IHP Magazine - February/March 2013

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Continuing EducationN-Acetyl Cysteine: a versatile interventionBy Colin MacLeod, ND

Dr Erika Schwartz, MDBioidentical Hormone Therapy provider and educator Continuing

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MCT’s and Alzheimer’s DiseaseBy William R Ware, PhD

DHEA in FertilityBy Heidi Fritz, MA, ND

Molecular chaperones Part IBy Jovana Lubarda, PhD, et al.

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Maximum Allowable Limit

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Seroyal Results

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4 www.ihpmagazine.com l February/March 2013

from the publisher

As spring approaches a fresh start awaits all of us... IHP has undergone some tremendous changes as-of late, changes we are very pleased with: we have created the Journal of

IHP, and we have welcomed a talented, energetic, and experienced new Associate Editor in Chris Habib. Excited to see IHP continue to grow into 2013 and beyond!

The Natural Health Products Directorate of Health Canada has pledged enforcement of their recently- created requirements for natural health products. This should serve to bring clarity on where things stand between many brands in the marketplace.

Reflecting on the year that was has me rethinking the role of technology in my life... As much as I embrace technology I have come to notice that in many ways it has made people somewhat antisocial. People are walking around typing away on their mobile devices instead of taking in their surroundings... My New Year’s resolution this year is less time with devices, more time spent picking up a phone and calling someone.

Overall it has been an excellent start to what is shaping up to be an incredible year... Enjoy the ride!

Sanjiv JagotaPublisher

Happy New Year!

Connect With Us

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Tel: 1.866.562.9131 | Fax: [email protected] www.stfrancisherbfarm.com

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Rene CaisseCanadian operating room nurse Rene Caisse learned of this herbal formula in 1922 from a patient who had recovered from cancer with a mix of herbs given to her by an Ojibwe medicine man. A few months later, Caisse’s aunt was diagnosed with metastatic stomach cancer. Caisse decided to employ the newfound treatment and administered the tea. Her aunt recovered and lived another 21 years, cancer-free. Caisse opened a clinic in Bracebridge, Ontario in 1933 and began using the formula with cancer patients.

Royal Cancer Commission and Dr. Benjamin GuyattA Royal Cancer Commission was set up in 1938 to investigate Caisse’s work. Dr. Benjamin Guyatt, a University of Toronto professor of anatomy, spent time in her clinic as an independent observer. He testi�ed at the Commission, noting that, “… I saw patients come in, in very bad shape, and the next time I went along I found improvement in a number of those cases.” As a result, he prompted the Canadian Medical Association to investigate her work. (Glum 1988)

Mary McPherson �ere has been some controversy over the authentic formula used by Caisse. Mary McPherson is the only person, besides Caisse herself, who prepared the tea for use in her clinic. On December 23, 1994, McPherson divulged the recipe in her own handwriting, in a sworn a�davit (McPherson 1994). It is this same formula, originally published in Gary Glum’s 1988 book, that St. Francis Herb Farm makes, both in the original tea format as well as in a convenient tincture formula.

AlterativeSt. Francis Herb Farm’s Four Herb Tea and �e ‘4’ Herb Formula (tincture) are alterative combinations designed speci�cally to support detoxi�cation 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.

The herbs In terms of speci�c indications relating to the individual ingredients, medieval German philosopher, herbalist, and religious, St. Hildegard of Bingen, used burdock (Arctium lappa) to treat cancerous tumours (Kemper 1999). Taking the history of its use as a folk remedy for abnormal growths as their point of departure, scientists Dombradi and Foldeak (1966) screened burdock for antitumor activity and noted signi�cant properties.

Meanwhile, J. Milton Welch, M.D. classes sheep sorrel as an alterative, calling it “a great cancer remedy” (Welch 1882). Fellow Eclectic physician John M. Scudder, M.D. adds regarding sheep sorrel that, “… Its use in the treatment of cancer has been quite extensive, and if we can believe the reports given, it has proven fully as successful as any other remedy.” (Scudder 1884)

Alma Hutchens (1973) describes traditional use of slippery elm (Ulmus rubra) for both female reproductive tract cancers and stomach cancer. Turkey rhubarb (Rheum palmatum) is considered a mild laxative and valued as a restorative for the entire digestive system.

References: Statistics Canada, Leading Causes of Death in Canada, 2009. Accessed online at http://www.statcan.gc.ca/

Gary Glum, Calling of an Angel, Los Angeles: Silent Walker Publishing; 1988, p. 22 and pp. 39-41.

K Kemper, “Burdock”, Longwood Herbal Task Force. 1999. Accessed from: http://www.mcp.edu/herbal/default.htm

Dombradi CA and Foldeak S, “Screening Report on the Antitumor Activity of Puri�ed Arctium Lappa Extracts,” Tumori 52:173, 1966.

Mary McPherson, A�davit. Scanned version accessed online January 10, 2013 from: http://goo.gl/B2uuG

JM Welch, �e Medical Flora of Kansas.Transactions of the National Eclectic Medical Association, Vol. X, 1882-83

JM Scudder, Speci�c Medication and Speci�c Medicines. Cincinnati: Wilstach, Baldwin & Co: 1884.

Alma R. Hutchens, Indian Herbalogy of North America. Windsor, ON: Merco; 1973, pp. 252-3.

Terry Vanderheyden, ND (Research Consultant)

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.

Terry Vanderheyden, ND, has practiced in Ontario since graduating from the CCNM in 1994, specializing in homeopathic, nutritional, and botanical therapies. He also works as a consultant for St. Francis Herb Farm, Inc. Terry lives in Barry’s Bay with his wife Laurie and their six children.

Product Monograph for IHP, Feb 2013

By Terry Vanderheyden, ND

Products Professionals Prefer®


February/March 2013 l www.ihpmagazine.com 7

Publisher | Sanjiv Jagota (416) 203-7900 ext 6125

Editor-in-Chief | Philip Rouchotas, MSc, ND (416) 203-7900 ext. 6109

Associate Editor | Christopher Habib, ND

Art Director | James March

Design | Sarah Vincett

Production | Erin Booth (416) 203-7900 ext. 6110

ContributorsAngela MacNeil, MSc, ND, Christopher Habib, NDPhilip Rouchotas, MSc, ND

President | Olivier Felicio(416) 203-7900 ext. 6107 Vice President Operations | Frank Shoniker (416) 203-7900 ext. 6109

Controller & Operations | Melanie Seth (416) 203-7900 ext. 6114

Finance Administrator | Henry Fonseca(416) 203-7900 ext. 6127

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Sanjiv Jagota | Tel: (416) 203-7900 ext 6125 Email: [email protected]

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ihp magazine is pleased to review unsolicited submissions for editorial consideration under the following conditions: all material submitted for editorial consideration (photo-graphs, 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, elec-tronic, internet, disc, etc.) without the consent of, or the payment of compensation to, the party providing such material. Please direct submissions to the Editor, ihp magazine.

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contents


30 Dr Erika Schwartz, MD Training integrative healthcare providers for delivery

of Bioidentical Hormone Therapy

38 Paradigm Health Group Leaders in innovation

42 The Journal of IHP Peer-reviewed articles on clinically relevant topics

4 Publisher’s Letter

11 Research News

19 Industry News

24 Calendar

26 Product Profiles

43 Editor’s Letter

45 Peer Review Board

47 Editorial Board

73 Continuing Education: N-Acetyl-Cysteine: a versatile intervention

Coming Next Issue

➜ Psychiatry: concerns with conventional treatments

➜ CRP40 Part II: a treatment for neurodegenerative disease?

➜ Cortisol and blood pressure

This Issue: February/March 2013 • Vol. 6 • No. 1

DepartmentsCover Story

Clinic Profile

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research news


Fruit, vegetable, and antioxidant intakes are lower in older adults with depression

This study examined the cross-sectional associations between clinically diagnosed depression and intakes of antioxidants, fruits, and vegetables in older adults. Antioxidant, fruit, and vegetable intakes were assessed in 278 elderly participants (144 with depression, 134 without depression) using a food frequency questionnaire

that was administered between the years 1999 and 2007. All participants were aged 60 years or older. Vitamin C, lutein, and beta cryptoxanthin intakes were significantly lower among individuals with depression than in comparison participants (P<0.05). In addition, fruit and vegetable consumption, a primary determinant of antioxidant intake, was lower in individuals with clinical depression. In multivariable models controlling for age, sex, education, vascular comorbidity score, body mass index, total dietary fat, and alcohol; vitamin C, beta cryptoxanthin, fruits, and vegetables remained significant. Antioxidants from dietary supplements were not associated with depression. Antioxidant, fruit, and vegetable intakes were lower in individuals with late-life depression than in comparison participants. The authors conclude that these associations may partially explain the elevated risk of cardiovascular disease among older individuals with depression and point to the importance of antioxidant food sources rather than dietary supplements. J Acad Nutr Diet. 2012 Dec;112(12):2022-7. PMID: 23174689

CBT causes an improvement in quality of life in patients with chronic musculoskeletal pain

This randomized controlled study examined the effectiveness of cognitive behavioral therapy (CBT) in a group of patients with chronic pain. Chronic pain causes functional incapacity and compromises an individual’s affective, social, and economic life. CBT is a psychotherapeutic approach that targets maladaptive behaviours and cognitive processes by utilizing goal-oriented procedures. It is generally used for a variety of health conditions, including anxiety, mood disorders, substance abuse, disordered eating, and psychotic disorders. This randomized clinical trial employed two parallel groups comprising 93 patients with chronic pain. Forty-eight patients were submitted to CBT and 45 continued the standard treatment. The visual analogue, hospital anxiety and depression, and quality of life SF-36 scales were applied. Patients were evaluated before and after ten weeks of treatment.When the Control Group and CBT were compared, the CBT group had a reduction of depressive symptoms (p=0.031) and improvement in the domains ‘physical limitations’ (p=0.012), ‘general state of health’ (p=0.045), and ‘limitations by emotional aspects’ (p=0.025).Therefore, CBT was effective and showed an improvement in more domains of quality of life when compared to the Control Group, after ten weeks of treatment. ArqNeuropsiquiatr. 2012 Nov;70(11):864-8. PMID: 23175199

Caffeinated and caffeine-free beverages and risk of type 2 diabetes

This study prospectively examined the association of caffeinated compared with caffeine-free beverages, including coffee, tea, sugar-sweetened beverages (SSBs), and carbonated artificially sweetened beverages (ASBs), with Type 2 Diabetes (T2D) risk. 74,749 women from the Nurses’ Health Study (NHS, 1984-2008) and 39,059 men from the Health Professionals Follow-Up Study (HPFS, 1986-2008) were followed. After major lifestyle and dietary risk factors were controlled for, caffeinated and caffeine-free SSB intake was significantly associated with

a higher risk of T2D in the NHS (RR per serving: 13% for caffeinated SSB, 11% for caffeine-free SSB; P < 0.05) and in the HPFS (RR per serving: 16% for caffeinated SSB, 23% for caffeine-free SSB; P < 0.01). Only caffeine-free ASB intake in NHS participants was associated with a higher risk of T2D. Conversely, the consumption of caffeinated and decaffeinated coffee was associated with a lower risk of T2D. Only caffeinated tea was associated with a lower T2D risk among NHS participants (RR per serving: 5%; P < 0.0001). The authors conclude that SSB intake was associated with a higher risk of T2D and coffee intake was associated with a lower risk of T2D.Am J ClinNutr. 2012 Nov 14.PMID: 23151535

012-019.IHP_Research2.indd 11 2013-02-01 3:11 PM

research news


Meta-analysis of probiotics during helicobacter pylori eradication therapy

This meta-analysis examined whether Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparations could improve Helicobacter pylori (H. pylori) eradication rates and limit side effects. This study included all parallel controlled trials comparing Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparations supplementation or not during H. pylori eradication therapy. Statistical analysis was performed with the Stata version 11.0 software. Subgroup analysis and sensitivity analysis were also performed. The results included ten clinical trials in the meta-analysis. Eradication odds ratio (OR) was available for 1469 patients (708 in probiotics supplementation group and 761 in the control group). The pooled OR by intention-to-treat analysis and by per-protocol analysis in the probiotics supplementation versus without probiotics was 2.066 [95% confidence interval (CI), 1.398-3.055] and 2.321 (95% CI, 1.715-3.142), respectively. The pooled OR of incidence of total side effects was significantly decreased in the probiotics supplementation group (OR=0.305; 95% CI, 0.117-0.793) by the random model without significant publication bias. Therefore, this study showed that Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparations during initial H. pylori eradication therapy in adults may have beneficial effects on eradication rate and incidence of total side effects. J Clin Gastroenterol. 2012 Oct 17.PMID: 23090045

Patient-reported experiences with first-time naturopathic care for type 2 diabetes

This study provides the first report of the perceptions of persons with type 2 diabetes of their first experiences with naturopathic care for their diabetes. This study was conducted in a naturopathic clinic at Bastyr University in Washington. Following their participation in a one-year prospective cohort study of adjunctive naturopathic care for diabetes, twenty-two patients were interviewed

about their experiences working with a naturopathic physician (ND). Using a content analysis approach, nine dominant themes were identified. Three themes characterized the nature of the ND-patient interaction: 1) patient-centered, 2) holistic health rather than diabetes focused, and 3) collaborative. Five themes characterized the content of the clinical encounter: 1) individualized and detailed health promotion, 2) counseling that promoted self-efficacy, 3) pragmatic and practical self-care recommendations, 4) novel treatment options that fostered hopefulness, and 5) patient education that addressed both diabetes self-care and general health. A ninth theme was cross-cutting: the contrast between ND care and conventional medical care. The results of this study indicate that the routine clinical approach used by NDs is consistent with behaviour change theory and clinical strategies found most effective in promoting self-efficacy and improving clinical outcomes. PLoS One. 2012;7(11):e48549. PMID: 23144900

Exercise for cancer-related fatigue during and following treatment: a meta-analysis

This meta-analysis examined the improvements in fatigue due to exercise training. Articles were retrieved using Google Scholar, MEDLINE, PyscINFO, PubMed, and Web of Science databases. Seventy studies involving 4881 cancer patients during or following treatment were utilized. Articles were included when they utilized randomized allocation to exercise or non-exercise and had outcome measures of cancer-related fatigue at baseline and post-intervention. Effect sizes were computed and the quality of the studies was evaluated. A random effects model was used to estimate sampling error and population variance. The evidence

demonstrated that exercise significantly reduced cancer-related fatigue by a mean effect change of 0.32 (0.21, 0.43) and 0.38 (0.21, 0.54) during and following cancer treatment, respectively. During treatment, patients with lower baseline fatigue scores and higher exercise adherence had the largest improvements. After treatment, those who were in trials with a longer duration between treatment completion and exercise initiation had the largest improvements. Those in trials with shorter exercise program lengths and wait-list comparisons also had the largest improvements. Therefore, the authors conclude that exercise has a palliative effect and reduces cancer-related fatigue for cancer patients both during and following cancer treatment. Am J Prev Med. 2012 Aug;43(2):e1-24. PMID: 22813691


PROGRESSIVE NUTRITIONAL THERAPIES OMEGESSENTIAL™

Progressive OmegEssential™ is a high potency blend of cold water, wild caught, purified fish oil along with a family of strategic support nutrients. Fish Oils for the Maintenance of Good Health

As a source of omega-3 fatty acids, namely EPA and DHA, fish oils aid in the maintenance of good health, help support cognitive health/brain function and cardiovascular health (NHPD Monograph: Fish Oil). Fontani, et al (2005) conducted a study to evaluate the effect of omega-3 supplementation on cognitive performance in 33 normal healthy men and women (aged 22 – 51 years) during a 35-day period. Tests involving different types of attention were used, along with the Profile of Mood States (POMS). Results showed a mood profile with increased vigour and reduced anger, anxiety and depression states after omega-3. Furthermore, findings indicated that omega-3 supplementation is associated with an improvement of attentional and physiological functions, particularly those involved in complex cortical processing. Higher consumption of fish and omega-3 fatty acids has been associated with a lower risk of coronary heart disease (CHD). Hu, et al (2002) examined the association between fish and omega-3 fatty acid consumption and risk of CHD in women. Dietary consumption and follow-up data from 84,688 female nurses (aged 34 to 59 years) free from cardiovascular disease and cancer were compared from validated questionnaires. The outcomes indicated that women who consumed more fish and fish oil (omega-3 fatty acids) significantly reduced their risk of heart disease (particularly CHD deaths) by 30%, compared to women who rarely ate fish. Similarly, a prospective, nested case-control analysis was performed among apparently healthy men, who had no evidence of prior heart disease by Albert, et al (2002) to address the hypothesis that long-chain omega-3 fatty acids found in fish are associated with a reduced risk of sudden death from cardiac causes. The fatty-acid composition of whole blood in 184 men was compared with the previously collected blood of 94 men, in whom sudden death occurred as the first manifestation of cardiovascular disease. The study reported that men who consumed long-chain omega-3 fatty acids had a significantly reduced risk of sudden death. Dosage

Indication: Fish Oil Supplement. Helps support cardiovascular health, brain function and healthy mood balance. Adults (≥ 19 years) Dosage

Softgels: Take 2 softgels with breakfast and 2 softgel with dinner for a total of 4 softgels per day. Liquid: Take 1 tsp (5ml) daily with food.

Interactions

Omega-3 fatty acids may increase the risk of bleeding when taken with anticoagulants, aspirin, ginkgo biloba or ginseng (Mason, 2001). Therefore, medical supervision is required. Based on human studies, fish oils may lower blood pressure when taken in certain doses and have additive effects in patients treated with anti-hypertensives (Prisco, et al, 1998). Use with caution. Quality Assurance

Parameter Test Specifications Microbial Total Count USP Less than 1,000 cfu/g Yeast & Mold USP Less than 100 cfu/g Escherichia coli USP Negative Salmonella spp USP Negative Staphylococcus aureus USP Negative Heavy Metal Arsenic USEPA Less than 0.25 ppm Cadmium USEPA Less than 0.25 ppm Lead USEPA Less than 0.25 ppm Total Mercury USEPA Less than 0.25 ppm

References

Albert C, et al (2002). Blood Levels of Long-Chain n-3 Fatty Acids and the Risk of Sudden Death. The New England Journal of Medicine, Vol. 346 No. 15: 1113-1118, April 11.

Fontani G, et al (2005). Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects. European Journal of Clinical Investigation, 35: 691-699.

Hu F, et al (2002). Fish and Omega-3 Fatty Acid Intake and Risk of Coronary Heart Disease in Women. The Journal of the American Medical Association, Vol. 287 No. 14, April 10.

Jellin JM, et al (2006). Pharmacist’s Letter/Prescriber’s Letter Natural Medicines Comprehensive Database.8th ed. Stockton, CA: Therapeutic Research Faculty.

Mason P. Dietary Supplements. 2nd ed. London: Pharmaceutical Press; 2001.

NHPD Monograph. (2006). Fish Oil, August 8.

Prisco D, et al (1998). Effect of medium-term supplementation with a moderate dose of n-3 polyunsaturated fatty acids on blood pressure in mild hypertensive patients. Thromb Res. 1:105-12.

