advance for the team; offering of localized hyperthermia treatments for cancer. The continued pursuit of cutting- edge technologies and treatments necessitated the creation of the Cancer Care Centre to accommodate the growing patient base seeking such services. The establishment of both local and whole body hyperthermia treatments are the newest gems in the team’s pursuit of offering the very best in available cancer treatment options. Gurdev highlights Locoregional Hyperthermia (LRHT) as an incredibly effective and truly integrative treatment. He describes it as truly integrative because “it is not a stand alone therapy. It works best in conjunction with chemotherapy

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COVER STORY

LRHT is anticipated in the management of solid tumours. “For leukemias, lymphomas, testicular cancer, conventional treatments are the key. Integrative Oncology has less to offer in the primary treatment of these patients”. After two years of experience with LRHT in which over 3,000 treatments were applied, Gurdev is thrilled that IHC is now offering fever range whole body hyperthermia (WBHT). WBHT applied in the fever range involves heating the core body temperature to 40 degrees celsius for five to six hours. This is used to augment chemotherapy in metastatic disease, as well as in leukemias and lymphomas.

and radiation. We have clearly seen patients having highlyimproved responses to conventional treatment when we apply LRHT”. “The key is coordinating the hyperthermia treatments with the patients chemotherapy/ radiation schedule”. Gurdev also describes the therapy as an important tool for palliative care, and as having a role as a monotherapy. “We have seen LRHT alone, in advanced and refractory patients, achieve reduction in tumour burden, improve QOL, and improve survival”. Gurdev highlights that the greatest success with

The team has done an incredible job of creating positive working relationships with surrounding conventional and integrative oncologists. Referrals from other ND’s and local oncologists are a frequent occurrence. Gurdev continues to have a special working relationship with the team at the Lions Gate Hospital chemotherapy clinic, further ensuring integrative oncology reaches as many patients as possible. Gurdev maintains the ambition of serving as a residency site for the FABNO program, although progress in this area has met with some obstacles. A Canadian site is yet to serve as a residency ihpmagazine.com { September 2012 IHP | 43

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COVER STORY

facility for the FABNO designation, and many of the obstacles centre upon this. Likewise, the process of the naturopathic education research counsel (NERC) securing funding for the residents is another obstacle. Although having taken several years of diligence to deliver, the centre is 99%+ poised to meet this milestone, with the residency program linked to, or â&#x20AC;&#x153;offered throughâ&#x20AC;?, Bastyr University. Residents from Canada and the USA will be accepted. The offering of LRHT at the facility has resulted in the arrival of patients from across Canada, the USA, and even as far away as New Zealand and South Africa. The Integrated Health Clinic and the newly created Cancer Care Centre have been offering leading- edge cancer treatments for many years prior to the arrival of LRHT, and several strategies remain mainstays in addition to the welcomed arrival of LRHT. Such strategies include IV vitamin C, dichloroacetate (DCA), working with patients to improve diet and implement exercise, as well as nutritional/ nutraceutical/ functional food/ botanical supplementation. 44 | IHP September 2012 } ihpmagazine.com

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COVER STORY

Gurdev involves himself with many projects outside of practice, including roles on the Board of OncANP, the Editorial Board of the International Journal on Oncothermia, and the Board of Governors of CCNM. Gurdev highlights a very critical aspect of cancer care across Canada and most industrialized nations; far too much attention is centred on cancer treatment. The best way to combat cancer is through prevention, and also through better screening. Early detection for most cancers is a major determinant of survival and QOL. Gurdev is a powerful advocate for improvements in screening technologies, as well as improvement in access to screening services. This important message is disseminated through the many avenues Gurdev gives back to the profession in an educational role. Dr. Karen Parmar, Cofounder of the Integrated Health Clinic, has temporarily taken a step back from the practice. The arrival of her forth son, two horses, and a hobby farm have become her priorities in the immediate future, as has home-schooling of their eldest two sons for the past two years. She has plans of rejoining the team in the future, continuing her work in the areas of women’s health, pediatrics, and fertility. Karen maintains her role as the President of the College of Naturopathic Physicians of BC. We at IHP feel the immense contributions of the Parmar’s to the profession is often over shadowed by their tremendous advances in clinical therapeutics their patients have come to be so grateful for. The Integrated Health Clinic and the Cancer Care Centre have established themselves as a centre of excellence for integrative medicine in Canada and beyond. The hundreds of ND’s who will have their careers molded by the efforts of Karen and Gurdev is among their greatest professional achievements. • ihpmagazine.com { September 2012 IHP | 45

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TM

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

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PRODUCT mOnOgRaPh

PRODUCT MONOGRAPH OIL OF OREGANO

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

Human studies

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

Animal and In vitro studies

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

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

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

Toxicology

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

References

Canbek M, Uyanoglu M, Bayramoglu G, Senturk H, Erkasap N, Koken T, Uslu S, Demirustu C, Aral E, Husnu Can Baser K. Effects of carvacrol on defects of ischemia-reperfusion in the rat liver. Phytomedicine. 2008 Jan. De Vincenzia M et al. Constituents of aromatic plants: carvacrol. Fitoterapia 2004; 75(7-8): 801-804. Force M et al. Inhibition of enteric parasites by emulsified oil of oregano in vivo. Phytother Res. 2000 May;14(3):213-4. Lambert RJ, Skandamis PN, Coote PJ, Nychas GJ. A study of the minimum inhibitory concentration and mode of action of oregano essential oil, thymol and carvacrol. J Appl Microbiol. 2001 Sep;91(3):453-62. Nostro A, Roccaro AS, Bisignano G, Marino A, Cannatelli MA, Pizzimenti FC, Cioni PL, Procopio F, Blanco AR. Effects of oregano, carvacrol and thymol on Staphylococcus aureus and Staphylococcus epidermidis biofilms. J Med Microbiol. 2007;56(Pt 4):519-23. Nostro A et al. Susceptibility of methicillin-resistant staphylococci to oregano essential oil, carvacrol and thymol. FEMS Microbiol Lett. 2004;230(2):191-5. Salgueiro LR et al. Chemical composition and antifungal activity of the essential oil of Origanum virens on Candida species. Planta Med. 2003 Sep;69(9):871-4. Santoyo S, Cavero S, Jaime L, Ibañez E, Señoráns FJ, Reglero G. Supercritical carbon dioxide extraction of compounds with antimicrobial activity from Origanum vulgare L.: determination of optimal extraction parameters. J Food Prot. 2006;69(2):369-75. Uyanoglu M, Canbed M, Aral E, Husnu Can Baser K. Effects of carvacrol upon the liver of rats undergoing partial hepatectomy. Phytomedicine 2008; 15(3): 226-9. ihpSept10_NAHS_Ad.indd 2 058.IHP NAHS mono.indd 1 IHPAPR2012_10055_North_American_Herb_and_Spice_FP2.indd 2

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CLINIC PROFILE

Holly Fennell, ND InsideOut Health Solutions

By Angela MacNeil, MSc, ND â&#x20AC;˘ Photography by Stacey Rosenblum

I

HP is excited to profile a highly successful and motivational Naturopathic Doctor, Holly Fennell. Holly founded InsideOut Health Solutions in 2005; the clinic is centrally located at Yonge and Summerhill in Toronto. Starting in a 500 square foot clinic, her practice quickly outgrew the space. The clinic now occupies the fourth floor of her building and is 1600 square feet. InsideOut is comprised of Holly, Erin Truscott, ND, three registered massage therapists (Douglas Aboud, Heather Atkinson, Andrea Purdy), a psychotherapist (Lori Dennis), a social worker (Nelson Parker), and an office manager (Jaene Castrillon). Holly sees an average of 10-15 patients each day. Erin Truscott, ND, assists by running IV shifts that can accommodate up to seven patients at a time. Holly graduated from CCNM with the recognition that she needed a better understanding of how the healthcare system operated in Ontario. She had a mandate to understand the benefits of the system and to determine what was lacking. She realized that a truly collaborative approach among healthcare practitioners was rare but absolutely necessary for the success of an integrated clinic.

Her motivation in opening InsideOut was to create an integrative health care centre that fostered confidence and acceptance of naturopathic medicine and naturopathic doctors as primary health care providers. She believes that naturopathic medicine serves the community best through a collaborative approach Many patients consider Holly as their case manager; she involves their entire healthcare team, including family doctors, oncologists, physiotherapists, and chiropractors, among others. To provide exemplary care, Holly believes that she must understand and appreciate the contribution of every practitioner on the team, striving to add value by filling in the gaps in treatment management and by incorporating naturopathic modalities into patient care. She notes that although it is important to remain humble, it is essential to assert confidence when inserting herself into the healthcare team. Holly has found that sharing individually tailored, concrete treatment plans of action with both patients and their healthcare teams has proven highly beneficial. She feels that this practice effectively pulls everyone together and fosters a team approach. In Hollyâ&#x20AC;&#x2122;s experience, medical doctors appreciate

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CLINIC PROFILE

The InsideOut Health Solutions Team: Holly Fennell, BA (Hon), ND: Naturopathic Doctor and Clinic Owner Erin Truscott, B.Sc (Hons), ND: Naturopathic Doctor Lori Dennis, MA: Psychotherapist Nelson Parker, M.S.W., R.S.W: Social Worker Douglas Aboud, RMT: Registered Massage Therapist Heather Atkinson, RMT: Registered Massage Therapist Andrea Purdy, RMT: Registered Massage Therapist Jaene Castrillon: Office Assistant this communication. In addition, she finds that this direct communication can unburden patients who may be anxious about discussing naturopathic treatment options with their physicians and medical team. Holly re-iterated throughout the interview that it is not the patient’s responsibility to convince medical doctors that naturopathic doctors are highly skilled practitioners providing evidence-based recommendations; instead, this is the naturopathic doctor’s responsibility. Referrals from medical doctors have contributed to the tremendous success that InsideOut has achieved. Holly has a close professional relationship with world-renowned sports physician, Dr. Anthony Galea, whom she has known since 2005 when the Toronto Argonauts hired her to be part of their medical team; Holly was the first naturopathic doctor ever hired by the Canadian Football League. She toured with the Argonauts for four seasons and was on the front lines as she huddled with the team doctors on the field at every game. This professionally life-changing experience drove her to formulate and develop an electrolyte product that would serve as a superior alternative to the commercially available products that Holly considered inadequate. This product was quickly adapted by many players and continues to be used by several professional athletes and doctors. Holly considers Dr. Galea a powerful mentor and says that his compassion as a physician drives her to excel in patient care. Holly also works closely with highly sought after plastic surgeon, Dr. Trevor Born whose clinics are state-of-the-art surgical facilities, devoted to providing the latest surgical and non-surgical breakthroughs in cosmetic and reconstructive plastic surgery. Dr Born has remarkably influenced Holly’s career and he refers patients to her for pre- and post-operative care. He has even taken her into his post-operative suite to treat patients that can benefit from IV therapy immediately following surgery. In fact, after several years of working together, Dr. Born and Holly identified

the key nutrients required for healing and health maintenance and created a line of pre- and post-operative supplements. The line has been a huge success and has bridged the naturopathic and medical communities in a very positive way (to learn more, visit http://tmbcosmeticsurgery.com/medical-spa/nutritionalsupplements.html). Finally, Dr.Vineet Nikore, an emergency room doctor, sports medicine doctor, and pain specialist, is another source of referrals for InsideOut. Holly considers him to be a wealth of knowledge and is proud that he respects her skills and training as a naturopathic doctor. She believes that he exemplifies the most important quality in a doctor: openness. Dr.Nikore has a keen interest in how naturopathic medicine can aid his patients’ care. It is evident that Holly works hard to develop relationships with medical experts in multiple fields. She believes that this has been a major contributing factor to her success and growth as a clinician. It even guides the choices of nutraceutical companies and laboratories that InsideOut associates with. She does not support one brand but the best products from many different companies. Holly is grateful for the support from companies such as Douglas Labs, Pascoe, and Biotics Research. She stocks her dispensary with companies that stand behind their products both scientifically and ethically. The clinic also offers many integrated laboratory tests by such companies as Metametrix, Doctor’s Data, and Gamma Dynacare. Holly has developed relationships with the group of experts employed by these companies and maintains regular contact with them for current research in the field and on products. Holly is passionate about excellence in patient care and management and IHP is grateful that she allowed us a glimpse into her practice. The success that InsideOut Health Solutions has cultivated should be motivational for healthcare providers to collaborate and create stronger bridges amongst various professions. • ihpmagazine.com { September 2012 IHP | 49

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METAGENICS NUTRAGEMS COQ10 300 NutraGems by Metagenics features chewable gels containing advanced, emulsified Coenzyme Q10 (CoQ10) designed to provide general support for cardiovascular health, energy production, antioxidant protection, and overall wellness and healthy aging. CoQ10, also known as ubiquinone, is a fat-soluble substance present in most human cells, with the highest concentrations in the heart, liver, kidney, and pancreas (Aberg 1992). CoQ10 is synthesized in the human body and is also obtained from the diet. Meat, fish, nuts, and some oils are the main dietary sources of CoQ10 (Pravst 2010). CoQ10 is an essential cofactor in the synthesis of mitochondrial adenosine triphosphate (ATP) and therefore a key component of the mitochondrial respiratory chain (Ernster 1995). Since most cellular functions depend on adequate supply of ATP, CoQ10 is essential for the health of virtually all tissues and organs. CoQ10 as the reduced form is also an antioxidant, protecting membranes from oxidation (Mellors 1966), inhibiting the peroxidation of lipoprotein lipids (Stocker 1991), and may also have a role in regenerating other antioxidants such as vitamin E (Sohal 2004). Due to its lipophilicity and high molecular weight, CoQ10 from oral supplementation is absorbed slowly from the gastrointestinal tract; the uptake mechanism is similar to that of vitamin E. Depending on the delivery forms of CoQ10, the Tmax is approximately 6 â&#x20AC;&#x201C; 8 h (Bhagavan 2006). CoQ10 is transported via the lymphatics to the circulation (Katayama 1972). The majority of CoQ10 is eliminated via biliary and fecal excretion. The elimination half-life is approximately 33 â&#x20AC;&#x201C; 34 h (Tomono 1986; Greenberg 1990). Genetic CoQ10 deficiencies can occur as a result of defects of ubiquinone biosynthesis (primary deficiencies) or due to other causes (secondary deficiencies); major clinical phenotypes include encephalomyopathy, severe infantile multisystemic disease, cerebellar ataxia, isolated myopathy, and nephritic syndrome (Quinzii 2011). Various studies have shown that oral administration of CoQ10 improves signs and symptoms associated with CoQ10 deficiencies (Quinzii 2011). Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors, or statins, inhibit the synthesis of cholesterol by inhibiting mevalonate, a main precursor of both cholesterol and CoQ10. Studies have shown that statin therapy reduced serum and muscle CoQ10 levels (Folkers 1990; Ghirlanda 1993; Watts 1993; Paiva 2005). It has been hypothesized that mitochondrial dysfunction through depletion of CoQ10 is one underlying pathophysiology of statin-induced myopathy (Thompson 2003). Preliminary clinical trials have found CoQ10 prevent or improve statin-associated myalgic symptoms (Thibault 1996; Kim 2001; Caso 2007). Because of its bioenergetic role and antioxidant properties, CoQ10 has been investigated in numerous studies for its potential benefit for cardiovascular health. A recent meta-analysis based on 12 clinical trials found that CoQ10 had the potential to lower systolic and diastolic blood pressure in hypertensive patients (Rosenfeldt 2007); this effect is likely related to the improvement in endothelial function (Tiano 2007). Myocardial depletion of CoQ10 has been observed in heart failure and the severity of symptoms is associated with the severity of CoQ10 deficiency (Folkers 1985). At least 2 meta-analyses investigating CoQ10 supplementation in chronic heart failure reported improvement in stroke volume, ejection fraction, cardiac output, cardiac index, or end diastolic volume index (Soja 1997; Sander 2006). CoQ10 may be valuable as an adjunctive clinical therapy of cardiovascular disease (Greenberg 1990; Langsjoen 1999; Molyneux 2008). Health Canada Natural Health Product monograph states that CoQ10 helps maintain and/or support cardiovascular health (HealthCanada 2007). Two clinical studies found that CoQ10 supplementation may be efficacious in preventing migraine headaches (Rozen 2002; Sandor 2005). One larger study found that CoQ10 deficiency may be common in pediatric and adolescent migraine, and CoQ10 supplementation may result in clinical improvement (Hershey 2007). Health Canada Natural Health Product monograph states that CoQ10 helps reduce the frequency of migraine headaches and associated nausea and vomiting when taken as a prophylactic (HealthCanada 2007). Mitochondrial respiratory chain dysfunction and oxidative stress are key features of some neurodegenerative disorders. Preliminary data from pilot clinical trials of high-dose CoQ10 for early-stage patients showed some potential benefit of CoQ10 in improving motor function, slowing progression, and improving some clinical symptoms (Beal 2002; Shults 2002; Horstink 2003). Large-scale controlled trials investigating CoQ10 and neurodegenerative health are currently underway. Preliminary data also found that CoQ10 may improve semen quality, sperm count, or sperm motility in infertile men with idiopathic oligoasthenoteratospermia (Balercia 2009; Safarinejad 2009). There are other preliminary data indicating a potential benefit of CoQ10 in several other indications (Littarru 2010). CoQ10 has an excellent safety record. It is well tolerated, with few potential drug interactions. Only minor adverse effects such as gastrointestinal upset and headache were reported (Rosenfeldt 2007). 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References

Aberg, F., E. L. Appelkvist, et al. (1992). Arch Biochem Biophys 295(2): 230-4. Balercia, G., E. Buldreghini, et al. (2009). Fertil Steril 91(5): 1785-92. Beal, M. F. (2002). Free Radic Res 36(4): 455-60. Bhagavan, H. N. and R. K. Chopra (2006). Free Radic Res 40(5): 445-53. Caso, G., P. Kelly, et al. (2007). Am J Cardiol 99(10): 1409-12. Ernster, L. and G. Dallner (1995). Biochim Biophys Acta 1271(1): 195-204. Folkers, K., P. Langsjoen, et al. (1990). Proc Natl Acad Sci U S A 87(22): 8931-4. Folkers, K., S. Vadhanavikit, et al. (1985). Proc Natl Acad Sci U S A 82(3): 901-4. Ghirlanda, G., A. Oradei, et al. (1993). J Clin Pharmacol 33(3): 226-9. Greenberg, S. and W. H. Frishman (1990). J Clin Pharmacol 30(7): 596-608. HealthCanada. (2007). "Natural Health Product Monographs: Coenzyme Q10." Retrieved March 5, 2012,

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from http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licenprod/monograph/mono_coenz-q10-eng.php. Hershey, A. D., S. W. Powers, et al. (2007). Headache 47(1): 73-80. Horstink, M. W. and B. G. van Engelen (2003). Arch Neurol 60(8): 1170-2; author reply 1172-3. Katayama, K. and T. Fujita (1972). Chem Pharm Bull (Tokyo) 20(12): 2585-92. Kim, W. S., M. M. Kim, et al. (2001). Invest New Drugs 19(1): 81-3. Langsjoen, P. H. and A. M. Langsjoen (1999). Biofactors 9(2-4): 273-84. Littarru, G. P. and L. Tiano (2010). Nutrition 26(3): 250-4. Mellors, A. and A. L. Tappel (1966). J Biol Chem 241(19): 4353-6. Molyneux, S. L., J. M. Young, et al. (2008). Clin Biochem Rev 29(2): 71-82. Paiva, H., K. M. Thelen, et al. (2005). Clin Pharmacol Ther 78(1): 60-8. Pravst, I., K. Zmitek, et al. (2010). Crit Rev Food Sci Nutr 50(4): 269-80. Quinzii, C. M. and M. Hirano (2011). Biofactors 37(5): 361-5. Rosenfeldt, F. L., S. J. Haas, et al. (2007). J Hum Hypertens 21(4): 297-306. Rozen, T. D., M. L. Oshinsky, et al. (2002). Cephalalgia 22(2): 137-41. Safarinejad, M. R. (2009). J Urol 182(1): 237-48. Sander, S., C. I. Coleman, et al. (2006). J Card Fail 12(6): 464-72. Sandor, P. S., L. Di Clemente, et al. (2005). Neurology 64(4): 713-5. Shults, C. W., D. Oakes, et al. (2002). Arch Neurol 59(10): 1541-50. Sohal, R. S. (2004). Methods Enzymol 378: 146-51. Soja, A. M. and S. A. Mortensen (1997). Mol Aspects Med 18 Suppl: S159-68. Stocker, R., V. W. Bowry, et al. (1991). Proc Natl Acad Sci U S A 88(5): 164650. Thibault, A., D. Samid, et al. (1996). Clin Cancer Res 2(3): 483-91. Thompson, P. D., P. Clarkson, et al. (2003). JAMA 289(13): 1681-90. Tiano, L., R. Belardinelli, et al. (2007). Eur Heart J 28(18): 2249-55. Tomono, Y., J. Hasegawa, et al. (1986). Int J Clin Pharmacol Ther Toxicol 24(10): 536-41. Watts, G. F., C. Castelluccio, et al. (1993). J Clin Pathol 46(11): 1055-7.

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Feature Galectin-3 and MCP

Galectin-3 An emerging treatment target; role of MCP Isaac Eliaz, MD, MS, Lac, and Heidi Fritz MA, ND

C

hronic illnesses such as cancer, cardiovascular disease, diabetes and others share common metabolic and inflammatory derangements. Novel epidemiological forecasts predict that a new category of diseases may soon be established, classifying these chronic illnesses as â&#x20AC;&#x153;Elevated Galectin-3 Diseases.â&#x20AC;?

Galectin-3 has been shown to be involved in a large number of biological processes, including inflammation, proliferation, and fibrosis. In cardiovascular disease, it is implicated in mediating fibrosis (Lin 2009), while in cancer it appears to be active in promoting metastasis and angiogeneisis (Iurisci 2000). For instance, galectin-3 on the cell surface promotes interactions with glycans on adjacent cell surfaces, promoting tumor cell adhesion, invasion, and dissemination (Yu 2011). Conversely, suppression of galectin-3 expression in animal models results in reduced tumor growth and metastasis (Honjo 2001). Circulating galectin-3 may also play a role in the inhibition of anti-tumor T-cell activity (Peng 2008).

Galectin-3 is a beta-galactoside binding lectin, ie, a carbohydrate binding protein with an affinity for beta-galactoside containing glycans (Iurisci 2000), expressed by epithelial and immune cells (Yu 2010). Several ligands for galectin-3 have been described, including lysosomal-associated membrane proteins 1 and 2, IgE, laminin & fibronectin, and Mac-2 BP (aka 90K) (Iurisci 2000, Yu 2010); and the biological function of galectin-3 is the subject In 2011, the groundbreaking PREVEND study (Prevention of increasing research. Although the molecule is normally present of REnal and Vascular ENd-stage Disease) found that elevated in the body at relatively low concentrations, levels are greatly serum galectin-3 predicted a two-fold increase in all cause increased in a variety of chronic diseases, granting galectin-3 Heidi Fritz, MA, ND Isaac Eliaz MD, MS, LAc utility as a marker of disease risk Research Fellow Amitabha Medical Clinic and Healing and progression (Iurisci 2000). Canadian College of Naturopathic Medicine Center Notably, galectin-3 appears to be hfritz@ccnm.edu 7064 Corline Ct., Suite A an active biomarker, as opposed Bolton Naturopathic Clinic Sebastopol, CA 95472 to other surrogates such as 64 King St W ieliaz@sonic.net C-reactive protein (CRP). Bolton, Ontario, L7E1C7

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Feature Galectin-3 and MCP mortality among the general population (deBoer 2011, 2012). A total of 7968 people were following for ten years, with overall mortality being 15.6% in the highest quintile, compared to 7.7% in the lowest quintile (De Boer 2011, 2012). For each standard deviation increase in galectin-3, there was a corresponding 46% increase risk in all cause mortality, HR 1.46 (95% CI 1.37-1.56, unadjusted), and this remained upon adjustment for age, gender, and classical risk factors (but not hs-CRP), HR 1.09 (1.01-1.19, p=0.036) (deBoer 2012). Galectin-3 can be expressed in the nucleus, cytoplasm, mitochondrion, cell surface, extracellular space, circulate freely in the blood stream (Brown 2012), and can be measured in blood samples as well as in tumor tissue samples. Normal serum levels range from 5.4-26.2 ng/mL in 95% of the population based on an analysis conducted by the BGM lab on 1099 samples from healthy patients (BG Medicine 2011). Recently, a blood test for galectin-3 has been approved by the FDA for use in assessing prognosis in patients with chronic heart failure (FDA 2012). The Role of Galectin-3 in Chronic Disease Processes Cancer

Galectin-3 is over-expressed on the surface of cancer cells (Saleh 2009), where it affects tumor growth through several mechanisms. First, galectin-3 acts as a cell surface adhesion molecule that allows cancer cells to aggregate (Tinari 2001). Second, galectin-3 promotes the dissemination of cancer through the circulatory system, representing an important mechanism for cancer metastasis (Wang 2012). Finally, galectin-3 is also involved in angiogenesis (Nangia-Makker 2000, Yu 2007, Wang 2009, Zhao 2009). Evaluation of galectin-3 is gaining recognition as an assessment tool in oncology, in particular as a diagnostic marker and as a prognostic marker for different cancers (Brown 2012, Chiu 2010). Studies of galectin-3 in oncology to date have focused predominantly but not exclusively on levels of galectin-3 expression in tumor tissue, rather than on circulating galectin-3, which is the basis of the test in heart failure. Tumor expression of galectin-3 may be elevated or suppressed depending on the cancer type and/ or stage; ie., “decreased expression of galectin-3 ... detected in breast cancer, colonic cancer, prostate cancer and head and neck cancer compared to that of corresponding normal tissues, [and increased] galectin-3 expression ... in pancreatic, vulvar and colonic carcinomas compared to normal tissues” (Brown 2012). More research on the topic is anticipated to be published in the very near future, however, studies of circulating galectin-3 thus far demonstrate an association with increased risk of cancer, and particularly with increased risk of metastasis. The reason for the apparent lack of consistency in effect between tissue expression levels and circulating levels in not known at this time. As reported above, the PREVEND study found increased all cause mortality associated with circulating galectin-3 (deBoer 2012); for

cancer specific mortality, there was a 41% increased risk among the highest quintile, HR 1.41 (1.28-1.56), unadjusted; though this relationship became insignificant after adjustment. Iurisci et al examined circulating galectin-3 in 99 cancer patients compared with 50 healthy subjects, finding that levels were significantly higher in cancer patients (p=0.014) (2000). Interestingly, when breast cancer patients only (n=35) were compared to normal subjects, there was no significant difference in galectin-3 levels, however, patients with metatstatic breast cancer had significantly higher galectin-3 compared to those with non-metastatic disease (p<0.032) (Iurisci 2000). Similar results were found for patients with gastrointestinal (GI) cancer (n=25), non-samll cell lung cancer (n=26). Among healthy subjects, median levels were 62ng/mL (range 20-313, 95th percentile 184.3 ng/mL), while maximum levels were found among patients with metastatic GI cancers: median 320ng/mL, range 20-950m/L) (Iurisci 2000). Saussez et al evaluated circulating galectin-3 in 102 patients with head and neck squamous cell carcinomas (HNSCCs) (2008). Galectin-3 levles were significantly higher in cancer patients compared to controls, median 3.2 and 2.39 ng/mL, respectively (p=0.03), and a threshold value of 4.3 ng/mL enabled discrimination between groups at 90% specificity and 36% sensitivity (Saussez 2008). Notably, galectin-3 levels were significantly higher among five patients with metastatic disease compared with the 97 with localized tumors. Further analysis showed a “weak, but nevertheless significant, prognostic value in terms of periods of survival for HNSCC patients” based on being over or under 4.3 ng/mL (Saussez 2008). Finally, levels of galectin-3 were found to decrease in response to treatment (chemo and/ or radiation and/ or surgery) of the primary tumor, compared to pre-treatment (p=0.001). Other members of the galectin family have been found to be elevated in patients with breast and colorectal cancer (Barrow 2011). More research is clearly needed to better evaluate the best use of this test in routine practice, however in the meantime galectin-3 holds immense potential as a cancer prognostic marker. In addition, human trials monitoring the effect on galcetin-3 levels in response to cancer treatment are currently lacking (Pieters 2006), however this presents an intriguing area for future research. It is also worth noting that there is little report in the medical literature of any pharmaceutical galectin-3 inhibitors; instead, the primary agent discussed in review articles thus far has been a natural agent, modified citrus pectin (Pieters 2006). Cardiovascular Disease

As mentioned above, the galectin-3 blood test has recently received FDA approval as a prognostic test for chronic heart failure (2012). Several large studies have shown that elevated levels of plasma galectin-3 are significantly associated with higher risk of death in ihpmagazine.com { September 2012 IHP | 53

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Feature Galectin-3 and MCP patients with acute decompensated and chronic heart failure (De Boer 2011a, DeBoer 2011b, Lok 2010, Shah 2010). In the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study, 1492 patients with ischaemic systolic heart failure were found to differentially respond to statin drugs according to their levels of galectin-3 (Gullestad 2010). Among patients who received rouvastatin, those whose plasma galectin-3 was below the median (≤19.0 ng/mL) had a 1) lower event rate [hazard ratio (HR) 0.65; 95% confidence interval (CI), 0.46-0.92; P= 0.014] and 2) lower total mortality (HR 0.70; 95% CI, 0.50-0.98; P= 0.038) compared with placebo. Notably, there was no benefit from rouvastatin in patients with higher levels of galectin-3. Another key study was the HF-ACTION study (Felker 2012). In this study, galectin-3 levels were analyzed in 895 patients with chronic heart failure caused by left ventricular systolic dysfunction. Higher galectin-3 levels were associated with measures of heart failure severity, including “higher New York Heart Association class, lower systolic blood pressure, higher creatinine, higher amino-terminal proB-type natriuretic peptide (NTproBNP), and lower maximal oxygen consumption” (Felker 2012). Cardiac fibrosis is gaining significant attention as an important risk factor in cardiac disease, in particular chronic heart failure (CHF) (deFilippi 2010), and galectin-3 plays a central role in mediating fibrosis (Liu 2009). At a site of injury/inflammation, galectin-3 is secreted into the extracellular space, activating resting fibroblasts into matrix-producing fibroblasts, thus promoting fibrosis (Liu 2009). Galectin-3 has also been found to beneficially impact other mechanisms associated with heart failure, including myofibroblast proliferation, inflammation and fibrogenesis, tissue repair, and ventricular and tissue remodeling (Liu 2009). Other Chronic Disease

Preclinical evidence suggests that elevated galectin-3 levels may be linked to an array of other chronic diseases, including autoimmune disease. Levels of circulating galectin-3 have been associated with active disease in patient’s with Behcet’s disease (Ozden 2011), juvenille arthritis (Ezzat 2011), and inflammatory bowel disease (Frolova 2009); while increased local levels have been documented in patients with liver disease (Honsawek 2011, Wanninger 2011) and asthma/ chronic obstructive pulmonary disease (Pilette 2007). Preliminary in vivo studies have found that achieving reductions in circulating galactin-3 levels delivers therapeutic benefit for the diseases in question: arthritis (Forsman 2011, Wang 2010A), inflammatory gastrointestinal conditions (Fowler 2006, Srikanta 2010), hepatic disease (Honsawek 2011, Iacobini 2011), and asthma (Zuberi 2004). FDA Approved Galectin-3 Serum Assay

The direct link between galectin-3 and numerous acute and chronic disease states gives this novel molecule an important

role in diagnostics and cardiovascular therapeutics, and this is becoming more widely accepted among the medical community, especially with the advent of a galectin-3 serum assay that can now accurately measure this “active” biomarker. This inexpensive blood test can also be used by practitioners to assess cancer risk and progression, cirrhosis of the liver, kidney fibrosis, and other inflammation/fibrosis related conditions for which early detection is critical for optimal clinical outcome. Approximately 20% of patients exhibit changes in their galectin-3 levels every three months, and current evidence supports checking glactin-3 levels twice annually in those with stable disease (McCullough 2011). Furthermore, according to McCullough “doubling in galectin-3 level over the course of 6 months, irrespective of baseline value, identifies a high-risk patient in whom additional care … could be warranted” (2011). (See Figure 1 below outlining the reference ranges for normal and elevated serum galectin-3 in relation to disease risk). Unlike the “bystander” biomarker C-reactive protein (CRP) that only indicates the presence of inflammation, elevated circulating galectin-3 is recognized as an “active” or “culprit” biomarker, since research shows that it actively mediates progression of numerous chronic illnesses. This means that galectin-3 is also a potentially important therapeutic target. Targeting Galectin-3 with Modified Citrus Pectin

Although there are strong associations between galectin-3 levels and heart failure prognosis, and an impressive body of preclinical research linking galectin-3 levels to a variety of diseases, at present there is a lack of human interventional data on therapies that can lower galectin-3. There is preliminary but promising data coming out of preclinical studies however, with respect to modified citrus pectin for galectin-3 inhibition (Kidd 1996, Nangia-Makker 2002B, Olano-Martin 2003). (See Figure 2 for recommended dosages). MCP is a form of citrus pectin that has been modified to a specific molecular weight and structure which allows it to be absorbed into the circulation and lends it its specific therapeutic properties. MCP is a complex polysaccharide fiber of repeating galacturonic acid groups with neutral sugar side chains. Regular (unmodified) citrus pectin derived from the pith of citrus fruit has a molecular weight of about 50-300 kiloDaltons, and a degree of esterification over 70%. These characteristics make regular pectin far too large to enter the blood stream. MCP can easily enter the circulation, however, when modified through a specific enzymatic process to achieve a molecular weight of 3-13 kiloDaltons, a degree of esterification under 10%, and its present specific structure (Eliaz 2006, Zhao 2008, Pieters 2006, Kidd 1996). Since galectin-3 is a beta-galactoside binding protein, and MCP is rich in beta-galactose, MCP has the ability to bind galectin-3, blocking galectin-3’s harmful effects (NangiaMakker 2002A).

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Feature Galectin-3 and MCP MCP is the only natural galectin-3 inhibitor demonstrated in published research that can modify the expression of galectin-3 through the natural galectin-binding affinity of its specific molecular structure, based on these authors’ literature review. For instance, a study in prostate cancer cells found that Gal-3 inhibition by antagonist GCS-100, a modified citrus pectin (MCP) product, increased cisplatin-induced apoptosis of PC3 cells (Wang 2010B). A mouse study found that MCP reduced colon cancer metastases to the liver (Liu 2008). In an animal model of an endothelial cancer, modified citrus pectin (MCP) caused a dose-dependent reduction in cancer cell survival by blocking galectin-3’s anti-apoptotic function (Johnson 2007). Furthermore, MCP sensitized cancer cells to doxorubicin such that the in vitro IC(50) of doxorubicin was reduced by 10.7-fold (Johnson 2007). Another study using breast and colon cancer xenografts models (transplanting cancer cell lines into animals and assessing growth) found that MCP was able to reduce growth, angiogenesis, and metastasis (NangiaMakker 2002B). Another study found that MCP was able to decrease the adhesion of cancer cells to matrix (Inohara 1994). One study found that MCP can induce activation of NK cells in a leukemia model (Ramachandran 2011). Yan found that MCP has antiproliferative effects in prostate cancer cells (2010). In addition, by inhibiting galectin-3’s anti-apoptotic function and enhancing apoptosis induced by cytotoxic drugs, MCP holds the potential to dramatically increase the efficacy of conventional chemotherapy (Najmeh 2012), as well as natural and botanical compounds. These synergistic effects have been demonstrated in preclinical studies (Johnson 2007, Wang 2010B) and warrant further investigation in human clinical trials. MCP: Beyond galectin-3

Two uncontrolled studies have examined the effect of MCP in cancer patients (Azemar 2007, Guess 2003). One study found a

significantly higher PSA doubling time while on MCP for one year, compared to baseline in seven of 10 subjects (Guess 2003), while Azemar found that MCP increased ratings of quality of life overall after eight weeks (2007). Anti cancer effects were variable, with 11 of 29 assessable patients rated as having stable disease after 8 weeks (2 cycles), while 15 had progressive disease. Side effects included mild GI upset (flatulence, dyspepsia) and pruritis. MCP has been shown to possess chelating activity in humans. As reported previously in IHP, MCP is a safe and potentially effective chelator of heavy metals and radioactive particles (Gallant 2010). MCP does not deplete essential minerals as other chelation therapies often do, and four uncontrolled trials show that patients reduced their toxic metal load by up to 76% (Eliaz 2006, Zhao 2008). MCP was dosed as 5g three times daily for three to six months. Conclusion

As this important body of research continues to expand, galectin-3 testing is expected to become an integral component of cardiovascular and other screening panels -- as routine as assessing cholesterol levels. There are a number of major laboratories that currently offer galectin-3 testing and with this simple assay, practitioners can gain more accurate insight into the risk, progression and advancement of numerous chronic inflammatory diseases. With the emergence of further research, galectin-3 is poised to become an important marker of cancer prognosis. Conversely, we can observe our patients experiencing significant clinical improvements, through firstline lifestyle modifications as well as through use of agents that can reduce inflammation and expression of galectin-3 - key among them, use of MCP. •

Galectin-3 Reference Ranges

Figure 1: Reference Ranges for Galectin-3 Serum Levels

Extreme Risk: > 17.8 ng/ml

Increased Risk: 14.0-17.8 ng/ml

Desired Levels: General: < 14.0 ng/ml Cancer: < 12.0 ng/ml CHF: < 12.0 ng/ml

• CHF Patients: Levels > 17.8 ng/ml are associated with extreme increase in risk of cardiac event in CHF patients. • Levels > 17.8 ng/ml pose extreme risk for cancer, CHF, and fibrosis in general population.

• Levels between 14.0-17.8 ng/ml are associated with increased risks for cancer, CHF, fibrosis, and overall mortality in general populations.

• For screening and prevention/general population, desired levels are 14 ng/ml or below. • For cancer and CHF patients, desired levels are below 12 ng/ml.

It’s important to recognize that while the mortality risk for patients with advanced progressive congestive heart failure increases significantly with galectin-3 levels over 17.8 ng/ ml, -- in the general population, any levels above 14 ng/ml already imposes significant increase in overall long term mortality risk. Approximately 20% of individuals have changes in their circulating Galectin-3 levels every 3 months that are associated with important changes in risk.

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Feature Galectin-3 and MCP Figure 2: Modified Citrus Pectin (MCP) Dosages per Condition and Corresponding Galectin-3 Serum Levels.

No Known Medical Conditions

Cardiovascular, Hepatisis, Inflammation/Fibrosis Conditions

• < 14 ng/ml: 5 g/day

• < 12 ng/ml: 5 g/day

• 14-17.8 ng/ml: 10 g/day

• 12-14 ng/ml: 10 g/day

• > 17.8 ng/ml: 15 g/day

• > 14 ng/ml: 15 g/day

Active Cancer/ Post Cancer Treatment

• Active Cancer: 15 g/day • > 17.8 ng/ml: 20-25 g/day

• Long term maintenance or at least 3 years post therapy: • < 12 ng/ml: 5 g/day

• 12-14 ng/ml: 10 g/day

• 14-17.8 ng/ml: 15 g/day

• > 17.8 ng/ml: 20-25 g/day

References Azemar M, Hildenbrand B, Haering B, Heim ME, Unger C. Clinical benefit in patients with advanced solid tumors treated with modified citrus pectin: a prospective pilot study. Clin Med: Oncol 2007, 1:73-80

Ezzat MH, El-Gammasy TM, Shaheen KY, Osman AO. Elevated production of galectin-3 is correlated with juvenile idiopathic arthritis disease activity, severity, and progression. Int J Rheum Dis. 2011 Oct;14(4):345-52.

Barrow H, Guo X, Wandall HH, Pedersen JW, Fu B, Zhao Q, Chen C, Rhodes JM, Yu LG. Serum galectin-2, -4, and -8 are greatly increased in colon and breast cancer patients and promote cancer cell adhesion to blood vascular endothelium. Clin Cancer Res. 2011 Nov 15;17(22):7035-46.

Felker GM, Fiuzat M, Shaw LK, Clare R, Whellan DJ, Bettari L, Shirolkar SC, Donahue M, Kitzman DW, Zannad F, Piña IL, O’Connor CM. Galectin-3 in ambulatory patients with heart failure: results from the HF-ACTION study. Circ Heart Fail. 2012 Jan 1;5(1):72-8.

BG Medicine Inc. BGM Galectin-3 (Galectin-3 Assay). Document: LAB-IVD-001 R07. March 2011.

FDA, Food and Drug Administration. Galectin-3 in vitro diagnostic assay. Updated 17 June 2012. URL http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/ classification.cfm?ID=627 Accessed 20 June 2012.

Brown ER, Doig T, Anderson N, Brenn T, Doherty V, Xu Y, Bartlett JM, Smyth JF, Melton DW. Association of galectin-3 expression with melanoma progression and prognosis. Eur J Cancer. 2012 Apr;48(6):865-74. Chiu CG, Strugnell SS, Griffith OL, Jones SJ, Gown AM, Walker B, Nabi IR, Wiseman SM. Diagnostic utility of galectin-3 in thyroid cancer. Am J Pathol. 2010 May;176(5):2067-81. deFilippi , CR, Felker, GM. Galectin-3 in Heart Failure—Linking Fibrosis, Remodeling, and Progression. U.S. Cardiology. 2010;7;1: 3–6. de Boer RA, van Veldhuisen DJ, Gansevoort RT, Muller Kobold AC, van Gilst WH, Hillege HL, Bakker SJ, van der Harst P. The fibrosis marker galectin-3 and outcome in the general population. J Intern Med. 2012 Jul;272(1):55-64. De Boer RA. Galectin-3 Levels & Mortality from All Causes in the General Population: PREVEND The Prevention of Renal and Vascular End-stage Disease (PREVEND) study results presented at the European Society of Cardiology (ESC) Congress (Aug) 2011a, in Paris, France. “Galectin-3, Cardiovascular Risk Factors and Outcome in the General Population.” De Boer RA, Lok DJ, Jaarsma T, van der Meer P, Voors AA, Hillege HL, et al. Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med. 2011b;43;1:60-8. De Boer RA, Voors AA, Muntendam P, van Gilst WH, van Veldhuisen DJ. Galectin-3: a novel mediator of heart failure development and progression. Eur J Heart Fail. 2009;11:811–7. 37. Weigert J, Neumeier M, Wanninger J, Bauer S, Farkas S, Scherer MN, et al. Serum galectin-3 is elevated in obesity and negatively correlates with glycosylated hemoglobin in type 2 diabetes. J Clin Endocrinol Metab. 2010;95;3:1404-11. Eliaz I, Hotchkiss A, Fishman M, Rode D. The effect of modified citrus pectin on urinary excretion of toxic elements. Phytother Res 2006, 20:859-864.

Forsman H, Islander U, Andréasson E, Andersson A, Onnheim K, Karlström A, et al. Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis. Arthritis Rheum. 2011;63;2:445-54. Fowler M, Thomas RJ, Atherton J, Roberts IS, High NJ. Galectin-3 binds to Helicobacter pylori O-antigen: it is upregulated and rapidly secreted by gastric epithelial cells in response to H. pylori adhesion. Cell Microbiol. 2006;8;1:44-54. Frol’ová L, Smetana K Jr, Borovská D, Kitanovicová A, Klimesová K, Janatková I, Malícková K, Lukás M, Drastich P, Benes Z, Tucková L, Manning JC, André S, Gabius HJ, Tlaskalová-Hogenová H. Detection of galectin-3 in patients with inflammatory bowel diseases: new serum marker of active forms of IBD? Inflamm Res. 2009 Aug;58(8):503-12. Gallant J, Rouchotas P. Modified citrus pectin (MCP): heavy metal chelator, possible cancer treatment. IHP Sept 2010: 58-61. Guess BW, Scholz MC, Strum SB, Lam RY, Johnson HJ, Jennrich RI. Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study. Prostate Cancer Prostatic Dis 2003;6:301-304. Gullestad L, Ueland T, Kjekshus J, Nymo SH, Hulthe J, Muntendam P, Adourian A, Böhm M, van Veldhuisen DJ, Komajda M, Cleland JG, Wikstrand J, McMurray JJ, Aukrust P; on behalf of the CORONA Study Group. Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Eur Heart J. 2012 Apr 26. Honjo Y, Nangia-Makker P, Inohara H, Raz A. Down-regulation of galectin-3 suppresses tumorigenicity of human breast carcinoma cells. Clin Cancer Res. 2001 Mar;7(3):661-8. Honsawek S, Chongsrisawat V, Praianantathavorn K, Theamboonlers A, Poovorawan Y. Elevation of serum galectin-3 and liver stiffness measured by transient elastography in biliary atresia. Eur J Pediatr Surg. 2011;21;4:250-4.

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Feature Galectin-3 and MCP Iacobini C, Menini S, Ricci C, Fantauzzi CB, Scipioni A, Salvi L, et al. Galectin-3 ablation protects mice from diet-induced NASH: a major scavenging role for galectin-3 in liver. J Hepatol. 201;54;5:975-83. Inohara H, Raz A. Effects of natural complex carbohydrate (citrus pectin) on murine melanoma cell properties related to galectin-3 functions. Glycoconj J. 1994 Dec;11(6):527-32. Iurisci I, Tinari N, Natoli C, Angelucci D, Cianchetti E, Iacobelli S. Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res. 2000 Apr;6(4):1389-93 Johnson KD, Glinskii OV, Mossine VV, Turk JR, Mawhinney TP, Anthony DC, Henry CJ, Huxley VH, Glinsky GV, Pienta KJ, Raz A, Glinsky VV. Galectin-3 as a potential therapeutic target in tumors arising from malignant endothelia. Neoplasia. 2007 Aug;9(8):662-70.

Ramachandran C, Wilk BJ, Hotchkiss A, Chau H, Eliaz, I Melnick SJ. Activation of human T-helper/inducer cell, T-cytotoxic cell, B-cell, and natural killer (NK)-cells and induction of natural killer cell activity against K562 chronic myeloid leukemia cells with modified citrus pectin. BMC Complementary and Alternative Medicine. 2011;11:59. Saleh HA, Feng J, Tabassum F, Al-Zohaili O, Husain M, Giorgadze T. Differential expression of galectin-3, CK19, HBME1, and Ret oncoprotein in the diagnosis of thyroid neoplasms by fine needle aspiration biopsy. Cytojournal. 2009 Sep 18;6:18. Saussez S, Lorfevre F, Lequeux T, Laurent G, Chantrain G, Vertongen F, Toubeau G, Decaestecker C, Kiss R. The determination of the levels of circulating galectin-1 and -3 in HNSCC patients could be used to monitor tumor progression and/or responses to therapy. Oral Oncol. 2008 Jan;44(1):86-93.

Kidd P. A new approach to metastasis cancer prevention: modified citrus pectin (MCP), a unique pectin that blocks cell surface lectins. Altern Med Rev 1996;1:4-10.

Shah RV, Chen-Tournoux AA, Picard MH, van Kimmenade RR, Januzzi JL. Galectin-3, cardiac structure and function, and long-term mortality in patients with acutely decompensated heart failure. Eur J Heart Fail. 2010;12;8:826-32.

Lin YH, Lin LY, Wu YW, Chien KL, Lee CM, Hsu RB, Chao CL, Wang SS, Hsein YC, Liao LC, Ho YL, Chen MF. The relationship between serum galectin-3 and serum markers of cardiac extracellular matrix turnover in heart failure patients. Clin Chim Acta. 2009 Nov;409(1-2):96-9.

Srikanta BM, Sathisha UV, Dharmesh SM. Alterations of matrix metalloproteinases, gastric mucin and prostaglandin E(2) levels by pectic polysaccharide of swallow root (Decalepis hamiltonii) during ulcer healing. Biochimie. 2010;92;2:194-203.

Liu HY, Huang ZL, Yang GH, Lu WQ, Yu NR. Inhibitory effect of modified citrus pectin on liver metastases in a mouse colon cancer model. World J Gastroenterol 2008, 14:7386-7391.

Tinari N, Kuwabara I, Huflejt ME, Shen PF, Iacobelli S, Liu FT. Glycoprotein 90K/ MAC-2BP interacts with galectin-1 and mediates galectin-1-induced cell aggregation. Int J Cancer. 2001 Jan 15;91(2):167-72.