Product MonograPh


research news


Chocolate consumption and stroke in men

This prospective cohort and meta-analysis investigated the association between chocolate consumption and the risk of stroke in men and conducted a meta-analysis to compile the available evidence from prospective studies. 37,103 men were followed prospectively in the Cohort of Swedish Men. A food-frequency questionnaire was used at baseline to assess for chocolate consumption. Cases of first

stroke were obtained from the Swedish Hospital Discharge Registry. For the meta-analysis, pertinent studies were identified using PubMed and EMBASE databases. Study-specific results were combined using a random-effects model. The results of the study showed that during 10.2 years of follow-up, there were 1,995 incident cases of stroke, including 1,511 cerebral infarctions, 321 hemorrhagic strokes, and 163 unspecified strokes. It was found that high chocolate consumption was associated with a lower risk of stroke. The multivariable relative risk of stroke comparing the highest quartile of consumption (62.9g/week) with the lowest (0g/week) was 0.83 (95% CI 0.70-0.99). This did not differ by stroke subtypes. In the meta-analysis of 5 studies, the overall relative risk of stroke for the highest versus lowest category of consumption was 0.81 (95% CI 0.73-0.90), suggesting moderate chocolate consumption may lower stroke risk. Br Dent J. 2012;213(11):559. PMID: 23222329

Recovery of probiotic in tonsil tissue after oral administration

This randomized, double-blind, placebo-controlled study was conducted to determine whether consumption of probiotic Lactobacillus rhamnosus GG (GG) would lead to the recovery of GG in tonsil tissue. After 3 weeks’ daily consumption of GG as a single strain (twenty patients), GG as a part of a multispecies combination (17 patients) or placebo (20 patients), tonsil tissue samples were collected from fifty-seven young adults during tonsillectomy due to chronic or recurrent tonsillitis. Strain-specific real-time PCR was used to detect GG in the tonsil tissue. GG was recovered in the tonsil sample of 40% of the subjects in the GG group, 41% in the multispecies group and 30% in the placebo group. In all subjects with positive recovery of GG in the tonsil tissue, GG was also recovered in the fecal sample taken at the start of the intervention and at the time of the tissue sample collection, which indicates more persistent adherence of the probiotic. Therefore, the results of this study demonstrate that GG can be recovered from tonsil tissue after oral administration as a single-strain probiotic or as a part of a multispecies probiotic combination. Br J Nutr. 2012 Oct 24:1-7.PMID: 23092692

Vitamin B-12 and folate deficiencies predict cognitive decline

This prospective epidemiological study investigated the cognitive significance of low plasma vitamin B-12 concentrations and the role that folate status plays. The authors evaluated vitamin B-12 and folate during an 8-year period. The Framingham Heart Study was used to provide data for analysis. Five hundred forty-nine individuals with a mean age of 74.8 were studied. The measurements included a mini-mental status examination (MMSE), plasma folate, vitamin B-12, methylmalonic acid, homocystieine, demographic factors, and body mass index. The results showed that MMSE scores declined by 0.24 points

per year over the follow-up period. The decline was significantly faster in cohort members who were in the bottom two plasma vitamin B-12 quintile categories. No cognitive advantage was associated with plasma vitamin B-12 in higher categories. In those with lower vitamin B-12 levels, a plasma folate concentration greater than 20.2 nmol/L was associated with a 1-point per year decline, as was the use of supplemental folate. The authors conclude that plasma vitamin B-12 levels from 187 to 256.8 pmol/L predict cognitive decline. In addition, having vitamin B-12 levels in this range or below with high plasma folate or using supplemental folate predicts rapid cognitive decline. J Am Geriatr Soc. 2012;60(8):1457-64.PMID: 22788704

research news


Omega-3 polyunsatured fatty acids slow cognitive decline and improve cardiometabolic risk markers

This randomized controlled cross-over study examined the impact of omega-3 polyunsaturated fatty acids (PUFA) on age related cognitive

decline and cardiometabolic risk factors. Previous studies have not examined the possible relation between cardiometabolic factors and cognitive performance. This study looked at a five week intake of long chain omega-3 PUFA in healthy individuals. 3 grams daily were consumed during 5 weeks, separated by a 5 week washout period in a cross-over placebo controlled manner. 40 healthy middle aged to elderly subjects participated in the study. Cognitive performance was determined by tests measuring working memory and selective attention. The results showed that omega-3 PUFA supplementation resulted in better performance in working memory tests. The omega-3 PUFA lowered plasma triglycerides and systolic blood pressure. In addition, they also lowered fasting glucose, and s-TNF-alpha and all were inversely related to performance in cognitive tests. The authors conclude that the intake of omega-3 PUFA improves cognitive performance in healthy subjects after 5 weeks compared to placebo. There is also a potential of dietary prevention strategies by increasing omega-3 PUFA intake in order to delay the onset of metabolic disorders and the associated cognitive decline.Nutr J. 2012;11(1):99.PMID: 23173831

Effect of essential oil aromatherapy on heart rate and blood pressure

This study examined the use of aromatherapy to measure its impact on heart rate and blood pressure. 100 healthy spa workers in Taiwan were recruited from various spa centers. Three repeated measurements of resting heart rate, systolic blood pressure, and diastolic blood pressure were taken of each spa worker in a study room. Participants were exposed to essential

oil vapour that was generated from an ultrasonic atomizer for two consecutive hours. The total volatile organic compound level in the study room was measured. The results showed that for times from 15 minutes to 60 minutes after the start of exposure, the volatile organic compound level was significantly associated with reduced 15 minute mean blood pressure and heart rate. After exposures of more than 1 hour, the volatile organic compound levels were associated with increased 15 minute mean blood pressure and heart rate. The authors conclude that exposure to essential oil aromatherapy for 1 hour can be an effective method of relaxation as indicated by decreases in heart rate and blood pressure. However, prolonged exposure for longer than 1 hour to essential oils may be harmful to cardiovascular health. Eur J PrevCardiol. 2012. PMID: 23197402

Bioavailability comparison of two forms of vitamin K2 (MK-4 and MK-7)

This study examined two vitamin K2 homologues, menaquinone-4 (MK-4) and menaquinone-7 (MK-7). Vitamin K2 plays a role in bone health and cardiovascular health and both forms have been used as nutrients in food and as nutritional supplements. This study investigated the bioavailability of nutritional doses when administered to healthy Japanese women. A single dose of MK-4 (420 ug or 945 nmol) or MK-7 (420 ug or 647 nmol) was administered in the morning to participants together with a standardized breakfast. MK-7 was

well absorbed and reached maximum serum level after 6 hours of intake and was detected up to 48 hours after intake. MK-4 was not detectable in the serum of all subjects at any time point. Consecutive administration of MK-4 (60 ug or 135 nmol) or MK-7 (60 ug or 92 nmol) for one week demonstrated that MK-4 supplementation still failed to increase serum MK-4 levels. Consecutive administration of MK-7 successfully increased MK-7 levels. The authors conclude that MK-4 present in food does not contribute to the vitamin K status as measured by serum vitamin K levels. MK-7 was significantly associated with increases in vitamin K levels and may be important for extrahepatic tissues. Nutr J. 2012;11:93. PMID: 23140417


industry news


Disconnect between patients and doctors over symptom burden in Ulcerative ColitisThe results of an international survey called ‘Mind the Gap’ assessed patients’ and healthcare professionals’ differing perceptions of ulcerative colitis and were presented during the United European Gastroenterology Week. On average, patients reported almost six flare ups in the previous year while physicians reported almost four. Pain was ranked as very important for patients while physicians ranked urgency and stool frequency the highest. These key differences identified that improved communication between patients and their physician or specialist and better patient education would potentially address these issues.

Canadian surgical first to remove cancer from the liverAt the London Health Sciences Centre, Dr. Roberto Hernandez-Alejandro completed the first of a two stage surgery to remove cancer from the liver. Formally called an associating liver partition and portal vein ligation for stage hepatectomy, or ALPPS procedure, the surgical first is that both stages of the hepatectomy, or removal of the liver, are completed in one week to ensure that cancer does not spread to other parts of the liver.

Takeda marks one billion treatments with gastric ulcer drug PantoprazoleTakeda Pharmaceuticals International recently announced that over one billion treatment courses of its gastrointestinal product Pantoprazole have been administered around the world. Initially launched in 1994 in Germany, pantoprazole is a proton pump inhibitor used to treat acid related disease and is available as a prescription treatment and over-the-counter product. Daily Pantoprazole maintenance therapy for up to 15 years for severe acid-peptic disease is effective and well tolerated. Historically, no major safety concerns were identified in large clinical trials. No evidence of an enhanced risk for gastric carcinoma has been observed in assessments of laboratory and histological parameters.

Six medical heroes named Canada’s 2013 Hall of Fame inductees The Canadian Medical Hall of Fame is the only national Hall of Fame in the world dedicated to celebrating medical heroes. It creates a tribute to those who through discovery and innovation have contributed to better health in Canada and the world. The 2013 inductees are Dr. Antoine Hakim, Dr. David MacLenna, Dr. Claude Roy, Dr. Arnold Naimark, Dr. Bette Stephenson, and the Late Dr. Ian Rusted.The 2013 Induction Ceremony, presented by BMO Harris Private Banking, will be held in Halifax on May 2. Biographies of the current laureates are available on the Canadian Medical Hall of Fame website.

Health Canada approves Bio-K+® for reduction of C. difficile infections in hospitalsHospital acquired C difficile infection remains a common cause of morbidity and mortality. An estimated 1% of patients admitted to hospital in Canada acquire C difficile, and an estimated 10% of them die regardless of their basis for admission to the hospital. Bio-K+® is the first natural health product to have a Health Canada approved claim for reducing risk of acquiring C difficile infection. Makers Bio-K Plus International Inc call upon health care providers and hospital administrators across the country to make coadministration of probiotics with antibiotics in hospital settings a standard of care. They estimate adopting such a standard would save the Canadian healthcare system over $200 million per year.

Health experts urge Canadian women to get their PAP testThe Federation of Medical Women of Canada and the Society of Obstetricians and Gynaecologists of Canada launched their annual campaign titled ‘National Pap Test Campaign’. Healthcare professionals across Canada took a stand against cervical cancer by hosting public Pap test clinics in their community.

Integrated Diabetes Management Program provides rapid improvements in patient careIn Canada, approximately 2 million people have diabetes. The University of Ottawa Heart Institute reported that over 40% of their inpatients are diagnosed with diabetes. As a result, they implemented a program in May 2011 to identify and manage every patient with diabetes admitted as an inpatient. They trained nurses to serve as diabetes specialists. These champions utilized peer-to-peer training to other nurses, doctors, dietitians, and residents that centered on a new guideline and educational tool box designed to walk staff through the steps to identifying and managing diabetes. A year and a half after initially being implemented, the guideline became a mandatory medical directive. After implementation of the program, 85% of patients had their doctors notified of their diabetic status compared with only 26% before the program. More importantly, the average HbA1c in diabetic inpatients dropped by almost 2%, to the target level considered reflective of well-managed diabetes.

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industry news


Study cautions provinces about tendering generic medicinesA new study called “Tendering generic drugs: What are the risks?” was commissioned by the Canadian Generic Pharmaceutical Assocation (CGPA). According to the study, tendering generic drugs in Canada could cause many negative consequences such as potential drug shortages because of less redundancy in the drug supply system, less manufacturing of generic drugs in Canada, less customer services offered by generic suppliers to pharmacies, the closure of some pharmacies, and others. The study discusses how tendering removes the incentive for generic pharmaceutical manufacturers to mount legal challenges to invalid or non-infringement patents on brand-name drugs. The authors argue that tendering has important implications and is only one of the approaches that can be used to procure generic drugs.

Ontario Brain Institute partners with University of TorontoThe Ontario Brain Institute is working with the Graduate Enterprise Internship Program and the Engineering Career Centre – Faculty of Applied Science and Engineering at the University of Toronto to provide work internships in the province’s scientific industry. These internships provide six months of employment with a southern Ontario-based company. Ontario is at the forefront of global neuroscience research and ranks fourth in the world in terms of brain research. These internships will provide graduates with the skills and experience they need to build careers in the neurotechnology industry. Large genetic study shows evidence of link between inflammation and heart diseaseThe University of Ottawa Heart Institute participated in the largest genetic study of coronary artery disease to date. The study was published in the scientific magazine Nature. 15 genetic regions were newly associated with the disease, bringing the total to 46. The research team also identified 104 independent genetic variants that are highly likely to be associated with the disease. These discoveries have helped other doctors from the Heart Institute identify biological pathways that underlie the disease and showed that lipid metabolism and inflammation play a significant role. These findings show clear evidence that several of the genetic risk factors for coronary artery disease function through known inflammatory pathways, which could pave the way for developing new therapies.

Health Canada suspends License of Chemical Testing Laboratory for falsified resultsHealth Canada suspended the License of Chemi Pharmaceutical Inc. of Mississauga, Ontario after uncovering falsified testing results during the course of an inspection. As a precautionary step, companies that had testing done by Chemi Pharmaceutical are being asked to temporarily halt sales of those products until their safety can be confirmed. Health Canada has not seen any indication that the health of Canadians has been compromised.

Atrium Innovations announces 2012 third quarter financial resultsAtrium Innovations Inc, a globally recognized leader in the development, manufacturing and commercialization of innovative, science-based dietary supplements released its results for the third quarter ending September 30th, 2012. Total revenue growth was organic at 11% over last year, or 14% on a currency-neutral basis, to reach $107.6 million. Total branded revenue recorded solid organic growth of 13%, on a currency-neutral basis. “The results for the third quarter were in line with Management’s outlook and reflect the continued focus and priority placed on organic growth across all our brands. Total branded revenue growth of 13% for the quarter over last year represents our best performance in over 4 years. The exceptional performance of Retail Branded in North America must be highlighted with growth of just over 40% over 2011. Total revenues in Europe were under pressure due to difficult economic conditions in the Netherlands.” said Pierre Fitzgibbon, President and CEO. “Our industry continues to grow at a healthy pace. We are well positioned to take advantage of it, and our commitment to improving revenue from organic growth is showing tangible results. We will focus throughout 2013 on optimizing our U.S. manufacturing environment as we complete the implementation of our ERP program”, concluded Mr. Fitzgibbon.

New treatment for Obstructive Sleep Apnea available in CanadaVentus Medical has announced the introduction of its proprietary Provent Sleep Apnea Therapy into Canada. Provent Therapy is an innovative, non-invasive treatment for obstructive sleep apnea. This is a scientifically validated and user-friendly approach that uses nasal expiratory positive airway pressure to keep a patient’s airway open during sleep. Over 1 in 4 Canadian adults are at high risk of obstructive sleep apnea. Continuous positive airway pressure is the primary treatment, but not all patients can tolerate it as a long term treatment. Provent Therapy improved quality of sleep while reducing sleep apnea, daytime sleepiness and snoring in clinical studies in the US. It is easy to use, portable and discreet for use at home or when travelling.

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industry news


The probiotic is being sold under the name Qiara and is being endorsed by some professionals as an alternative to antibiotics that have proven ineffective in some situations due to drug resistance in breastfeeding women.

New drug targets aggressive Non-Hodgkin’s LymphomaAn international research team led by two laboratories from Weill Cornell Medical College have developed a new experimental drug to target an aggressive form of lymphoma, called activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). An experimental small molecule agent called MI-2 irreversibly inactivates a key protein, MALT1, that is responsible for driving the growth and survival of lymphoma cells. In their study, the researchers showed that the MI-2 inactivates any MALT1 it comes into contact with and also does so without any apparent toxicity in animal models.

Social Media changing the behaviour of health care practitionersA recent study analyzed the factors that influence the adoption and use of social media by physicians to share medical information. The authors developed a survey that was emailed to 1695 practicing oncologists and primary care physicians in the United States. Responses from 485 physicians were analyzed. Overall, almost one in four physicians used social media daily or many times daily to scan or explore medical information and 14% contributed new information through social media. Physicians largely had favourable attitudes toward the use of social media and most perceived social media to be beneficial, engaging, and a good way to get high-quality information. A majority of the physicians also identified that social media enabled them to care for patients more effectively and improve the quality of patient care they delivered. The main factors influencing physician’s usage or share information was perceived ease of use and usefulness.

Health Canada gives nurse practitioners more prescribing authorityHealth Canada has published new regulations to grant more prescribing authority to nurse practitioners (NPs), midwives and podiatrists. NPs are registered nurses with additional education, advanced nursing experience, and who work collaboratively with other health care providers. Current legislation and regulation authorize NPs to independently diagnose and treat health conditions, but with limited prescription authority. The new regulations allow NPs across Canada (except Yukon) to prescribe controlled substances under the federal Controlled Drug and Substances Act. This will help to provide more timely and comprehensive care to patients. First public information service devoted to gut microbiota now onlineGut Microbiota World Watch is a new online platform aimed at increasing knowledge and understanding of gut microbiota and its importance for health and quality of life. The intestines are populated with a universe of lifeforms called gut microbiota that perform a variety of vital functions, including functioning as part of the immune system. Launched by the Gut Microbiota and Health section of the European Society of Neurologastroenterology and Motility, this public information service will provide the latest news about gut microbiota. It will act as a point of reference for gut microbiota issues and offer information in straight-forward and easy to understand language. The composition of gut microbita is unique to each individual and evolves throughout the entire life. It is affected by external factors, including conditions of birth, diet, environment, or use of antibiotics. The information service can be accessed at gutmicrobiowatch.org.

ENDECE Neural presents remyelination findings at 2013 Biotech ShowcaseDr. James Yarger, CEO of ENDECE Neural, will discuss the company’s novel therapeutic for directly inducing remyelination of demyelinated axons to treat neurological diseases such as Multiple Sclerosis (MS). Currently there are no drugs commercially available for remyelination in MS, or any other disease associated with demyelination. ENDECE Neural may have one of the first compounds with the ability to directly induce remyelination. This new therapeutic could potentially be used alone or in combination with other immunosuppressant or anti-inflammatory therapies to help restore function and mobility in MS patients.

Potent Antibodies neutralize HIV and offer potential new therapyResearchers at The Rockefeller University have shown that a therapeutic approach harnessing proteins from the human immune system can suppress HIV in mice without need for daily application. Five different antibodies effectively suppressed HIV-1 replication and kept the virus at bay for 60 days after termination of therapy, which has a longer half-life. These potent antibodies were recently discovered. Called broadly-neutralizing antibodies, they were identified and cloned from HIV patients whose immune systems had a high ability to neutralize HIV. Recently, these antibodies have also been shown to prevent HIV from infecting non-human primates, leading to the potential for a vaccine in humans. Breast milk probiotic launched in Australia: world firstBiosearch Life’s Hereditum probiotic strain Lactobacillus fermentum Lc40 is being sold in sachet form and it is marketed for pregnant and breastfeeding mothers. Studies have shown that certain strains of probiotics such as this one can improve the immune system of the mother and infant. In addition, it can prolong breastfeeding by reducing the incidence of mastitis, which the World Health Organization ranks as the number one reason mother’s cease breastfeeding.

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Hair Grow Technology’s Bio-Fen® product line is continually movingforward! We are introducing our two latest versions; Bio-Fen® Plus forMen and Bio-Fen® Plus for Women. These products have beenassigned Natural Product Numbers (NPN’s) by the Natural HealthProducts Directorate (NHPD) of Health Canada.

We recognize that both men and women experience androgenicalopecia (AGA, or male / female pattern baldness) and have madesome improvements to the original formulation based on the latestscience to address their specific needs. You will notice that we nowhave additional complementary (Health Canada Approved) healthclaims on each product.

What causes hereditary hair loss?Each hair grows from a pocket in the skin called the hair follicle.During its growing phase the follicle has a bulb-shaped bottom, thecenter of which is called the dermal papilla. The paplla is fed by verysmall blood vessels, which bring it food, oxygen and remove wastes.The papilla is highly sensitive to hormones and chemicals secreted bythe body (or ingested as a medicine) which impacts hair growth It isbelieved that some individuals have a genetic predisposition to areceding hairline (most common in men) or hair (follicle) thinningover larger areas of the scalp (more common in women). These condi-tions result from hormonal changes caused by an enzyme in the der-mal papilla called 5-alpha-reductase. This enzyme breaks down thehormone testosterone into dihyrotestosterone (DHT). Over a period oftime, an over abundance of DHT causes the hair follicle to degrade andshortens the active phase of the hair, eventually leading to thinnerhair and eventual hair loss.

How does Bio-Fen® PLUS work?We are bringing you two new products with double the number ofcapsules and triple the number of health claims for men and fourtimes the number of health claims for women, As in the previous for-mulation, the fenugreek seed extract in both new formulas reducesexcess blood lipid levels (hyperlipidemia). Fenugreek contains β-sitos-terol, an active plant sterol, which has been shown to inhibit 5-alpha-reductase activity – the enzyme responsible for converting excess

testosterone to DHT(which is the primary molecule thatcauses hair loss). The SDG from flax lignans inboth formulas also decreases excess cholesterol - the build-ing block of testosterone. Based on new research on the rate of metab-olism of SDG in flax lignans (8-12 hours on average), the dosage in bothproducts has been revised from once a day to twice a day for optimumresults.

Twice the Strength! Double the Power!

Bio-Fen® Plus for Men:The mechanism that causes AGA in men follows the same pathwaythat results in benign prostatic hyperplasia (BPH). For example, theprescription drug finasteride also works by blocking the enzyme 5α-reductase and is used as a treatment for both BPH and AGA. For AGA itis marketed under the brand name of Propecia, but the exact samemolecule for BPH is sold under the name of Proscar.

As before, the saw palmetto extract inhibits the enzyme 5-alpha reductase, and this action slows down the conversion of testosterone todihydrotestosterone (or DHT) – the overabundance of which causes theminiaturization of hair follicles. This activity of the saw palmetto alsohelps to relieve the urinary symptoms of mild to moderate BPH formen.

The saw palmetto that originally was an extract standardized to 45%free fatty acids, esters, and sterols while the new formula is a 4:1 extractto support the BPH claim. The product still contains these molecules forhair loss, but they are now at proprietary amounts based on our researchso that the competition cannot duplicate our formula.

Bio-Fen® Plus for Men will also help to:• Relieve the urologic symptoms associated with mild to moderate

benign prostatic hyperplasia - BPH (e.g. weak urine flow, incomplete voiding, frequent daytime and night time urination).

• Reduce elevated blood lipid levels / hyperlipidemia.