Liu YH, D’Ambrosio M, Liao TD, Peng H, Rhaleb NE, Sharma U, André S, Gabius HJ, Carretero OA. N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin. Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H404-12.

Wang YG, Kim SJ, Baek JH, Lee HW, Jeong SY, Chun KH. Galectin-3 Increases the Motility of Mouse Melanoma Cells by Regulating MMP-1 Expression. Exp Mol Med. 2012 Mar 21. [Epub ahead of print]

Lok DJ, Van Der Meer P, de la Porte PW, Lipsic E, Van Wijngaarden J, Hillege HL, et al. Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study. Clin Res Cardiol. 2010;99;5:323-8. McCullough PA, Olobatoke A, Vanhecke TE. Galectin-3: a novel blood test for the evaluation and management of patients with heart failure. Rev Cardiovasc Med. 2011;12(4):200-10. Najmeh T, Houri S, Parvin M, Firouzeh B, Arash HN, Abdolfattah S, Ebrahim H. Combination effect of PectaSol and Doxorubicin on viability, cell cycle arrest and apoptosis in DU-145 and LNCaP prostate cancer cell lines. Cell Biology International 2012, Immediate Publication, doi:10.1042/CBI20110309. Nangia-Makker P, Conklin J, Hogan V, Raz A. Carbohydrate-binding proteins in cancer, and their ligands as therapeutic agents. Trends Mol Med 2002; 8:187-192.A Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, et al. Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. J Natl Cancer Ins 2002;94:1854-1862.B Nangia-Makker P, Honjo Y, Sarvis R, Akahani S, Hogan V, Pienta KJ, et al. Galectin-3 induces endothelial cell morphogenesis and angiogensis. Am J Pathol 2000, 156:899-909. Olano-Martin E, Rimbach GH, Gibson GR, Rastall RA. Pectin and pecticoligosaccharides induce apoptosis in in vitro human colonic adenocarcinoma cells. Anticancer Res 2003;23:341 346. Özden MG, Caycı YT, Tekin H, Çoban AY, Aydın F, Sentürk N, Bek Y, Cantürk T, Turanlı AY. Serum galectin-3 levels in patients with Behçet’s disease: association with disease activity over a long-term follow-up. J Eur Acad Dermatol Venereol. 2011 Oct;25(10):1168-73. Peng W, Wang HY, Miyahara Y, Peng G, Wang RF. Tumor-associated galectin-3 modulates the function of tumor-reactive T cells. Cancer Res. 2008 Sep 1;68(17):7228-36. Pienta KJ, Naik H, Akhtar A, Yamazaki K, Replogle TS, Lehr J, et al. Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst 1995;87:348-353.

Wang CR, Shiau AL, Chen SY, Cheng ZS, Li YT, Lee CH, et al. Intra-articular lentivirus-mediated delivery of galectin-3 shRNA and galectin-1 gene ameliorates collagen-induced arthritis. Gene Ther. 2010;17;10:1225-33.A Wang Y, Nangia-Makker P, Balan V, Hogan V, Raz A. Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment. Cell Death Dis. 2010 Nov 18;1:e101.B Wang Y, Nangia-Makker P, Tait L, Balan V, Hogan V, Pienta KJ, et al. Regulation of prostate cancer progression by galectin-3. Am J Pathol. 2009;174;4:1515-23. Wanninger J, Weigert J, Wiest R, Bauer S, Karrasch T, Farkas S, Scherer MN, Walter R, Weiss TS, Hellerbrand C, Neumeier M, Schäffler A, Buechler C. Systemic and hepatic vein galectin-3 are increased in patients with alcoholic liver cirrhosis and negatively correlate with liver function. Cytokine. 2011 Sep;55(3):435-40. Weigert J, Neumeier M, Wanninger J, Bauer S, Farkas S, Scherer MN, et al. Serum galectin-3 is elevated in obesity and negatively correlates with glycosylated hemoglobin in type 2 diabetes. J Clin Endocrinol Metab. 2010;95;3:1404-11. Yan J, Katz A. PectaSol-C modified citrus pectin induces apoptosis and inhibition of proliferation in human and mouse androgen-dependent and- independent prostate cancer cells. Integr Cancer Ther 2010;9:197-203. Yu LG, Andrews N, Zhao Q, McKean D, Williams JF, Connor LJ, et al. Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancerassociated MUC1 causes increased cancer cell endothelial adhesion. J Biol Chem. 2007;5;282(1):773-81. Yu LG. Circulating galectin-3 in the bloodstream: An emerging promoter of cancer metastasis. World J Gastrointest Oncol. 2010 Apr 15;2(4):177-80. Zaia Povegliano L, Oshima CT, de Oliveira Lima F, Andrade Scherholz PL, Manoukian Forones N. Immunoexpression of galectin-3 in colorectal cancer and its relationship with survival. J Gastrointest Cancer. 2011 Dec;42(4):217-21. Zhao ZY, Liang L, Fan X, Yu Z, Hotchkiss AT, Wilk BJ, et al. The role of modified citrus pectin as an effective chelator of lead in children hospitalized with toxic lead levels. Altern Ther Health Med 2008, 14:34-38.

Pieters RJ. Inhibition and detection of galectins. Chembiochem. 2006 May;7(5):721-8.

Zhao Q, Guo X, Nash GB, Stone PC, Hilkens J, Rhodes JM, et al. Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. Cancer Res. 2009;69;17:6799-806.

Pilette C, Colinet B, Kiss R, André S, Kaltner H, Gabius HJ, Delos M, Vaerman JP, Decramer M, Sibille Y. Increased galectin-3 expression and intra-epithelial neutrophils in small airways in severe COPD. Eur Respir J. 2007 May;29(5):914-22.

Zuberi RI, Hsu DK, Kalayci O, Chen HY, Sheldon HK, Yu L, et al. Critical role for galectin-3 in airway inflammation and bronchial hyperresponsiveness in a murine model of asthma. Am J Pathol. 2004;165;6:2045-53.

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ITI Cortisol Manager ad for ETCanada.indd 1 IHPAPR2012_XXXX_ADVERTISER_Product_FP.indd 1

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Cortisol Manager Technical Data TM

DESCRIPTION: Cortisol Manager dietary supplement has been shown to reduce cortisol levels in human subjects.* The supplement combines an effective dose of phosphatidylserine with documented stress-reducing ingredients and cortisol-balancing botanicals to help relieve occasional sleeplessness at night while also providing all-day stress reduction.* Cortisol Manager promotes relaxation and supports a healthy sleep cycle without the use of habit forming ingredients.* This safe and natural formula increases the ability to fall asleep, stay asleep, and will not cause morning grogginess.* Cortisol Manager features: · Patented ingredients – Sensoril® brand Ashwagandha, US Patent 6,713,092 – Suntheanine® brand L-Theanine, US Patent Nos. 6,589,566 & 6,297,280 · Clinically effective level of phosphatidylserine20 · Fast acting formulation: Reduced cortisol levels after only 24 hours* †† · Safe and effective: No morning grogginess and no habit-forming ingredients* ††

When exposed to internal or external stress, the brain sends a message to the adrenal glands to increase cortisol secretion. The body responds by providing a surge in energy, increasing mental alertness, and raising blood pressure, thereby preparing the body for the “fight-or-flight” response.2 While this response provides an effective mechanism for coping with an acute stressor, increased or prolonged exposure to stress can lead to disruptions to normal cortisol levels. Disruptions in cortisol balance, in turn, can lead to changes in body chemistry, altering the balance of hormones and affecting the systems of the body. Research has shown that maintaining healthy cortisol levels can reduce stress, relieve occasional sleeplessness and fatigue, and optimize immune system and neurological function.*3,4,5 HOW IT WORKS: Cortisol Manager Study The effectiveness of Cortisol Manager dietary supplement was examined in a preliminary, open-label study involving 21 volunteers.6 The combination was taken each night, and results were assessed using salivary cortisol measurements as well as self-assessment questionnaires. According to the Zung Anxiety Self-Assessment, Cortisol Manager produced a statistically significant reduction in stress over the course of the 28-day study.* After 2 weeks scores reduced from from a baseline of 39.8 to 35.5 (p=0.04); after 4 weeks from 39.8 to 32.7 (p=0.005).5 Additionally, the participant survey revealed that:5 · 71% of participants felt more relaxed during the day* · 71% experienced improved sleep* · 64% achieved deeper sleep, while 57% felt they fell asleep more easily* · 57% felt their stress level was reduced* · 57% felt they were better able to handle stressful situations* CONCLUSION: Cortisol Manager dietary supplement has been shown to promote stress-relief and quality sleep by balancing levels of cortisol, the stress hormone.* This safe and natural formulation promotes relaxation with no habit-forming ingredients and no morning grogginess.* Cortisol Manager supports healthy cortisol levels, which in turn can help reduce stress, relieve occasional sleeplessness and fatigue, and optimize immune system and neurological function.* References:

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

Hillier SG. Diamonds are forever: The cortisol legacy. J Endocrinol 2007;195:1-6. Papadimitriou A, Priftis KN. Regulation of the hypothalamic-pituitary-adrenal axis. Neuroimmunomodulation 2009;16(5):265-71. Epub 2009 Jun 29. Melamed S, Ugarten U, Shirom A, Kahana L, Lerman Y, Froom P. Chronic burnout, somatic arousal and elevated salivary cortisol levels. J Psychosom Res. 1999 Jun;46(6):591-8. Capaldi Ii VF, Handwerger K, Richardson E, Stroud LR. Associations between sleep and cortisol responses to stress in children and adolescents: a pilot study. Behav Sleep Med. 2005;3(4):177-92. Prinz PN, Bailey SL, Woods DL. Sleep impairments in healthy seniors: roles of stress, cortisol, and interleukin-1 beta. Chronobiol Int. 2000 May;17(3):391-404. An open label pilot study of the safety and effectiveness of a cortisol-reducing combination in healthy adults. 2006. Unpublished. Archana R, Namasiviayam A. Antistressor effect of withania somnifera. J Ethnopharm. 1999;64:91-93. Bhattacharya A. Anti-oxidant effect of Withania somnifera glycowithanolides in chronic footshock stress-induced perturbations of oxidative free radical scavenging enzymes and lipid peroxidation in rat frontal cortex and striatum. J Ethnopharmacol. 2001 Jan;74(1):1-6. Bhattacharya SK. Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress. Pharmacol Biochem Behav. 2003 Jun;75(3):547-55. Ziauddin M. Studies on the immunomodulatory effects of Ashwagandha. J Ethnopharmacol. 1996;50:69-76. Ito K. Effect of l-theanine on the release of alpha-brain waves in human volunteers. Nippon Nogeikagaku Kaishi. 1998;72:153-157. Juneja LR, Chu DC, Okubo T, Nagato Y, Yokogoshi H. L-theanine - a unique amino acid of green tea and it’s relaxation effect in humans. Trends in Food Science & Technology. 1999;10:199-204. Yokogoshi H, Mochizuki M, Saitoh K. Theanine-induced reduction of brain serotonin concentration in rats. Biosci Biotechnol Biochem. 1998 Apr;62(4):816-7. Kuribara H. The anxiolytic effect of two oriental herbal drugs in Japan attributed to honokiol from magnolia bark. J Pharm Pharmacol. 2000 Nov;52(11):1425-9. Kuribara H, Stavinoha WB, Maruyama Y. Honokiol, a putative anxiolytic agent extracted from magnolia bark, has no diazepam-like side-effects in mice. J Pharm Pharmacol. 1999 Jan;51(1):97-103. Kuribara H, Stavinoha W, Maruyama Y. Behavioural pharmacological characteristics of honokiol, an anxiolytic agent present in extracts of Magnolia bark, evaluated by an elevated plus-maze test in mice. J Pharm Pharmacol 1998;50:819-26. Kalman D, Feldman S, Feldman, et al. Effect of a proprietary Magnolia and Phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial. Nutrition Journal 2008;7:11:1-6. Pan Y, Wang FM, Qiang LQ, Zhang DM, Kong LD. Icariin attenuates chronic mild stress-induced dysregulation of the LHPA stress circuit in rats. Psychoneuroendocrinology. 2010 Feb;35(2):272-83. Epub 2009 Jul 23. Hellhammer J. Effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) on the endocrine and psychological responses to mental stress. Stress. 2004 Jun;7(2):119-26. Monteleone P. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans. Neuroendocrinology. 1990 Sep;52(3):243-8. Benton D. The influence of phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. Nutr Neurosci. 2001;4(3):169-78.

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Benefit

Ingredient Ashwagandha (Withania somnifera)

Several studies have shown that ashwagandha enhances energy levels and stress resistance.*7-8 The herb reduces levels of corticosterone, a stress hormone closely related to cortisol.*9 Research has also documented ashwagandha’s moodenhancing effects.*9 In addition, ashwagandha helps promote healthy immune system function by increasing red and white blood cell counts and platelet counts*10

L-Theanine

L-theanine is an amino acid known to promote relaxation and stress reduction by inducing muscle relaxation, reducing occasional anxiety, and maintaining blood pressure already within normal limits.* L-theanine increases the activity of alpha brain waves— the type associated with increased feelings of relaxation.*11 It also increases the concentration of certain neurotransmitters, including serotonin and dopamine, which promote muscle relaxation and provide relief for occasional sleeplessness.*12,13

Magnolia (Magnolia officinalis)

Magnolol and honokiol extracts, derived from magnolia, have promoted relaxations in animal studies.*14–16 In a randomized, placebo controlled study supplementation with a combination of extracts of magnolia and phellodendron resulted in a decrease in transitory anxiety.17

In a preliminary open label study involving 21 volunteers.

BACKGROUND: The Cortisol Connection Cortisol, often referred to as the “stress hormone”, is produced by the adrenal cortex in response to stress. Cortisol is therefore intricately involved in many physiological functions, including the regulation of healthy blood sugar metabolism, maintenance of healthy blood pressure levels already within normal limits, establishment of healthy immune system function, and promotion of the body’s natural anti-inflammatory response.1

1. 2.

The following chart summarizes the benefits of each of the ingredients in Cortisol Manager

Epimedium Flavonoids in Epimedium koreanum has been shown in animals to (Epimedium koreanum) support a healthy response to stress by the hypothalamic-pituitaryadrenal axis.*18 Phosphatidylserine

Extracted from soy lecithin, phosphatidylserine has been clinically shown to significantly reduce serum adrenocorticotropin (ACTH) and cortisol levels and salivary cortisol levels following mental stress.*19 It also reduces plasma levels of epinephrine, norepinephrine, ACTH and cortisol after exposure to physical stress.*20 This phospholipid is a critical structural component of neuronal cells and helps promote a positive mood, by decreasing feelings of stress.*21

Supplement Facts Serving Size: 1 tablet Amount per tablet Sodium 5 mg Stress-Reducing Proprietary Blend* 250 mg ashwagandha (Withania somnifera) (Sensoril® brand) root and leaf extract and L-theanine (Suntheanine® brand) Cortisol-Reducing Proprietary Blend* 225 mg magnolia (Magnolia officinalis) bark extract standardized to contain 2% honokiol and 1% magnolol and epimedium (Epimedium koreanum) aerial part extract Phosphatidylserine 50 mg

%DV*** <1%*** **

**

**

***Percent Daily Values (DV) are based on a 2,000 calorie diet. **Daily Value not established.

Other ingredients: dextrose, cellulose, modified cellulose gum, modified cellulose, magnesium stearate, stearic acid, titanium dioxide color, soy lecithin, and carnauba wax. Warnings: If pregnant, nursing, taking prescription drugs, or if you suffer with chronic insomnia, consult your healthcare practitioner prior to use. Keep out of reach of children. Contains no sugar, yeast, wheat, gluten, corn, dairy products, artificial flavoring, preservatives, or ingredients of animal origin. All colors used are from natural sources. Sensoril® is protected under U.S. Patent 6,713,092 and is a trademark of Natreon, Inc. Suntheanine®, a patented form of L-Theanine, is a trademark of Taiyo International, Inc.

Cortisol Manager 30ct Integrative Therapeutics - 70453

Cortisol Manager 90ct Integrative Therapeutics – 70459

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Feature CoQ10

and

CoQ10

Heart Failure A review of evidence â&#x20AC;˘ William R Ware, PhD

William R Ware, PhD Emeritus Professor, Faculty of Science University of Western Ontario London, Ontario, Canada N6G1R3 warer@rogers.com

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Feature CoQ10

Heart failure is a significant contributor to mortality and morbidity in the U.S. and the developed world. It is typical for heart failure patients to have low levels of coenzyme Q10, which is an integral cofactor for the mitochondrial respiratory chain involved in generating adenosine triphosphate, the major cellular energy source. Coenzyme Q10 is also a potent antioxidant and membranes stabilizer. Since its discovery in 1957, on the basis of a number of studies it has been used therapeutically for heart failure, but this work is largely ignored. Lack of bioavailability is also an issue, but this has been addressed and highly bioavailable products developed. This research is also ignored. It is well known that statin therapy dramatically reduces coenzyme Q10 levels and before the first statin was introduced, inclusion of this coenzyme was considered and rejected. Since coenzyme Q10 is not a prescription drug, most mainstream medical practitioners do not recognize it as a useful supplement or therapeutic agent. Nevertheless, in the context of heart failure, there is evidence that if the blood levels of this cofactor are considerably elevated through supplementation with highly bioavailable products, the impact on the grade of heart failure and the quality of life is highly significant. Beneficial results have been observed when this cofactor is used to treat the side effects of statin treatment and in particular myopathy. The association between dosing levels and outcomes is discussed. There are integrative cardiologists who claim that based on years of clinical experience, they could not effectively practice without this supplement.

C

oenzyme Q10 (Q10), also known as ubiquinone, was discovered in 1957 and there followed a considerable amount of research with animals, humans and cell cultures. Many international symposia were held with hard cover proceedings that gather dust on library shelves. Q10 is found in all human cells and is a potent antioxidant, cell membrane stabilizer, and an essential enzyme in the mitochondrial respiratory chain where it is involved in the generation of ATP(Greenberg 1990, Sinatra 2005) Low Q10 has been associated with a number of disorders and its therapeutic use recently reviewed (Villalba 2010). Low levels of Q10 play a role in heart failure, angina and hypertension (Tran 2001). This is important since heart failure contributes significantly to mortality and morbidity in the U.S. and other developed countries. Depending on symptom severity, heart dysfunction, and other factors, in Canada heart failure can be associated with an annual mortality of between 5% and 50% (Arnold 2006). The importance of Q10 for heart function is illustrated by five clinical trials cited by in a recent review with significant improvements found in endpoints of ejection fraction, pulmonary artery pressure, stroke volume, cardiac output, and functional capacity and quality of life associated with supplementation (Lee 2011). Food is only a minor source of this cofactor. The pathway that leads to the endogenous synthesis of Q10 is also the pathway to cholesterol. Drugs called HMG-CoA reductase inhibitors, better known as statins, inhibit this pathway with the resultant large decrease in both cholesterol and Q10. Concern over the impact

of the widespread use of statins in this context is mounting as the pressure intensifies to have everyone on statins, from toddlers to the frail elderly. Q10 is not viewed with enthusiasm by mainstream medicine, although a systematic review published in 2003 (Rosenfeldt 2003) noted non-significant trends toward increased ejection fraction and reduced mortality associated with Q10 therapy and another study published in 2006 found Q10 enhanced systolic function with HF (Sander 2006). It is not a prescription drug and in the context of heart failure, recent studies can be cited which suggest it is ineffective. As will be discussed below, this conclusion is contrary to a considerable body of older literature and the experience of integrative cardiologists (Sinatra 2005, Sinatra 2009a, Sinatra 2009b). Instead, several anti-hypertension drugs, digoxin and aldosterone receptor antagonists are the standard of practice along with devices that help the heart beat and contract properly. Heart transplants and end-of-life care are discussed in guidelines. Mainstream medicine would no doubt point to the following two recent studies as evidence that Q10 is not an important issue in heart failure. In 2011 a study was published (Fumagalli 2011) which reported on a small randomized placebo controlled trial involving 67 patients with heart failure (HF) randomized to receive for eight weeks either a placebo plus the usual care or a combination of a Q10 preparation, viewed as of enhanced bioavailability, and creatine plus the usual care. The Q10 dose was 34 mg/day, a

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Feature CoQ10

rather low dose. Outcomes were exercise tolerance, peak oxygen consumption from an exercise test and what was called a sickness impact profile. Small improvements were found, mostly of no statistical significance or of small and questionable clinical significance. Q10 blood levels were not reported in spite of the novel nature of the Q10 source. In 2010 a sub-study of the CORONA study examined the impact of rosuvastatin (Crestor) and Q10 levels on heart failure (McMurray 2010). This was an industry-sponsored study with the majority of the investigators having close financial ties to the sponsor. The average age of subjects was about 72. Serum Q10 was measured but the only intervention was with rosuvastatin. All the subjects had significant to severe heart failure. It was observed that patients with lower Q10 levels at baseline were older and had more advanced heart failure (HF). The statin reduced the mean Q10 levels in each of three tertiles of Q10 from 0.49 to 0.35, 0.75 to 0.46 and 1.10 to 0.53 µg/ml respectively. Mortality was significantly higher among patients in the lowest vs. highest Q10 tertile, but the difference was not significant on multivariate analysis and Q10 was not found upon extensive statistical manipulation to be an independent predictor of either worsening or fatal HF, nor did statin treatment result in worse outcomes. The message: concern over statins, Q10 and HF is not justified. The Q10 levels need to be put in perspective. The range of Q10 serum levels in self-reported normal, healthy individuals is quite large. In one study of healthy individuals, the distribution of blood Q10 levels was found to be <0.4 µg/L, 2%; 0.4-1.6 µg/mL, 81%; and > 1.6 µg/mL 17% (Lu 2007). The age range was infant to 94 years. There was no gender dependence.

A study published in 2008 does not support the view of Q10 as unimportant. This study (Molyneux 2008) examined the relationship between Q10 blood levels and survival among patients with chronic heart failure (CHF). Two hundred thirty six patients, mean age 77, admitted to hospital with HF were followed for a mean of 2.7 years. The mean Q10 blood level was 0.58 µg/mL. They found a significant difference in survival over the period studied (about 4 years) when a cut-point of 0.63 µg/ mL was used (survival of about 65% vs. 45%). Patients below this cut point had a range of Q10 blood levels of 0.11 to 0.63 whereas those above had a range of 0.63 to 1.50 µg/mL. Important perspective concerning Q10 and HF can be gained by considering the views of Dr. Peter H. Langsjoen, a cardiologist who has been involved on Q10 research since 1985 and has published extensively in this area. He was recently interviewed and the transcript is available on the internet (Langsjoen 2011). He points out that early on, it was believed that if HF patients typically had Q10 levels around 0.5 µg/mL and normal individuals had levels of around 1µg/mL, then when one was trying to treat HF, the use of supplementation to bring the value up to about 1µg/mL was indicated. When this was tried, not much improvement was seen. Further research revealed that there was a significant blood level threshold at about 2.5 µg/ml above which HF patients appeared to have some benefit and severe HF patients were helped by supplementation once the level achieved was greater than 3.5 µg/mL. This was pointed out in a 2008 paper in Biofactors (Langsjoen 2008). Even in an earlier paper (Langsjoen 1999) in the same journal the threshold of > 3.5 µg/mL blood level was discussed and justified. The results of years of research are clearly being ignored.

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Feature CoQ10 In the study by Fumagalli et al, Q10 levels were not measured and the dose was very low. It was thus not surprising that small or non-significant results were obtained. The authors were aware of the 1999 paper which recommended and justified therapeutic levels > 3.5 µg/mL for HF patients. But in this study with a novel source of Q10, the levels achieved were not reported and were probably too low. In the study by McMurry et al the range of Q10 serum levels was too low to be of significance in the context of serious HF, especially in multivariate analysis looking for an independent effect and the lowering of Q10 caused by the statin was probably too small to be of significance in this cohort of patients, many with a need for very high levels. The most interesting study and one which should not have been ignored when the above studies were designed appears to be that of Langsjoen and Langsjoen (Langsjoen 2008). They report on seven consecutive patients who had worsening HF (NYHA Class IV) who were on maximal medical therapy and taking large doses of the ubiquinone form of Q10 which was not, from their point of view concerning the importance of the >3.5 µg/ mL threshold, adequately elevating blood levels in the context of severe HF. Some patients were taking 900 mg/day and still well below the threshold. This could have been written up and presented as a negative study demonstrating that without a doubt Q10 supplementation did not work at all for severe HF. Not so. Patients were switched from an average dose of ubiquinone of 450 mg/day to the ubiquinol form at an average dose of 580 mg/day with a change in average blood Q10 from 1.6 to 6.5 µg/mL. The table below provides the detailed results of ejection fraction (EF) and NYHA class change indicating the decline in the severity of HF after ubiquinol was used rather then ubiquinone. Ubiquinol is the reduced form and the most prevalent form in humans.

The HF class changes listed above are impressive and obviously of huge significance to most of the patients involved. Note the high baseline Q10 levels, which are at the upper extreme of the modern laboratory reference range, and yet the individuals had Class IV HF which was then strongly impacted by changing the supplement to achieve greater bioavailability and thus achieving much higher Q10 levels. Note also the individual variations. This table in fact nicely states the case for treating HF patients to a high target even if their Q10 levels are already high by traditional standards. Four out of seven patients regressed to NYHA I or II. These results suggest the urgent need for a much larger study, but if it has been done it does not appear to have been published. Even before Langsjoen and Langsjoen carried out their case study, other studies confirmed that while ubiquinone bioavailability was increased when administered in a capsule where the chemical was dispersed in an oil, much higher levels of blood Q10 could be achieved by replacing the oxidized form with ubiquinol (Bhagavan 2007, Hosoe 2007). In fact, Hosoe et al found that supplementation with 300 mg ubiquinol in oil over a period of 28 days raised the Q10 level on average from 0.66 to 7.28 µg/mL. This level was much higher than that achieved with a single dose (2.56 µg/ mL) and thus there is a cumulative effect which must be taken into account in evaluating single dose studies. They found these higher serum levels safe, consistent with a recent safety study (Hidaka 2008). They used Kaneak QH, a Japanese ubiquinol preparation which is available today over the internet from several supplement suppliers. Another comparable preparation is LiQ-NOL CoQ10 which also uses the ubiquinol from Kaneka.

Case #

Blood Q10 Change (µg/mL)

EF % Change

NYHA Class HF Change*

Treatment Duration (Mo)

1

2.0 -> 9.3

15 -> 60

IV -> I

20

2

0.9 -> 2.6

35 -> 50

IV -> III

3

3

1.5 -> 8.9

10 -> 10

IV -> III

12

4

1.7 -> 5.1

35 -> 60

IV -> I

10

5

1.5 -> 5.6

30 -> 55

IV -> II

9

6

2.0 -> 5.7

10 -> 20

IV -> III

10

7

1.6 -> 6.5

22 -> 39

IV -> II

10

*Class I HF is asymptomatic. Class II involves mild shortness of breath and/or angina with little limitation of ordinary activity. Class III involves significant limitation of activity due to symptoms, even to the point of problems walking short distances. Class IV is sufficiently severe as to apply mostly to bed ridden patients.

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Feature CoQ10 It has been reported that serious side effects accompany statin use, and that these can be treated and reduced by Q10 supplementation. For example, a small randomized controlled trial reported in 2007 (Caso 2007) was conducted with patients suffering from myopathic symptoms thought to be associated with statin treatment. Supplementation with Q10 (100 mg/day soft-gel) while continuing statin treatment resulted after 30 days in 40% reduction in pain and 38% pain associated interference with daily activities, whereas there were no significant changes in these endpoints in the control group. Similar results were reported in 2005 for patients treated with Q10 after discontinuing statin therapy because of a variety of side effects attributed to this class of drug (Langsjoen 2005). A more comprehensive alternative approach to heart failure and preventing and treating heart disease in general involves not only Q10 but L-Carnatine and D-Ribose, an approach called Metabolic Cardiology, developed and promoted by the cardiologist Stephen Sinatra on the basis of extensive anecdotal clinical evidence (Sinatra 2005, Sinatra 2009a, Sinatra 2009b). In this context, other micronutrients studied which also appear REFERENCES Arnold,P., Liu,P., Demers,C., Dorian,P. and Giannetti,N. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006. Can J Cardiol 2006; 22(1): 23-45. Bhagavan,H.N. and Chopra,R.K. Plasma coenzyme Q10 response to oral ingestion of coenzyme Q10 formulations. Mitochondrion 2007; 7 Suppl: S78-S88. Caso,G., Kelly,P., McNurlan,M.A. and Lawson,W.E. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol 2007; 99(10): 1409-1412. Fumagalli,S., Fattirolli,F., Guarducci,L., Cellai,T., Baldasseroni,S., Tarantini,F., Di,B.M., Masotti,G. and Marchionni,N. Coenzyme Q10 terclatrate and creatine in chronic heart failure: a randomized, placebo-controlled, double-blind study. Clin Cardiol 2011; 34(4): 211-217. Greenberg,S. and Frishman,W.H. Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol 1990; 30(7): 596-608. Hidaka,T., Fujii,K., Funahashi,I., Fukutomi,N. and Hosoe,K. Safety assessment of coenzyme Q10 (CoQ10). Biofactors 2008; 32(1-4): 199-208. Hosoe,K., Kitano,M., Kishida,H., Kubo,H., Fujii,K. and Kitahara,M. Study on safety and bioavailability of ubiquinol (Kaneka QH) after single and 4-week multiple oral administration to healthy volunteers. Regul Toxicol Pharmacol 2007; 47(1): 19-28.

to provide benefit include omega-3 fatty acids, the B-family of vitamins, and vitamin D (Lee 2011). A reasonable conclusion appears to be that HF patients are significantly helped by Q10 supplementation, but the dose must be individualized and blood levels measured to test the impact of the intervention. One can not generalize on the oral dose because of the wide variation in both commercial preparations and individual absorption. Thus monitoring and treating to a target serum levels is essential. As pointed out by Langsjoen in the interview cited above, it took some time before it was demonstrated that using doses of 100 mg/day of ubiquinone was not very effective in many cases of HF and early studies found in many cases only small effects. In his interview, Langsjoen is emphatic that there are no side effects or drug interactions to high doses of Q10. He does however point out that Q10 therapy for HF, once heart function improves, reduces the need for some of the “standard treatment” drugs and in particular blood pressure medications. In fact, Q10 had been used to treat hypertension (Wyman 2010). • Lee,J.H., Jarreau,T., Prasad,A., Lavie,C., O’Keefe,J. and Ventura,H. Nutritional assessment in heart failure patients. Congest. Heart Fail. 2011; 17(4): 199-203. Lu,J. and Frank,E.L. Measurement of coenzyme Q10 in clinical practice. Clin Chim. Acta 2007; 384(1-2): 180-181. McMurray,J.J., Dunselman,P., Wedel,H., Cleland,J.G., Lindberg,M., Hjalmarson,A., Kjekshus,J., Waagstein,F., Apetrei,E., Barrios,V., Bohm,M., Kamensky,G., Komajda,M., Mareev,V. and Wikstrand,J. Coenzyme Q10, rosuvastatin, and clinical outcomes in heart failure: a pre-specified substudy of CORONA (controlled rosuvastatin multinational study in heart failure). J Am Coll Cardiol 2010; 56(15): 1196-1204. Molyneux,S.L., Florkowski,C.M., George,P.M., Pilbrow,A.P., Frampton,C.M., Lever,M. and Richards,A.M. Coenzyme Q10: an independent predictor of mortality in chronic heart failure. J Am Coll Cardiol 2008; 52(18): 1435-1441. Rosenfeldt,F., Hilton,D., Pepe,S. and Krum,H. Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart failure. Biofactors 2003; 18(1-4): 91-100. Sander,S., Coleman,C.I., Patel,A.A., Kluger,J. and White,C.M. The impact of coenzyme Q10 on systolic function in patients with chronic heart failure. J Card Fail. 2006; 12(6): 464-472. Sinatra,S.T., 2005. The Sinatra solution. Basic Health Publications, North Bergen, NJ. Sinatra,S.T. Metabolic cardiology: an integrative strategy in the treatment of congestive heart failure. Altern. Ther Health Med 2009a; 15(3): 44-52.

Langsjoen,P. Congestive heart failure and the clinical uses of coenzyme Q10. Interview by K. R. Hamilton. http://www. prescription2000. com/images/stories/ transcripts/2011-09-08-peter-langsjoen-chf-coenzyme-q10-transcript. pdf 2011.

Sinatra,S.T. Metabolic cardiology: the missing link in cardiovascular disease. Altern. Ther Health Med 2009b; 15(2): 48-50.

Langsjoen,P.H. and Langsjoen,A.M. Supplemental ubiquinol in patients with advanced congestive heart failure. Biofactors 2008; 32(1-4): 119-128.

Tran,M.T., Mitchell,T.M., Kennedy,D.T. and Giles,J.T. Role of coenzyme Q10 in chronic heart failure, angina, and hypertension. Pharmacotherapy 2001; 21(7): 797-806.

Langsjoen,P.H., Langsjoen,J.O., Langsjoen,A.M. and Lucas,L.A. Treatment of statin adverse effects with supplemental Coenzyme Q10 and statin drug discontinuation. Biofactors 2005; 25(1-4): 147-152.

Villalba,J.M., Parrado,C., Santos-Gonzalez,M. and Alcain,F.J. Therapeutic use of coenzyme Q10 and coenzyme Q10-related compounds and formulations. Expert Opin Investig. Drugs 2010; 19(4): 535-554.

Langsjoen,P.H. and Langsjoen,A.M. Overview of the use of CoQ10 in cardiovascular disease. Biofactors 1999; 9(2-4): 273.

Wyman,M., Leonard,M. and Morledge,T. Coenzyme Q10: a therapy for hypertension and statin-induced myalgia? Cleve. Clin J Med 2010; 77(7): 435-442.

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Feature Cachexia

Cancer induced cachexia (CIC) Effective integrative management Rishi Mehta, BSc, ND (Cand), and Philip Rouchotas MSc, ND

Abstract Cancer induced cachexia (CIC) is a syndrome of muscle wasting accompanied by anorexia with or without loss of adipose tissue. Underlying CIC is a complex interaction of proinflammatory cytokines that act centrally on the hypothalamus and peripherally to increase catabolism and resting energy expenditure, while decreasing protein synthesis. The presence of CIC is an important prognostic indicator in cancer patients. Nutritional strategies utilized by naturopathic doctors have been proven to slow down this condition, induce weight gain, and improve cancer related outcomes. Such therapies include high EPA fish oil, melatonin, L-carnitine, and branched chain amino acids and/ or whey protein.

C

ancer induced cachexia (CIC) is a multifactorial syndrome Cachexia is a therapeutic target of high importance in cancer characterized by loss of skeletal muscle, accompanied by patients due to its strong prognostic significance (Burckhart anorexia and (sometimes) loss of adipose tissue (Fearon 2010). It is widely recognized that cachexia leads to poorer cancer 2011). A number of underlying metabolic derangements are implicated outcomes, and is reported as the direct cause of death in up to in CIC, and associated symptoms may include malnutrition, anemia, 20-40% of cancer patients (Fox 2009). Recently, Yang et al found fatigue, and decreased muscle strength & impaired physical function. that, among a large cohort of lung cancer patients (n=14,751), Cachexia, defined as a loss of body weight greater than 5%, leads to those who showed weight loss (15.8% average) at time of diagnosis poor performance, poor quality of life, increased complications, and had significantly shorter survival time compared to those who did higher mortality rate among cancer patients (Burckart 2010, Fearon 2011). Targeted nutritional interventions Mehta Rishi, BSc, ND (Cand). Philip Rouchotas MSc, ND are an important part of cachexia prevention and Intern, Canadian College of Integrated Healthcare Practitioners management. This paper reviews several key agents Naturopathic Medicine Editor- in- Chief that can improve outcomes in cachexia, among them rmehta@ccnm.edu philip@ihpmagazine.com fish derived omega-3 fatty acids (EPA and DHA), Bolton Naturopathic Clinic melatonin, branched chain amino acids (BCAAs), 64 King St W, Bolton, Ontario, L7E1C7 l-carnitine, and whey protein. ihpmagazine.com { September 2012 IHP | 65

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Feature Cachexia not, 6.4 versus 9.2 mo, P < 0.001 (2011). Similar results have been found for other cancers as well, including colorectal cancer and pancreatic cancer, with up to two fold greater increase in risk of death (HR = 2.26; CI 1.18-4.32; P = 0.014) reported (Bachmann 2008, Thoreson 2012). Some teams have used serum albumin as a marker of malnutrition and cachexia, and low levels have been associated with decreased survival in ovarian, breast, and other cancers (Asher 2011, Lis 2003, Polterauer 2010). Cancer related weight loss is associated with decreased tolerance to anticancer therapy, and significantly predicts toxicity from cancer treatment (Fearon 2011, Ross 2004). Naito found that cachexia is associated with altered oxycodone pharmacokinetics due to decreased albumin levels (an important drug binding and transporting protein), resulting in increased levels of free drug and increased incidence of central adverse reactions (2012). Despite this, cachexia remains under-recognized in patients, and under-treated as a clinical entity (Churm 2009, Spiro 2006). The molecular mechanisms underlying CIC are still being elucidated, however, pro-inflammatory cytokines such as IL-1, IL-2, IL-6, interferon gamma and TNF α have a key role in mediating cancer cachexia (Macdonald 2003). IL-6 is a key cytokine in iniating multiple proinflammatory pathways including the acute phase response, and is known to be produced by the tumor microenvironment (Oshima 2012, Zamarron 2011). The inflammatory basis of CIC distinguishes it from age related sarcopenia or frank starvation (Pepersack 2011), and presents the therapeutic rationale for intervention with agents such as EPA, NSAIDS, and celecoxib, a COX-2 inhibitor. Ultimately, these pro-inflammatory cytokines initiate a cascade of events in the hypothalamus and peripherally that results in detrimental metabolic changes, including increased catabolism (proteolysis and lipolysis) and resting energy expenditure, reduced muscle protein synthesis, and anorexia (Burckart 2010). According to a more simple summation by Fearon, “The pathophysiology [of cachexia] is characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism” (2011). Various definitions of CIC have been used. Two recent sets of diagnostic criteria are outlined in Table 1. These criteria by Fearon are recently proposed in a consensus statement published in Lancet Oncology (2011), while those by Evans are older and incorporate biochemical parameters (2008). Recently, work has been done to establish staging of cachexia. Precachexia is defined as “weight loss ≤5%, with anorexia and metabolic changes” (Fearon 2011). Cachexia is as defined below (Fearon 2011). Refractory cachexia is variable in terms of severity, with the presence of procatabolic state; cancer not responsive to anticancer treatment; low performance score; and <3 months expected survival (Fearon 2011). A proposed algorithm in terms of assessment and management is adapted in Figure 1.

Table 1: Diagnostic Criteria for Cancer Induced Cachexia

Fearon 2011

Evans 2008

1) Weight loss of at least 5% over the past 6 months; OR

1) Weight loss of at least 5% in 12 months or less, (or BMI <20kg/ m2); AND

2) BMI <20 kg/m2 and weight loss of at least 2%; OR

2) 3 of 5 from: i) Decreased muscle strength ii) Fatigue iii) Anorexia iv) Low fat-free mass index v) Abnormal biochemistry: Increased inflammatory markers (CRP, IL-6), Anemia (Hb < 12 g/dL), Low serum albumin (< 3.2 g/dL)

3) Loss of appendicular skeletal muscle mass consistent with sarcopenia as determined by DEXA or CT scan or BIA assessment

Note: For Evans, the criteria from both 1) and 2) must be met. Screening Weight loss, BMI or direct measure of muscularity

Staging Precachexia

Cachexia

Refractory cachexia

Assessment Severity Phenotype • Anorexia and food intake • Catabolic drive • Muscle mass and strength • Function and psychosocial effect

Management Precachexia

Cachexia

Refractory cachexia

Monitor Preventive intervention

Multimodal management according to phenotype (with prioritisation of reversible contributory factors)

Symptom palliation Psychosocial support Ethical discussion regarding nutritional support

Figure 1: Management algorithm for cancer cachexia Patients should be screened for cachexia, then undergo detailed assessment. All patients require optimum oncological and general medical management. Once patients with cachexia have been phenotyped, a detailed multimodal management plan (including nutrition, exercise, anti-inflammatory strategies, and other adjuncts) can be established, BMI-body-mass index. (adapted from Fearon 2011)

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Feature Cachexia Nutritional Interventions Fish Derived Omega-3 Fatty Acids

Fish oil is rich in the omega-3 polyunsaturated fatty acids eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), and has been shown to suppress the production of proinflammatory cytokines in both healthy volunteers and cancer patients, leading to weight stabilization, improved immune function, and better cancer treatment outcomes (Barber 2001, Wigmore 2000). Evidence on use of EPA in various cancer types is summarized in Table 2. A 2007 systematic review found that oral supplements enriched with omega-3 fatty acids increased weight gain, increased appetite, improved quality of life and reduced post-surgical morbidity in patients with advanced pancreatic and upper gastrointestinal cancer (Colomer 2007). Not all trials have shown such promising effects (Fearon 2006), however, though the reason may have to do with cancer stage, study duration, and differences between cancer types and phenotypes. Although the dosages used in clinical trials shows some variability, a dose of at least 2g EPA per day is recommended. No serious

side effects have been reported in the trials reviewed; minor side effects typically include fishy aftertaste and mild nausea or GI symptoms. Melatonin

Melatonin (N-acetyl-5-methoxytryptamine) is a chronobiological hormone secreted by the pineal gland that is responsible for maintaining circadian rhythms. Melatonin acts as a potent antioxidant, immune modulating agent, antitumor, and antitoxic agent with respect to reducing radiation and chemotherapy induced toxicity (Seely 2011, Vijayalaxmi 2002). A recent meta analysis by Seely et al including 21 RCTs showed that melatonin alongside chemo and/ or radiation therapy improves survival (reduction in one year mortality, RR = 0.60; 95% CI = 0.54-0.67) and decreases toxicities of treatment, including asthenia, leucopenia, nausea and vomiting, hypotension, and thrombocytopenia (2011). Preliminary trials have shown an effect of melatonin on cachexia. In a randomized controlled trial, 24 patients with advanced gastrointestinal cancer were randomized to receive fish oil or melatonin (Persson 2005). For the fish oil group, 13 patients received

Table 2. Human trials of EPA for treatment of cancer cachexia

Reference/ Design

Dose

Outcomes

Wigmore 2000 Uncontrolled study N=26 advanced pancreatic cancer patients

EPA 1 g/day starting dose; then increased to 6g/day over four weeks, and then a maintenance dose of 6 g/ day was administered for total of 12wk

Before starting EPA, all patients had been losing weight at a rate of 2 kg/mo. After four weeks of EPA, patients had a median weight gain of 0.5 kg (p = 0.0009 compared to baseline), and this continued through the study, with stabilization of the acute-phase response and performance status. Overall survival from diagnosis in this study was 203 days.

Barber 2001 Uncontrolled study N=20 weight losing pancreatic cancer patients

Nutritional supplement providing 600 kcal and 2g of EPA/d x3wk

Decrease in IL-6 (from median 16.5 to 13.7 ng/ml, P = 0.015), and a fall in the proportion of patients excreting proteolysis inducing factor (from 88% to 40%, P = 0.008). Associated with median weight gain of 1 kg, P = 0.024.

Weed 2011 Uncontrolled study N=31 patients undergoing surgery for head & neck cancer

Protein/ energy rich nutritional supplement providing approx 1.5-2.0g EPA/d perioperatively

Mean weight gain was 0.71 kg at admission and 0.66 kg at discharge. At discharge lean body mass increased by 3.20 kg (p < .001) and fat decreased by 3.19 kg (p < .001).

Bayram 2009 RCT N= 52 pediatric cancer patients

Protein/ energy dense supplement providing 2g EPA/d compared to no supplement for 3-6mo

At 3mo, fewer patients in the supplement group had loss of body weight (P = 0.001) or BMI (P = 0.002). Remission rate was significantly (P = 0.036) higher in the treatment group as compared to controls.

Murphy 2011 A&B RCT N=40 patients undergoing firstline chemo for NSCLC

EPA 2.2g/d + standard of care (SOC) chemo compared to SOC alone

Patients receiving EPA maintained weight (0.5 Âą 1.0 kg) (P = .05), while the control group had weight loss of 2.3 Âą 0.9 kg and patients with the greatest increase in plasma EPA concentration after supplementation had the greatest gains in muscle (r(2) = 0.55; P = .01). In addition patients in the EPA group had an increased response rate group (60.0% vs 25.8%, P = .008) and one-year survival tended to be greater in the EPA group (60.0% vs 38.7%; P = .15).

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Feature Cachexia the equivalent of 4.9 g EPA and 3.2 g DHA/d, while the melatonin group (n=11) were given 18 mg melatonin/d. After four weeks, five of the 13 patients (38%) in the fish oil group and 3 of 11 patients (27%) in the melatonin group showed weight stabilization or gain. Notably, after combining both interventions, 63% of individuals responded, suggesting an additive effect from the combination. In another study, Lissoni et al found that among 100 patients with untreatable metastatic solid tumours, those receiving supportive care plus melatonin (20 mg/day orally in the evening x2mo) versus supportive care alone showed slower weight loss and decrease in TNF levels: â&#x20AC;&#x153;The per cent of weight loss greater than 10% was significantly higher in patients treated by supportive care alone than in those concomitantly treated by MLT, with no difference in food intake (P < 0.01)â&#x20AC;? (1996). Branched Chain Amino Acids

The branched chain amino acids consist of leucine, isoleucine, and valine, and these may act indirectly by modulating serotonin activity in the hypothalamus. In the brain, the synthesis of neurotransmitters such as serotonin, dopamine, and norepinephrine are dependent upon the availability of the aromatic amino acids (tryptophan, phenylalanine, and tyrosine) respectively (Fernstrom 2005). Branched chain amino acids are thought to counteract the effects of anorexia by competing with tryptophan for entry through the blood brain barrier (Inui 2002). In cancer serotonin levels can be elevated as a result of increased plasma tryptophan. Through competition, BCAAs allow less serotonin in the brain, and result in a reduction in the amount of hypothalamic activity contributing to anorexia (Inui 2002). In addition BCAAs possess anabolic effects peripherally in skeletal muscle (Laviano 2005).

In terms of BCAA supplementation in increasing lean body mass, clinical trials have been inconsistent in elucidating its effects on skeletal muscle synthesis in humans (Choudry 2006). To date, trials have largely been small and variable and there is no clear positive or negative benefit to BCAA supplementation. The evidence regarding BCAA supplementation in severe catabolic patients is more encouraging. Studies regarding this particular patient population have used more objective outcome measures such as decreases in urinary nitrogen excretion to show benefits. L-Carnitine

L-carnitine is an amino acid derivative and important cofactor in facilitating mitochondrial fatty acid metabolism within muscle tissue. L-carnitine is responsible for the transportation of fatty acids across the mitochondrial membrane in exchange for acetyl CoA, a byproduct of fatty acid oxidation (Fritz 2011). Maintaining this shuttle system 1. ensures substrate (fatty acids) for the production of ATP through beta oxidation in the mitochondria; and 2. prevents inhibition of glucose metabolism, which could happen through inhibition of pyruvate dehydrogenase by buildup of acetylCoA within the mitochondria (Fritz 2011). Some forms of chemotherapy have been shown to deplete carnitine, in part through impaired renal reabsorption (Hockenberry 2009, Mancinelli 2007). Open label studies of L-carnitine in cancer patients have shown improvements in lean body mass and fatigue (Gramignano 2005, Graziano 2002); RCTs of L-carnitine in combination with other agents in the treatment of cachexia have shown a superior combined effect on measure of cachexia, prognostic scores, and inflammatory cytokines (Maccio 2012, Mantanovi 2010). Whey Protein

In a double blind prospective study, 28 cancer patients with anorexia were given an oral supplement consisting of branched chain amino acids 4.8 g three times daily for seven days (Le Bricon 1996). In the BCAA- treated group, the incidence of anorexia decreased from 100% to 45% by the end of the study. In the placebo group, the incidence of anorexia remained at 84%. The authors concluded that BCAA supplementation can safely be administered for the treatment of cancer-induced anorexia (Le Bricon 1996).