Bio-Fen® Plus for Women:The women’s formula is almost the same as the men’s formula. Themechanisms and results for the women formula is the same. The onlydifference is it contains silicon and iron instead of saw palmetto.Silicon has been shown to contribute to hair shaft strength and thushealthy hair growth. It also contains iron which helps prevent irondeficiency. A number of studies have related sub-clinical iron deficien-cy in women to diffuse hair loss/alopecia.

The increased amount of SDG and other revisions to the regulationsallow us to make some additional health claims for Bio-Fen® Plus for Women.

Bio-Fen® Plus for Women will also help to: • Reduce elevated blood lipid levels/hyperlipidemia

• Prevent iron deficiency.

• Metabolize carbohydrates, fats and proteins.

How long must I use Bio-Fen® Plus? Bio-Fen® Plus for Men capsules are usually effective at stopping hairloss within the first two months. However, since healthy hair growsonly about 1 cm each month, it may take up to three months beforeyou notice that hair growth is increased or the rate of hair loss isdecreased. Anyone experiencing new growth should see it within fourmonths. In some people the original pigmentation may come back.Once you stop completely your hair growth pattern will slowly go backto the point where you started. However, some people may be able togo with a lower maintenance dose.

Why has the recommended dose doubled?Based on new research on the rate of metabolism of SDG in flax lignans (8-12 hours on average), the dosage in both products has beenincreased to twice a day for optimum results. The flax lignan extract inthe original formulation was 100 mg standardized to 20% SDG x 1capsule per day, which equaled to 20 mg/day of SDG. The new formulations have 200 mg per capsule of flax lignan extractstandardized to 50% SDG x 2 caps/day equals 200 mg/day of SDG. As such, one is getting 10 times the amount of SDG per day!.

How safe is Bio-Fen® Plus? The ingredient combination in Bio-Fen® Plus is generally safe for mostadults. However, the following cautions are advised:

For Men:Consult a health care practitioner prior to use to exclude a diagnosis ofprostate cancer, or if you have diabetes. For BPH or elevated blood lipidlevels, consult a health care practitioner if symptoms persist or wors-en. People sensitive to niacin may experience flushing of the skin thatis generally mild and transient. Discontinue use if you experiencehypersensitivity to flax, such as an allergy (may occur in rare cases).

For Women:Consult a health care practitioner prior to use if you are pregnant or ifyou have diabetes. Consult a health care practitioner if elevated bloodlipid levels persist or worsen. People sensitive to niacin may experienceflushing of the skin that is generally mild and transient. Discontinueuse if you experience hypersensitivity to flax, such as an allergy (mayoccur in rare cases). Because of the iron content, some people mayexperience constipation, diarrhea and/or vomiting. Keep out of thereach of children. There is enough iron in this package to seriouslyharm a child.

Available at Health Food Stores andIndependent Pharmacies

Hair Grow Technology Inc. • 1-866-424-7745 • www.biofen.com


BIO-FEN for Men and Women

Bio-Fen represents a line of products approved by Health Canada for hair growth and restoration. Bio-Fen Plus for Men and Bio-Fen Plus for Women are both oral natural health products (NHPs) which support hair growth in men and women with hereditary androgenic alopecia (AGA), or female/male pattern baldness. Bio-Fen contains a combination of herb extracts and vitamins & minerals that are known to inhibit the enzyme 5 -reductase (5AR), a key pathway implicated in the progression of AGA. AGA Pathophysiology One of the primary causes of hair loss is a high level of the male hormone, dihydrotestosterone (DHT) within the hair follicle (Hoffmann 2002). DHT is produced from testosterone in the testes (males), the adrenal glands, and the follicle. After a period of time, an over abundance of DHT causes the hair follicle to degrade and shortens the active phase of the hair, eventually leading to thinning hair and eventual hair loss. There is a familial tendency for stepwise miniaturization of the hair follicle and an increase in the ratio of telogen (resting phase) to anagen (growth phase) hairs, which is promoted by systemic and local effects of androgens. Although everyone produces DHT, only those with a higher number of androgen receptors in their hair follicles, binding sites for DHT, and greater androgen sensitivity experience hair loss (Prager 2002). 5AR is responsible for the conversion of testosterone to dihydrotestosterone, which binds to the same androgen receptor, but with five-fold greater affinity. (Hoffmann 2002, Trueb 2002)

Flax Flax lignans inhibit the enzyme 5AR, thus balancing formation of the male hormones that are responsible for hair loss (Evans 1995). Flax lignans are converted by the body to enterolactones, which compete with estrogen and testosterone for receptor binding, and increase sex hormone binding globulin (SHBG), resulting in lower levels of free (ie active) estrogen and testosterone. Flaxseed has been shown to reduce serum levels of 17-beta-estradiol and estrone sulfate (Hutchins 2001), and results in a shift in estrogen metabolism to favor the less biologically active estrogens (Brooks 2004). Fenugreek Fenugreek has been used traditionally as an oral and topical treatment for hair loss. Plant sterols contained in fenugreek such as -sitosterol have been shown to block DHT receptor sites (Prager 2002, see below). Saw Palmetto (men’s product) Saw palmetto extract is a potent inhibitor of 5 -reductase, resulting in decreased tissue DHT (Prager 2002). In a pilot study of 26 men with mild to moderate AGA, treatment with a combination of lipophilic saw palmetto extract 200mg and beta-sitosterol 50mg improved symptoms by up to 60%, as scored by blinded assessors (Prager 2002). In a meta analysis by the Cochrane group, saw palmetto has also been found to be effective as a treatment for symptoms of BPH (Wilt 2002). Silica (women’s product) Silica is a trace mineral that has been found to increase hydroxyproline concentration in connective tissue (Barel 2005). In a randomized, double blind, placebo controlled study, 50 women with damaged skin were treated orally with 10mg silica as orthosilicic acid (OSA) daily for 20 weeks. The treatment group reported a significant decrease in visual analog scale ratings of hair brittleness (Barel 2005). A second randomized, double blind, placebo controlled trial conducted in 50 women with brittle hair found that 10mg silica as OSA for 9 months significantly improved hair elasticity, breakage, and diameter (thickness) (Wickett 2007). B vitamins are support healthy cell growth and division, and facilitate optimal hormone metabolism. Medicinal ingredients per capsule in both the men’s and women’s: Fenugreek (Trigonella foenum graecum) seed extract 4:1 ....................................................260 mg

(dry equiv 1040mg) Flax lignans, standardized to 50% SDG ...............................................................................100 mg d-calcium pantothenate (Vitamin B5) ..................................................................................10.4 mg Niacinamide (Vitamin B3) ...................................................................................................10.3 mg Pyridoxine HCl (Vitamin B6) ...............................................................................................2.0 mg Riboflavin (Vitamin B2) .......................................................................................................1.6 mg Folic acid ..............................................................................................................................95 mcg Biotin ....................................................................................................................................250 mcg Men’s also has: Saw palmetto berry extract 4:1 .............................................................................................125 mg

(dry equiv. 500 mg) Women’s also has: Silicon (silicon dioxide) ........................................................................................................40 mg Iron (ferric citrate) ................................................................................................................20 mg Recommended use: one capsule twice daily (60 capsules per bottle). Bio-Fen® Plus capsules are usually effective at stopping hair loss within the first two months. Anyone experiencing new growth should see it within four months. Once Bio-Fen is stopped, the hair growth pattern will slowly return to its original point, however some people may be able to continue with a lower maintenance dose. Bio-Fen has been approved by Health Canada and has received a unique NPN number. In addition to being approved for hair growth applications, Bio-Fen has been approved for additional health benefits

Contraindications: The ingredient combination in Bio-Fen Plus for Men/Women is generally safe for most adults. Bio-Fen should not be used by patients with diabetes, or known hypersensitivity to any ingredients. References Brooks JD, et al. Am J Clin Nutr. 2004 Feb;79(2):318-25. Evans BA, et al. 1995 Nov;147(2):295-302. Hoffmann R. Clin Exp Dermatol. 2002 Jul;27(5):373-82. Hutchins AM,et al. Nutr Cancer. 2001;39(1):58-65. Prager N, et al. 2002 Apr;8(2):143-52. Trüeb RM. Exp Gerontol. 2002 Aug-Sep;37(8-9):981-90. Wickett RR, et al Arch Dermatol Res. 2007 Dec;299(10):499-505. Wilt T et al. Cochrane Database Syst Rev. 2002;(3):CD001423.

Saw palmetto (Serenoa repens)Standardized (lipophillic) Serenoa extract has been found to be a potent inhibitor of 5α-reductase, resulting in decreased tissue DHT. An open-label, dose response study was conducted on 42 healthy males to determine the effect of a combination of carotenoid astaxanthin and saw palmetto berry lipid extract on DHT and testosterone levels (Angwafor 2008). The men were divided into two groups: one group received 800 mg/day of the combination supplement and the other group received 2000 mg/day of the supplement for 14 days. ANOVA-RM showed significant within-group increases in serum total testeosterone and significant 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 testeosterone or the decrease of DHT; therefore both doses were effective (Angwafor 2008).

Another study tested liposterolic extract of Serenoa repens (LSESr) and beta-sitosterol in the treatment of males (23-64 years of age) with mild to moderate AGA. Six of 10 (60%) subjects were rated as improved at the final visit, thus establishing 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 study by Chittur et al sought to determine whether blockade of inflammation using LSESr and two anti-inflammatory agents (carnitine and thioctic acid) could alter the expression of molecular markers of inflammation (Chittur 2009). It was found that the combination suppressed lipopolysaccharide-activated gene expression of chemokines associated with pathways involved in inflammation and apoptosis.The study concluded that 5-alpha reductase inhibitors in combination with blockade of inflammatory processes could represent a new two-pronged approach in the treatment of AGA.

Fenugreek SeedsFenugreek seeds contain 5% to 30% protein, steroid saponins, sterols, flavonoids and alkaloids (notably trigonelline and choline). Steroid saponins bind and eliminate extra cholesterol and hormones in the body; DHT is made from testosterone, which is in turn is made from cholesterol. Therefore, when excess cholesterol is eliminated, less DHT can be made (Stark 1993). In a study of 20 adults who consumed 12.5g and 18.0g of germinated fenugreek seed powder for one month, higher levels of consumption resulted in a significant reduction in total cholesterol and low-density lipoprotein (LDL) levels (Sowmya 1999).

Flax lignansFlax 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 2009). Flaxseed interventions reduced total and LDL cholesterol by 0.10 mmol/L (95% CI: -0.20, 0.00 mmol/L) and 0.08 mmol/L (95% CI: -0.16, 0.00 mmol/L), respectively. Significant reductions 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).

VitaminsIn a Polish study of 46 women who had symptoms of diffuse alopecia, calcium pantothenate was orally administered twice a day in doses of 100 mg for four to five months, and vitamin B6 was injected every day for 20 to 30 days and repeated again after six months (Brzezińska-Wcisło 2001). It was determined that vitamin B6 administered parenterally for a few weeks induces improvement in the hair condition in a subset of women and reduces hair loss.

Recommended adult dose: One capsule per day

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.

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.

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.

Serenoa repens monograph. Alternative Medicine Review 1998;3:227-9.

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

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

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

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

PRODUCT MONOGRAPHBio-FenBio-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 of fenugreek seeds, saw palmetto berries and flax lignans, as well as specific vitamins. Each ingredient is known to possess inhibitors of the enzyme 5α-reductase. These inhibitors are responsible for relieving symptoms associated with hereditary AGA. 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 the receptor five-fold more avidly than the parent compound (Sinclair 1998).

Medicinal Ingredients Dose Per Capsule

Fenugreek (Trigonella foenum graecum) seed extract 4:1

260 mg

Saw palmetto berry extract containing 45% free fatty acids

160 mg

Flax lignans, standardized to 20% secoisolariciresinol diglucoside (SDG)

100 mg

D-calcium pantothenate (Vitamin B5) 10.40 mg

Niacinamide (Vitamin B3) 10.25 mg

Pyridoxine HCl (Vitamin B6) 2 mg

Riboflavin (Vitamin B2) 1.58 mg

Folic acid 0.095 mg

Biotin 400 mcg

Non-Medicinal Ingredients

Inert microcrystalline cellulose and vegetable-based magnesium stearate in a veggie-based capsule

.


calendar


FEBRUARYFebruary 8-10Functional Medicine Advanced Practice ModulesOrganized by: Institute for Functional MedicineTampa, FloridaFor more information, visit http://www.functionalmedicine.org

February 9Diagnosis & Therapy using Constitutional Medicine I - Fundamentals of IridologyOrganized by: Pascoe CanadaVancouver, British ColumbiaFor more information, visit http://www.pascoecanada.com

February 10Diagnosis & Therapy using Constitutional Medicine II - In-Depth IridologyOrganized by: Pascoe CanadaVancouver, British ColumbiaFor more information, visit http://www.pascoecanada.com

February 134th Annual LTC Applied Research Education DayOrganized by: Ontario Long Term Care AssociationToronto, OntarioFor more information, visit http://www.oltca.com/en/events/ared_index.html

February 13-15Foundations in Food ScienceOrganized by: Guelph Food Technology Centre (GFTC)Guelph, OntarioFor more information, visit http://www.gftc.ca/courses-and-training

February 15-17OncANP ConferenceOrganized by: OncANPPhoenix, ArizonaFor more information, visit http://www.oncanp.org

February 21Practice Opportunity 2013Organized by: CMCC

Toronto, ONFor more information, visit http://www.cmcc.ca

February 22-24Obstetric Ultrasound: Setting the Standard for 2013Organized by: Mount Sinai HospitalToronto, OntarioFor more information, visit http://www.mountsinai.on.ca/education

February 26Integrative Approaches to Cancer Care WebinarOrganized by: NDOToronto, OntarioFor more information, visit http://www.ndontario.com

February 27 - March 2The 5th International Conference on Fetal Alcohol Spectrum Disorder Organized by: University of British Columbia Interprofessional Continuing EducationVancouver, British ColumbiaFor more information, visit http://www.interprofessional.ubc.ca/fasd/default.asp

MARCHMarch 6Get Unstuck Now Instruction Manual to Reach Your Destiny WebinarOrganized by: NDOToronto, OntarioFor more information, visit http://www.ndontario.com

March 14Tony Moore Internal Medicine Conference 2013Organized by: ScrippsSan Diego, CaliforniaFor more information, visit http://www.scripps.org

March 14-17ICIM’s 56th CongressOrganized by: Integrative Medicine ConferenceWashington, DCFor more information, visit www.integrativemedicineconference.com

March 20-21Food Science: Introduction to Food ScienceOrganized by: Guelph Food Technology Centre (GFTC)Guelph, OntarioFor more information, visit http://www.gftc.ca/courses-and-training

March 23-24Reclaim the BrainOrganized by: SeroyalPortland, OregonFor more information, visit http://www.seroyalseminars.com

APRILApril 4-7First Line Therapy Certification Organized by: MetagenicsToronto, OntarioFor more information, visit http://www.metagenics.com

April 11-12CHFA West ConferenceOrganized by: CHFAVancouver, British ColumbiaFor more information, visit http://www.chfa.ca

April 13-14Improve Clinical Outcomes & Elevate Your PracticeOrganized by: SeroyalToronto, OntarioFor more information, visit http://www.seroyalseminars.com

MAYMay 3-9Naturopathic Medicine WeekOrganized by: CANDFor more information, visit http://www.cand.ca

JUNEJune 7-9Health FusionCAND’s bi- annual conferenceOrganized by: CANDOttawa, OntarioFor more information, visit http://www.cand.ca/index.php

027.IHP_Calendar-issue 31-v2.indd 24 13-02-01 2:47 PM

20 13

Call for Nominations 2013Do you know someone who has made a significant contribution to the field of Complementary & Alternative Medicine in Canada?

Nominations are now being accepted for the $250,000 Dr. Rogers Prize for Excellence in Complementary & Alternative Medicine

Nominations close: Friday, May 31, 2013, 5:00 pm PST

Prize to be presented at the Gala Award Dinner in Vancouver, BC on Thursday, September 26, 2013

Nominations and information: www.drrogersprize.org

Dr. Roger Prize Recipients Catalysts in the Field of CAM

$250,000 Prize realizes exponential impact in the future of health careThe Dr. Rogers Prize highlights the important contributions of comple-mentary and alternative medicine to health care. Awarded biennially, it is intended to recognize and reward people who have made signifi-cant contributions in the field. The largest prize of its kind in North America, the first Dr. Rogers Prize was awarded in 2007.

True pioneers in CAM, previous recipients of the prize have used the award to continue their groundbreaking work. Dr. Hal Gunn and Dr. Badri Rickhi, co-recipients of the 2009 prize, have each used the award to further research in their respective fields. Dr. Gunn, co-founder of InspireHealth, has utilized the funds for the Research Department at InspireHealth, as well as the development and research of Site Specific Immunotherapies, a novel cancer immunotherapy treatment that stimulates that body’s innate immune system. Having achieved success with a spiritual approach to treatment of adult depression, Dr. Rickhi, Research Chair at the Canadian Institute of Natural and Integrative

Medicine, has used the prize to develop and test a similar internet-based approach to treating adolescents. Dr. Rickhi firmly believes in keeping an open mind in the treatment of illness. “If we stay in the box, what we’re trying to do is become better technicians. If we go outside the box – for me – that is what being a scientist is about.”2011 winner, Dr. Marja Verhoef, Research Chair in Complementary Medicine at the University of Calgary recognizes the importance of collaboration and is passionate about Whole Systems Research. She will use the Prize to improve the quality of CAM research and the CAM research training opportunities.

“CAM treatment systems can only be done justice by research that acknowledges their complexity and the interconnectedness of the various treatment elements,” says Dr. Verhoef. “It is not acceptable to say that we don’t have such methodological approaches. If that is so – we need to develop them.”


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Carlson Laboratories

The Very Finest Fish Oil is a good source of omega-3 fatty acids EPA & DHA, and is available in both lemon and orange flavors. The important omega-3s help support cardiovascular health and brain function. Freshness, potency & purity of Carlson fish oils is always guaranteed.

PASCALLERG® - Direct help from nature

PASCALLERG® is considered safe and effective for all ages for the treatment of allergies. A 1999 retrospective study examined the usefulness of PASCALLERG® among 3,499 children aged 1-12 (including 1483 between ages 1-6). The effectiveness for hay fever, skin allergies, bronchial asthma, and other diseases (such as eczema, food allergies, food intolerances, dermatitis etc) were examined. Positive experiences were reported by 91% of therapists for hay fever and skin allergies, and 80% of therapists for bronchial asthma. Dosage was within the recommended daily dose. 44% of patients required two weeks of treatment or less for acute conditions while 47% for chronic conditions. For more information, please visit www.pascoecanada.com.

Vascular Relax BP

Vascular Relax BP is a powerful combination of minerals and herbal extracts for vascular smooth muscle relaxation, endothelial function, and overall circulatory health. Vascular Relax BP contains magnesium, hawthorn, olive leaf, grape seed and pomegranate. Magnesium supports healthy cellular electrolyte function and vascular smooth muscle cells. Both hawthorn and olive leaf have a long history of traditional use for maintaining cardiovascular health. Grape seed has been shown to maintain healthy collagenase, elastase and hyaluronidase enzyme activity. Pomegranate offers antioxidant and vascular benefits.

DIM® Enhanced

DIM® Enhanced, provided by Douglas Laboratories, is a microencapsulated form of diindolylmethane, with curcumin, green tea, and wasabia designed to support healthy estrogen detoxification, hormone balance and immune health. Microencapsulated DIM by BioResponse® is a patented, absorption-enhancing formulation to ensure proper assimilation by the body. During the body’s natural detoxification processes, potentially detrimental molecules such as hormone metabolites, alcohol, drugs and air pollutants are removed from the blood stream via the liver. Healthy hormone detoxification is a crucial part of the normal functioning of the immune system.

Maximum Strength Fish Oil

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NFH’s NAC SAP

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product profiles

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AOR’s most comprehensive heart health formula: Co-enzyme Q10 helps inhibit LDL oxidation and free radical production while P5P reduces toxic homocysteine. Curcumin lowers cholesterol and reduces inflammation, and Arjuna increases blood flow. Antioxidant hydroxytyrosol prevents LDL oxidation and helps regulate blood pressure, and Powergrape delivers protective polyphenols and flavonols.

Ortho • Heart

Ortho • Heart contains fast acting ingredients that help maintain a healthy blood pressure. Potassium nitrate and a high-nitrate mixed vegetable concentrate supply nitric oxide (NO) for vasodilation. Hibiscus extract functions as an ACE-inhibitor, and chlorogenic acid has blood pressure-reducing effects. Vitamin C is beneficial for blood vessel tissue repair.