Whey protein supplementation contributes to adequate protein intake, while supplying all the essential amino acids in order to maximize muscle protein synthetic activity and optimal immune function. Whey contains high concentrations of the BCAAs as well as beta-lactoglobulin, alpha-lactalbumin, bovine serum albumin, lactoferrin, immunoglobulins, lactoperoxidase enzymes, glycomacropeptides, lactose, and minerals (AltMedRev 2008). Human evidence shows that whey protein is rapidly absorbed and can effectively stimulate muscle protein synthesis (FSR) (Deutz 2011).

In a study of patients with intraabdominal adenocarcinoma and receiving total parenteral nutrition (TPN), the effects of a solution containing 19% BCAAs was compared to an isocaloric, isonitrogenous formula containing 50% BCAAs (Hunter 1989). In the high BCAA group, the following outcomes were observed in comparison to the low BCAA group: increase in whole body protein synthesis and breakdown (p<0.05); increased synthesis rate of albumin (P< 0.05); and reduction in tyrosine oxidation, suggesting improved protein utilization.

Use of a high protein, high leucine whey formula was investigated in 25 cancer patients prior or after chemotherapy treatment (Deutz 2011). The whey group (n = 13) received a formula containing 40g of protein based on casein, whey, and free leucine, while the control group (n =12) was given 24g of casein alone. Results showed that the fractional rate of muscle protein synthesis (FSR) significantly increased from 0.073 (SD: 0.023) to 0.097 (SD: 0.033) (p = 0.0269) in the whey group but not in the control group, showing the superior effects of a whey and leucine containing protein supplement.

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Feature Cachexia A small trial examining the effect of whey on cancer progression was conducted among seven patients with metastatic cancer (five breast, one liver, one pancreas) (Kennedy 1995). Whey protein was supplemented at 30g daily for six months. In six patients, baseline blood lymphocyte GSH (glutathione) levels were substantially elevated, according to authors, “reflecting high tumour GSH levels” (Kennedy 1995). After treatment with whey, two patients exhibited “signs of tumour regression, normalization of haemoglobin and peripheral lymphocyte counts and a sustained drop of lymphocyte GSH levels towards normal” (Kennedy 1995). Two patients showed tumour stabilization and increased haemoglobin levels. Three patients had disease progression. The authors conlcuded that “whey protein concentrate might deplete tumour cells of GSH and [thereby] render them more vulnerable to chemotherapy” (Kennedy 1995). In addition to effects on tumor cell levels of GSH, whey protein has been shown to possess anticancer activity in animals by increasing GSH concentration in healthy tissues, thereby stimulating immune function through the GSH pathway (Bounous 2000). Glutathione is depleted in conditions of immune deficiency, for example HIV and cachexia;

under these circumstances, whey protein acts as a cysteine donor to replenish GSH, since cysteine is the crucial limiting amino acid for intracellular GSH synthesis (Bounous 2000). Conclusion

Naturopathic interventions used for treatment in cancer cachexia are based on good human level evidence and may offer important advantages to cancer patients, particularly in combination. These include high EPA fish oil, melatonin, branched chain amino acids, L-carnitine, and whey protein supplementation. These agents have a good safety profile in that little or no interactions with chemotherapy have been observed in human trials. While evidence suggests benefit from the application of each of these nutrients in isolation, a much stronger impact can reasonably be anticipated from their combined application, thus targeting multiple pathways and factors underlying the pathophysiology of cancer cachexia. Coauthor Reshi Mehta would like to thank Dr Kieran Cooley, Dr Douglas Andrews, and Dr Philip Rouchotas for their guidance in the compilation of this manuscript. •

Table 3. Human studies of L-carnitine for cancer cachexia

Design

Outcomes

Reference

Randomized phase III N=1-4 advanced gynecological cancer patients 4 months

The combination of megestrol acetate (MA) plus L-carnitine (4g/d), celecoxib, and antioxidants (including 600mg alpha lipoic acid) was superior to MA alone for the following outcomes: lean body mass, resting energy expenditure, fatigue, and global quality of life. The combination arm decreased IL-6, TNF-alpha, CRP, and ROS significantly, while there was no change with MA alone.

Maccio 2012

Randomized phase III n = 332 4 months

Most effective regimen observed was arm 5 where patients received the agents : 1) Medroxyprogesterone acetate (MPA) (500 mg/day) or megestrol acetate (MA) (320 mg/day) 2) Oral eicosapentaenoic acid (EPA)-enriched (2.2 g/day) 3) L-carnitine (4 g/day) 4) Thalidomide (200 mg/day) Resting energy expenditure decreased significantly (p=0.044). Fatigue improved significantly in this group (p=0.047). L-carnitine and fish oil alone showed improvements in performance scores (ECOG PS) and the Glasgow prognostic score (GPS).

Mantovani 2010

Open Trial n = 12 LC 6 g/day 4 weeks

Significant improvements in appetite, lean body mass and fatigue were observed in the patients supplemented with l-carnitine.

Gramignano 2005

Open Trial n = 50 4 g/day 1 week

Fatigue improved in 45 patients and Functional Assessment of Cancer TherapyFatigue Score increased from 19.4 (+ 6.4 SD) to 34.9 (+ 5.4 SD) (p<0.001) at the end of the trial.

Graziano 2002

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Feature Cachexia References: Altern Med Rev. Whey protein. Monograph. 2008 Dec;13(4):341-7. Asher V, Lee J, Bali A. Preoperative serum albumin is an independent prognostic predictor of survival in ovarian cancer. Med Oncol. 2011 Jul 7. [Epub ahead of print] Bachmann J, Heiligensetzer M, Krakowski-Roosen H, Büchler MW, Friess H, Martignoni ME. Cachexia worsens prognosis in patients with resectable pancreatic cancer. J Gastrointest Surg. 2008 Jul;12(7):1193-201. Barber MD, Fearon KCH, Tisdale MJ, McMillan DC, Ross JA. Effect of a Fish OilEnriched Nutritional Supplement on Metabolic Mediators in Patients With Pancreatic Cancer Cachexia. NUTRTION AND CANCER 2001 40(2):118-124 Bayram I, Erbey F, Celik N, Nelson JL, Tanyeli A. The use of a protein and energy dense eicosapentaenoic acid containing supplement for malignancy-related weight loss in children. Pediatr Blood Cancer. 2009 May;52(5):571-4. Bounous G. Whey protein concentrate (WPC) and glutathione modulation in cancer treatment. Anticancer Res. 2000 Nov-Dec;20(6C):4785-92. Bruera E, Strasser F, Palmer JL, Willey J, Calder K, Amyotte G, Baracos V. Effect of Fish Oil on Appetite and Other Symptoms in Patients with Advanced Cancer and Anorexia/Cachexia: A Double-Blind, Placebo-Controlled Study. J Clin Oncol 2003 Jan;21(1):129-134 Burckart K, Beca S, Urban RJ, Sheffield-Moore M. Pathogenesis of muscle wasting in cancer cachexia: targeted anabolic and anticatabolic therapies. Curr Opin Clin Nutr Metab Care. 2010 Jul;13(4):410-6. Choudry HA, Pan M, Karinch AM, Souba WW. Branched-chain amino acidenriched nutritional support in surgical and cancer patients. J Nutr. 2006 jan;136(1 Suppl):314S-8S Churm D, Andrew IM, Holden K, Hildreth AJ, Hawkins C. A questionnaire study of the approach to the anorexia-cachexia syndrome in patients with cancer by staff in a district general hospital. Support Care Cancer. 2009 May;17(5):503-7. Colomer R, Moreno-Nogueira JM, Garcia-Luna PP, Garcia-Peris P, Garcia-deLorenzo A, Zarazaga A, Quecedo L, del Llano J, Usán L, Casimiro C. N-3 fatty acids, cancer and cachexia: a systematic review of the literature. Br J Nutr. 2007 May;97(5):823-31

Kennedy RS, Konok GP, Bounous G, Baruchel S, Lee TD. The use of a whey protein concentrate in the treatment of patients with metastatic carcinoma: a phase I-II clinical study. Anticancer Res. 1995 Nov-Dec;15(6B):2643-9. Laviano A, Muscaritoli M, Cascino A, Preziosa I, Inui A, Mantovani G, Rossi-Fanelli F. Branched-chain amino acids: the best compromise to achieve anabolism? Curr Opin Clin Nutr Metab Care. 2005 Jul;8(4):408-14. Le Bricon T. Effects of administration of oral branched-chain amino acids on anorexia and caloric intake in cancer patients. Clin Nutr. 1996 Dec;15(6):337 Lis CG, Grutsch JF, Vashi PG, Lammersfeld CA. Is serum albumin an independent predictor of survival in patients with breast cancer? JPEN J Parenter Enteral Nutr. 2003 Jan-Feb;27(1):10-5. Lissoni P, Paolorossi F, Tancini G, Barni S, Ardizzoia A, Brivio F, Zubelewicz B, Chatikhine V. Is there a role for melatonin in the treatment of neoplastic cachexia? Eur J Cancer. 1996 Jul;32A(8):1340-3. Macciò A, Madeddu C, Gramignano G, Mulas C, Floris C, Sanna E, Cau MC, Panzone F, Mantovani G. A randomized phase III clinical trial of a combined treatment for cachexia in patients with gynecological cancers: evaluating the impact on metabolic and inflammatory profiles and quality of life. Gynecol Oncol. 2012 Mar;124(3):417-25. MacDonald N, Easson AM, Mazurak VC, Dunn GP, Baracos VE. Understand and managing cancer cachexia. J Am Coll Surg. 2003 Jul;197(1):143-61 Mancinelli A, D’Iddio S, Bisonni R, Graziano F, Lippe P, Calvani M. Urinary excretion of L-carnitine and its short-chain acetyl-L-carnitine in patients undergoing carboplatin treatment. Cancer Chemother Pharmacol. 2007 Jun;60(1):19-26. Mantovani G. Randomised phase III clinical trial of 5 different arms of treatment on 332 patients with cancer cachexia. Eur Rev Med Pharmacol Sci. 2010 Apr;14(4):292-301. Murphy RA, Mourtzakis M, Chu QS, Baracos VE, Reiman T, Mazurak VC. Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with nonsmall cell lung cancer receiving chemotherapy. Cancer. 2011 Apr 15;117(8):1775-82. A 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. B

Deutz NE, Safar A, Schutzler S, Memelink R, Ferrando A, Spencer H, van Helvoort A, Wolfe RR. Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food. Clin Nutr. 2011 Dec;30(6): 759-68

Naito T, Tashiro M, Yamamoto K, Ohnishi K, Kagawa Y, Kawakami J. Impact of cachexia on pharmacokinetic disposition of and clinical responses to oxycodone in cancer patients. Eur J Clin Pharmacol. 2012 Mar 23. [Epub ahead of print]

Donohoe C, Ryan AM, Reynolds JV. Cancer Cachexia: Mechanisms and Clinical Implications. Gastroenterol Res Pract. 2011 Jun;2011:1-13

Oshima H, Oshima M. The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models. J Gastroenterol. 2012 Feb;47(2):97-106.

Evans WJ, Morley JE, Argilés J, Bales C, Baracos V, Guttridge D, Jatoi A, KalantarZadeh K, Lochs H, Mantovani G, Marks D, Mitch WE, Muscaritoli M, Najand A, Ponikowski P, Rossi Fanelli F, Schambelan M, Schols A, Schuster M, Thomas D, Wolfe R, Anker SD. Cachexia: a new definition. Clin Nutr. 2008 Dec;27(6):793-9.

Pepersack T. For an operational definition of cachexia. Letter. Lancet Oncol. 2011 May;12(5):423-4.

Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011 May;12(5):489-95.

Persson C, Glimelius B, Rönnelid J, Nygren P. Impact of fish oil and melatonin on cachexia in patients with advanced gastrointestinal cancer: a randomized pilot study. Nutrition 2005 Feb;21(2):170-8. Polterauer S, Grimm C, Seebacher V, Rahhal J, Tempfer C, Reinthaller A, Hefler L. The inflammation-based Glasgow Prognostic Score predicts survival in patients with cervical cancer. Int J Gynecol Cancer. 2010 Aug;20(6):1052-7.

Fearon KC, Barber MD, Moses AG, Ahmedzai SH, Taylor GS, Tisdale MJ, Murray GD. Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia. J Clin Oncol. 2006 Jul 20;24(21):3401-7.

Ross PJ, Ashley S, Norton A, Priest K, Waters JS, Eisen T, Smith IE, O’Brien ME. Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers? Br J Cancer. 2004 May 17;90(10):1905-11.

Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005 Jun;135(6 Suppl):1539S-46S

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 Metaanalysis of Randomized Trials. Integr Cancer Ther. 2011 Oct 21. [Epub ahead of print]

Fox KM, Brooks JM, Gandra SR, Markus R, Chiou CF. Estimation of Cachexia among Cancer Patients Based on Four Definitions. J Oncol. 2009;2009:693458. Fritz, H. L-carinitine: cardiovascular applications. IHP February/March 2011: 40-44. Gramignano G, Lusso MR, Madeddu C, Massa E, Serpe R, Deiana L, Lamonica G, Dessi M, Spiga C, Astara G, Macciò A, Mantovani G. Efficacy of l-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy. Nutrition. 2006 Feb;22(2):136-45 Graziano F, Bisonni R, Catalano V, Silva R, Rovidati S, Mencarini E, Ferraro B, Canestrari F, Baldelli AM, De Gaetano A, Giordani P, Testa E, Lai V. Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients. Br J Cancer. 2002 Jun;86(12):1854-7 Gullett N, Rossi P, Kucuk O, Johnstone PA. Cancer-induced cachexia: a guide for the oncologist. J Soc Integr Oncol. 2009 Fall;7(4):155-69. Hockenberry MJ, Hooke MC, Gregurich M, McCarthy K. Carnitine plasma levels and fatigue in children/adolescents receiving cisplatin, ifosfamide, or doxorubicin. J Pediatr Hematol Oncol. 2009 Sep;31(9):664-9.

Spiro A, Baldwin C, Patterson A, Thomas J, Andreyev HJ. The views and practice of oncologists towards nutritional support in patients receiving chemotherapy. Br J Cancer. 2006 Aug 21;95(4):431-4. Thoresen L, Frykholm G, Lydersen S, Ulveland H, Baracos V, Prado CM, Birdsell L, Falkmer U. Nutritional status, cachexia and survival in patients with advanced colorectal carcinoma. Different assessment criteria for nutritional status provide unequal results. Clin Nutr. 2012 Jun 11. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009 Apr;89(2):381-410 Vijayalaxmi, Thomas CR Jr., Reiter RJ, Herman TS. Melatonin: from basic research to cancer treatment clinics. J Clin Oncol. 2002 May;20(10):2575-601 Weed HG, Ferguson ML, Gaff RL, Hustead DS, Nelson JL, Voss AC. Lean body mass gain in patients with head and neck squamous cell cancer treated perioperatively with a protein- and energy-dense nutritional supplement containing eicosapentaenoic acid. Head Neck. 2011 Jul;33(7):1027-33. Wigmore SJ, Berber MD, Ross JA, Tisdale MJ, Fearon KC. Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer. 2000 36(2):177-84

Hunter DC, Weintraub M, Blackburn GL, Bistrian BR. Branched chain amino acids as the protein component of parenteral nutrition in cancer cachexia. Br J Surg. 1989 Feb;76(2):149-53.

Yang R, Cheung MC, Pedroso FE, Byrne MM, Koniaris LG, Zimmers TA. Obesity and weight loss at presentation of lung cancer are associated with opposite effects on survival. J Surg Res. 2011 Sep;170(1):e75-83.

Inui A. Cancer Anorexia-Cachexia Syndrome: Current Issues in Research and Management. CA Cancer J Clin 2002;52:72-91

Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 2011;7(5):651-8.

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Manufacturers of Hypo-al ler gen ic Nutritional Sup ple ments

XanthiTrim

What Is It? XanthiTrim promotes thermogenesis and energy expenditure to support healthy fat metabolism and metabolic rate when combined with a healthy diet and exercise.*

Uses For XanthiTrim Weight Management: XanthiTrim contains 300 mg of Xanthigen® per serving, a synergistic combination of fucoxanthin from brown seaweed and pomegranate seed oil. In a 16-week, randomized study, Xanthigen® supported healthy weight management and fat metabolism in volunteers. This was attributed in part to its ability to encourage resting energy expenditure and thermogenesis, the body’s natural ability to dissipate caloric energy as heat from the mitochondria of adipose tissue. This results in oxidation and utilization of fats rather than fat storage. In this study, Xanthigen® also maintained healthy liver fat metabolism and function, healthy inflammatory balance, and healthy triglyceride levels. Subjects were on a moderately calorie-restricted diet. GreenSelect® Phytosome is a proprietary, caffeinefree extract from green tea, that is 1 part GreenSelect® green tea to 2 parts phophatidylcholine. This allows for greater absorption of epigallocatechin gallate, or EGCG, one of the primary components known to support healthy metabolism. Green tea has demonstrated the ability to promote resting energy expenditure and thermogenesis in a number of clinical studies. A 90-day study involving GreenSelect® Phytosome revealed its ability to support healthy weight management and body composition in subjects following a calorie-restricted diet.*

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Feature Low Dose Naltrexone

Low Dose Naltrexone Role as adjunct cancer treatment â&#x20AC;˘ Heidi Kussmann, ND, FABNO

Abstract Research in the area of naltrexone has shown both promise and controversy for cancer treatment. Ongoing validation regarding the differing mechanisms of action, the dosage, and the timing of the dose is required. In reviewing the mechanism of action for low-dose naltrexone, more were identified than originally anticipated, which range from a vague endogenous immune response to a complex mechanisms involving LDN affecting a blockade at the OGF-OGFr axis. This article presents the historical use of naltrexone, the current information about the low-dose options and use recommendations, the receptors involved with some controversial effects on cancer with respect to mechanisms of action, and calls for more evidence in the form of phase three clinical trials.

Heidi Kussmann, ND, FABNO Cancer Treatment Centers of America 600 Parkway North, Newnan, GA 30265 Heidi.Kussmann@ctca-hope.com

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Feature Low Dose Naltrexone

Naltrexone – Mechanism of Action in Treatment of Cancer

The task of bringing together single dimension information from laboratory research examining cellular, vascular, and endocrine events to understand the three dimensional mechanisms of disease in the human body is daunting. The reliance upon research and scientific principles weighs heavy in cancer where much is unknown about disease progression, especially in the form of metastasis or recurrence. Currently information is elucidated about mechanisms of action, from which arise more questions and theories, which in turn provokes the critically-thinking reader to utilize the available information to the best of their abilities. An example of the evolution of a treatment that was first presented as novel and which is now entering the realm of evidence-based medicine is that of low dose Naltrexone (LDN) for use in autoimmune disease and cancer. For the purpose of this article, LDN and its effects in cancer will be the primary focus. There is little clinical or research evidence beyond the level of dramatic reports from Dr.’s Bihari, Berkson and Rubin (Berkson 2009) to support the use of LDN in treatment of cancer. The authors present case reports of three people diagnosed with pancreatic cancer, treated successfully with the use of Alpha Lipoic Acid and LDN, and call for clinical trials for further investigation of their protocol. In elucidating the mechanism of action for this success they suggested an endogenous immune response. Suffice to say it is a start, and a proposed mechanism of action may eventually create further research to prove or disprove. Further, there is recent evidence in cell studies elucidating more than one anti-cancer mechanism of LDN. Low-dose Naltrexone (LDN) presents itself with complexity: there are different receptors involved, and the resulting effects of LDN on cancer have varied widely. This article reviews the recent data regarding the mechanisms of action and the proposed resulting effects of LDN in treatment of cancer. Naltrexone History in Brief

Naltrexone is used to treat opioid substance abuse and acts by blocking opioid receptors in the brain. It was approved by the US FDA in 1984 in 50 mg dose increments as a competitive narcotic antagonist, for the purpose of stopping or reducing the effects of a heroin or opium overdose and/or for the reduction of opioid withdrawal symptoms (Lowdosenaltrexone.org May 4 2010). For

the purposes of opioid blockade this 50mg ‘high dose’ Naltrexone is in tablet form for oral consumption away from meals. Depending upon the type of addiction there are different prescription regimens ranging from daily to every other day schedules (PubMed Health 2011). There is very little understood about Naltrexone beyond opioid blockade as the patent expiry led to it becoming dormant as a prescription item for a number of years. For the treatment of addiction, ‘high-dose’ Naltrexone exerts opposite effects on the Mu Opioid Protein (MOP) receptor at the plasma membrane, and can inhibit secretion of opioids in both brain and adrenal glands via beta endorphins and enkephalins (Figure 1). Naltrexone has been used to treat opioid overdose, opioid addiction (Gonzalez 2004) and addictions to other substances such as alcohol (Chick 2000, Davidson 1999). Naltrexone is conventionally dosed up to a maximum of 350 mg QD. This high-dose use is limited by the adverse effects which are similar to opioid withdrawal and these effects can even occur in patients without previous exposure to opioids (Hollister 1981). In contrast the Low-dose naltrexone (LDN) dose ranges from 0.1-4.5 mg QD and has not produced adverse effects. The off-label use of low-dose Naltrexone started with Dr. Bihari and has been in use since the 1980’s, subsequently described via case report as an anti-cancer strategy in 2009 by Berkson and Rubin. LDN has been used off-patent for treatment of autoimmune illnesses and cancer since the late 1980’s. It is compounded into tablets or a powder which is mixed with water for oral consumption. Comparative absorption data and information on suppository or injectable doses is limited and unreliable at this time. LDN interacts with opioid analgesics such as Hydrocodone, Oxycodone, Oxymorphone and other opiate/opioid narcotics and thus should be avoided in such instances. It is recommended to gradually reduce the intake and then eliminate the use of any opioid narcotic for 10-12 days before starting LDN. The compounded powder for oral consumption of LDN has a shorter, temperature-sensitive shelf-life and a bitter taste when taken on its own, in comparison to the compounded LDN tablet for oral consumption (Figure 2) (Fawcett 1997). Receptor Review

Transmembrane receptors in the human body regulate the majority of cellular metabolism and physiology. The largest group of receptors belongs to a group coupled to G-proteins (G-Protein-

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Feature Low Dose Naltrexone

OGFr determines the properties of cell proliferation (Zagon 2003). Ongoing phase one and two trials on squamous cell carcinoma of the head and neck and hepatocellular cancer respectively are investigating how OGF binds and activates the OGFr to inhibit angiogenesis and tumor cell growth (Clinicaltrials.gov 2010A, Clinicaltrials.gov 2010B).

Coupled Receptors, or GPCRs) (Lefkowitz 2007). The superfamily of GPCRs regulates metabolism, including cellular replication; they are the targets for drug therapy in treatment of cancer and autoimmune disease (Jacoby 2006, Pierce 2002). The genes encoding µ-, δ-, κ-, ζ- and nociceptin Opioid Proteins (MOP- Figure 1, DOP, KOP, OGFr, NOP respectively) belong in the super-family of the GPCRs (Brown 2008, Corbett 2006, Wang 2001) are the transmembrane receptors targeted in the treatment of narcotic abuse (Wang 2001), and are suggested to be the target in the treatment of autoimmune disease (Zagon 2009) and cancer with LDN (Brown 2008). However, more recent research has indicated that the regulatory effect on cancer cell growth extends beyond that of the MOP and to an endogenous opioid factor also referred to as Met5-Enkephalin or Opioid Growth Factor (OGF, Figure 3), and its receptor the ζ-opioid receptor or Opioid Growth Factor Receptor (OGFr). OGF has a role in growth inhibition and

Naltrexone (Figure 2) was approved by the US FDA in 1984 in 50mg doses (max dose 350mg) and acts as a narcotic antagonist. It is used to treat and stop heroin or opium overdoses and withdrawal (Gonzalez 2004), and to treat substance addiction such as alcoholism (Chick 2000, Davidson 1999). Since the patent expired other uses have thus been investigated. In the 1990’s Dr. Bihari first used LDN to treat people with AIDS and then later on to treat people with cancer (Bihari 1995, Lowdosenaltrexone.

Figure 1. The µ-Opioid Receptor

Figure 2. Chemical structure of Naltrexone (PubChem 2010)

Naltrexone – Past, Present and Future

H O

O

H

H

N

O H

O

Figure 3. Chemical structure of 5’Met-enkaphalin

O

HO

NH2

N H

H N O

O N H

H N O

O

S OH

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Feature Low Dose Naltrexone

org May 18 2010). There have been reports of successful treatment of various cancers (Berkson 2009, Dagleish 2005, Hytrek 1996, Zagon 2000), AIDS (Bihari 1995, Gekker 2001), Multiple Sclerosis (Cree 2010), Autism (Panskepp 1991), and autoimmune disorders such as Crohn’s Disease (Smith 2007) and fibromyalgia (Brown 2008). Sustained release naltrexone (32mg) has now completed investigation in Phase 2 trials with bupropion for the treatment of obesity (Clinicaltrials.gov 2010B). Naltrexone – Mechanisms of Action

As an opioid antagonist, high dose (50mg – 350mg) naltrexone blocks secretion of opioids in the brain and adrenal glands via the MOP. At low dose (3-4.5mg) nocturnal dose-timing of naltrexone is hypothesized to block opioid receptor expression (MOP, DOP, KOP) and increases circulation of met-enkephalin (Figure 3) and beta-endorphin for up to six hours. The MOP is hypothesized to play a role in the various responses of the immune system to stress, infection and malignant transformation (Makman 1994). LDN has several proposed theoretical mechanisms of action depending on whether the treatment is targeted for cancer or autoimmune disease. An recent cell study investigation revealed controversy. In the anti-cancer role of LDN the OGF/OGFr axis can be allosterically modulated to create multi-dimensional effects on signaling pathways for cellular replication. Allosteric modulation is also demonstrated by the human immune system and readers will recall that the subtypes of Th cells are allosterically modulated to create immune functionality. According to the investigator Dr. Ian Zagon at Penn State University (e-mail communication May 12, 2010): “All human cancers are equipped with the OGF/OGFr axis and depend on it for regulation of cell proliferation. NTX (naltrexone) works by blocking the OGF-OGFr axis. It causes an up-regulation. If the dose is low enough, you allow time for OGF to interact with OGFr to cause a depression in cell proliferation. If you give repeated low doses or a high dose you get up-regulation but no interaction between peptide and receptor. Since the OGF-OGFr axis is tonically active - it is on all the time and watching over the pace of cell proliferation by inhibitory pathways, blockade of OGF-OGFr by naltrexone continuously allows cells to be unregulated in cell division and you have more cells produced.” For the purpose of illustrating further the complexity of this drug there are several mechanisms of action proposed in treatment of the following different types of cancer:

• In neuroblastoma, the low (3-4.5mg) and high dose (100 mg) naltrexone administered demonstrated a direct modulating effect on oncogenesis. The low dose naltrexone elevated opiate receptors and circulating beta endorphin and met-enkephalin through the four to six hour receptor blockade (McLaughlin 1987) and resulted in decreased oncogenesis. • A small study of 14 patients with untreatable metastatic solid tumors treated with melatonin (20mg hs) and naltrexone(100mgQD) to augment Interleukin-2 therapy demonstrated that lymphocyte production is amplified compared with melatonin and IL-2 therapy alone (Lissoni 2002). • In Nude mice with colon cancer (HT-29) treated with 0.1mg/ kg naltrexone demonstrated that tumorigenicity was inhibited by opioids via a 2.5 increase in plasma met5-enkephalin in naltrexone-treated mice and an 85% reduction of binding capacity of 3H-Met5-enkephalin in tumor tissue when compared to the control group (Hytrek 1996). • In pancreatic cancer MIA PaCa-2 clonal cell lines the singlelow-dose naltrexone-induced amplification of the OGFr axis delayed the G1/S inter-phase of the cell cycle via CDK inhibition of p16 or p21, causing a decrease in CDK4/CDK2 activity and RB protein phosphorylation, thus halting DNA synthesis and subsequent cell growth (Zagon 2007). It remains to be determined how LDN exerts its effects via either an independent or combined extracellular or cytoplasmic effect on cancer cell replication. These give rise to the confirmation that often LDN is not a single therapy provided in isolation of other cancer treatment, and that there are pharmacokinetic properties to LDN which affect enkephalin production, lymphocyte production, and cyclin dependent kinases on control of the cell cycle. Summary

The number of cancer survivors alive compared to those seeking a cure can be described as an inverse relationship. There is a distinct lack of cancer survivors, in spite of all the enormity of efforts ongoing to seek a cure. Research in the area of naltrexone has shown both promise and controversy for cancer treatment and requires ongoing validation regarding the differing mechanisms

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Feature Low Dose Naltrexone

of action, the dosage, and the timing of the dose and the type of cancer. In reviewing the mechanism of action for low-dose naltrexone, more were identified than originally elucidated by historical data and case reports. An endogenous immune response has been suggested via case report as one possible theory, as well as an increase in enkephalins, lymphocytes, and allosteric blockade at the OGF-OGFr axis. It is a daily challenge to understand the intended and untoward influences of naltrexone upon tumor cell

growth because of the differing receptors involved and to tailor a specific protocol based upon the current evidence for people with cancer. In looking to the future use of LDN, there is a need for collaborative effort between the research bench and the patient that may provide more information regarding the mechanisms of tumor initiation, progression and promotion to help extend the limit of one’s knowledge, skills and judgment when treating the complex disease of cancer. •

References Berkson BM, Rubin DM, Berkson AJ. Revisiting the ALA/N (alpha-lipoic acid/lowdose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases. Integr Cancer Ther. 2009 Dec;8(4):416-22. Bihari B. Efficacy of low dose naltrexone as an immune stabilizing agent for the treatment of HIV/AIDS [letter]. AIDS Patient Care. 1995 Feb;9(1):3. Brown N, Panskepp J. Low-dose naltrexone for disease prevention and quality of life. Med Hypotheses. 2008;72(3):333-7. Chick J, Anton R, Checinski K, Croop R, Drummond DC, Farmer R, Labriola D, Marshall J, Moncrieff J, Morgan MY, Peters T, Ritson B. A multicentre, randomized, double-blind, placebo-controlled trial of naltrexone in the treatment of alcohol dependence or abuse. Alcohol Alcohol. 2000 Nov-Dec;35(6):587-93. Clinicaltrials.gov. http://www.cancer.gov/clinicaltrials/search/view?cdrid=599953&ver sion=HealthProfessional&protocolsearchid=8291854. Accessed Nov 2010A. Clinicaltrials.gov. http://clinicaltrials.gov/ct2/show/NCT00711477. Accessed Nov 2010B. Corbett AD, Henderson G, McKnight AT, Paterson SJ. 75 years of opioid research: the exciting but vain quest for the Holy Grail. Br J Pharmacol. 2006 Jan;147 Suppl 1:S153-62. Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010 Aug;68(2):145-50.

Lefkowitz RJ. Seven transmembrane receptors: something old, something new. Acta Physiol (Oxf). 2007 May;190(1):9-19. Lissoni P, Malugani F, Malysheva O, Kozlov V, Laudon M, Conti A, Maestroni G. Neuroimmunotherapy of untreatable metastatic solid tumors with subcutaneous lowdose interleukin-2, melatonin and naltrexone: modulation of interleukin-2-induced antitumor immunity by blocking the opioid system. Neuro Endocrinol Lett. 2002 Aug;23(4):341-4. Lowdosenaltrexone.org. www.lowdosenaltrexone.org. Accessed May 4 2010. Lowdosenaltrexone.org. www.lowdosenaltrexone.org/ldn_and_cancer.htm. Accessed May 18 2010. Makman M. Morphine receptors in immunocytes and neurons. Adv Neuroimmunol. 1994;4:69-82. McLauMghlin PJ, Zagon I. Modulation of human neuroblastoma transplanted into nude mice by endogenous opioid systems. Life Sci. 1987;41:1465-72. Panksepp J, Lensing P, Leboyer M, Bouvard MP. Naltrexone and other potential new pharmacological treatments of autism. Brain Dysfunc. 1991;4:281-300. Pierce KL, Premont R, Lefkowitz RJ. Seven transmembrane receptors. Nat Rev Mol Cell Biol. 2002;3(9):639-50. PubChem. http://pubchem.ncbi.nlm.nih.gov. Accessed Nov 2010.

Dalgleish A, Whelan M. Novel immunotherapeutic approaches to prostate cancer. Curr Opin Mol Ther. 2005 Feb;7(1):30-4.

PubMed Health. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000853/ accessed July 17 2011.

Davidson D, Palfai T, Bird C, Swift R. Effects of naltrexone on alcohol selfadministration in heavy drinkers. Alcohol Clin Exp Res. 1999 Feb;23(2):195-203.

Smith J, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon I. Low-dose naltrexone therapy improves active Crohn’s disease. Amer J Gastroenterology. 2007;102(4):820-8.

Fawcett JP, Morgan NC, Woods DJ. Formulation and stability of naltrexone oral liquid for rapid withdrawal from methadone. Ann Pharmacother. 1997 Nov;31(11):1291-5. Gekker G, Lokensgard J, Peterson PK. Naltrexone potentiates anti-HIV-1 activity of antiretroviral drugs in CD4+ lymphocyte cultures. Drug Alc Depend. 2001;64:257-63. Gonzalez G, Oliveto A, Kosten TR. Combating opiate dependence: a comparison among the available pharmacological options. Expert Opin Pharmacother. 2004 Apr;5(4):713-25. Hollister LE, Johnson K, Boukhabza D, Gillespie HK. Aversive effects of naltrexone in subjects not dependent on opiates. Drug Alcohol Depend. 1981 Aug;8(1):37-41. Hytrek SD, McLaughlin PJ, Lang CM, Zagon IS. Inhibition of human colon cancer by intermittent opioid blockade with naltrexone. Cancer Lett. Mar 29, 1996;101(2):159-64. Jacoby E, Boulehal R, Gerspacher M, Seuwen K. The 7 TM G-protein-coupledreceptor target family. ChemMedChem. 2006;1(8):761-82.

Wang D, Rachal KM, Bilsky EJ, Sadee W. Inverse Agonists and neutral antagonists at mu opioid receptor (MOR): possible role of basal receptor signaling in narcotic dependence. J Neurochem. 2001;77(6):1590-600. Zagon IS, McLaughlin P. Opioids and the apoptotic pathway in human cancer cells. Neuropeptides. 2003;37:79-88. Zagon IS, Rahn KA, Turel KP, McLaughlin PJ. Endogenous Opioids Regulate Expression of Experimental Autoimmune Encephalomyelitis: A New Paradigm for the Treatment of Multiple Sclerosis. Exp Biol Med. 2009;234(11):1383-92. Zagon IS, Roesener CD, Verderame MF, Ohlsson-Wilhelm BM, Levin RJ, McLaughlin PJ. Opioid growth factor regulates the cell cycle of human neoplasias. Int J Oncol. 2000;17:1053-61. Zagon IS, Verderame MF, Hankins J, McLaughlin PJ. Overexpression of the opioid growth factor receptor potentiates growth inhibition in human pancreatic cancer cells. International Journal of Oncology. 2007;30(4):775-783.

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Product MonograPh Bio-Fen MGN-3 COMPOUND Bio-Fen Plus is an oral natural health product usedARABINOXYLAN in the treatment of hereditary androgenic alopecia (AGA) for male or female pattern baldness. Without treatment, AGA is progressive, and causes social distress in many affected men and women (Sinclair 1998). Bio-Fen Plus contains extracts of fenugreek saw palmetto berries and flax lignans, as wellfirst as developed specific vitamins. Each ingredient is knownresponse to possess inhibitors theshown enzyme MGN-3 by Ecomax seeds, is a science-based, patented immune-enhancing complex in Japan. Arabinoxylan is a biological modifier that hasofbeen to 5α-reductase. inhibitors responsible forcounts relieving symptoms associated with augment the immune These response, includingare increasing NK cell and activity, and has been used bothhereditary for general AGA. immune support as well as an immunotherapy in cancer One of the primary causes of Arabinoxylans hair loss is a high level ofpresent the male hormone (DHT) within the hair follicle (Vierhapper, patients (Ghoneum 1998A&B, 1996). are naturally in the cell walls dihydrotestosterone of grasses; MGN-3 arabinoxylans are produced from hydrolyzed rice bran2001). utilizing enzymes Hyphomycetes mycelia mushroom Standard 2010). Each capsule MGN-3 delivers 250mg5-α-reductase of arabinoxylan catalyzes compound. Forderived peoplefrom withtheAGA, their follicles have a greater(Natural number of androgen receptors toofwhich DHT attaches. the enzymatic conversion of testosterone to dihydrotestosterone, which binds to the receptor five-fold more avidly than the parent compound (Sinclair 1998).

Activity MGN-3/ arabinoxylan has been shown to increase natural killer activity in vivo (Ghoneum 1998A); augment maturation and activation of dendritic cells in vitro (Cholujova 2009, Vitamins Saw palmetto (Serenoa repens) phagocytosis and cytokines TNF-alpha; and IL-6 (Ghoneum Ghoneum 2011); augment macrophage 2004); and enhance intracellular killing of microbes by phagocytic cells in In a Polish study of 46 women who had symptoms of diffuse alopecia, calcium Standardized (lipophillic) Serenoa extract has been found to be a potent inhibitor vitro (Ghoneum 2008). pantothenate was orally administered twice a day in doses of 100 mg for four to of 5α-reductase, resulting in decreased tissue DHT. An open-label, dose response five months, and vitamin B6 was injected every day for 20 to 30 days and repeated study was conducted on 42 healthy males to determine the effect of a combination again after six months (Brzezińska-Wcisło 2001). It was determined that vitamin of carotenoid astaxanthin and saw palmetto berry lipid extract on DHT and B6 administered parenterally for a few weeks induces improvement in the hair testosterone levels (Angwafor 2008). The men were divided into two groups: condition in a subset of women and reduces hair loss. one group received 800 mg/day of the combination supplement and the other In addition, the systematic review by the Natural Standard group summarizes four group received 2000 mg/day of the supplement for 14 days. ANOVA-RM showed additional reports conducted by the same group as the study above (Ghoneum et significant within-group increases in serum total testeosterone and significant al), which are not available through Pubmed. The authors the studies as Medicinal Ingredients dosedescribe Per capsule decreases in serum DHT from baseline in both dose groups (P=0.05). There “preliminary low quality human trials and case studies” based on before and after was no significant difference between dose groups with regard to the increase of Fenugreek(2012). (Trigonella foenum comparisons Results suggestgraecum) that MGN-3 may able to increase natural killer 260bemg testeosterone or the decrease of DHT; therefore both doses were effective (Angwafor seedactivity extract cells/ in 4:1 cancer patients: 2008). • Ghoneum 1998A: 32 cancer patients (prostate cancer, breast cancer, multiple Saw palmetto berry extract containing 160 mg myeloma, leukemia) given 3g/d MGN-3 orally. Treatment resulted in a “significant Another study tested liposterolic extract of Serenoa repens (LSESr) and beta45% free fatty acids increase in NKcell in all types of malignancies, although individuals varied in their sitosterol in the treatment of males (23-64 years of age) with mild to moderate AGA. responses to MGN-3” (Ghoneum 1998A). Flax lignans, standardized to 20% Six of 10 (60%) subjects were rated as improved at the final visit, thus establishing • Ghoneum 1998B: 24 patients given three different100 concentrations of 15, 30, and mg secoisolariciresinol diglucoside (SDG) and NK cell activity showed a small, the effectiveness of 5α-reductase inhibitors against AGA (Prager 2002). Chronic 45mg/kg daily. Peripheral blood lymphocyte inflammation of the hair follicle is considered to be a contributing factor for AGA. A significant increase in the treatment group. D-calcium pantothenate (Vitamin B5) 10.40 mg study by Chittur et al sought to determine whether blockade of inflammation using • Ghoneum 1996: 27 patients with prostate (n=7), breast (n=7), cervix (n=2), multiple LSESr and two anti-inflammatory agents (carnitine and thioctic acid) could alter myeloma (n=8),(Vitamin and leukemia givenmg 3g of MGN-3 daily, Niacinamide B3) (n=3) cancer types were 10.25 the expression of molecular markers of inflammation (Chittur 2009). It was found in addition to conventional therapy. NK activity was examined at two weeks, three Pyridoxine HCl (Vitamin 2 mg increase in NK activity. that the combination suppressed lipopolysaccharide-activated gene expression of months, and six months; andB6) there was a large, significant Loading dose of 3000mg can be reduced to 1000mg with no loss of efficacy. chemokines associated with pathways involved in inflammation and apoptosis. • Ghoneum 1995:reported a large, significant increase in parameters of the immune Riboflavin B2) 1.58 mg The Trials study concluded that 5-alpha reductase inhibitors in combination with response (not(Vitamin described) in five patients with breast cancer to assess the effect of MGNClinical blockade of inflammatory processes could represent a new two-pronged approach 3Folic on theacid immune response. Immune Enhancement 0.095 mg Diabetes in the treatment of AGA. for its ability to prevent the common cold among the Arabinoxylan was investigating • Biotin Arabinoxylan-rich fibre has been shown to improve400 glycemic mcg control in patients with elderly in a randomized, double blind, placebo controlled cross-over trial conducted diabetes, however the dose required to achieve this is considerable, with up to 15g daily Fenugreek in Japan (Maeda Seeds 2004). Fifty elderly people aged from 70 to 95 years were given non-Medicinal Ingredients used (Lu 2004). Fenugreek seeds contain 5% to 30% protein, steroid saponins, sterols, flavonoids arabinoxylan derivatives of hydrolyzed rice bran or water-soluble rice bran (placebo) for and The alkaloids (notably score trigonelline and choline). Steroidthesaponins bind and six weeks. total symptom for the common cold among control treatment Inert microcrystalline cellulose and vegetable-based magnesium Dosing hormones in thegroup. body;The DHT is made from groupeliminate was three extra times cholesterol higher than and that for the treatment average duration in a veggie-based capsuleper day • stearate General immune support: 500-600mg of symptoms was 2.6 daysisforinRB whereas it was only 1.2 days for HRB. Evidence of testosterone, which turn is made from cholesterol. Therefore, when excess • Cancer: 3g daily for up to six months in patients with various cancer types (including immunomodulatory activity wasless alsoDHT observed in laboratory tests (but not cholesterol is eliminated, can be made (Stark 1993). In adescribed). study of 20 multiple myeloma, leukemia, andcapsule cancersper of the Recommended adult dose: One day prostate, breast, cervix) adults who consumed 12.5g and 18.0g of germinated fenugreek seed powder for • Diabetes: 1-12g of arabinoxylan-rich fiber has been used daily. Cancer one month, higher levels of consumption resulted in a significant reduction in total Preclinical studiesand have shown thatlipoprotein MGN-3 has anti-tumor, proapoptotic effect cholesterol low-density (LDL) levels (Sowmya 1999). Toxicology in cancer cells (Badr 2003, Ghoneum 2011B, 2003, Gollapudi 2008). Bang et al. The Natural Standard review found that “MGN-3 appears to be relatively non-toxic” investigated the efficacy of arabinoxylan rice bran (MGN-3) alongside conventional Flax lignans (2012). Arabinoxylan has been used clinically in Japan and is reported to be well therapy forreduces the treatment of 68 of hepatocellular carcinoma patientscholesterol (stage I and II) in the Flax the amount DHT produced by reducing levels tolerated at the recommended doses over short periods of time (under three months). (2010). TheAcontrol group received conventional only.2008 Patients in the body. meta-analysis of 28 studies betweentherapy 1990 and showed thatMGN-3 flaxseed In animal studies, MGN-3 was found to be without acute toxic effects at oral dosages groupsignificantly showed: (i) lower recurrence of the disease, 31.6% (12/38), asconcentrations compared to (Pan reduces circulating total and LDL-cholesterol up to 36g/kg, nearly 1000-fold higher than the human dose used in cancer patients. 46.7%2009). (14/30) for theinterventions control; (ii) higher survival afterLDL the second year,by 35%, Flaxseed reduced total and cholesterol 0.10asmmol/L Human trials found that doses of 45mg/kg daily for two months, or 3mg/kg daily for compared 6.7% for 0.00 the control; (iii) significantly lower alpha-fetoprotein a (95%toCI: -0.20, mmol/L) and 0.08 mmol/L (95% CI: -0.16, 0.00level, mmol/L), six months, resulted in no abnormalities of blood chemistry or liver enzymes (SGOT 38% decrease (p =Significant 0.0001), asreductions compared were to baseline value, while the flaxseed control showed no respectively. observed with whole (-0.21 and and SGPT) (Natural Standard 2012). significant change; and (iv) a significant decrease in tumor volume, in contrast to the -0.16 mmol/L, respectively) and lignan (-0.28 and -0.16 mmol/L, respectively) control, which showed no significant change. supplements (Pan 2009).

References Angwafor F III, Anderson ML. An open label, dose response study to determine the effect of a dietary supplement on dihydrotestosterone, testosterone and estradiol levels in healthy males. J Int Soc Sports Nutr 2008;5:12. Ghoneum M. Int J Immunotherapy 1998;14:89-99. B References Ghoneum M,et al. 87th Meeting of the American Association Cancer Researchin1996. Arabinoxylane from Rice BranL.(MGN-3), Int. Journal of Immunotherapy XIV.(2): 89-99,1998effectiveness on hair growth Brzezińska-Wcisło Evaluation of vitamin B6 and calcium pantothenate from clinical and Annual trichographic aspects for treatment of for diffuse alopecia women. Wiad Lek 2001;54:11-8. Ghoneum MH. American Association for Cancer Research Special Conference: The interface between basic and Badr El-Din NK, et al. Cancer. 2008;60(2):235-44. research 1995. Chittur S, Parr B,Res. Marcovici G. Inhibition of inflammatory gene expression in keratinocytes using aapplied composition containing carnitine, thioctic acid and saw palmetto extract. Evid Based Bang MH, et al. Anticancer 2010 Dec;30(12):5145-51. Complement Alternat Med 2009. Ghoneum M., Drew University. “Enhancement of Human Natural Killer Cell Activity by Modified Cholujova D, et al. Int J ImmunopatholPharmacol. 2011 Oct-Dec;24(4):941-8. A Gollapudi S, eton al.blood Cancerlipids. Detect Am Prev. J2008;32(1):1-6. PanM,A,etYu D, Demark-Wahnefried W, Franco OH, Lin X. Meta-analysis of the effects of flaxseed interventions Clin Nutr 2009;90:288-97. Ghoneum al. Neoplasma. 2011;58(2):118-23. B Lu ZX, et al. Eur J ClinNutr. 2004 Apr;58(4):621-8. Ghoneum M, etN, al. Bickett Int J ImmunopatholPharmacol. 2008 G. Jan-Mar;21(1):87-95. Prager K, French N, Marcovici A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia. J Altern Complement Med 2002;8:143-52. Maeda H, et al. Biofactors. 2004;21(1-4):185-7. Ghoneum M, et al. Int J ImmunopatholPharmacol. 2004Sep-Dec;17(3):283-92. Natural Standard, The.Arabinoxylan monograph. Updated 2012. http://naturalstandard.com/databases/herbssuppleSerenoa repens Alternative Medicine Review 1998;3:227-9. Ghoneum M, et al. Cancermonograph. Lett. 2003 Nov 10;201(1):41-9. ments/all/arabinoxylan.asp#undefined Accessed 11 August 2012. Ghoneum M. 6thR.International Congress on Anti-Aging and Bio-Medical Technologies 1998. A Sinclair Male pattern androgenetic alopecia. BMJ 1998;317:865-9. Sowmya P, Rajyalakshmi P. Hypocholesterolemic effect of germinated fenugreek seeds in human subjects. Plant Foods Hum Nutr 1999;53:359-65. Stark A, Madar Z. The effect of an ethanol extract derived from fenugreek (Trigonella foenum-graecum) on bile acid absorption and cholesterol levels in rats, Br J Nutr 1993;69:277-87. Vierpper H, Nowotny P, Maier H, Waldhausl W. Production rates of dihydrotestosterone in healthy men and women and in men with male pattern baldness: determination by stable isotope/ dilution and mass spectrometry. J Clin Endocrinol Metab 2001;86:5762-4.

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Integrated Healthcare Practitionersâ&#x20AC;&#x2122; Dietary and Nutritional Supplement, and Herbal Remedies Management Program Author: Christopher Habib, ND and Gurdev Parmar, ND, FABNO 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.