GENESTRA BRANDS™ Super EFA Liquid - Orange and new Strawberry Flavours GENESTRA BRANDS™ fish oils are omega-3 science leaders. GENESTRA BRANDS™ Super EFA Liquid incorporates cutting edge NEO-3™ natural EPA/DHA enrichment processes for demonstrated efficacy, stability and superb palatability.· Naturally enriched EPA & DHA via NEO-3™process keeps natural triglyceride form without using alcohol or chemicals; extracts toxic contaminants to virtually undetectable levels; and delivers less oily, cleaner taste.

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NEURAPAS® balance – Vitality and Motivation

NEURAPAS® balance is a well-tolerated herbal remedy that produces favorable results in the treatment of mental illnesses, particularly those with imbalanced mood, because of its well-balanced composition and various pharmacological effects. In addition, because of the unique synergy – meaning smaller amounts of St. John’s wort achieve the same therapeutic effect - NEURAPAS® balance has been shown to have no side effect on liver enzymes at therapeutic doses. Therefore the concern for side effects traditionally observed with St. John’s wort is not a problem with NEURAPAS® balance.

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UBQHTM, a patented form of ubiquinol in an exclusive,clinically studied delivery system

Integrative TherapeuticsTM introduced the first stable ubiquinol product to the practitioner market in 2006. UBQH supplementation results in a greater sustained plasma level of total CoQ10 than traditional CoQ10 supplementation.*

For many patients, supplementation with CoQ10 is not enough. Genetic predisposition and aging can limit the body’s ability to convert ubiquinone (CoQ10) to its active form, ubiquinol (QH).

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TECHNICAL DATA

DescriptionCoenzyme Q10, or CoQ10, is dynamically cycled between two stable states: ubiquinone, the fully oxidized (energy supporting) state that shuttles electrons, and ubiquinol, the fully reduced (antioxidant) state that releases electrons. Ubiquinol is an extremely unstable compound and converts to ubiquinone upon exposure to light or oxygen.1 However, research has led to the development of a method to stabilize ubiquinol. UBQH contains Kaneka QH™, patented (US10/501,698 US Appl. # 20050147598), stabilized, active ubiquinol.2 Studies have shown that in older individuals, supplementation with stable ubiquinol resulted in greater sustained plasma levels of the active form of CoQ10 (ubiquinol).3

UBQH:• Exclusive, patented formulation containing ubiquinol • Availableineither50mgor100mgsoftgels• Efficientdeliverysystem—especiallyimportantforindividuals

requiring high dose CoQ10 • Hastheserumimpactofupto162%thatofCoQ10(ubiquinone)2• Showntoincreaseleftventricularfunction*4

• Nosignificantadverseeffectsreportedduringsafetyandtoxicologicalstudies† Total CoQ10 measurement consists of the sum of both ubiquinone and ubiquinol levels. For most people, the Total CoQ10 measurement is approximately 97% ubiquinol and 3% ubiquinone.

BackgroundCoQ10,anessentialcomponentofcellularenergyproduction,wasfirstisolatedfrombeefheartmitochondriain1957byFrederickCrane,PhDattheUniversityofWisconsinEnzymeInstitute.5In1958,a team of researchers led by Karl Folkers, PhD determined the precise chemical structure of CoQ10 (2,3 dimethoxy-5 methyl-6 decaprenyl benzoquinone), synthesized it, and successfully produced it by fermentation.6 That same year, another team of scientists led by RA Morton, PhD isolated the same substance from mitochondria and named it ubiquinone because of its widespread (ubiquitous) occurrence in nature.7

Inthelate1970s,CoQ10researchdramaticallyincreasedasthetechnologytoproducelargequantitiesof pure CoQ10 was perfected and the ability to accurately measure its presence in blood and tissue samples was developed. To date, CoQ10 has been the subject of more than 4,000 studies, eleven internationalconferences,and,in1978,theNobelPrizeinChemistry.BritishbiochemistPeterMitchell,PhDwasawardedtheNobelPrizeforhiscontributiontotheunderstandingofbiologicalenergytransferwhich includes the vital role of CoQ10 in energy transfer systems.8

This large body of evidence has established that CoQ10 supplementation can improve cell energy production and extend cell life by enhancing cellular mitochondrial levels of CoQ10, thus supporting allphysicalsystems,includingsupportofcardiac,neurological,periodontal,skin,andimmunehealth.* Ithasalsobeenpreviouslydemonstrated(throughresearchutilizingIntegrativeTherapeutics’VitalineCoQ10) that supplementation with coenzyme Q10 raises serum and mitochondrial levels of CoQ10, therebysupportinghealthycellularrespiration.*

How It WorksMost of the cells in the human body contain mitochondria, small organelles that make adenosine triphosphate(ATP),theenergy-richcompoundthatfuelsthebody’sactivities.ThesynthesisofATPwithin the mitochondria is a highly complex, multi-stepped process involving a series of biochemical reactions called the electron transport chain.9 As ATP cannot be stored, it must be replaced as it is used. This means that ATP production is an ongoing event. While ATP can be produced by a number of distinct cellular processes, the majority of ATP is generated by the electron transport chain.8,10

CoQ10isanaturalnutrientthat’sfoundinthemitochondria.Calleda“coenzyme”becauseofitsuniqueability to participate in chemical reactions and remain unchanged, CoQ10 assists in two vital cellular activities:ATPproductionandfreeradicalscavenging.*8 To carry out these activities, mitochondrial CoQ10 continuously cycles from ubiquinone, its ATP production state, to ubiquinol, its antioxidant free radicalscavengingstate.*11

As previously stated, the generation of ATP within the electron transport chain is a complex process. Eachstepresultsinthebuildingupofenergy.UbiquinonecontributestoATPproductionbytheshuttling or transporting of electrons. Similar to people in a bucket brigade passing buckets of water to one another, ubiquinone passes electrons from one enzyme complex to another.12 To meet the considerable energy needs of cellular activities, the electron transport chain makes considerable quantities of ATP.7

The electron transport chain also creates an enormous amount of free radicals – about 1 trillion oxygen radicals per cell every day. Most of these oxygen radicals are contained within the membrane folds of the mitochondria; however, about two percent are able to get free, generating toxinsthatpresentasignificantdangertotheentirecell.*13,14,15 The antioxidant form of CoQ10, ubiquinol, scavenges free radicals within the mitochondria and cell membranes.1

While free radical formation is harmful to all cells, it is especially dangerous to cells with high biologic activity,suchasheartandbraincells.*ThehighestconcentrationofCoQ10isfoundincardiovascular(heart)andnervoussystem(brain)cellstoprotecttheirvitalfunctions.*10,11 Ubiquinol is an important antioxidantbecauseitispresentatsiteswherefreeradicalsinflictsignificantdamage.*1,5,7

Whilemorethan90%oftheCoQ10foundinahealthyperson’splasmaisinitsreducedform,ubiquinolis highly unstable and reverts back to ubiquinone when it is exposed to air and light.16 This is why, until very recently, only ubiquinone has been available in supplement form. The process of stabilizing ubiquinol outside of the body took several years to test and perfect.17 The KanekaQH in UBQH ubiquinolhastheinnateabilitytobeabsorbedmoreefficientlythanubiquinone.WhilesupplementalCoQ10 must be cycled to ubiquinol for absorption, the Kaneka QH in UBQH is able to avoid this reduction reaction as it is already in the reduced state. UBQH is especially helpful for those individuals whoseDNAcannotproperlyprocessCoQ10orthosethatareexperiencinganaturaldeclineinCoQ10productionassociatedwithaging.*

Scientific ResearchWhen individuals have substandard plasma levels of (total) CoQ10 (<2.0 g/ml), CoQ10 supplementation frequentlyfailstoprovideanadequatetherapeuticresponse,evenatdosesupto900mg/day.*18,19 Many individuals respond poorly, if at all. A study by Watson demonstrated a mean plasma CoQ10 level of only 1.7 g/ml in the treatment group with only two of 30 patients (ages 18-75 years old) having a level greater than 2.0 g/ml.18TheKhattatrial,whichincludedfifty-fiveparticipants(meanage=64years),demonstrated a mean plasma CoQ10 level of 2.2±1.2 g/ml indicating that some patients on treatment had levels as low as 1.0 g/ml.19

A recent clinical study of seven adult men and women (ages 58-78) with low serum CoQ10 levels (mean level 1.4 g/ml) and corresponding left ventricular output decreases investigated their response to Kaneka QH supplementation.4 Follow-up data showed an increase in mean plasma CoQ10 levels from 1.6mcg/mlto6.5mcg/ml,aswellasanimprovementinleftventricularfunctionfrom22%upto39%.

A2011studydemonstratedtheabilityofubiquinoltosupporthealthylipidmetabolism.*20 The study included 53 healthy men who were given 50 mg of Kaneka QH ubiquinol three times daily for two weeks. The researchers reported that supplementation with ubiquinol was shown to support healthy LDLcholesterolmetabolism.*

Inanexperimentwhichusedananimalmodelofaging,ubiquinolsupplementationwasassociated

with healthier aging (as determined by skin, eye, skeletal and general health) in comparison to aging intheboththeCoQ10andcontrolgroup.*21 The control group in this experiment experienced double the senescence scores in mid-life when compared to the ubiquinol group, while the CoQ10 supplementedgrouphadsenescencescoresapproximately1.5timesashighastheubiquinolgroup.*Increasedsenescencescoresareanindicationofthesignsofaging.*

Stability and SafetyThe safety, absorption, and bioavailability of ubiquinol have been established. Acute toxicity and safety studies of ubiquinol including genotoxicity tests, Ames, chromosome, and micronucleus tests have all been negative.21

Inarecentplacebo-controlledsafetytrial,singledosesofKanekaQHweregivento15healthyvolunteers (5 males and 5 females for the 150 mg dose and 5 males for the 300 mg dose).22Nosafetyconcerns were noted, no changes in standard laboratory tests were observed, and no adverse events werereportedindosesofupto300mgforuptotwoweeksafterthestudy’scompletion.Inthebioavailability arm of the study, 78 healthy volunteers (10 males and 8 females each for placebo, 90 mg,150mg,and300mgdosegroups)receivedKanekaQHfor4-weeks.NoclinicallyrelevantchangesinducedbyKanekaQHwerenotedinthesubjects’standardlaboratorytests,physicalexamination,vitalsigns,orelectrocardiograph(ECG)readingsinanydosagegroup.

ConclusionKanekaQHinUBQHisthesameformofCoQ10thatispresentinover90%ofthehumanbloodstream.16UBQHwouldbeappropriateforolderadults,individualspresentingwithNQ01geneticinefficiencies,orthoserequiringhigherdosesofCoQ10duetoconditionsthatareassociatedwithreducedbloodCoQ10levels.*Requiringnoconversionfromubiquinonetoubiquinol,UBQHisreadytosupportnervoussystemandcardiovascularhealthinthesepopulations.*

References1. Littarru GP, Tiano L. Bioenergetic and antioxidant properties of coenzyme Q10: recent developments. Mol

Biotechnol 2007;37:31-7. 2. Unpublished data. Kaneka Corporation. January 19, 2005.3. Unpublished data. Kaneka Corporation. July, 20044. Langsjoen PH, Langsjoen AM. Supplemental ubiquinol in patients with advanced congestive heart failure.

Biofactors 2008;32:119-28.5. Crane F, Hatefi Y, Lester R, Widmer C. Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta

1957;25: 220-1.6. Langsjoen P H. Introduction to CoQ10. Available at: http://faculty.washington.edu/ely/coenzq10.html. Accessed

March 14, 2008. 7. Morton RA. Ubiquinone. Nature 1958;182:1764-7.8. Barry R. The Power of Kaneka QH: The Key to Energy, Vitality, and a Healthy Heart. Sherman Oaks, CA: Health

Point Press; 2008: 1-48.9. Porth CM, Carroll EW. Mitochondria. In: Porth CM. Pathophysiology: Concepts of Altered Health States. 6th ed.

Philadelphia, Pa; Lippincott; 2004:8-9.10. Guyton AC, Hall JE. Mitochondria. In: Textbook of Medical Physiology. 9th ed. Philadelphia, Pa: WB Saunders;

2001:16-17.11. Coenzyme Q10. Monograph. Altern Med Rev 2007;12:159-68. 12. Fleming T., ed. Coenzyme Q10. In: PDR® for Nutritional Supplements. Montvale, NJ: Medical Economics

Company; 2001: 103-106.13. Sohal RS, Forster MJ. Coenzyme Q, oxidative stress and aging. Mitochondrion 2007;7:S103-11. 14. Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol 2003;552:335-44.15. Cadenas E. Mitochondrial free radical production and cell signaling. Mol Aspects Med 2004;25:17-26.16. Ruiz-Jiménez J, Priego-Capote F, Mata-Granados JM, Quesada JM, Luque de Castro MD. Determination of

the ubiquinol-10 and ubiquinone-10 (coenzyme Q10) in human serum by liquid chromatography tandem mass spectrometry to evaluate the oxidative stress. J Chromatogr A 2007;1175:242-8.

17. Ueda T, Ono T, Moro M, Kitamura S, Ueda Y. Method of stabilizing reduced coenzyme Q10. Patent application number US 2005/0008630 A1. January 13, 2005.

18. Watson PS, Scalia GM, Galbraith A, Burstow DJ, Bett N, Aroney CN Lack of effect of coenzyme Q on left ventricular function in patients with congestive heart failure. J Am Coll CARDIol 1999;33:1549-1552.

19. Khatta M, Alexander BS, Krichten CM, Fisher ML, Freudenberger R, Robinson SW, et al. The effect of coenzyme Q10 in patients with congestive heart failure. Annals of Internal Medicine 2000;132:641-648.

20. Schmelzer C, Niklowitz P, Okun JG, Haas D, et al. Ubiquinol-induced gene expression signatures are translated into altered parameters of erythropoiesis and reduced low density lipoprotein cholesterol levels in humans. IUBMB Life. 2011;63(1):42-8.

21. Unpublished data. Kaneka Corporation. October 22, 2003.22. Hosoe K, Kitano M, Kishida H, Kubo H, Fujii K, 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;47:19-28.

UBQHTM 50 mg Ubiquinol FactsServing Size: 1 softgel (50 mg) Amount per softgel DV%**

Calories 5 Calories from fat 5 Total Fat 0.5 g <1%**Reduced Form Coenzyme Q10 (as Ubiquinol) (Kaneka QH™) 50 mg **

UBQHTM 100 mg Ubiquinol FactsServing Size: 1 softgel (100 mg) Amount per softgel DV%**Calories 5 Calories from fat 5 Total Fat 0.5 g <1%**Reduced Form Coenzyme Q10 (as Ubiquinol) (Kaneka QH™) 100 mg ****Daily Value (DV) not established.

Other ingredients: See label for most current information.

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cover story


Dr Erika Schwartz,

MDTraining integrative healthcare

providers for delivery of Bioidentical Hormone Therapy

By Philip Rouchotas MSc, NDPhotography by Babar Khan

Dr. Erika Schwartz is the go-to physician for all types of healthcare providers looking to train in prevention and wellness. In that context she is perhaps best known for her role as physician educator in the methodology and science of bioidentical hormone replacement therapy for prevention and wellness. Her career, however, started in a very different area of medicine. At the age of 28, Dr. Erika was the Medical Director of a major trauma centre in New York City. Five years later she went into the private practice of internal medicine and developed a highly successful practice for the following fifteen years affiliated with three hospitals and on the board of a New York medical school. What lead this well- respected, classically- trained physician to seek a new approach to patient management? “I didn’t like the style of medicine I was practicing... everything was disease focused... I was waiting for people to get sick while doing testing and sending them home to wait for something to go wrong”, was her reply.

cover story


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Dr. Erika’s career path is as unique as the life path that brought her to her current position. Born in Bucharest, Romania, she graduated from an American high school in Rome, then off to the “Big Apple” to attend college and medical school in New York City. Graduating from medical school in 1975, Dr. Erika’s internship, residency and fellowship focused on internal medicine and critical care, all disease centered practices. Twenty years into the practice of this conventional type of medicine, Dr. Erika found herself asking more questions than the system had answers for... By the early 1990’s, her interest in prevention was firmly established.

Dr. Erika researched physicians in New York and California that were engaged in the practice of integrative medicine and found few credible resources and no formal training available in the area. Dr.Erika found herself spending countless hours researching available data and training in the practices of integrative medicine. Her role today as a leading educator in prevention and bioidentical hormones for clinical practitioners stems from Dr. Erika’s personal frustration with the lack of quality education and training in areas considered outside conventional medicine.

Erika has written a highly successful series of books aimed at educating the general public on principles of wellness and disease prevention. Her first book, entitled Natural Energy (From Tired to Terrific in 10 Days) (1999) reviewed and highlighted the importance of CoEnzyme Q10 and L- carnitine in fighting fatigue. We at IHP are in total agreement that these two agents are crucial in maintaining healthy mitochondrial function, an area receiving more and more attention as the focus of care shifts to health maintenance rather that disease treatment.

Dr. Erika attributes tremendous importance to hormone balance as a means of preventing chronic diseases in the 21st century. “Running out of hormones is unhealthy. Using human identical hormones as replacement opens the door to true disease prevention. Prevention strategies are likely to fail if people feel drained, exhausted, depressed, and generally unwell. Using human identical hormones to create much needed hormone balance leads to improved mood, energy, and general well being allowing a person to be able to address the multiple lifestyle factors (diet, exercise, sleep) responsible for disease prevention”.

Dr. Erika’s second book was published in 2002, and we feel it important to point out it was published three months before the results of the Women’s Health Initiative study demonstrated the use of synthetic (pregnant horse urine) estrogen as a source of higher risk for heart disease, strokes and cancer. In her book, The Hormone Solution, Dr. Erika raised concerns about synthetic hormone replacement therapies (estrogen derived from pregnant mare’s urine), while highlighting the advantages of human identical hormone therapy (also known as bioidentical or natural hormones) and discussed the impact on overall health when individualized hormone therapies are provided for each patient. In 2004 Dr Erika authored her next book “The 30 Day Natural Hormone Plan”, reinforcing the importance of hormone health and simultaneously providing useful tools for implementing health sustaining plans for diet, exercise, relationships, and sleep. In 2007 Erika published Hormone Solution for your Daughter, which showcased the role of hormones in balancing the health of teenagers, and reviewed important skills for parenting, diet, exercise, relationships and sleep.

Treatment with bioidentical hormones has witnessed various methods of usage. Dr. Erika applies a concept of therapy we found incredibly unique; unlike the conventional approach of “treat to a target blood level”, Dr.Erika adopts the approach of “treat until the person feels well and then assess blood levels. Those are then the target blood levels for the individual in question”. It is an approach that may result in “higher than typically used in compounding ” levels of hormones being prescribed, yet is an approach that is truly individualized, and inherently identifies each patient’s particular optimum hormone levels. The approach may be applied to a broad array of treatment plans, not isolated to the application of bioidentical hormones.

cover story


cover story



cover story


“The book is intended for the public, yet delivers an important message to physicians as well; physicians need to change their attitudes. They have to become patient partners and serve the patient rather than their own egos. The book teaches patients to take responsibility for their own care, to trust themselves and not allow others to dictate their path to wellness. Ultimately, there is no reason to be sick!”


cover story


cover story

035-040.IHP_CoverStory5.indd 34 2013-02-04 3:00 PM

cover story


Dr. Erika has emerged as a leading authority in the education of healthcare providers. In 2007, along with a few other key opinion leaders in the field of prevention she founded the not for profit organization Bioidentical Hormone Initiative www.bhionline.org www.bioidenticalhormoneinitiative.org Through this organization and its affiliation with a New York medical school, Dr. Erika is able to offer practitioners clinical in office and seminar format training on the use of bioidentical hormone therapy. The seminars Dr. Erika teaches are not just about how to use bioidentical hormones in your practice; they are powerful examples of patient advocacy, and a tremendous and effective tool in bridging the gap between conventional and integrative healthcare providers. The seminars attract practitioners from all disciplines leading to successful much needed inter-professional relationships that result in truly integrative care for the patients and mutual respect and information sharing.

Dr. Erika has a new book in the works. The book focuses on helping patients take responsibility for their own healthcare by giving them the tools and confidence necessary to avoid bad medical decisions. “The book is intended for the public, yet delivers an important message to physicians as well; physicians need to change their attitudes. They have to become patient partners and serve the patient rather than their own egos. The book teaches patients to take responsibility for their own care, to trust themselves and not allow others to dictate their path to wellness. Ultimately, there is no reason to be sick!” she affirms.