Dichloroacetate (DCA) Application in cancer management Abstract

Most cancer cells use anaerobic glycolysis for energy production, despite the fact that oxygen is present. This is termed the Warburg effect and results from mitochondrial dysfunction, which prevents mitochondria-based glucose oxidation. As a result, cancer cells upregulate glucose receptors and significantly increase glucose uptake, creating a large difference between malignant cells and normal cells. Glycolysis results in lactic acidosis and this can facilitate tumour growth by breaking down the extra-cellular matrix allowing for expansion, increasing cell mobility and metastatic potential, and by activating angiogenesis. Dichloroacetate (DCA) is known to environmental scientists as a by-product of water chlorination and is a metabolite of industrial solvents. In this regard, it has been implicated in a variety of life-threatening toxicities and considered a human health hazard. However, DCA has been known for years to physicians and researchers as an investigational drug for certain metabolic diseases such as inborn errors of mitochondrial function in children, as well as a potentially promising therapy for cancer. DCA works by stimulating mitochondrial function and by inhibiting the family of regulatory pyruvate dehydrogenase kinases (PDK). This activates pyruvate dehydrogenase (PDH) and at the expense of glycolysis, reverses the Warburg effect, diminishing the growth advantage of highly glycolytic tumours. DCA has been studied in multiple different formats: in vitro, in vivo, as monotherapy, and in conjunction with other drugs. It has shown signs of benefit in multiple cancers, including glioblastoma, ovarian cancer, endometrial cancer, breast cancer, lung cancer, colorectal cancer, and in metastatic carcinomas. The evidence available for DCA in the treatment of various cancers is reviewed. Clinical pearls from the practice of Gurdev Parmar, coauthor if this article and a Fellow of the American Board of Naturopathic Oncology are provided.

Christopher Habib, ND Clinic Director Mahaya Forest Hill 102-73 Warren Road Toronto, ON M4V 2R9 info@chrishabibnd.com

Gurdev Parmar, ND, FABNO Integrated Health Clinic 2nd floor- 23242 Mavis Ave Fort Langley, BC V1M2R4 info@integratedhealthclinic.com

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Continuing Education Lesson

Introduction

Most cancer cells use anaerobic glycolysis for energy production, despite the fact that oxygen is present. This is termed the Warburg effect and results from mitochondrial dysfunction, which prevents mitochondria-based glucose oxidation (Bayley 2012). Since glucose oxidation is far more efficient at generating ATP compared with glycolysis, cancer cells upregulate glucose receptors and significantly increase glucose uptake. This creates a large difference between malignant cells and normal cells and offers the potential for a very selective therapeutic target, since glycolysis is not seen in normal tissue apart from skeletal muscle during strenuous exercise (Michelakis 2008). Glycolysis results in lactic acidosis, which has the ability to cause toxicity to surrounding tissues and to the cancer cells themselves. However, lactic acidosis can facilitate tumour growth by breaking down the extra-cellular matrix allowing for expansion, increasing cell mobility and metastatic potential, and by activating angiogenesis (Gatenby 2004). Thus, the metabolic remodeling in cancer cells that primarily utilize glycolysis may provide a survival advantage. Dichloroacetate (DCA) is known to environmental scientists as a by-product of water chlorination and is a metabolite of industrial

solvents (Stacpoole 2011). In this regard, it has been implicated in a variety of life-threatening toxicities and considered a human health hazard (IRAC 2004). However, DCA has been known for years to physicians and researchers as an investigational drug for certain metabolic diseases such as inborn errors of mitochondrial function in children, as well as a potentially promising therapy for cancer. DCA works by stimulating mitochondrial function and by inhibiting the family of regulatory pyruvate dehydrogenase kinases (PDK) (Papandreou 2011). This activates pyruvate dehydrogenase (PDH) and at the expense of glycolysis, reverses the Warburg effect, diminishing the growth advantage of highly glycolytic tumours. DCA has been studied in multiple different formats: in vitro, in vivo, as monotherapy, and in conjunction with other drugs. It has shown signs of benefit in multiple cancers, including glioblastoma, ovarian, endometrial, breast, lung, colorectal, and in metastatic carcinomas (Michelakis 2008). This article will review the evidence available for DCA in the treatment of various cancers. Clinical pearls from the practice of Gurdev Parmar, coauthor of this article and a Fellow of the American Board of Naturopathic Oncology are also provided.

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Continuing Education Lesson

Mechanism of Action

A metabolic modulator, DCA is a small molecule and when taken orally can achieve 100% bioavailability (Bonnet 2007). Due to its limited size, DCA can penetrate into the traditional chemotherapy sanctuary sites, including the brain (Michelakis 2008). In vitro, DCA activates PDH by inhibiting PDK and acts in a dose-dependent fashion. This results in a decrease of lactate levels in both the blood and the cerebrospinal fluid by more than 60% (Stacpoole 1989). The metabolic fate of glucose; either entry into glycolysis within the cell cytoplasm or oxidation within the mitochondria via the Krebâ&#x20AC;&#x2122;s cycle; is controlled by the gate-keeping mitochondrial enzyme, PDH. Thus, the activation of PDH shifts cell metabolism away from anaerobic glycolysis and towards glucose oxidation. The activation of PDH also causes numerous other anti-cancer effects within the cell. DCA has an effect on the polarization of the mitochondrial membrane, due to the enhanced activity of PDH. Several human cancer cells have high mitochondrial membrane potential, including non-small cell lung cancer, breast cancer, and glioblastoma cell lines, when compared with non-cancer cell lines (Bonnet 2007). By decreasing the polarization potential, DCA causes an opening of mitochondrial transition pores. This allows the movement of reactive oxygen species, such as hydrogen peroxide, and cytochrome c from the mitochondria to the cytoplasm of the cell, inducing apoptosis through the activation of caspases (Seth 2011). Neoplastic cell lines also express a lower level of potassium channels, which contributes to apoptosis resistance. The mitochondrial remodeling that occurs due to DCA has another downstream effect, since mitochondria also control calcium concentrations and calcium and potassium concentrations are related. DCA upregulates and actives potassium channels in cancer cells, but not in normal cells. This inhibits tumour growth without causing toxicity (Bonnet 2007). The initial half-life with the first dose of DCA is less than an hour, but this half-life increases to several hours with subsequent doses. With chronic use, serum levels plateau (Mori 2004). In clinical trials for lactic acidosis, sepsis, burns, and cirrhosis, doses have ranged from 25 to 100mg/kg per day orally or intravenously (Stacpoole 2003). Evidence

DCA has been studied for the treatment of glioblastomas (GBM). In GBM cell lines from 49 patients, DCA reversed mitochondrial hyperpolarization and did not affect the polarization of normal brain tissue (Michelakis 2010). Five

consecutive patients with primary GBM were also treated with DCA. Three of these patients had recurrent GBM with disease progression after several chemotherapies and standard treatment, and thus were considered appropriate for palliative therapy. The remaining two patients were newly diagnosed after debulking surgery and DCA was administered in addition to standard treatment. Patients were treated with a starting dose of 12.5mg/kg orally twice a day for 1 month, at which point the dose was increased to 25mg/kg orally twice a day. Following this, a dose de-escalation protocol was initiated, whereby the dose was decreased by 50% when dose-limiting toxicity occurred. The patients were followed for 15 months. None had hematologic, hepatic, renal, or cardiac toxicity. Peripheral neuropathy was the only apparent toxicity and it resolved when the dose was decreased to 6.25mg/kg orally twice a day. Three of the patients showed evidence of radiologic regression on MRI. Four of the patients were clinically stable at month 15 of DCA therapy and alive at month 18 (Michelakis 2010). In one study examining the use of DCA on ovarian cancer cell lines, the researchers utilized mitaplatin, a compound with two DCA units appended to a platinum center that when reduced also releases cisplatin, a common chemotherapy drug (Dhar 2009). Platinum compounds are used in half of all cancer therapies (Galanski 2005). However, the use of cisplatin to treat malignancies has been limited because of side effects and acquired resistance, which is a failure to execute apoptosis despite initiation of the apoptotic cascade (Siddik 2003). The combination of cisplatin and DCA provides a dual killing mechanism. Through this unique mechanism, mitaplatin attacks both nuclear DNA with cisplatin and mitochondria with DCA selectively in cancer cells. A separate study examined the use of DCA alone on epithelial ovarian cancer cells. These cancer cells are under intrinsic oxidative stress that alters metabolic activity and reduces apoptosis. DCA was able to reverse the increased oxidative stress and induce apoptosis (Saed 2011). A study of DCA on endometrial cell lines showed that DCA treatment initiated apoptosis in five low to moderately invasive cancer cell lines and had no effect on a non-cancerous cell line (Wong 2008). Two highly invasive endometrial adenocarcinoma cell lines were found to be resistant to DCA-induced apoptosis. Thus, DCA does not have evidence of efficacy in some cancer types. Tumour acidity is a driving force in invasion and metastases and the buffering of extracellular acidity can inhibit the spread of metastases. This was shown in a mouse model for metastatic breast cancer (Robey 2011). In this study, DCA alone or in

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A recent study examining lung carcinoid cell lines utilized DCA in combination with other platinum-based chemotherapeutic drugs, including satraplatin and picoplatin (Fiebiger 2011). The carcinoid cell lines were sensitive to the majority of chemotherapeutics in vitro. Even in highly chemoresistant cell lines, DCA was able to inhibit their growth by 22% and sensitized the cells to some of the platinum-based drugs (Fiebiger 2011). In a study of colorectal cancer cells, DCA was tested alone and in combination with 5-Fluorouracil (5-FU), the classical chemotherapy agent that has been the first line regimen for treating colorectal cancer (Meyerhardt 2005). Four human cell lines were treated in total. Cell cycle and apoptosis were measured by flow cytometry and the expression of apoptosisrelated molecules was assessed by western blot. The results showed that DCA inhibited the viability of colorectal cancer cells and had a synergistic anti-proliferation effect in combination with 5-FU (Tong 2011). Therefore, DCA appears to be helpful when used in combination with other chemotherapy drugs. Finally, a recent case report has investigated the use of DCA for cancer treatment in a palliative setting (Khan 2011). A 71-year-old male with poorly differentiated carcinoma of unknown primary metastatic origin to the right leg and liver achieved excellent palliation of leg pain by using oral DCA after failing conventional therapy (Khan 2011). This patient was treated with 500mg three times a day (the equivalent of 21mg/kg) on a 2 week on and 1 week off cycle. After 8 months, the patient was able to eliminate the use of opiates, including morphine, and did not experience any side effects from DCA treatment. To help prevent peripheral neuropathy, the patient was simultaneously treated with R+ alpha lipoic acid (ALA), acetyl L-carnitine, and benfotiamine (Khan 2011). These additional therapies may be useful for patients undergoing DCA therapy. Clinical Pearls

Dr. Gurdev Parmar, ND, FABNO is the founder and medical director of the Integrated Health Clinic in Fort Langley, British

Columbia. Dr. Parmar has been supervising patient’s using oral DCA for several years, and has now used it in well over a hundred patients. Patients are typically started at 15mg/kg/day in divided doses, either 2 weeks on and 1 week off, or 5 days on and 2 days off. In Dr. Parmar’s opinion, the break is critical for limiting the only known significant side effect of reversible peripheral neuropathy. The dose is then titrated up to 40-50mg/kg/day, by increments of 7.5mg/kg/day every 1-3 months, depending on the patient’s Karnofsky score and co-morbidities. Dr. Parmar rarely exceeds an oral dose of 45 to 50 mg/kg/day. Dr. Parmar has also used IV DCA for the past year, and has treated approximately 30 patients with the IV form of DCA. The starting dose used was 20mg/kg per IV, once to twice weekly. Many patients were escalated up to 50mg/kg per IV once to twice weekly. In conjunction with this treatment, IV ALA and Intravenous Vitamin C are administered. In addition, an oral supplement regime of ALA, acetyl-L-carnitine, and vitamin B1 are recommended to help limit neuropathy, and doubled to treat it if it does occur. When patients develop neuropathy, they are asked to stop DCA treatment altogether until symptoms start to improve. At that point, they are started at 7.5mg/kd/day and slowly titrated to the highest tolerated dose, not to exceed the dose that previously caused the neuropathy.

Continuing Education Lesson

combination with bicarbonate did not increase systemic alkalosis. DCA monotherapy was not effective in reducing tumour size or metastases or improving survival time. This outcome may be a function of hypoxia in the tumour microenvironment (Robey 2011). However, in another study of breast cancer cells, DCA was studied in combination with arsenic trioxide, a drug that is typically used in promyeloid leukemia (Sun 2011). The combination of the drugs was more effective at inhibiting cell proliferation and inducing cell death than either drug alone.

In terms of side effects that have been noted, Dr. Parmar has had one patient develop motor and sensory, seemingly central nervous system related symptoms. This patient developed symptoms including confusion, twitching, fatigue and muscle weakness. This occurred in the absence of any peripheral neuropathy in the hands and feet, and at a dose of 47 mg/kg/day. This patient was however also receiving several adjunctive therapies concurrently to the DCA, which included herbs that could have induced the drug, or down-regulated its metabolism and excretion. In fact, he was taking over 30 different herbal preparations previously prescribed by a herbalist, including very high doses of artemisinin, a known neurotoxic agent (Schmuck 2002). Dr. Parmar has had several patients that have had a significant response to DCA, with partial to complete responses on imaging, due to DCA monotherapy. One patient with stage IV colorectal cancer who was no longer receiving conventional therapy due to lack of benefit, had no evidence of disease after almost a year of DCA therapy. Another colorectal cancer patient was rapidly metastasizing prior to DCA therapy. For two years since she initiated DCA therapy, her disease has been stable. Finally, several patients with GBM have received

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Continuing Education Lesson

DCA alongside local-regional hyperthermia, which has led to significant improvements on repeated MRI and contrast CT. Dr. Parmarâ&#x20AC;&#x2122;s Integrated Health Clinic is currently working to collate this information on a database, with plans for publication thereafter. He is particularly interested in the tumour microenvironment, and the positive metabolic and immunogenic effects of hyperthermia alongside novel treatments such as DCA. Conclusion

After many years of use, the only documented side effect of DCA is dose-dependent reversible peripheral neuropathy (Michelakis 2008). DCA activates PDH and shifts the metabolism of cancer cells towards glucose oxidation. In addition, DCA decreases the polarization potential of the mitochondria, causing an opening of mitochondrial transition pores and leading to apoptosis. There is direct preclinical evidence of anticancer effects of References Bayley JP, Devilee P. The Warburg effect in 2012. Curr Opin Oncol. 2012;24(1):6267. Bonnet S, Archer SL, Allalunis-Turner J, Jaromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007;11(1):37-51. Chen LB. Mitochondrial membrane potential in living cells. Annu Rev Cell Biol. 1988;4:155-181. Dhar S, Lippard SJ. Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate. Proc Natl Acad Sci U S A. 2009;106(52):22199-22204. Fiebiger W, Olszewski U, Ulsperger E, Geissler K, Hamilton G. In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines. Clin Transl Oncol. 2011;13(1):43-49. Galanski M, Jakupec MA, Keppler BK. Update of the preclinical situation of anticancer platinum complexes: novel design strategies and innovative analytical approaches. Curr Med Chem. 2005;12(18):2075-2094. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891-899. IARC (International Agency for Research on Cancer). Dichloroacetic acid. IARC Monogr Eval Carcinog Risks Hum. 2004;84:359-402. Khan A. Use of oral dichloroacetate for palliation of leg pain arising from metastatic poorly differentiated carcinoma: a case report. J Palliat Med. 2011;14(8):973-977. Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer. 2008; 99(7):989-994. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurty MS, Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010;2(31):31ra34. Mori M, Yamagata T, Goto T, Saito S, Momoi MY. Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS. Brain Dev. 2004;26(7):453-8.

DCA with glioblastoma, ovarian, endometrial, breast, lung, and colorectal cancer. Though DCA appears more effective in combination with other chemotherapy drugs, it is not effective in all cell lines. The lack of mitochondrial hyperpolarization in certain types of cancer including lymphomas, neuroblastomas, and sarcomas indicates that DCA may not be effective in these cases (Chen 1988). There is limited evidence for the direct use of DCA in human patients, but funding for trials is a challenge since DCA is a generic drug and industry support may be limited. DCA treatment is still considered experimental is not endorsed by the authors. DCA therapy should only be used as an adjunct to current best practices and does not replace standard of care. Clinical experiences from the practice of a Fellow of the American Board of Naturopathic Oncology support the general safety and efficacy of the supervision of patients wanting to receive the experimental treatment of DCA, both orally and intravenously. â&#x20AC;˘ Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005;352(5):476-487. Papandreou I, Goliasova T, Denko NC. Anticancer drugs that target metabolism: Is dichloroacetate a new paradigm? Int J Cancer. 2011;128(5):1001-1008. Robey IF, Martin NK. Bicorbonate and dichloroacetate: evaluating pH altering therapies in a mouse model for metastatic breast cancer. BMC Cancer. 2011;11:235. Saed GM, Fletcher NM, Jiang ZL, Abu-Soud HM, Diamond MP. Dichloroacetate induces apoptosis of epithelial ovarian cancer cells through a mechanism involving modulation of oxidative stress. Reprod Sci. 2011;18(12): 1253-1261. Schmuck, G, Roehrdanz E, Haynes RK, Kahl R. Neurotoxic mode of action of artemisinin. Antimicrob Agents Chemother. 2002; 46(3):821-827. Seth P, Grant A, Tang J, Vinogradov E, Wang X, Lenkinski R, Sukhatme P. Ontarget Inhibition of Tumor Fermentative Glycolysis as Visualized by Hyperpolarized Pyruvate. Neoplasia. 2011; 13(1):60-71. Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22(47):7265-7279. Stacpoole PW. The dichloroacetate dilemma: environmental hazard versus therapeutic goldmine--both or neither? Environ Health Perspect. 2011;119(2):155158. Stacpoole PW. The pharmacology of dichloroacetate. Metabolism. 1989;38(11):11241144. Stacpoole PW, Nagaraja NV, Hutson AD. Efficacy of dichloroacetate as a lactatelowering drug. J Clinc Pharmacol. 2003;43(7):683-691. Sun RC, Board PG, Blackburn AC. Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells. Mol Cancer. 2011;10:142. Tong J, Xie G, He J, Li J, Pan F, Liang H. Synergistic antitumor effect of dichloroacetate in combination with 5-fluorouracil in colorectal cancer. J Biomed Biotechnol. 1011;740564. Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I. Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol. 2008;109(3):394-402.

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1. The Warburg effect refers to which of the following phenomena: a) most cancer cells use anaerobic glycolysis for energy production despite the fact that oxygen is present b) most cancer cells use glucose oxidation (Kreb’s cycle) for energy production because oxygen is present c) cancer cells’ elevated metabolism utilizes available glucose in the environment, effectively starving normal cells d) all of the above 2. Which of the following is true about the uses of DCA? a) DCA is a by-product of water chlorination and a metabolite of industrial solvents b) DCA is a considered a human health hazard by the IARC c) DCA improves mitochondrial function, so has been used as an investigational drug for certain inborn errors of mitochondrial function in children d) all of the above 3. Which of the following describes the mechanism by which DCA works? a) DCA inhibits the regulatory pyruvate dehydrogenase kinases (PDK) and activates pyruvate dehydrogenase (PDH), which upregulates the Kreb’s cycle b) DCA inhibits glycolysis and reverses the Warburg effect, c) DCA diminishes the growth advantage of highly glycolytic tumours d) all of the above 4. DCA has been found to reduce lactic acid in the blood and CSF by up to 90% . a) true b) false 5. DCA exerts pro-apoptotic effects by reducing mitochondrial membrane hyperpolarization, and thereby increasing the permeability of the mitochondrial membrane to reactive oxygen species; these signal for apoptosis when they are present in the cytosol. a) true b) false

6. In a report of 5 patients with glioblastoma, treatment with DCA resulted in: a) significant cardiac toxicity b) tumor regression in 3 patients on MRI c) disease stabilization in all 5 patients d) all of the above 7. In vitro studies suggest that DCA may be able to reverse resistance to cisplatin chemotherapy. a) true b) false 8. A case report of a patient with advanced metastatic cancer who had failed conventional therapy found that DCA was able to: a) induce complete regression of the tumor b) provide palliation resulting in elimination of the need for opiates c) improve survival d) all of the above 9. Clinically, Dr Parmar utilizes an on-off protocol to limit development of reversible peripheral neuropathy: patients are typically started at 15mg/kg/day in divided doses, either 2 weeks on and 1 week off, or 5 days on and 2 days off, and rarely exceed an oral dose of 45 to 50 mg/kg/day. a) true b) false

Continuing Education Lesson

Questions

10. Which of the following combination of nutritional agents is used to help prevent the development of peripheral neuropathy alongside DCA? a) Benfotamine, methylcobalamin, and folic acid b) Benfotamine, melatonin, and acetyl-L-carnitine c) Benfotamine, alpha lipoic acid, and actyl-L-carnitine d) Benfotamine, alpha lipoic acid, and methylcobalamin

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

Area of Clinical Focus:

Size of Practice (# of Doctors): 0-5 5-10 10 & up

Years of Practice:

0-5

5-10

10 & up

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CALENDAR EVENTS September September 13-16 Parenteral Therapy Certification Course and Refresher Course Organized by: Ontario Association of Naturopathic Doctors Toronto, Ontario For more information, visit www.oand.org September 14-16 10th Annual International Restorative Medicine Conference Organized by: Association for the Advancement of Restorative Medicine San Diego, California For more information, visit http:// restorativemedicine.org September 15 Pascoe Therapies: Beyond the Basics Organized by: Pascoe Kitchener/Waterloo, Ontario For more information, visit http://www. pascoecanada.com September 19 Promoting Healthy Bones with Lifestyle Therapies Organized by: Metagenics Inc. Webinar For more information, visit www. metagenics.com September 19 Treating Patients with Cancer: The Role of Integrative Primary Care in Oncology Organized by: Emerson Ecologics Webinar For more information, visit http://www. emersonecologics.com September 20 Healthy Aging and Regeneration Organized by: Ontario Association of Naturopathic Doctors Webinar For more information, visit www.oand.org

September 20-23 Perinatal Support Group Facilitator Training Organized by: Bastyr University Kenmore, Washington For more information, visit http://www. bastyr.edu

October 9 Winterize Your Immune System – Dodge the Cold and Flu Bullet Organized by: Metagenics Inc. Webinar For more information, visit www. metagenics.com

September 22-23 Nova Scotia Naturopathic Conference 2012 Organized by: Nova Scotia Association of Naturopathic Doctors Halifax, Nova Scotia For more information, visit www.nsnc.info

October 13-14 Pediatric Health: Natural Cures for Common Childhood Ailments Organized by: Seroyal Vancouver, British Columbia For more information, visit www. seroyalseminars.com

September 24 Dietary Fibre and Novel Foods: A Regulatory Update Organized by: Guelph Food and Technology Centre Guelph, Ontario For more information, visit http://www. gftc.ca/courses-and-training

October 17 Holistic Approach to Dental and Oral Health Organized by: Ontario Association of Naturopathic Doctors Webinar For more information, visit www.oand.org

September 28-30 The Evolution of Disease & Biotherapeutic Drainage™ for Individualized Medicine Organized by: Seroyal Toronto, Ontario For more information, visit www. seroyalseminars.com September 28-30 2012 Lifestyle Medicine Summit: Taking the Chronic out of Illness Organized by: Metagenics Inc. Dana Point, California For more information, visit www. metagenics.com

October October 3-4 Building a Successful Practice Business Symposium Organized by: Ontario Association of Naturopathic Doctors Toronto, Ontario For more information, visit www.oand.org

October 17 Canadian Nutrition Labelling Organized by: Guelph Food and Technology Centre Guelph, Ontario For more information, visit http://www. gftc.ca/courses-and-training October 17 Constitutional/Traditional Immune Support Organized by: Emerson Ecologics Webinar For more information, visit http://www. emersonecologics.com October 18-20 Aging in a Changing World: Canadian Association on Gerontology’s 41st Annual Scientific and Educational Meeting Organized by: Canadian Association on Gerontology Vancouver, British Columbia For more information, visit http://www. cagacg.ca