IHP is grateful to Dr. Schwartz for taking the time to allow us to showcase her work to you. Dr. Erika is an incredible, energized, brilliant physician whose presence motivates you to ask yourself “what else can I do to help others”... Her parting words for me seem an ideal way to end this story: “you are only as good as the last past patient you helped make well”. ■


TM

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

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PRODUCT mOnOgRaPhPRODUCT MONOGRAPH

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

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

Animal and In vitro studiesCarvacrol for oral candidiasis in immunocompromised rats was found to be as effective as treatment with Nystatin, reducingthe 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 speciesprimarily due to extensive lesion of the plasma membrane (Salgueiro 2003).Carvacrol has potent antimicrobial activity against several microbial species, including Staphylococcus aureus, Bacillussubtilis, Escherichia coli, Psuedomonas aeruginosa, Candida albicans, and Aspergillus niger; out of these, Candida albicanshas been found most susceptible (Santoyo 2006). Carvacrol and thymol are thought to exert an additive effect by disruptingbacterial membrane integrity (Lambert 2001). Oregano has been shown to inhibit Methicillin resistant strains of Staph.

aureus and epidermis, and attenuates biofilm formation in vitro (Nostra 2004; 2007).ToxicologyEssential 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, indicaterelative safety of Oregano oil.Carvacrol was shown to be hepatoprotective against ischemia and reperfusion injury in rats; both carvacrol and silymarinhad similar beneficial effects on AST and ALT levels (Canbek 2007). Carvacrol also increased liver regeneration rate in ratsafter 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).

ReferencesCanbek 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 oforegano 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 oforegano, 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. FEMSMicrobiol 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 withantimicrobial 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 partialhepatectomy. Phytomedicine 2008; 15(3): 226-9.

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

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clinic profile


Paradigm Health Group

By: Angela MacNeil, MSc, ND

Leaders in innovation

IHP is proud to introduce Paradigm Health Group, a 2000 square foot integrative medicine clinic in Calgary, Alberta. Dr. Jason Ahlan and Dr. Trevor Hoffman founded

Paradigm after working together at the Integrative Medicine Institute of Canada (IMI), a collaboration amongst medical doctors, naturopathic doctors, dentists, and other healthcare professionals. When IMI closed its doors in 2007, these highly enthusiastic naturopathic doctors opened Paradigm with the vision that “by doing what we love, taking care of our patients one at a time, we can translate that to a positive experience for all.”

Dr. Ahlan and Dr. Hoffman recognized that successful individual naturopathic practices can be extremely difficult to establish. Believing that “there is power in numbers”, they opted to build a strong medical practice comprised of six naturopathic doctors with different backgrounds, strengths, and specialities, who are each held to the same level of excellence. Paradigm offers comprehensive care to patients that strongly consists of in-house cross-referrals. In an attempt to provide patients with the best care possible, Paradigm realizes that practitioners must sometimes acknowledge when another practitioner can provide superior care, especially considering the broad range of services offered, including prolotherapy, photoactivated platelet rich plasma injection therapies, nutrient IVs, chelation therapy, ozone therapy, ultraviolet blood irradiation, neural therapy, and mesotherapy. On the horizon, services offered will also include ultrasound guided injection therapies and adipose derived stem cell therapies. Numerous programs are offered that address stress, sleep, cancer, sports medicine and performance enhancement, pain management, autoimmunity, Firstline Therapy (FLT), allergies/sensitivities and related disorders, and detoxification. Detailed descriptions of these services and programs can be found on Paradigm’s website (http://www.paradigmhealth.ca). Paradigm strives to offer a wide variety of therapies in an effort to address numerous patient needs.

In addition to the naturopathic doctors, the clinic boasts an

amazing network of 15 in-house/affiliated medical doctors with different specialities, and a broad referral network that includes chiropractors, massage therapists, physiotherapists, and holistic nutritionists. This network has contributed immensely to Paradigm’s success and the practitioners feel very fortunate to have these ties.

An effective networking strategy employed by Paradigm is the attendance of medical conferences; this serves to further the knowledge base within the clinic while simultaneously increasing contacts. In recent months alone, Paradigm practitioners have attended prestigious conferences world-wide, including the Restorative Medicine Conference, the Ironman Hawaii Sports Medicine Conference, the American College for Advancement in Medicine, and the American Academy of Orthopaedic Medicine. Since naturopathic medicine is a rapidly expanding field, staying on the cutting edge of research requires

043-044.IHP_Clinic-issue31-v2.indd 38 13-02-01 12:20 PM

clinic profile


training from experts around the world. Admittedly, these conferences are costly to attend but the practitioners note that the education, improved experience, and expanded network they confer are priceless and have had tremendous impacts on the practice’s success.

In addition to a strong focus on continuing education, Paradigm is represented at the Canadian Institute of Natural and Integrative Medicine (CINIM), a registered charitable organization that conducts scientific research in complementary/alternative medicine (CAM). CINIM was the first of four Canadian institutions to become involved with the United States Consortium of Academic Health Centres for Integrative Medicine whose membership includes 51 highly esteemed academic medical centers and affiliate institutions, including Harvard, Yale, and the Mayo Clinic. Dr. Ahlan is one of only three naturopathic doctors in this collaboration, representing the University of Calgary Medical School. CINIM was developed in response to public demand for information about alternative therapies and access to these therapies.

Several of Paradigm’s practitioners are also involved with the Pure North S’Energy Foundation, a non-profit initiative that focuses on the delivery of innovative preventative and integrative health and wellness strategies. Pure North includes a comprehensive team of expert health and dental care professionals including physicians, naturopathic doctors and nurses that travel throughout Canada providing first-rate personalized services to populations who cannot afford integrative medicine. At last count, this funded program has taken the team to multiple sites internationally, seeing almost 15,000 patients from the firefighters in the Slave Lake disaster, to the Native American communities in Inuvik, to the off-shore oil sites in the North Sea of Scotland. Paradigm’s practitioners also belong to a wide array of boards and advisory councils that include Winsport Canada, Hockey Canada, Alpine Canada, Bobsleigh Canada, The Calgary Flames Hockey

Club, College of Naturopathic Doctors of Alberta (CNDA), and the Competancy Committee for Restricted Activities for the CNDA.

Paradigm offers patients a broad range of evidence-based diagnostic tests to verify clinical diagnoses and treatment of various health challenges. Diagnostic testing is offered from Rocky Mountain Analytical, Doctor’s Data, PharmaSan Labs, NeuroScience, Genova Diagnostics, Metametrix, and Meridian Valley. Paradigm practitioners consider themselves fortunate as the majority of their patients receive blood work through affiliated medical doctors as part of diagnostic work-ups. The clinic also offers a dispensary that features the best products from a variety of companies, including AOR, Douglas Labs, Metagenics, Priority One, Restorative Formulations, Bioclinic Naturals, BioMed, Genestra, Vitanica, Pascoe, and Heel.

When Paradigm was established, a focus was placed on billable square feet so that all 10 treatment rooms are full at all times. As a business model, Paradigm focuses on maximizing efficiency, running approximately 100 intravenous treatments per week and seeing roughly

60 patients per day. Paradigm has also fully transitioned to electronic medical records (EMR) and despite the large financial investment and steep learning curve, this has opened many doors for the clinic. Although patient records are paperless, all new patients receive a binder that outlines the clinic’s comprehensive referral network, patient expectations, and success stories. Believing that marketing starts at home, Paradigm attempts to offer services of value, and this means taking care of each and every patient first. Consequently, word of mouth is Paradigm’s most powerful marketing tool.

IHP is thoroughly impressed with the success Paradigm has achieved and is thankful that we were given a glimpse into this cutting edge practice. A nice way to conclude is reiterating a statement from Dr. Ahlan: “[you] must follow what you love, by doing that you will always be successful." ■

Paradigm Health Group Team Members (www.paradigmhealth.ca):

➢ Dr. Jason Ahlan, ND CCT: Clinic Owner, Director, Naturopathic Doctor➢ Dr. Trevor Hoffman, ND: Clinic Owner, Director, Naturopathic Doctor➢ Dr. Chris Schlee, ND CCT: Naturopathic Doctor➢ Dr. Arden Baker-Hadley, ND MSOM: Naturopathic Doctor➢ Dr. Rhiannon Owens, ND CCT: Naturopathic Doctor➢ Dr. Jana Exner, ND: Naturopathic Doctor➢ Dr. Stuart Wilkinson, MD: Medical Doctor➢ Brenda Atkinson: Clinic Manager➢

043-044.IHP_Clinic-issue31-v2.indd 39 13-02-01 12:21 PM

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1

2

3

p49 Medium Chain Triglycerides (MCT’s) An alternative approach to the treatment of Alzheimer’s disease by William R Ware, PhD Faculty of Science, University of Western, Canada

p56 DHEA Outcomes in female fertility by Heidi Fritz, MA, ND Research Fellow, Canadian College of Naturopathic Medicine,

Bolton Naturopathic Clinic, Bolton, Ontario, Canada

p65 Molecular chaperones as 21st century solutions for neurodegenerative disorders

A look at catecholamine-regulated protein 40 (CRP40) by Jovana Lubarda, Sarah E Groleau, Nancy Thomas,

Zdenek B Pristupa, Ram K Mishra, Joseph P Gabriele Department of Psychiatry and Behavioural Neurosciences,

McMaster University, Hamilton, Ontario, Canada

p73 N-Acetyl Cysteine A versatile intervention by Colin MacLeod, ND Kinesis Health Associates, Dartmouth, Nova Scotia, Canada

The Journal of

11

2

3

2

3

CECE

045.IHP_Feature Contents.indd 42 13-02-01 3:24 PM

editor’s letter


Receiving a diagnosis of Alzheimer’s disease, or Parkinson’s, is to most as devastating and fear- provoking as the experience we immediately associate with a cancer diagnosis. Typically

symptoms are already present, and it doesn’t take out tech-savvy elders long to learn the prognosis of such a condition. This issue of the journal includes a review of the emerging roles of medium chain triglycerides in Alzheimer’s management from a frequent contributor, William R Ware. We are also grateful to present Part I of a two- part series on CRP-40 from an esteemed team of neuropsychiatry researchers from McMaster University, as their paper bring us up-to-speed on molecular chaperones. Part II delves into unique and exciting prospects for the not-to-distant future application of these molecules in neurodegenerative disease treatment.

Heidi Fritz provides a thorough review of the role of DHEA in improving fertility outcomes in women. Colin MacLeod, a rare and welcomed East Coast contributor provides the issues continuing education lesson with an excellent review of an array of clinical applications for oral and IV administration of N-acetyl cysteine.

Best Regards,

Philip Rouchotas, MSc, NDEditor-in-Chief

We invite questions or comments. [email protected]

Neurodegeneration

046.IHP_EditorLetter.indd 43 2013-02-01 3:29 PM

44 www.ihpmagazine.com l November/December 2012

Publisher | Sanjiv Jagota (416) 203-7900 ext 6125

Editor-in-Chief | Philip Rouchotas, MSc, ND (416) 203-7900 ext. 6109

Associate Editor | Christopher Habib, ND

Art Director | James March

Design | Sarah Vincett

Production | Erin Booth (416) 203-7900 ext. 6110

ContributorsChristopher Habib, ND, Philip Rouchotas, MSc, ND

Heidi Fritz, MA, ND, William R. Ware, PhDColin MacLeod, ND, Jovana LubardaSarah E. Groleau, Nancy Thomas,

Zdenek B. Pristupa, Ram K Mishra, Joseph P. Gabriele

President | Olivier Felicio(416) 203-7900 ext. 6107

Vice President Operations | Frank Shoniker (416) 203-7900 ext. 6109

Controller & Operations | Melanie Seth (416) 203-7900 ext. 6114

Finance Administrator | Henry Fonseca(416) 203-7900 ext. 6127

Advertising Information

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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 publica-

tion 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

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providing such material. Please direct submissions to the Editor, ihp magazine.

007.IHP_Masthead_V2.indd 44 2013-02-01 3:10 PM

peer review


Aoife Earls, MSc, ND Trafalgar Ridge Chiropractic and Acupuncture2387 Trafalgar Rd, Unit 7AOakville, Ontario L6H [email protected]

Berchman Wong, ND 718 - 33 Canniff StToronto, Ontario M6K [email protected]

Betty Rozendaal, BES, MA, NDThornhill Naturopathic Health Clinic12A Centre StreetThornhill, Ontario L4J [email protected]

Carol Morley, ND Zawada Health 201 City Centre Drive Suite 404 Mississauga, Ontario L5B 2G6 [email protected]

Colin MacLeod, NDAlderney Chiropractic164 Ochterloney St.Dartmouth, NS B2Y [email protected]

Daniel Watters, BSc, ND Rosedale Wellness Centre 365 Bloor St East Toronto, Ontario M4W 3L4 [email protected]

David W Lescheid, BSc, PhD, NDLichtentaler Strasse 4876530 Baden-Baden, Germany

David Miller, BSc, ND662 Gustavus St.Port Elgin ON [email protected]

Elizabeth Cherevaty, BSc, ND Healing Foundations Naturopathic Clinic111 Norfolk St., 2nd FloorGuelph, Ontario N1H [email protected]

Karam Bains, BSc, NDElixir Health, Multiple [email protected]

Erin Balodis, BSc, MSc, NDKingswood Chiropractic Health Centre1210 Hammonds Plains RoadHammonds Plains, NS B4B [email protected]

Erin Psota, BSc, ND 626 King St West, Suite 201 Toronto, Ontario M5V 1M7 [email protected]

Faryal Luhar, ND Healthwise Wellness 4250 Weston Rd Toronto, Ontario M9L1W9 [email protected]

Heidi Fritz, MA, ND Research Fellow Canadian College of Naturopathic Medicine 1255 Sheppard Ave East Toronto, Ontario M2K 1E2 [email protected]

Isaac Eliaz, MD, MS, LAcAmitabha Medical Clinic & Healing Center7064 Corline Ct # A Sebastopol, CA [email protected]

Jacob Scheer, DC, ND, MHSc 2100 Finch Ave. W. #206 North York, Ontario M3N 2Z9 [email protected]

Jiselle Griffith, BSc, ND The Health Hub Integrated Clinic35 Hayden St, Suite 109Toronto, Ontario M4Y [email protected]

Jordan Robertson, BSc, ND Lakeshore Clinic 2159 Lakeshore Road Burlington, Ontario L7R 1A5 [email protected]

Judah Bunin, BSc, MSc, ND, DrAcFredericton Naturopathic Clinic10-150 Cliffe StFredericton, NB [email protected]

Peer Review Board Members

051-052.IHP_Peer Review.indd 45 13-01-30 4:01 PM

peer review


Kelly Brown, BSc, NDHealthview Therapy Centre5118 Roblin BlvdWinnepeg, Manitoba R3R [email protected]

Leigh Arseneau, ND The Naturopathic Institute of Advanced Medicine 122 Simcoe St North Oshawa, Ontario L1G 4S4 [email protected]

Lindsay Bast, BSc, NDGreenwood Wellness ClinicPO Box 189 1400 Greenwood Hill Rd. Wellesley, ON N0B 2T0 Louise Wilson, BSc, ND 320 Queen St S Bolton, Ontario L7E 4Z9 [email protected]

Makoto Trotter, NDZen-tai Wellness Centre120 Carlton Street, Suite 302,Toronto, ON M5A 4K2 [email protected] Mandana Edalati, BA, NDWellness Naturopathic Centre Suite 213-1940 Lonsdale Ave North Vancouver, British Columbia V7M 2K2 [email protected]

Melanie DesChatelets, BSc, ND True Health Studio 200-4255 Arbutus St Vancouver, British Columbia V6J 4R1 [email protected]

Misa Kawasaki, BSc, NDMeridian Wellness13085 Yonge Street, Suite 205Richmond Hill, ON L4E [email protected] Nicole Egenberger, BSc, ND Remede Naturopathics 214 Sullivan Street Suite 3B New York, New York 10012 [email protected]

Raza Shah, BSc, NDSt. Jacobs Naturopathic1-9 Parkside DriveSt. Jacobs, Ontario N0B [email protected]

Rochelle Wilcox, BA, NDLiving Well Integrative Health Centre2176 Windsor StreetHalifax, NS B3K [email protected]

Sarah Vadeboncoeur, ND Ottawa Integrative Health Centre 1129 Carling Ave Ottawa, Ontario K1Y [email protected]

Scott Clack, ND Touchstone Naturopathic Centre 950 Southdown Rd, Unit B5 Mississauga, Ontario L5J 2Y4 [email protected]

Shawna Clark, ND Forces of Nature Naturopathic Clinic 2447 1/2 Yonge St Toronto, Ontario M4P 2E7 [email protected]

Stephanie Swinkles, DDS Elmsdale Dental Clinic 4-269 Highway 214 Elmsdale, Nova Scotia N2S 1K1 [email protected]

Susan Coulter, BSc, NDRoots of Health2-497 Laurier AveMilton, ON L9T [email protected]

Sylvi Martin, BScN, ND Fusion Chiropractic and Integrative Health 735 Danforth AvenueToronto, Ontario M4J [email protected]

Tanya Lee, BSc, ND The Health Centre of Milton 400 Main St East Suite 210 Milton, Ontario L9T 1P7 [email protected]

Terry Vanderheyden, ND Bayside Naturopathic Medicine 118 Bay Street Barry’s Bay, Ontario KOJ 1B0 [email protected]

Theresa Jahn, BSc, NDLiving Well Integrative Health Centre2176 Windsor StreetHalifax, NS B3K [email protected]

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editorial board


Ben Boucher, MDDr. 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, NDDr 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, MDDr 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.

IHP Editorial Board Members

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

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

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editorial board


Pardeep Nijhawan, MD, FRCP(C), FACGDr. 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, FABNODr. 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, FRCSCDr. 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, MScDr Seely is a naturopathic doctor and director of research at the Canadian College of Naturopathic Medicine (CCNM). Dugald completed his masters of science in cancer research from the University of Toronto with a focus on interactions between chemotherapy and natural health products. In his current role as director of research, Dugald is the principal investigator for a number of clinical trials, and is actively pursuing relevant synthesis research in the production of systematic reviews and meta-analyses. Ongoing projects include three multi-centred randomized clinical trials and a comprehensive CIHR synthesis review of natural health products used for cancer. Dugald is currently a member of Health Canada’s Expert Advisory Committee for the Vigilance of Health Products and is a peer reviewer for the Canadian Adverse Reaction Newsletter.

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An alternative approach to the treatment of Alzheimer’s diseaseWilliam R Ware, PhDFaculty of ScienceUniversity of Western OntarioLondon, Ontario, Canada [email protected]

If one takes a realistic view, modern medicine appears to have little of real significant to offer patients with Alzheimer’s disease. Treatments are symptomatic and do not significantly decelerate or prevent progression. Behavioural and psychiatric challenges of great concern to caregivers are attacked with powerful drugs not approved for these indications, and have serious and sometimes permanent adverse effects. A new approach appears desperately needed. While it has been known for decades that Alzheimer’s diseases is associated with impaired cerebral glucose metabolism, only recently has this observation begun to attract serious attention and now some even call Alzheimer’s disease Type 3 diabetes. This article addresses therapeutic approaches to cerebral hypoglycemia which directly or indirectly involve providing an alternative brain fuel to counteract decreased glucose metabolism. The alternative fuel consists of ketone bodies produced by ketogenesis in the liver. Clinical studies and limited randomized controlled trials have provided evidence for both the biological plausibility of this alternative approach and its efficacy and safety in the treatment of mild cognitive impairment and Alzheimer’s disease. In addition, what appear to be highly satisfactory oral precursors of the required ketone bodies are natural products readily available in many health food stores. This has generated considerable anecdotal evidence recently reviewed in a book by a respected physician that makes an important contribution to this field.

Medium Chain Triglycerides (MCT’s)

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IntroductionMainstream medicine treats early to

moderate stages of Alzheimer’s disease (AD) with cholinesterase inhibitors (Aricept, Exelon, Razadyne and rarely Cognex). For moderate to severe stages, memantine (Ebixa), a drug that regulates the activity of glutamate, a chemical involved in learning and memory, is frequently employed. While aggressive combination therapies can produce small decreases in the frequently relentless increase of dementia or deteriation in daily living scores, progression remains (Atri 2008). “Currently available treatments for AD are symptomatic and do not decelerate or prevent the progression of the disease” (Herrmann 2011). There is considerable support for this view (Farrimond 2012, Galvin 2012, Lanctot 2009, Popp 2011).

In the US there are no drugs approved for dealing with behavior and psychiatric challenges associated with AD which cause significant problems for caregivers. However, the whole arsenal of antidepressants, anxiolytics and antipsychotics are widely used off-label. The problems and side effects associated with these drugs, both transient and permanent, can be significant (Breggin 2008). While these drugs modify symptoms, their adverse effect profile casts doubt on their true utility. Conventional therapies and the small changes they can affect provide false hope (Breggin 2008, Herrmann 2011). A new approach seems desperately needed.

The Brain Hypometabolism HypothesisThere is growing interest in this hypothesis,

initiated in 2005 by Suzanne de la Monte, that Alzheimer’s disease and type 2 diabetes have a number of pathologic features in common (de la Monte 2005). It was suggested that impaired glucose metabolism and impaired

insulin action in the brain, which in part leads to mitochondrial dysfunction and decreased energy production, could be significantly responsible for the pathology observed as AD develops. This led to the suggestion that AD be called Type 3 diabetes. However, the notion that there is a connection between AD and decreased glucose metabolism (hypometabolism) in the brain goes back at least several decades (Hoyer 1970), and there is growing interest in this phenomenon (Yao 2011). Abnormalities in metabolism have been linked to brain insulin and insulin-like growth factor resistance with disruption of signalling pathways that regulate neuronal survival, energy production, gene expression and brain plasticity (de la Monte 2012b). The use of PET scans with a metabolic tracer have provided significant and extensive evidence supporting the presence of hypometabolism and the notion of Type 3 diabetes, and its mechanistic details are the subject of current research (de la Monte 2012a).

A recent review of brain hypometabolism (Cunnane 2011) points out the potential for a vicious cycle generated by brain damage associated with hypometabolism. The authors suggest that this cycle can be effectively broken by sustained improvement in brain metabolism, which can be achieved with ketone bodies acting as replacement fuel. Brain hypometabolism now appears to be an attractive target in AD therapy (Costantini 2008)

Ketone Bodies--A Replacement Brain FuelThe three so-called ketone bodies are water

soluble compounds (acetone, acetoacetate and beta-hydroxybutyrate) produced in the liver from fatty acids (ketogenesis). Ketone bodies bypass insulin controlled cellular entry and can serve as energy sources in the mitochondria of tissues including the brain. It was once accepted that upon weaning, the brain was limited solely to glucose for metabolic energy. This view has changed as the neuroprotective potential of ketone body administration has been shown for neurodegenerative conditions, epilepsy, hypoxia/ischemia and traumatic brain injury,

“Modern medicine appears to have little of real significant to offer patients with Alzheimer’s disease.”

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and that there is an age-related therapeutic potential for ketone bodies as an alternative substrate (Prins 2008, White 2011). Also dietary ketosis has been shown to enhance memory in mild cognitive impairment, and there is evidence of protection against neuronal insults, an increase in metabolic efficiency relative to glucose, and in general such diets appear to some extent to mitigate neurodegenerative mechanisms (Krikorian 2012, Veech 2004). Perspective regarding the role of ketones in brain metabolism can be gained by considering that during starvation or very low carbohydrate intake, the liver turns to making ketones (Owen 1967). This defence mechanism evolved eons ago and was likely necessary for human survival.

Starvation is obviously not a practical therapeutic intervention. Neither is a severely ketogenic diet for many patients. Adherence to a classical ketogenic diet is a serious problem since about 90% of energy must come from fat. An obvious solution is an oral supplement or “medicinal food” that provides a source of the needed ketone bodies. Either natural or synthetic medium chain triglycerides (MCT) are obvious sources.

Oral Medium-Chain Triglycerides To Treat Alzheimer’s Disease

One of the prominent researchers in the field of brain hypometabolism, Samuel Henderson, was instrumental in the development of a MCT-based product to treat AD called AC-1202, which contained one MCT and could be taken as a dissolved powder. It was patented and tested in several trials and recently a multicenter randomized controlled trial reported (Costantini 2008, Henderson 2009). The compound rapidly elevated serum ketone bodies in patients with AD and resulted in significant improvement in cognitive scores in those with mild to moderate AD when compared to a placebo. MCT oil ingestion has also been found in a placebo controlled study to preserve brain function during hypoglycaemia in intensively treated patients with Type 1 diabetes (Page 2009). Some would consider these results convincing evidence concerning the biological plausibility of the hypometabolic hypothesis.

AC-1202 is available only by prescription and approved by the FDA as a “medicinal food” called Axona. It contains only one ketone generating MCT. Coconut oil and MCT oil are natural sources generating several ketone bodies and offering flexible dosing throughout the day.

The leading advocate of MCT oil and coconut oil is Dr. Mary Newport, M.D., a paediatrician and director of a neonatal ICU at a Florida hospital. In 2008 her husband had moderately advanced AD that was progressing significantly. She first heard of the use of MCTs for AD in 2008 when she came across reference to Henderson’s patent, found AC-1202 contained a MCT and ascertained that MCTs were present in coconut oil which was available at natural food and health food stores. She decided there was nothing to lose by trying coconut oil. This was a turning point in her husband’s life as well as hers. Results were remarkably rapid, AD progression apparently stopped, and over the following three to four years many cognitive and behavioural deficits were significantly reduced and many lost functions recovered. In her words, she “got her husband back.” This is detailed in Dr. Newport’s recent book (Newport 2011).

One of the most fascinating aspects of Dr. Newport’s husband’s change was that initially he was totally unable to draw a clock, a standard test in mental assessment, and a few weeks after starting coconut oil his clock, while not perfect, was significantly improved. This is illustrated in Dr. Newport’s book and in the article on the internet (Newport 2008). In addition, sequential MRI studies revealed that the progression of brain atrophy had been totally halted. It appears that conventional, approved treatments have never produced such a result, or in a significantly sustained manner, any of the above results, especially when the patient has fairly severe AD. Today, most of the interest in this intervention is among lay persons who become aware of MCT oil and coconut oil while doing an internet search for natural AD treatments, through the social media, by word-of-mouth or from Dr. Newport’s book (Newport 2011).

In this book, Dr. Newport provides details and a summary of anecdotal caregiver reports (60 cases) she received after the do-it-yourself treatment became popular. Unfortunately, there is uncertainty as to dose, source of MCTs, adherence, severity of the disease and the quality of reportage from caregivers concerning changes. Nevertheless, 90% of those who tried MCTs were observed to be improved, as indicated by better scores on tests, improved clock drawing, better cognition, more alertness, brighter outlook, improved awareness, less foggy or hazy behaviour, being able again to recognize people or places, being less distractible, and having a better sense of direction.

MCT oil yields higher serum ketone body levels than coconut oil, but the decline over time is more rapid

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than seen with coconut oil. Thus coconut oil taken with MCT oil helps smooth out daily fluctuations with higher average levels and coconut oil may have some other benefits not provided by the commercial MCT oils since it contains other fatty acids (Newport 2011). This influenced Newport’s final protocol which involved using an approximately 1:1 mixture of coconut oil and MCT oil at a dose of three tablespoons with each meal and two at bedtime. To avoid diarrhea, the only known adverse effect of MCTs reported, dose escalation is sometimes needed. It is important to note that while attention was paid to a healthy diet, the macronutrient intake of Dr. Newport’s husband was not drastically altered. In fact, the use of MCTs has the advantage of not requiring significant diet changes and can even be used along with conventional treatments.

Ketogenic DietsAn alternative to ingesting MCTs is to use a ketogenic

diet. Newport claims that the ketogenic diet is capable of producing up to 10 times or more ketone bodies than possible with the doses of MCTs commonly being used, and this becomes an attractive next step for those who do not respond to MCT therapy (Newport 2011). The ketogenic diet has been used to treat epilepsy and especially patients who failed to respond to antiepileptic drug therapy. The initial interest occurred in the early 1920s and then there was a long hiatus followed by recent renewed interest. There is now considerable evidence of efficacy in epileptic adults and children (Auvin 2012, Lambrechts 2012, Nam 2011). There has also been recent interest in ketogenic diets to treat Alzheimer’s disease (Kossoff 2012, McPherson 2012, Yao 2011). It has also been found that dietary ketosis enhances memory in mild cognitive impairment (Krikorian 2012). In addition, improvement in memory impaired adults has been correlated with orally induced increases in the serum level of the ketone body beta-hydroxybuterate (Reger 2004).

There are four recognized major ketogenic diets, the classical diet with 90% of calories from fat, the MCT diet, the modified Atkins diet and the low glycemic index diet. The MCT diet has been used since the 1970s and involves using coconut oil while limiting carbohydrates. The modified Atkins diet uses a very low carbohydrate induction diet (70% calories from fat, 24% from protein) as the permanent intervention, whereas the low glycemic diet has 45% from fat and 28% from protein with emphasis on carbohydrates selected for low glycemic index (Kossoff 2012).

ConclusionsWhat might be called the alternative fuel approach to

treating AD has strong biological plausibility. Limited results from clinical and randomized controlled trials provide evidence of efficacy and safety. Treating hypometabolism with a prescription MCT (Axona) has FDA approval for the indication of cognitive impairment. When trial data is combined with a large body of anecdotal evidence, the picture emerges suggesting AD patients appear to obtain much more benefit from this alternative approach than from conventional medical therapy.

Individuals with AD frequently have a mixture of vascular and AD-type abnormalities and some have dementia associated with Lewy bodies. Hypothyroidism, micronutrient deficiencies, heavy metal overload, etc., may also contribute to the symptomatic presentation and the alternative fuel approach would not be expected to impact some of these abnormalities. There is also an issue with genetics. In the AC-1202 clinical studies patients not carrying the E4 variant of the apolipoprotein gene (about half of those with AD) showed the highest response (Costantini 2008, Henderson 2009). However, Dr Newport’s husband is ApoE4+ and showed remarkable regression (Newport 2011).

It is disappointing that there is not more clinical trial evidence, but therapies involving natural MCT oil and coconut oil are of no interest to pharmaceutical companies, and the very nature of this therapy invites the criticism of not being adequately evidence based and in fact simply another quack treatment. Those who believe in the future of alternative treatments must recognize the necessity of tolerating these hostile views because meeting the demands of so-called evidence-based medicine will be a slow and frustrating adventure, and individuals with AD and their caregivers may be actively discouraged from trying a therapy with the potential for greater benefit than appears attainable by any other means. Judging by what Dr. Newport reports, many AD caregivers will not settle for what mainstream medicine has to offer and seek to circumvent the hostile attitude of modern medicine. They simply adopt the approach that “What is there to loose? We can do this at home...”; a view directly applicable to MCT therapy. Everything needed is available online or at the local health food store, including a mixture of MCT and coconut oil in the proportions used by Dr. Newport (sold as a salad dressing). Finally, the use of MCTs in primary prevention as one ages remains to be studied but intuitively would appear to have merit.

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References

Atri, A, Shaughnessy, LW, Locascio, JJ and Growdon, JH. Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord. 2008; 22(3): 209-221.

Auvin, S. Should we routinely use modified Atkins diet instead of regular ketogenic diet to treat children with epilepsy? Seizure. 2012; 21(4): 237-240.

Breggin, P, 2008. Brain-Disabling Treatments in Psychiatry. Springer Publishing Co., New York.

Costantini, LC, Barr, LJ, Vogel, JL and Henderson,ST. Hypometabolism as a thera-peutic target in Alzheimer’s disease. BMC Neurosci 2008; 9 Suppl 2: S16.

Cunnane, S, Nugent, S, Roy, M, Courchesne-Loyer, A, Croteau, E, Tremblay, S, Castel-lano, A, Pifferi, F, Bocti, C, Paquet, N, Begdouri, H, Bentourkia, M, Turcotte, E, Allard, M, Barberger-Gateau, P, Fulop, T. and Rapoport, SI. Brain fuel metabolism, aging, and Alz-heimer’s disease. Nutrition 2011; 27(1): 3-20.

de la Monte, SM. Brain insulin resistance and deficiency as therapeutic targets in Alz-heimer’s disease. Curr Alzheimer Res 2012a; 9(1): 35-66.

de la Monte,SM. Metabolic derangements mediate cognitive impairment and Alzhei-mer’s disease: role of peripheral insulin-resistance diseases. Panminerva Med 2012b; 54(3): 171-178.

de la Monte,SM and Wands, JR. Review of insulin and insulin-like growth factor ex-pression, signaling, and malfunction in the central nervous system: relevance to Alzhei-mer’s disease. J Alzheimers. Dis 2005; 7(1): 45-61.

Farrimond, LE, Roberts, E and McShane, R. Memantine and cholinesterase inhibitor combination therapy for Alzheimer’s disease: a systematic review. BMJ Open. 2012; 2(3).

Galvin, JE. Optimizing diagnosis and management in mild-to-moderate Alzheimer’s disease. Neurodegener. Dis Manag. 2012; 2(3): 291-304.

Henderson, ST, Vogel,JL, Barr, LJ, Garvin, F, Jones, JJ and Costantini, LC. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond) 2009; 6: 31.

Herrmann, N, Chau, SA, Kircanski, I and Lanctot, KL. Current and emerging drug treat-ment options for Alzheimer’s disease: a systematic review. Drugs 2011; 71(15): 2031-2065.

Hoyer, S. Brain metabolism and the incidence of cerebral perfusion disorders in organic psychoses. Dtsch. Z Nervenheilkd. 1970; 197(4): 285-292.

Kossoff, EH and Hartman, AL. Ketogenic diets: new advances for metabolism-based therapies. Curr Opin Neurol 2012; 25(2): 173-178.

Krikorian, R, Shidler, MD, Dangelo, K, Couch, SC, Benoit, SC and Clegg, DJ. Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol. Aging 2012; 33(2): 425-427.

Lambrechts, DA, Wielders, LH, Aldenkamp, AP, Kessels, FG, de Kinderen, RJ and Majoie, MJ. The ketogenic diet as a treatment option in adults with chronic refractory epilepsy: efficacy and tolerability in clinical practice. Epilepsy Behav 2012; 23(3): 310-314.

Lanctot, KL, Rajaram, RD and Herrmann, N. Therapy for Alzheimer’s Disease: How Effective are Current Treatments? Ther Adv Neurol Disord. 2009; 2(3): 163-180.

McPherson, PA and McEneny, J. The biochemistry of ketogenesis and its role in weight management, neurological disease and oxidative stress. J Physiol Biochem 2012; 68(1): 141-151.

Nam, SH, Lee, BL, Lee, CG, Yu, HJ, Joo, EY, Lee, J and Lee, M. The role of ketogenic diet in the treatment of refractory status epilepticus. Epilepsia 2011; 52(11): e181-e184.

Newport, M, 2008. What if there was a cure for Alzheimer’s disease and no one knew?

Newport, M, 2011. Alzheimer’s Disease. What If There Was A Cure? Basic Health Publi-cations, Inc, Laguna Beach, CA.

Owen, OE, Morgan, AP, Kemp, HG, Sullivan, JM, Herrera, MG and Cahill, GF, Jr. Brain metabolism during fasting. J Clin Invest 1967; 46(10): 1589-1595.

Page, KA, Williamson, A, Yu, N, McNay, EC, Dzuira, J, McCrimmon,RJ. and Sherwin, RS. Medium-Chain Fatty Acids Improve Cognitive Function in Intensively Treated Type 1 Diabetic Patients and Support In Vitro Synaptic Transmission During Acute Hypoglycemia. Diabetes 2009; 58(5): 1237-1244.

Popp, J and Arlt,S. Pharmacological treatment of dementia and mild cognitive impair-ment due to Alzheimer’s disease. Curr Opin Psychiatry 2011; 24(6): 556-561.

Prins,ML. Cerebral metabolic adaptation and ketone metabolism after brain injury. J Cereb Blood Flow Metab 2008; 28(1): 1-16.

Reger, MA, Henderson, ST, Hale, C, Cholerton, B, Baker, LD, Watson, GS, Hyde, K, Chapman, D. and Craft, S. Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol. Aging 2004; 25(3): 311-314.

Veech, RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins, Leukotrienes and Essential Fatty Acids 2004; 70(3): 309-319.

White, H and Venkatesh, B. Clinical review: ketones and brain injury. Crit Care 2011; 15(2): 219.

Yao, J, Rettberg, JR, Klosinski, LP, Cadenas, E and Brinton, RD. Shift in brain metabolism in late onset Alzheimer’s disease: implications for biomarkers and therapeutic interventions. Mol Aspects Med 2011; 32(4-6): 247-257.

The website of the company making Axona mentions caution when patients have a history of gastrointestinal problems, metabolic syndrome, uncontrolled diabetes and/or kidney disease. The extent to which these warnings apply to mixed MCT oil and coconut oil is unknown, but Dr. Newport reports only diarrhea.

Guidance and monitoring by a physician is always highly desirable. ■

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Fish oil has been reproducibly demonstrated to reduce the risk of sudden coronary death, as well as non-fatal cardiac events with a large magnitude of effect, in both patients recovering from a heart attack (secondary prevention) and in patients with no history of cardiovascular events (primary prevention) (Marchioli 2002, Yokoyama 2007). The Gissi Prevenzione trial, conducted in over 11 thousand patients, found that 1000mg daily of combined EPA+DHA for 3.5 years in addition to standard pharmaceutical therapy reduced the risk of sudden coronary death by 45% (RR 0.55, 95%CI 0.39–0.77), and reduced risk of all cause death by 21% (RR 0.79, 95% CI 0.66–0.93) (No authors 1999, Marchioli 2002). Other scientists have suggested that even doses as low as 250mg per day of combined EPA+DHA may be sufficient to obtain some level of benefit (Mozaffarian 2006).

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References

Aslan A, Triadafilopoulos G. Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. Am J Gastroenterol. 1992 Apr;87(4):432-7.Brunborg LA, Madland TM, Lind RA, Arslan G, Berstad A, Frøyland L. Effects of short-term oral administration of dietary marine oils in patients with inflammatory bowel disease and joint pain: a pilot study comparing seal oil and cod liver oil. Clin Nutr. 2008 Aug;27(4):614-22.Cawood AL, Ding R, Napper FL, Young RH, Williams JA, Ward MJ, Gudmundsen O, Vige R, Payne SP, Ye S, Shearman CP, Gallagher PJ, Grimble RF, Calder PC. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis. 2010 Sep;212(1):252-9.Gruenwald J, Petzold E, Busch R, Petzold HP, Graubaum HJ. Effect of glucosamine sulfate with or without omega-3 fatty acids in patients with osteoarthritis. Adv Ther. 2009 Sep;26(9):858-71.Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997 May;65(5 Suppl):1645S-1654S.Lim K, Han C, Dai Y, Shen M, Wu T. Omega-3 polyunsaturated fatty acids inhibithepatocellular carcinoma cell growth through blocking beta-catenin andcyclooxygenase-2. Mol Cancer Ther. 2009 Nov;8(11):3046-55.Madland TM, Björkkjaer T, Brunborg LA, Fröyland L, Berstad A, Brun JG. Subjective improvement in patients with psoriatic arthritis after short-term oral treatment with seal oil. A pilot study with double blind comparison to soy oil. J Rheumatol. 2006 Feb;33(2):307-10.

Marchioli R, Barzi F, Bomba E, et al; 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, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006 Oct 18;296(15):1885-99.No Authors. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999 Aug 7;354(9177):447-55. Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T. Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis. J Clin Gastroenterol. 2008 Apr;42(4):413-8.Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti- inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev. 2010 May;68(5):280-9.Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, OikawaS, 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 inhypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpointanalysis. Lancet. 2007 Mar 31;369(9567):1090-8.

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Carlson The Very FinestFish Oil provides a high quality, pure source of the omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs) EPA and DHA,derived from 100% Norwegian sources. Eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) are well known for their anti-inflammatory effects, exerted through competitive inhibition of the cyclooxygenase (COX-2) and lipooxygenase (LOX) enzymes (Lim 2009); and have been the subject of extensive scientific research for their benefit on cardiovascular health, mood and cognitive function, as well as a broad range of inflammatory conditions such as arthritis, inflammatory bowel disease (IBD), and liver disease (Wall 2010). Arguably the most important of these is the effect of EPA and DHA on cardiovascular health.

Fish oil has been reproducibly demonstrated to reduce the risk of sudden coronary death, as well as non-fatal cardiac events with a large magnitude of effect, in both patients recovering from a heart attack (secondary prevention) and in patients with no history of cardiovascular events (primary prevention) (Marchioli 2002, Yokoyama 2007). The Gissi Prevenzione trial, conducted in over 11 thousand patients, found that 1000mg daily of combined EPA+DHA for 3.5 years in addition to standard pharmaceutical therapy reduced the risk of sudden coronary death by 45% (RR 0.55, 95%CI 0.39–0.77), and reduced risk of all cause death by 21% (RR 0.79, 95% CI 0.66–0.93) (No authors 1999, Marchioli 2002). Other scientists have suggested that even doses as low as 250mg per day of combined EPA+DHA may be sufficient to obtain some level of benefit (Mozaffarian 2006).

Higher doses of EPA+DHA are required in order to impact cholesterol, however, in particular the triglyceride (TG) component. A dose of 2000 to 4000mg of combined EPA+DHA reduces fasting TG 25-30% and increases HDL cholesterol 1-3% (Harris 1997). Through this mechanism, higher doses of fish oil yield added benefits to cardiovascular health. EPA has also been shown to reduce the inflammatory activity of atherosclerotic plaques when incorporated into these arterial lesions, thus slowing their progression (Cawood 2010).