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BuildSaw & Prepare Vitamins palmetto (Serenoa repens) WheyStandardized protein isolate is a complete sourceextract of protein & helps meet requirement associated physical activity (Fulgoni 2008).ofExercise In a Polish studywith of 46 women who had symptoms diffuse increases alopecia, protein calcium (lipophillic) Serenoa has been found to the be ahigher potentprotein inhibitor requirements 1) up to 25% to maintain existing muscle mass, and 2) up to 50% to gain muscle mass (Lemon Dietary protein increases thermogenesis regulate pantothenate was 1997). orally administered twice a day in doses of 100and mghelps for four to of 5α-reductase, resulting in decreased tissue DHT. An open-label, dose response blood glucose. According to one study, even a 3% increase in protein (from 15 to 18% as a percent of total calories) was associated with greater fat loss and the ability to keep it off five months, and vitamin B6 was injected every day for 20 to 30 days and repeated study was conducted on 42 healthy males to determine the effect of a combination after six months (Paddon Jones 2008). again after six months (Brzezińska-Wcisło 2001). It was determined that vitamin of carotenoid astaxanthin and saw palmetto berry lipid extract on DHT and B6 administered parenterally for a few weeks induces improvement in the hair testosterone levels (Angwafor 2008). The men were divided into two groups: Branched chain amino acids (leucine, isoleucine, valine) are anabolic and promote muscle synthesis. In addition, research has shown that BCAAs decrease muscle protein breakdown condition in a subset of women and reduces hair loss. one group received 800 mg/day of the combination supplement and the other (catabolism) during exercise; improve motivation and performance by decreasing the mental perception of fatigue; improve reaction time during performance; lower levels of group receivedcortisol 2000 mg/day of the supplement 14 days. ANOVA-RM showed the stress hormone during recovery; reduce thefortypical delayed onset muscle soreness (DOMS) associated with exercise; reduce muscle fatigue associated with exercise significant increases in serum total testeosterone and significant (Howatson 2012,within-group Shimomura 2010). Medicinal Ingredients dose Per capsule decreases in serum DHT from baseline in both dose groups (P=0.05). There was no significant difference between dose groups with regard to the increase of Fenugreek (Trigonella foenum graecum) Fuel 260 mg testeosterone decrease of DHT; doses were effective (Angwafor activfuel+ providesora the balanced source of lowtherefore glycemicboth carbohydrates from brown rice, agave, and beet root, to4:1 replenish glycogen stores and improve endurance exercise seed extract 2008). and enhance recovery with improved subsequent exercise performance (el-Sayed 1997). 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Chronic Speedthe & Strength inflammation the hair follicle amino is considered be a contributing factor for AGA. A offset exercise induced depletion and diminished performance. According to a study Taurine is one of theofmost abundant acids intomuscle tissue. Supplementation helps D-calcium pantothenate (Vitamin B5) 10.40 mg studyinby2009, Chittur et al was sought to determine whether blockade of inflammation published taurine effective in decreasing lactate accumulation, which using limits the ongoing production of energy in the muscle cells and contributes to DOMS. LSESr and two anti-inflammatory agents (carnitine and thioctic acid) could alter Niacinamide (Vitamin B3) 10.25 mg the expression of molecular markers of electrolytes inflammation 2009). Itwhile was found Rehydrate & Replenish ingredients replace lost(Chittur during exercise, Go the Distance ingredients improve endurance. Creatine increases lean body mass, strength, and Pyridoxine HCl (Vitamin B6)intense physical activity 2 mg that the combination suppressedcreatine lipopolysaccharide-activated gene expression of in repetitive total workload capacity; in particular, improves strength, power and performance bouts of brief, highly (e.g. sprints, jumping, resistance training) (Bosco 1997). chemokines associated with pathways involved in inflammation and apoptosis. Riboflavin (Vitamin B2) 1.58 mg The study concluded that 5-alpha reductase inhibitors in combination with Directions: mixofone scoop (20.9g) of activfuel+ in one to aone a half cups approach (250-375mL toFolic taste)acid of pure water or juice. Take once daily before and/or during your physical blockade inflammatory processes could represent newand two-pronged 0.095 mg activity, needed based on body weight and exercise intensity. Rhodiola increases the body’s ability to handle stress, while thiamine helps reduce levels of lactate and improves in or theastreatment of AGA. oxygen concentration during exercise (Bautista-Hernández 2008). Biotin 400 mcg Fenugreek Seeds Figure 1. Targeted Dosing, to Body Weight andsterols, Exercise Intensity non-Medicinal Ingredients Fenugreek seeds contain 5%according to 30% protein, steroid saponins, flavonoids and alkaloids (notably trigonelline and choline). Steroid saponins bind and Inert microcrystalline cellulose and vegetable-based magnesium >200lb eliminate extra cholesterol and hormones in the body; DHT is made from stearate in a veggie-based capsule which is in turn is made from cholesterol. Therefore, when excess 150 -testosterone, 200lb cholesterol is eliminated, less DHT can be made (Stark 1993). In a study of 20 100 -adults 150 lbwho consumed 12.5g and 18.0g of germinated fenugreek seed powder for Recommended adult dose: One capsule per day one month, higher levels of consumption resulted in a significant reduction in total Light (30min) Medium (30-60min) Heavy (60-90min) Endurance (>90min) cholesterol and low-density lipoprotein (LDL) levels (Sowmya 1999). Green=1 svg; Yellow = 2svg; Red= 3svg Flax lignans the amount of DHT produced by reducing cholesterol levels in the TableFlax 1. reduces activfuel+ formula body. A meta-analysis of 28 studies between 1990 and 2008 showed that flaxseed References Action Dose significantly reduces circulating Ingredient total and LDL-cholesterol concentrations (Pan Bautista-Hernández VM, et al J Int Med Res. 2008 NovFlaxseed interventions reduced andisolate LDL cholesterol by 0.10 mmol/L Dec;36(6):1220-6. Build2009). & Prepare Wheytotal protein (bovine milk) 5.6g (95% CI: -0.20, 0.00 mmol/L) and 0.08 mmol/L (95% CI: -0.16, 0.00 mmol/L), Bosco C, et al. Int J Sports Med. 1997 Jul;18(5):369-72. L-leucine 333mg respectively. Significant reductions were observed with whole flaxseed (-0.21 and Duncan MJ, et al. J Sports Med Phys Fitness. 2012 -0.16 mmol/L, respectively) andL-isoleucine lignan (-0.28 and -0.16 mmol/L, respectively) Jun;52(3):280-5. 333mg supplements (Pan 2009). el-Sayed MS, et al. Comp Biochem Physiol A Physiol. 1997 L-valine 333mg Nov;118(3):789-803. Fuel

Howatson G, et al. J Int Soc Sports Nutr. 2012 May Oryza sativa: whole grain sprouted brown rice dry syrup 6.0g 8;9(1):20. References Beta vulgaris: organicstudy red beet root the effect of a dietary supplement on dihydrotestosterone, 1.5g testosterone Angwafor F III, Anderson ML. An open label, dose response to determine andVL, estradiol healthy males. J Fulgoni et al. Amlevels J Clinin Nutr. 2008 May;87(5):1554SInt Soc Sports Nutr 2008;5:12. 1557S. Agave tequilana: inulin from agave 1.0g Brzezińska-Wcisło L. Evaluation of vitamin B6 and calcium pantothenate effectiveness on hair growth from clinical and trichographic aspects for treatment in Metab. women. Wiad Laurent D,ofetdiffuse al. J Clinalopecia Endocrinol 2000 Lek Taurine 500mg Speed &2001;54:11-8. Strength Jun;85(6):2170-5. Chittur S, Parr B, Marcovici G. Inhibition of inflammatory gene expression in keratinocytes using a composition containing carnitine, thioctic acid and saw palmetto Evid Based Lemon PW, et al. Canextract. J Appl Physiol. 1997 Oct;22(5):494Kola acuminata: Kola nut seed extract (standardized to 10% naturally 500mg Complement Alternat Med 2009. 503.

occurring caffeine) in caffeinated version only

Paddon-Jones D, et al. Am J Clin Nutr. 2008 Pan A, Yu D, Demark-Wahnefried W, Franco OH, Lin X. Meta-analysis of the effects of flaxseed interventions on blood lipids. Am J Clin Nutr 2009;90:288-97. May;87(5):1558S-1561S. Rehydrate &Replenish Cocos nucifera: coconut water freeze dried powder 500mg Prager N, Bickett K, French N, Marcovici G. A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the Shimomura Y, et al. Int J Sport Nutr Exerc Metab. 2010 treatment of androgenetic alopecia. J Sodium Altern Complement (chloride)Med 2002;8:143-52. 50mg Jun;20(3):236-44. Serenoa repens monograph. Alternative Medicine (chloride) Review 1998;3:227-9. Potassium 15mg Sinclair R. Male pattern androgenetic alopecia. BMJ 1998;317:865-9.

Go the Distance

Creatine monohydrate

1.0g

Sowmya P, Rajyalakshmi P. Hypocholesterolemic effect of germinated fenugreek seeds in human subjects. Plant Foods Hum Nutr 1999;53:359-65.

Malus domestica: organic apple peel (Appleboost®)

300mg

Rhodiola rosea root extract (3% rosavin; 10:1=1000mg)

100mg

Vitamin B1 (thiamine hydrochloride)

10mg

Stark A, Madar Z. The effect of an ethanol extract derived from fenugreek (Trigonella foenum-graecum) on bile acid absorption and cholesterol levels in rats, Br J Nutr 1993;69:277-87. Vierpper H, Nowotny P, Maier H, Waldhausl W. Production rates of dihydrotestosterone in healthy men and women and in men with male pattern baldness: determination by stable isotope/ dilution and mass spectrometry. J ClinMagnesium Endocrinol Metab 2001;86:5762-4. (aspartate) 80mg

activfuel+ contains no artificial colours, flavours, sweeteners or preservatives, egg, wheat, gluten or yeast.

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EGCG SAP

PRODUCT MONOGRAPH GREEN TEA AND EGCG

Green tea, from the plant Camellia sinensis, originated in Southwest China 5000 years ago and was originally used as a medicine for various illnesses.(1) Recently, it has been identified that the polyphenolic constituents of green tea extracts are responsible for its pharmacological properties.(2) The major polyphenol found in green tea, belonging to the catechin family, is epigallocatechin gallate (EGCG). Green tea also contains lesser amounts of catechin, epicatechin, gallocatechin, gallocatechin gallate, epigallocatechin, and epicatechin gallate.(1, 2) EGCG is considered the most significant active component of green tea and is known to have powerful antioxidant and chemoprotective effects attributed to the flavan-3-ol structure linked to EGCG’s gallic acid.(3, 4) Currently, tea is the second most consumed beverage in the world.(1)

ANTHOCYANIDINS

Anthocyanidins belong to the flavonoids family and are polyphenols. They are natural antioxidants that are common components of fruits and vegetables, in particular edible berries.(5) They provide color and, depending on their pH and the presence of chelating metal ions, they are intensely colored in blue, violet or red.(6) Common anthocyanidins are cyanidin, delphinidin, malvidin, pelargonidin, peonidin, and petunidin.(6) The American diet provides as much as 180–215 mg/day of anthocyanidins attributed to an increase in commercially available berry extract consumption.(6, 7)

LYCOPENE

Lycopene is a natural carotenoid pigment synthesized by plants and microorganisms, and diet constitutes the primary source of lycopene for humans. The red color of tomatoes is due to the presence of lycopene. Biological actions for a variety of doses of dietary lycopene (5 to 150 mg/day) from foods and tomato oleoresin extract in humans include decreased serum lipid peroxidation, decreased serum LDL oxidation, decreased protein oxidation, increased total antioxidant potential and a trend toward decreased serum DNA oxidation.(8, 9)

ANTIOXIDANTS & REACTIVE OXYGEN SPECIES

Oxygen-derived free radicals known as reactive oxygen species (ROS) are generated through normal metabolic activity, lifestyle activities, and diet. Free radicals cause oxidative damage to lipids and proteins and compromise the integrity of genomic DNA(4). As such, they are widely recognized to be at the root of several degenerative diseases including cancer.(4) Antioxidants act as inhibitors at both the initiation and promotion stages of tumor promotion or carcinogenesis, and they function to protect cells against oxidative damage.(4) Other functions of antioxidants are to scavenge free radicals and to serve as inhibitors of neoplastic processes.(4) Due to their polyphenolic nature, anthocyanidins and EGCG are efficient antioxidants.(1) They scavenge reactive oxygen and nitrogen species, thus reducing damage to lipid membranes, proteins, and nucleic acids.(1, 6, 10) Moreover, green tea catechins allow for prolonged antioxidant protection beyond that of vitamin C (ascorbic acid)(11) and green tea catechins(11) and lycopene(12) have demonstrated greater antioxidant capacity than vitamin E (alpha-tocopherol) and β-carotene.(11, 12)

PGHS, NO) and inhibition of proliferation, and finally antiprogression via induction of programmed cell death (ROS, JNK, Caspase-3) and inhibition of metastasis (MMP’s).(6) Lycopene – Epidemiological studies have linked dietary intake of tomatoes and lycopene to prevention of prostate cancer and associated a 30–40% reduction in prostate cancer risk with high tomato or lycopene consumption.(14) Lycopene, at physiological concentrations, can inhibit human cancer cell growth by interfering with growth factor receptor signaling and cell cycle progression, specifically in prostate cancer cells, without evidence of toxic effects or apoptosis of cells. Furthermore, by up-regulating intercellular gap junction communication, cessation of cell division and induction of protective metabolizing enzymes in the liver, lycopene has also been found to inhibit proliferation of several types of cancer cells, including those of the prostate, breast, lung and endometrium.(15, 16)

Cardiovascular Disease

Green Tea and EGCG – Epidemiological studies have demonstrated a relationship between green tea consumption and decreased cardiovascular risk.(1) For heart disease protection, the potent antioxidant properties of polyphenols inhibit the formation of atherosclerotic plaques by reducing free radical damage to cells and preventing LDL cholesterol oxidation.(1) Anthocyanidins – Epidemiological studies also indicate that moderate intake of anthocyanins is associated with a lower risk of coronary heart disease (CHD)(10) by mechanisms such as maintaining vascular permeability.(5) Lycopene – Recent epidemiological studies have shown an inverse relationship between tissue and serum levels of lycopene and mortality from CHD, cerebrovascular disease, and myocardial infarction.(17) As a dietary antioxidant, lycopene prevents oxidation of LDL-cholesterol,(8) provides a hypocholesterolemic effect,(17) enhances LDL degradation, LDL particle size and composition, plaque rupture, and alters endothelial functions.(17) In addition, lycopene significantly decreased systolic and diastolic blood pressure in patients with grade-1 hypertension by 7% and 5%, respectively.(18)

Weight Loss

Studies suggest a role for catechins in the promotion of weight loss and increasingly more trials are exploring this area.(1) Research supports that observed changes in body composition following green tea or green tea extract consumption occur through sympathetic activation of thermogenesis and fat oxidation. These results appear to be attributable to components in green tea beyond its caffeine content, perhaps through a synergism with caffeine.(1)

SAFETY

Green tea and green tea extract have not been associated with having adverse effects in multiple toxicological tests. However, tannins and polyphenols in green and/or black tea may interfere with the absorption of calcium, iron and zinc but increase that of manganese and copper.(1, 19) It is not recommended that green tea extract be consumed by pregnant or nursing mothers. Anthocyanidins from berries and fruits are widely consumed and considered non-toxic and safe for human consumption. Lycopene from natural tomato oleoresin extract has Generally Recognized As Safe (GRAS) status with the US FDA.

REFERENCES 1.

NUTRITIONAL RESEARCH

2.

Green Tea and EGCG – Case-control and cohort studies have reported an inverse association between green tea consumption and cancers of the breast, colon and rectum, pancreas, stomach, ovary and lung in non-smoking women, as well as prevention of recurrence in stage I and II breast cancer patients.(2, 3)

4.

Cancer

More specifically, EGCG has been predicted to guard against carcinogenesis by blocking cell membrane receptors, repressing the catalytic activities of several P-450 enzymes including P-450 1A and 2B1, and enhancing cancer detoxification enzymes.

3.

5. 6. 7. 8. 9.

In in vitro studies, green tea polyphenols blocked nitrosamines, suppressed carcinogenetic activity in lung, breast, colon, and melanoma cancers, and inhibited estrogen receptor interaction in mammary cancer cell lines. Animal studies found significantly increased activity of antioxidant and detoxification enzymes (glutathione reductase, glutathione peroxidase, glutathione S-transferase, catalase, and quinine reductase) in the lungs, liver, and small intestine following green tea consumption.(13)

10.

Anthocyanidins – Studies have revealed that anthocyanidins can inhibit the growth of embryonic fibroblasts and of cancer cells derived from malignant human tissues from a variety of origins including lung, breast, uterus, vulva and colon.(7)

15.

The potential mechanisms of cancer chemoprevention by anthocyanidins include anti-initiation via antimutagenic effects and antioxidative effects, antipromotion via inhibition of transformation (ROS, MAP kinase, AP-1), anti-inflammatory effects (COX,

For more information visit: www.nfh.ca

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11. 12. 13. 14.

16. 17. 18. 19.

Cooper, R., D.J. Morré, and D.M. Morré. “Medicinal benefits of green tea: Part I. Review of noncancer health benefits”. Journal of Alternative and Complementary Medicine 11, No. 3 (2005): 521–528. Cooper, R., D.J. Morré, and D.M. Morré. “Medicinal benefits of green tea: Part II. Review of anticancer properties”. Journal of Alternative and Complementary Medicine 11, No. 4 (2005): 639–652. Moyers, S.B. and N.B. Kumar. “Green tea polyphenols and cancer chemoprevention: multiple mechanisms and endpoints for phase II trials”. Nutrition Reviews 62, No. 5 (2004): 201–211. Park, O.J. and Y.J. Surh. “Chemopreventive potential of epigallocatechin gallate and genistein: evidence from epidemiological and laboratory studies”. Toxicology Letters 150, No. 1 (2004): 43–56. Bagchi, D., C.K. Sen, M. Bagchi, and M. Atalay. “Anti-angiogenic, antioxidant, and anti-carcinogenic properties of a novel anthocyanin-rich berry extract formula”. Biochemistry (Moscow) 69, No. 1 (2004): 75–80. Hou, D.X. “Potential mechanisms of cancer chemoprevention by anthocyanins”. Current Molecular Medicine 3, No. 2 (2003): 149–159. Cooke, D., W.P. Steward, A.J. Gescher, and T. Marczylo. “Anthocyans from fruits and vegetables—does bright color signal cancer chemopreventive activity?”. European Journal of Cancer 41, No. 13 (2005): 1931–1940. Rao, A.V. “Processed tomato products as a source of dietary lycopene: bioavailability and antioxidant properties”. Canadian Journal of Dietetic Practice and Research 65, No. 4 (2004): 161–165. Rao, A.V. and S. Agarwal. “Bioavailability and in vivo antioxidant properties of lycopene from tomato products and their possible role in the prevention of cancer”. Nutrition and Cancer 31, No. 3 (1998): 199–203. Hou, D.X., K. Kai, J.J. Li et al. “Anthocyanidins inhibit activator protein 1 activity and cell transformation: structure-activity relationship and molecular mechanisms”. Carcinogenesis 25, No. 1 (2004): 29–36. Lotito, S.B. and C.G. Fraga. “Catechins delay lipid oxidation and alpha-tocopherol and beta-carotene depletion following ascorbate depletion in human plasma”. Proceedings of the Society for Experimental Biology and Medicine 225, No. 1 (2000): 32–38. DiMascio, P., S. Kaiser, and H. Sies. “Lycopene as the most efficient biological carotenoid singlet oxygen quencher”. Archives of Biochemistry and Biophysics 274, No. 2 (1989): 532–538. Bushman, J.L. “Green tea and cancer in humans: a review of the literature”. Nutrition and Cancer 31, No. 3 (1998): 151–159. Giovannucci, E. “Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature”. Journal of the National Cancer Institute 91, No. 4 (1999): 317–331. Agarwal, S. and A.V. Rao. “Tomato lycopene and its role in human health and chronic diseases”. Canadian Medical Association Journal 163, No. 6 (2000): 739–744. Heber, D. and Q.Y. Lu. “Overview of mechanisms of action of lycopene”. Experimental Biology and Medicine (Maywood) 227, No. 10 (2002): 920–923. Rao, A.V. “Lycopene, tomatoes, and the prevention of coronary heart disease”. Experimental Biology and Medicine (Maywood) 227, No. 10 (2002): 908–913. Englehard, Y.N., B. Gazer, and E. Paran. “Natural antioxidants from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study”. American Heart Journal 151, No. 1 (2006): 100. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Institute of Medicine, National Academies of Science, Washington, D.C. 2001.

© NFH Nutritional Fundamentals for Health 2012

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EGCG SAP

Science-based ultra antioxidant from green tea, berries, grapes and tomatoes Consuming green tea has been associated with lowered risk of several types of human cancers and cardiovascular disease. Epigallocatechin gallate (EGCG), a potent natural antioxidant, is the major chemopreventive agent in green tea. Evidence also suggests green tea extract and EGCG contribute to weight loss through increased fat oxidation and caloric expenditure. Anthocyanidins are colorful antioxidant compounds found in high concentrations in fruits and berries, that protect against oxidative stress and maintain DNA integrity. Anthocyanidins also act as anti-inflammatory and antimutagenic agents, and by helping maintain vascular permeability offer cardioprotection. In human trials, supplementation with lycopene, a potent carotenoid antioxidant, has improved blood pressure, lipid peroxidation, LDL-cholesterol oxidation, protein oxidation and symptoms of prostate cancer.

ACTIVE INGREDIENTS

Each NON-GMO vegetable capsule contains:

Camellia sinensis (green tea extract) (75% EGCG) . . . . . . . . . . . . . . 500 mg Solanum lycopersicum (tomato extract) (10% lycopene). . . . . . . . . . 50 mg Fruit blend (20% multi-anthocyanidins) . . . . . . . . . . . . . . . . . . . . . . . . 150 mg *Provided by 150 mg of a fruit blend extract of Vaccinium myrtillus, Vaccinium macrocarpon, Vaccinium corymbosum, Vitis vinifera (skin and seed), Prunus serotina, Fragaria × ananassa, Sambucus canadensis, Rubus idaeus. Contains no: Preservatives, artificial flavor or color, sugar, dairy, starch, corn, wheat, gluten, yeast, citrus or egg. EGCG SAP (ultra antioxidant) is available in the following sizes: 30 capsules per bottle AND 60 capsules per bottle.

Take 1 capsule daily with food or as directed by your health care practitioner.

ADULT DOSAGE

1 capsule provides 375 mg of epigallocatechin gallate (EGCG), 30 mg of multi-anthocyanidins, 5 mg of lycopene and <2.5 mg of caffeine. WARNING: Do not take if you are pregnant or breast-feeding.

INDICATION

Independent daily use of EGCG SAP supplies the body with potent antioxidants to improve whole body antioxidant status and contribute to amelioration of chronic disease processes such as cancer and cardiovascular disease. Green tea EGCG is also expected to contribute to increased thermogenesis.

RANGE OF SOURCES AND HIGH CONCENTRATION TO INCREASE EFFICACY

EGCG SAP provides a broad spectrum of antioxidants including catechins, polyphenols, anthocyanidins and carotenoids from green tea, cranberry, elderberry, bilberry, strawberry, cherry, raspberry, grape and tomato extracts. The very high-potency green tea extract in EGCG SAP is standardized to contain 98% polyphenols, 90% catechins and 75% EGCG, allowing for increased dose and efficacy with each capsule. Epicatechin, epicatechin gallate and epigallocatechin are other polyphenols present in this extract.

PURITY AND CLEANLINESS

Third party testing of finished product is done to ensure EGCG SAP is free of heavy metals, pesticides, volatile organics and other impurities.

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

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

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activfuel+ is an all-natural sports nutrition supplement specifically designed to fuel your body - both before and during your workout. With dosing tailored to your intensity, activfuel+ increases energy, improves performance and stamina while relieving fatigue. It also works to decrease physical stress and damage to the body, for faster recovery time. Containing only safe, natural, and research proven ingredients, and without artificial flavours, sweeteners or preservatives, activfuel+ is a convenient, great tasting addition to your workout â&#x20AC;&#x201C; Itâ&#x20AC;&#x2122;s your body and your workout, fuel it your way. See the monograph in this publication for full ingredients and research references.

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Available with Caffeine or Caffeine-free

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IHP September 2012 Edition  

IHP September 2012 Edition

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