In addition to effects on cardiovascular health, supplementation with EPA+DHA has been shown to improve several chronic inflammatory conditions, including liver damage in non-alcoholic steatohepatitis (Tanaka 2008); clinical improvement of ulcerative colitis and improvement of joint pain, and plasma markers of inflammation in patients with IBD (Aslan 1992, Brunborg 2008); and symptomatic improvements in both autoimmune arthritis (Madland 2006) and osteoarthritis (Gruenwald 2009).

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References

Aslan A, Triadafilopoulos G. Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. Am J Gastroenterol. 1992 Apr;87(4):432-7.Brunborg LA, Madland TM, Lind RA, Arslan G, Berstad A, Frøyland L. Effects of short-term oral administration of dietary marine oils in patients with inflammatory bowel disease and joint pain: a pilot study comparing seal oil and cod liver oil. Clin Nutr. 2008 Aug;27(4):614-22.Cawood AL, Ding R, Napper FL, Young RH, Williams JA, Ward MJ, Gudmundsen O, Vige R, Payne SP, Ye S, Shearman CP, Gallagher PJ, Grimble RF, Calder PC. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis. 2010 Sep;212(1):252-9.Gruenwald J, Petzold E, Busch R, Petzold HP, Graubaum HJ. Effect of glucosamine sulfate with or without omega-3 fatty acids in patients with osteoarthritis. Adv Ther. 2009 Sep;26(9):858-71.Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997 May;65(5 Suppl):1645S-1654S.Lim K, Han C, Dai Y, Shen M, Wu T. Omega-3 polyunsaturated fatty acids inhibithepatocellular carcinoma cell growth through blocking beta-catenin andcyclooxygenase-2. Mol Cancer Ther. 2009 Nov;8(11):3046-55.Madland TM, Björkkjaer T, Brunborg LA, Fröyland L, Berstad A, Brun JG. Subjective improvement in patients with psoriatic arthritis after short-term oral treatment with seal oil. A pilot study with double blind comparison to soy oil. J Rheumatol. 2006 Feb;33(2):307-10.

Marchioli R, Barzi F, Bomba E, et al; 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, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006 Oct 18;296(15):1885-99.No Authors. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999 Aug 7;354(9177):447-55. Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T. Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis. J Clin Gastroenterol. 2008 Apr;42(4):413-8.Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti- inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev. 2010 May;68(5):280-9.Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, OikawaS, 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 inhypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpointanalysis. Lancet. 2007 Mar 31;369(9567):1090-8.

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Heidi Fritz, MA, NDResearch Fellow, Canadian College of Naturopathic [email protected] Naturopathic Clinic64 King St W, Bolton, Ontario, L7E1C7

DHEA and DHEA-S are together the most abundant steroid hormones in the body, and function as weak androgens. In women, DHEA is mainly converted to testosterone, and to a lesser degree estrogen (Buster 1992). Androgen stimulation is thought to play a key role in early follicular development, with androgen receptor deficient mice showing problems with follicular development, ovulation, and ovarian response to gonadotropins that are similar to problems experienced by women with diminished ovarian reserve (DOR). Fuelled by an early case report showing a “dramatic and continuous” (Barad 2005) improvement in ovarian function over an 11 month self-treatment period with DHEA alongside weekly acupuncture, subsequent studies have since shown statistically significant improvements in clinical pregnancy rates, live birth rates, miscarriage rates, increased antral follicle count, number of retrievable mature oocytes and high quality embryos, reduced aneuploidy, and a reduction of IVF cycle cancellations. DHEA is currently in use as a treatment for DOR, and further investigations are warranted to determine whether DHEA may be of benefit in other related conditions such as premature ovarian failure.

DHEAOutcomes in female fertility

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IntroductionDehydroepiandrosterone (DHEA), and its sulphated

form DHEA-S, are weak adrenal androgens and the most abundant steroid hormone in the body (Andus 2003). DHEA acts as a precursor for other steroid hormones in the body, predominantly estradiol and testosterone via androstenedione (Gleicher 2012, Olech 2005). In women, DHEA is mainly converted to testosterone, and to a lesser degree estrogen (Buster 1992, Gleicher 2012). As a result, DHEA is used as a hormone replacement for older women, in which circumstance it has been shown to benefit bone health (Weiss 2009). DHEA has also been shown to possess anti-inflammatory effects through inhibition of NF-kappaB activation, as well as inhibition of IL-6 and IL-12 secretion via PPAR-alpha (Andus 2003), and has on the basis of this activity been utilized in various autoimmune conditions (Petri 2004, Andus 2003). These applications will be covered in detail in part II of this review. This review focuses on DHEA supplementation as a treatment for diminished ovarian reserve (DOR) and female infertility.

Review of Reproductive Physiology Grynnerup defines the follicle as “the basic functional

unit in the ovaries” (2012). The follicle consists of the oocyte in association with surrounding theca cells and granulosa cells; during follicular development, granulosa cells support the maturation of and interact with the oocyte, producing growth factors and hormones to direct follicular development. After ovulation, the granulosa cells become the corpus luteum and secrete progesterone. The number of follicles is set during embryonic development; over the course of a woman’s life, resting primordial follicles are recruited to become growing follicles, a process called initial recruitment that continues until the follicle pool is exhausted (Grynnerup 2012). Growing follicles either undergo atresia (most) or they undergo cyclic recruitment, an ongoing process that begins at puberty, which involves recruitment by FSH. A cohort of follicles is selected with each “cycle” of recruitment, only one of which is selected to become the dominant follicle that will reach ovulation. Figure 1 depicts the stages of follicular maturation. During early follicular development (pre-antral and antral stages), the granulosa cells secrete anti-Mullerian hormone (AMH). AMH inhibits excessive recruitment by FSH, which would lead to premature exhaustion of the follicle pool (Grynnerup 2012); however, since it is produced by the early pre-antral follicles, AMH can be used as a marker of the remaining growing follicular pool, and by extension the remaining primordial follicle pool, or ovarian reserve (Grynnerup 2012). Similarly, inhibin B is a less studied

but similar marker that is produced during the early to mid stages of follicular development; it inhibits pituitary release of FSH and may also serve as a marker of ovarian reserve (Sill 2009).

The mechanism by which DHEA impacts folliculogenesis is not well defined. Until recently, DHEA was thought to promote follicular development during the very early stages of follicular maturation (Gleicher 2012). This is perhaps surprising since androgens are considered detrimental in other conditions of impaired fertility such as polycystic ovarian syndrome (PCOS). Nonetheless, evidence based on animal studies shows that androgen receptor mediated function in granulosa cells is crucial to the development of preantral follicles at early stages of development and the prevention of follicular atresia (Gleicher 2012, Sen 2010). In mouse models, androgen receptor knock out animals (ARKO) share striking resemblances with women who suffer from DOR: they become subfertile, have defective folliculogenesis, lower numbers of antral (pre-ovulatory) follicles, fewer corpora lutea, higher rates of granulosa cell apoptosis, and ultimately develop premature ovarian failure (Hu 2004, Kimura 2007, Sen 2010, Shiina 2006, Walters 2007). When subjected to superovulation through gonadotropin administration, these mice ovulate fewer oocytes (Hu 2004).

In humans, intrafollicular androgen levels have been shown to increase granulosa cell AMH (anti-Mullerian hormone) production and decrease inhibin-B levels (Andersen 2008). The authors of this study speculate that this seemingly opposite effect on AMH and inhibin B respectively may reflect a dual activity of androgens on ovarian function: during the early stage of follicular differentiation, androgens induce FSH-receptor expression on granulosa cells, promoting FSH- stimulated follicular differentiation; however in the later (pre-ovulatory) stages, excess androgens may induce atresia of granulosa cells and inhibit LH receptor formation, thus inhibiting ovulation (Andersen 2008). This type of activity does appear to be profiled in conditions of androgen excess most notably PCOS, with hyper-development of follicles but failure of ovulation.

More recently, Hyman et al demonstrated that DHEA therapy was able to improve antral follicle count but not change AMH or inhibin B, suggesting that DHEA does not so much influence the early stages of follicular development (AMH and inhibin B are secreted at these stages) as it increases the rescue rate of the small antral follicles (later stage) from atresia (increased AFC) (2013). Other earlier studies showed conflicting results with respect to AMH, with one RCT reporting no change

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and one retrospective study reporting a large improvement (Gleicher 2010A, Yeung 2012). It is hoped that more research will be able to more clearly define the mechanism(s) of DHEA.

Over the past ten years or so, several investigations into the effect of DHEA supplementation in women with DOR and/ or poor responders to IVF have been conducted, following upon the heels of an initial case series in 2000 and an impressive case report in 2005 (Barad 2005, Casson 2000; both in Table 1). There are only two RCTs among 15 identified studies, in part due to the ethical difficulty of randomizing this particular population, with a highly time-sensitive condition, to an inactive arm (Gleicher 2011). Instead study designs include prospective, uncontrolled trials and case-control studies in which DHEA- treated cycles are compared to non-DHEA treated cycles in the same group of women.We include all human level interventional evidence pertaining to the treatment of infertility identified in Pubmed up to January 2013, using the terms “DHEA supplementation”.

Diminished Ovarian Reserve (DOR)According to the Society of Assisted

Reproductive Technology (SART), DOR does not consist of clearly defined criteria; rather it describes the number and quality of eggs remaining in a woman’s ovaries as assessed or estimated through a number of tests and prognostic factors (Practice Committee 2012).

The SART document describes DOR as referring to “women of reproductive age having regular menses whose response to ovarian stimulation or fecundity is reduced compared to those women of comparable age” (2012).

Tests/ factors often used to assess DOR include: day 3 FSH (>10 is considered a poor prognostic) and estradiol; antral follicle count (follicles measuring 2-10mm, normal count is >10); anti-mullerian hormone (AMH) (<1ng/mL is considered low); clomiphene citrate challenge (FSH >10 following treatment with clomiphene); age >35 years; family history of early menopause; single ovary or history of ovarian surgery, chemotherapy, or pelvic radiation (Practice Committee 2012).

Clinical EvidenceCollectively, the 14 reviewed studies

reported the following outcomes in women described as having DOR or as poor responders to IVF:

• Higher clinical pregnancy rates between 22.1- 28.4% with DHEA supplemented cycles (Barad 2007, Gleicher 2012, Gleicher 2010A, Sonmezer 2009, Weghofer 2012). Three of these trials were uncontrolled; in the one case-control study, the control group had a clinical pregnancy rate of 11.9%, versus 28.4% in the DHEA group, HR pregnancy 3.8 (95% CI 1.2-11.8, p<0.05) (Barad 2007). In the second study, the DHEA supplemented cycle resulted in pregnancy rates of 44.4% versus 0% after embryo transfer compared to the first un-supplemented cycle (p<0.01) (Sonmezer 2009).

Initial recruitment Cyclic recruitment

a

AMH

FSH

Primordial follicle

Small preantral

Large preantral

Antral 2-7 mm

Antral 8-12 mm Preovulatory

TRENDS in Endocrinology & Metabolism

b

Figure 1. Pre-ovulatory stages of follicular development

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• Higher live birth rate: 23.1% with DHEA compared to 4.0% (p=0.05) without DHEA (RCT evidence) (Wiser 2010).

• Lower miscarriage rate: 15.1% with DHEA, which was lower than the national average; odds of miscarriage was reduced by approximately half: OR 0.49 (0.25-0.94, p=0.04) (Gleicher 2009). The miscarriage rate was reduced at all ages but most especially so in women over 35 years of age.

• Improvements in the follicular microenvironment due to a better blood supply to the ovaries as measured by FF HIF1 levels (Artini 2012).

• Greater numbers of mature oocytes retrieved from selected follicles following ovarian stimulation (Artini 2012); and increased number of follicles >15mm (p=0.004), 17mm (p<0.05) and 10mm respectively (Hyman 2013, Sonmezer 2009, Yeung2012 RCT evidence).

• No significant change in AMH or FSH levels, but significantly increased antral follicle count and ovarian volume at wk 12 and 20 (RCT evidence, Yeung 2012; and Hyman 2013).

• Reduction in the number of aneuploidy embryos (p<0.029) (Gleicher 2010B) and increased embryo quality (p=0.04) (RCT evidence) (Wiser 2010).

• Increased good quality embryos at day two and three (p<0.05) (Barad 2006, Sonmezer 2009).

• Decrease in mean day three estradiol (p<0.01) (Sonmezer 2009).

• Reduction in cycle cancellation rates, 5.3% versus 42.1%, p<0.01 (Hyman 2013, Sonmezer 2009).

Of note, Gleicher et al investigated the effect of DHEA conversion to testosterone as a prognostic marker of the response to DHEA (2012). Androgen conversion was compared between conception and non-conception cycles. They found that the beneficial effect of DHEA on pregnancy rates was statistically associated with the efficiency of androgen conversion from DHEA, and the amplitude of testosterone gain; both younger women and certain FMR1 genotypes were found to convert more efficiently (Gleicher 2012).

In an excellent review, Gleicher and Barad briefly discuss other fertility related applications, for example the use of DHEA for idiopathic infertility and premature ovarian failure (POF) as distinct from DOR; however there is a lack of clinical evidence regarding these applications and the focus of published papers to date is on DOR (2011). Anecdotally, however, Gleicher et al report a handful of cases of POF at their and colleagues’ fertility centers that achieved pregnancy following several months use of DHEA, and are currently investigating this

more rigorously through a clinical trial(ClinicalTrials.gov ID#NCT00948857) (Gleicher2011, Mamas 2009).

CriticismSome have been critical of the use of DHEA in clinical

practice for the treatment of DOR. In a commentary article, Urman et al argue that the evidence in support of DHEA is not of sufficient quality to merit use in practice (2012). At the time of publication there was only retrospective or uncontrolled studies and one RCT in existence (Wiser 2010), the latter of which Urman critiques as underpowered to detect the effects on pregnancy and other endpoints that were reported (2012). Although one additional placebo controlled RCT has since reported similar benefit of DHEA on DOR (Yeung 2012), there is admittedly still a need for further RCT level evidence. In addition, Urman is of the opinion that DOR with low AMH and few antral follicles will not be amenable to pharmacological therapy of any sort: “It is unlikely that any medication will be of benefit in a woman harboring ovaries devoid of antral follicles. After all, one cannot stimulate what is not there” (Urman 2012). This statement does not however sufficiently explain the observations reported in several studies of DHEA that have been published, the majority of which have documented some level of improvement in markers of ovarian function associated with use of DHEA.

A recent study exploring the mechanism of DHEA in DOR suggested that rather than somehow increasing the set number of follicles a woman possesses, DHEA may instead increase the quality of the few existing, antral follicles (Hyman 2013). This study found that although DHEA had no impact on baseline AMH or inhibin B levels, which are secreted by early to mid stage follicles, the antral follicle count nonetheless improved. Authors concluded that “DHEA does not appear to exert influence via recruitment of pre-antral or very small antral follicles (no change in AMH and inhibin B), but rather by rescue from atresia of small antral follicles (increased AFC)” (Hyman 2013). There is clearly a need for further research to confirm the effect and mechanism of DHEA, however in the meantime a basis to utilize this promising therapy does appear to exist, particularly in women whose existing therapeutic options are limited.

DosingThe dosage generally used by studies reviewed here is

25mg three times per day. This is beyond that considered to be physiologic replacement dosages, typically considered to be 20-50mg/d for men and 10-30mg/d for women; however Olech points out that “higher dosages

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may be necessary for increasing suppressed DHEA and DHEAS levels secondary to chronic disease, adrenal exhaustion, and corticosteroid therapy” (2005). Indeed, higher dosages have been used in lupus, as will be reviewed in part II of this series.

Adverse Effects No serious side effects were reported by the studies

included in this review. Gleicher et al report having treated over 1000 women with DOR with DHEA 25mg three times daily and observing no serious side effects other than acne, hair loss, or oily skin (2011).

ConclusionDHEA is a weak adrenal androgen that appears to

positively influence early follicular development in women with diminished ovarian reserve (DOR). Two RCTs and 13 non-randomized studies in women with DOR show a promising role for DHEA in improving ovarian function and fertility. These studies suggest that DHEA can be dosed at 25mg three times daily for a minimum of six weeks up to three to four months for DOR. DHEA is a relatively safe agent with few side effects that may include acne, hair loss and oily skin. ■

Design Intervention Outcomes Reference

Prospective trial N= 32 poor responders

Age (mean) 37.63y

75 mg/d DHEA x 3mo prior to next IVF cycle

•Increased antral follicle count without change in AMH, inhibin B or FSH (P=0.0003).

• Increased peak estradiol (P=0.0005), # of follicles >15mm, MII oocytes and embryos.

• Decreased proportion of cancelled cycles (P=0.02).

Hyman 2013

Prospective cohortN= 213 women w DOR

Age (mean) 41.5 y

75mg/d DHEA x 6wk prior to IVF cycle.

• Clinical pregnancy rate 22.1%. • Benefits of DHEA on pregnancy rates were statistically associated with

efficiency of androgen conversion from DHEA to testosterone.

Gleicher 2012

Prospective studyN= 91 women w POA

Age (mean) 39.8 y

25mg micronized DHEA 3x/d x 6 wkprior IVF

• Clinical pregnancy rate 25.3%. • Total androgen concentrations were not associated with pregnancy;

however, in women with abnormal FMR1 genotypes, free testosterone significantly affected clinical pregnancy potential (P = 0.03).

• Authors concluded that “androgen deficiency [is] a subset of diminished ovarian reserve.”

Weghofer 2012

Non-randomized controlled trial

N= 24 poor responders (ESHRE criteria)

Age NR

25mg DHEA 3x per day x 3mo prior to IVF cycle.

Ctl: no treatment prior to IVF cycle

• Significant improvements in follicular microenvironment showing better blood supply to ovaries (FF HIF1 levels).

• The mean duration of ovarian hyper-stimulation treatment was significantly shorter (9.83 vs. 12.09 days; p = 0.023) in the DHEA group.

• Mature oocytes retrieved in selected follicles were significantly more numerous in DHEA-group (p = 0.018).

Artini 2012

RDBPCTN= 22 women with POI

25mg DHEA 3x per day x 16wks

• No significant change in serum AMH and FSH levels. • Antral follicle count and ovarian volume were significantly higher at wk 12

and 20, respectively, in the DHEA group. • Significantly more women in the DHEA group had at least one follicle >10

mm at wk 12, 16, and 20.

Yeung 2012

Case-control studyN= 15 women w DOR

Age (mean) 38.8 years; Previous IVF attempts >3; mean basal FSH

13.3

75mg/d DHEA x12wk prior to IVF

Ctl: no DHEA

• Progesterone levels on stimulation day 5 (p< 0.0001) and on the day of hCG administration (p < 0.0001) were significantly higher during DHEA treatment.

• There was no difference in the number of retrieved and fertilized oocytes.

Weissman 2011

Retrospective studyN= 120 consecutive

patients w DOR;Age (mean) 39 y

25mg DHEA 3x/d for b/w 30-120 days (mean 73 d)

• AMH improved significantly after DHEA supplementation over time (P=0.002).

• AMH improved longitudinally by approximately 60% (P<0.0002). • Women reaching IVF experienced a 23.64% clinical pregnancy rate, and

conceiving women showed significantly improved AMH concentrations compared with those who did not (P=0.001).

Gleicher 2010A

Table 1. DHEA in female fertility - human level evidence

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Design Intervention Outcomes References

Case control studyN= 22 women w DOR

age-matched to 44 infertility patients with

normal ovarian reserve;Age (mean) ~37 years

25 mg 3x/d micronized DHEA x at least 4 weeks

• DHEA supplementation significantly reduced the number (P = 0.029) and percentages (P < 0.001) of aneuploid embryos, when adjusted for relevant covariates.

• Interestingly, short term supplementation (4-12 weeks) resulted in greatest reduction in aneuploidy (-21.6%, 95% CI -2.871-46.031).

Gleicher 2010B

RCTN= 33 women w DOR;Age <42y (mean, 36.9 and 37.8 in DHEA and ctl groups respectively)

75 mg DHEA once a day, before starting and during

the next IVF cycle (minimum 6 weeks)

Ctl: same protocol w/o DHEA

Luteal phase vaginal progesterone was also given

to all women.

• The DHEA group demonstrated a non-significant improvement in estradiol levels on day of hCG (P = 0.09) and improved embryo quality during treatment (P = 0.04) between the first and second cycles.

• Patients in the DHEA group also had a significantly higher live birth rate compared with controls (23.1% versus 4.0%; P = 0.05), respectively.

• Six of seven deliveries were among patients with secondary infertility, having had a previous child, suggesting that these women have a better prognosis (P = 0.006).

Wiser 2010

Case control studyN= 73 DHEA supplemented

pregnancies at 2 fertility centers compared to

national US data

25mg 3x/d micronized DHEA x 2mo or until pregnancy.

• After DHEA supplementation the miscarriage rate at both centers was 15.1%.

• Compared to national data of IVF populations, OR miscarriage with DHEA supplementation was significantly lower, 0.49 (0.25-0.94; p = 0.04).

Gleicher 2009

Prospective studyN= 19 poor responders

Age (mean) 32.92 y

25mg 3x/d DHEA for at least 3 months prior to their

second IVF cycle.

• Favourable decrease in mean day 3 serum estradiol after DHEA supplementation (75.14 +/- 28.93 versus 43.07 +/- 11.77; P < 0.01).

• Increased number of >17 mm follicles (P < 0.05), MII oocytes (P < 0.05), top quality day 2 (P < 0.05) and day 3 embryos (P < 0.05) were achieved in DHEA-supplemented cycles.

• Reduction in cycle cancellation rates (5.3% versus 42.1%; P < 0.01), • Improved pregnancy rate per patient (47.4% versus 10.5%; P < 0.01) and

clinical pregnancy rate per embryo transfer (44.4% versus 0%; P < 0.01) after DHEA.

Sonmezer 2009

Case control studyN= 190 women w POA or DOR; 89 women on

DHEA; Age: DHEA 41.6; Ctl

40.0y

75mg/doral, micronized DHEA for up to 4 months

prior to IVF.

• Cumulative clinical pregnancy rates were significantly higher in the DHEA group: 25 (28.4%) pregnancies vs. 11 (11.9%) pregnancies.

• Relative hazard of pregnancy in DHEA group HR 3.8; 95% CI 1.2-11.8 (p < 0.05).

Barad 2007

Case control studyN= 25 women with

DOR who had one IVF cycle before and after

DHEA treatment. Age (mean) 39.9 y

25mg 3x/d micronized DHEA x 4mo.

After DHEA, there were significant increases in • fertilized oocytes (P < 0.001)• normal day 3 embryos (P = 0.001)• embryos transferred (P = 0.005) • average embryo scores per oocyte (P < 0.001).

Barad 2006

Case reportN= 42.7 year of age woman w severely decreased ovarian

reserve

Ovulation induction in combination with

acupuncture + DHEA supplementation

• In her first treatment cycle peak E2 was 1,211 pmol/mL.• After seven months of DHEA, peak E2 in cycle 8 was > 18,000 pmol/mL.• In cycle 9 gonadotropin stimulation was reduced by 25%. Peak E2 was

9,178 pmol/mL, resulting in retrieval of 17 oocytes (16 embryos). • There was a “dramatic and continuous” improvement in ovarian function

over the 11mo treatment period.

Barad 2005

Case seriesN= 5 poor responders

<41y

80 mg/d oral micronized DHEA x 2mo

• All five subjects had increased responsiveness with DHEA.• Peak estradiol increased from 266.3 pg/ml to 939.8 pg/ml. • One of the cycles resulted in a delivered twin pregnancy.

Casson 2000

Key: AMH anti mullerian hormone; b/w between; Ctl control; DOR diminished ovarian reserve; ESHRE European Society of Human Reproduction and Embryology; FF follicular fluid; HIF1 hypoxia inducible factor 1; NR not reported; POA premature ovarian aging; POI premature ovarian insufficiency; w with; w/o without.

Fritz2.indd 61 13-02-01 4:01 PM


References

Andersen CY, Lossl K. Increased intrafollicular androgen levels affect human granulosa cell secretion of anti-Müllerian hormone and inhibin-B. FertilSteril. 2008 Jun;89(6):1760-5.

Andus T, Klebl F, Rogler G, Bregenzer N, Schölmerich J, Straub RH. Patients with refractory Crohn’s disease or ulcerative colitis respond to dehydroepiandrosterone: a pilot study. Aliment Pharmacol Ther. 2003 Feb;17(3):409-14.

Artini PG, Simi G, Ruggiero M, Pinelli S, Di Berardino OM, Papini F, Papini S, Monteleone P, Cela V. DHEA supplementation improves follicular microenviroment in poor responder patients. GynecolEndocrinol. 2012 Sep;28(9):669-73.

Barad D, Brill H, Gleicher N. Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function. J Assist Reprod Genet. 2007 Dec;24(12):629-34.

Barad D, Gleicher N. Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Hum Reprod. 2006 Nov;21(11):2845-9.

Barad DH, Gleicher N. Increased oocyte production after treatment with dehydroepiandrosterone. FertilSteril. 2005 Sep;84(3):756.

Buster JE, Casson PR, Straughn AB, Dale D, Umstot ES, Chiamori N, Abraham GE. Postmenopausal steroid replacement with micronized dehydroepiandrosterone: preliminary oral bioavailability and dose proportionality studies. Am J Obstet Gynecol. 1992 Apr;166(4):1163-8; discussion 1168-70.

Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE.Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod. 2000 Oct;15(10):2129-32.

Gleicher N, Kim A, Weghofer A, Shohat-Tal A, Lazzaroni E, Lee HJ, Barad DH. Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR). J Assist Reprod Genet.2012 Dec 5. [Epub ahead of print]

Gleicher N, Barad DH. Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR). ReprodBiolEndocrinol. 2011 May 17;9:67.

Gleicher N, Weghofer A, Barad DH. Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS). ReprodBiolEndocrinol. 2010 Nov 10;8:140.

Gleicher N, Weghofer A, Barad DH. Improvement in diminished ovarian reserve after dehydroepiandrosterone supplementation. Reprod Biomed Online. 2010 Sep;21(3):360-5. B

Gleicher N, Ryan E, Weghofer A, Blanco-Mejia S, Barad DH. Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve: a case control study. ReprodBiolEndocrinol. 2009 Oct 7;7:108. doi: 10.1186/1477-7827-7-108.

Grynnerup AG, Lindhard A, Sørensen S. The role of anti-Müllerian hormone in female fertility and infertility - an overview. Acta Obstet Gynecol Scand. 2012 Nov;91(11):1252-60.

Hu YC, Wang PH, Yeh S, Wang RS, Xie C, Xu Q, Zhou X, Chao HT, Tsai MY, Chang C. Subfertility and defective folliculogenesis in female mice lacking androgen receptor. ProcNatlAcadSci U S A. 2004 Aug 3;101(31):11209-14.

Hyman JH, Margalioth EJ, Rabinowitz R, Tsafrir A, Gal M, Alerhand S, Algur N, Eldar-Geva T. DHEA supplementation may improve IVF outcome in poor responders: a proposed mechanism. Eur J Obstet Gynecol Reprod Biol. 2013 Jan 8. [Epub ahead of print]

Kimura S, Matsumoto T, Matsuyama R, Shiina H, Sato T, Takeyama K, Kato S. Androgen receptor function in folliculogenesis

and its clinical implication in premature ovarian failure. Trends EndocrinolMetab. 2007 Jul;18(5):183-9.

Mamas L, Mamas E. Premature ovarian failure and dehydroepiandrosterone.Fertil Steril. 2009 Feb;91(2):644-6.

Olech E, Merrill JT. DHEA supplementation: the claims in perspective. Cleve Clin J Med. 2005 Nov;72(11):965-6, 968, 970-1 passim.

Petri MA, Mease PJ, Merrill JT, Lahita RG, Iannini MJ, et al. Effects of prasterone ondisease activity and symptoms in women with active systemic lupus erythematosus. Arthritis Rheum. 2004 Sep;50(9):2858-68.

Practice Committee of American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. FertilSteril. 2012 Aug;98(2):302-7.

Sen A, Hammes SR. Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. MolEndocrinol. 2010 Jul;24(7):1393-403.

Shiina H, Matsumoto T, Sato T, Igarashi K, Miyamoto J, Takemasa S, Sakari M, Takada I, Nakamura T, Metzger D, Chambon P, Kanno J, Yoshikawa H, Kato S. Premature ovarian failure in androgen receptor-deficient mice. ProcNatlAcadSci U S A. 2006 Jan 3;103(1):224-9.

Sills ES, Alper MM, Walsh AP. Ovarian reserve screening in infertility: practical applications and theoretical directions for research. Eur J Obstet Gynecol Reprod Biol. 2009 Sep;146(1):30-6.

Sönmezer M, Ozmen B, Cil AP, Ozkavukçu S, Taşçi T, Olmuş H, Atabekoşlu CS. Dehydroepiandrosterone supplementation improves ovarian response and cycle outcome in poor responders. Reprod Biomed Online. 2009 Oct;19(4):508-13.

Traish AM, Kang HP, Saad F, Guay AT. Dehydroepiandrosterone (DHEA)—a precursor steroid or an active hormone in human physiology. J Sex Med. 2011 Nov;8(11):2960-82; quiz 2983.

Urman B, Yakin K. DHEA for poor responders: can treatment be justified in the absence of evidence? Reprod Biomed Online. 2012 Aug;25(2):103-7.

Walters KA, Allan CM, Jimenez M, Lim PR, Davey RA, Zajac JD, Illingworth P, Handelsman DJ. Female mice haploinsufficient for an inactivated androgen receptor (AR) exhibit age-dependent defects that resemble the AR null phenotype of dysfunctional late follicle development, ovulation, and fertility. Endocrinology. 2007 Aug;148(8):3674-84.

Weghofer A, Kim A, Barad DH, Gleicher N. The impact of androgen metabolism and FMR1 genotypes on pregnancy potential in women with dehydroepiandrosterone (DHEA) supplementation. Hum Reprod. 2012 Nov;27(11):3287-93.

Weiss EP, Shah K, Fontana L, Lambert CP, Holloszy JO, Villareal DT. Dehydroepiandrosterone replacement therapy in older adults: 1- and 2-y effects on bone. Am J Clin Nutr. 2009 May;89(5):1459-67.

Weissman A, Horowitz E, Ravhon A, Golan A, Levran D. Dehydroepiandrosterone supplementation increases baseline follicular phase progesterone levels. GynecolEndocrinol. 2011 Dec;27(12):1014-7.

Wiser A, Gonen O, Ghetler Y, Shavit T, Berkovitz A, Shulman A. Addition of dehydroepiandrosterone (DHEA) for poor-responder patients before and during IVF treatment improves the pregnancy rate: a randomized prospective study. Hum Reprod. 2010 Oct;25(10):2496-500.

Yeung TW, Li RH, Lee VC, Ho PC, Ng EH. A Randomized Double-Blinded Placebo-Controlled Trial on the Effect of Dehydroepiandrosterone for 16 Weeks on Ovarian Response Markers in Women with Primary Ovarian Insufficiency. J ClinEndocrinolMetab. 2012 Nov 8. [Epub ahead of print]

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The Journal of IHP


3Molecular chaperones as 21st century solutions for neurodegenerative disordersA look at catecholamine-regulated protein 40 (CRP40)Jovana Lubarda1, Sarah E. Groleau1, Nancy Thomas1, Zdenek B. Pristupa1, Ram K. Mishra1, Joseph P. Gabriele1*

1Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada*Corresponding Author: Joseph P. Gabriele

McMaster University1200 Main St. West HSC 4N81Hamilton, Ontario, CanadaL8N 3Z5Phone #: 905 525 9140 x22617Email: [email protected]

Lubarda.indd 65 2013-02-01 1:18 PM


The aging population in developed countries is experiencing an increase in the prevalence of neurodegenerative disorders that are placing a high burden on healthcare systems. The combined problems of lack of sustainable therapies and the absence of validated biomarkers for early diagnosis and intervention make these debilitating disorders a high priority for research. However, before biomarkers and therapies can be developed, scientists need to establish a clearer and more complete understanding of the molecular mechanisms behind neurodegeneration. Recently, researchers have linked the pathogenesis of many neurodegenerative disorders such as Parkinson’s (PD) and Alzheimer’s disease (AD) to abnormal protein folding, oxidative stress, and mitochondrial dysfunction. A specific class of proteins, called molecular chaperones (also known as heat-shock proteins), have emerged as potential targets for neuroprotection because of their ability to modulate abnormal protein folding and aggregation in disease states. We have discovered in our laboratory a novel molecular chaperone protein called Catecholamine-regulated protein 40 (CRP40; 40kDa) that is expressed solely in the central nervous system (CNS) and blood. Our preliminary findings indicate CRP40 is an alternative splice variant of a larger, ubiquitously-expressed protein called mortalin, which has been linked to protein homeostasis, pathophysiology of neurodegenerative disorders, and has been shown to protect neurons from oxidative stress. Studies on CRP40 have revealed the presence of a conserved heat-shock motif, upregulated expression under cell stress, as well as its ability to decrease aggregation of proteins, suggesting heat-shock like functions of this novel protein. Interestingly, evidence has revealed that CRP40 may play a role in neurodegenerative disorders characterized by impairments of the dopamine (DA) system, such as Schizophrenia (SCZ) and PD, through its ability to bind DA and colocalize with components of the DA-synthesis pathway. Our group has also discovered that CRP40 expression is dysregulated in human post-mortem SCZ and Parkinson’s brain samples – a compelling finding that requires further study. In this review, we present evidence that CRP40 may play a role in CNS disorders, particularly disorders related to abnormal protein folding and impairments of the dopaminergic system. Further study of CRP40 and its mechanisms may aid in increasing the understanding of molecular chaperone function in neurodegenerative disorders, which is essential for accelerating future developments of biomarkers and sustainable therapeutics.

Lubarda.indd 66 2013-02-01 1:18 PM

The Journal of IHP


3

Neurodegenerative disorders: How molecular chaperones play a role

Neurodegenerative diseases are increasing in prevalence in many developing countries and this trend is set to continue due to the rapidly aging population. They encompass a heterogeneous group of disorders that can be described by progressive and selective loss of neuronal systems that are anatomically or physiologically related. Despite research advances over the past several decades, critical challenges still remain in understanding the pathology and underlying mechanisms behind these debilitating disorders. Converging lines of evidence have suggested a common “protein-conformational” pathogenic pathway for AD, PD, familial amyotrophic lateral sclerosis (FALS), Huntington’s disease (HD) and related polyglutamine (polyQ) expansion diseases. Collectively, these disorders are characterized by the abnormal accumulation of insoluble neuronal or extracellular protein aggregates in the CNS (Hartl 2011, Muchowski 2005). However, the significance of these phenomena to the process of neurodegeneration is incompletely understood. Several groups have proposed that the formation of protein aggregates may be neuroprotective (Caughey 2003, Sisodia 1998). However, any perturbation of protein homeostasis can impair the ability of proteins to function properly and perform their diverse biological roles that are essential for life.

There is still some debate about whether the aggregates formed by disease proteins are toxic. Evidence has suggested that misfolded proteins can induce excitotoxicity or apoptosis via activation of caspase 3, and also affect neuronal synaptic function and axonal transport (Forman 2004). As well, toxic species in neurodegenerative disorders have been linked to various inflammatory responses, including increased oxidative stress, and mitochondrial dysfunction (Lin 2006). Indeed, there seems to be a common link between misfolded proteins and the resulting aberrations that occur in neurodegenerative disorders.

Protein quality or proteostasis is regulated by an

integrated network of proteins known as molecular chaperones. Molecular chaperones perform diverse roles in the cell including assisting with de novo protein folding, refolding of denatured proteins, protein trafficking, and degradation (Hartl 2011, Soti 2005). Numerous classes of molecular chaperones have been described thus far. Many of these proteins are also known as heat-shock proteins (Hsp) or stress proteins because it has been found that various cellular stresses upregulate their expression. These may include heat-shock, glucose deprivation, exposure to heavy metals, protein kinase C (PKC) stimulators, amino acid analogues, calcium increasing agents, ischemia, microbial infections and various hormones (Ellis 2006).

Different families of molecular chaperone proteins are classified according to their molecular weights and include the Hsp40, Hsp60, Hsp70, Hsp90, Hsp100, and small Hsp proteins (Ellis 2006). Heat-shock proteins are expressed in the cytosol, nucleus, mitochondria, and endoplasmic reticulum, and typically have long half-lives of about 48 hours (Ellis 2006). Although the function of these proteins is broad, the Hsp70s, Hsp90s, and the chaperonins (Hsp60s) are specifically involved in de novo protein folding and refolding. These classes of proteins are characterized as multi-component molecular machines that have the ability to recognize exposed hydrophobic amino-acid side chains of misfolded proteins and guide proper folding through adenosine triphosphate (ATP)- and cofactor- mediated mechanisms (Hartl 2011). Due to their various roles, molecular chaperones are currently being investigated in a variety of disorders.

Indeed, molecular chaperone proteins are emerging as important players in a number of neurodegenerative diseases characterized by aberrations in protein conformation. The purported roles of molecular chaperones in neurodegeneration may include the following: 1) control of potentially toxic structural changes in disease-related polypeptides; 2) regulation of aggregation of proteins by directing towards formation of less toxic species; 3) control of degradation of toxic

Lubarda.indd 67 2013-02-01 1:18 PM


agents and preservation of cellular degradation systems; 4) involvement in cell signalling and apoptotic events stimulated by abnormal protein aggregates, along with preservation of survival pathways; and 5) protection of mitochondria and neurons against oxidative stress evidenced in neurodegenerative disorders (Muchowski 2005). Further understanding of cellular chaperone networks will help to define their roles in neurodegenerative diseases where protein homeostasis has been impaired, and elucidate ways in which they may be manipulated to serve as possible therapeutic factors in these debilitating disorders.

Mortalin: an essential mitochondrial heat-shock protein

The heat-shock protein 70 (Hsp70; 70kDa) family represents one of the most ubiquitous classes of molecular chaperones. Mortalin, also known as the mitochondrial heat-shock protein (also referred to as mtHsp70 or Grp75), is an essential ubiquitously expressed molecular chaperone with multiple roles in mitochondrial biogenesis, maintenance of mitochondrial protein integrity, and regulation of import of mitochondrial proteins into the matrix (Deocaris 2008). Recently, mortalin has been implicated in neurogenesis and neurodegeneration processes and linked to AD, PD, as well as HD (Deocaris 2008). Also, since mortalin has been found to exert various cytoprotective functions that permit cell survival under stressful conditions, it has been implicated in cancer and aging systems (Kaul 2007).

Evidence for the involvement of mortalin in several human diseases has been accumulating over the past decade. Gabriele and colleagues (2010) studied the possible involvement of mortalin in the pathogenesis of SCZ and have shown that antisense knockdown of mortalin in the medial prefrontal cortex resulted in impairments of DA-mediated behaviours including prepulse inhibition and social interaction deficits (Gabriele 2010). Mortalin has also been implicated in AD through several studies. Osorio and colleagues (2007) showed differential expression of mortalin isoforms in hippocampi of AD patients. In another study using an animal model of AD, the ApoE knockout mouse model, it was shown that mortalin sustained AD-associated oxidative damage, suggesting the involvement of this protein in the pathogenesis of AD (Choi 2004). Mortalin has also been linked to neurodegeneration in PD based on interactions with PD-associated proteins,

including the redox-sensing DJ-1 protein that maintains mitochondrial function (Kaul 2007).

Mortalin is expressed from chromosome 5q31.1 (Kaul 1995). A recent study found that PD patients display mutations in the mortalin gene that have been associated with impaired mitochondrial function that is critical in protection from neurodegeneration (Burbulla 2010). Two of these mutations were located in the carboxyl-terminal substrate-binding domain of mortalin, indicating that this functional region of mortalin further characterization. The combined evidence from literature underscores the critical role of mortalin as an important mitochondrial stress protein in a variety of neurodegenerative disorders that needs to be investigated in more detail.

Interestingly, several studies have suggested that mortalin may play a role in brain ischemia, as it is upregulated following brain injury (Deocaris 2008). This protein may serve a protective function in ischemia by limiting the accumulation of reactive oxygen species in neurons (Liu 2005). Further, in vivo overexpression of mortalin in rat brain neurons and astrocytes following induction of ischemia significantly reduced infarct volume, improved neurological function and provided protection from oxidative damage in animals (Xu 2009).

Mortalin has been found to interact with the apoptosis-inducing factor (AIF) (Sun 2006). Normally, when AIF is released from the mitochondria, it may be translocated to the nucleus where it can cause caspase-independent apoptosis. It has been suggested that mortalin sequesters AIF and thus suppresses cell death (Sun 2006). Interestingly, this protective ability of mortalin was not retained in Hsp70 deletion mutants lacking the carboxyl-terminal (Ravagnan 2001). The functionality of the mortalin carboxyl-terminal was further confirmed in studies by Sun and colleagues (2006) who found that Hsp70 mutants lacking the entire amino-terminal domain and Hsp70 ATPase-deficient point mutants retained the ability to protect primary astrocytes against ischemic insults in vitro as well as to inhibit AIF translocation to the nucleus. This indicated that the carboxyl-terminal was indeed sufficient for protection against ischemic brain injury (Sun 2006).

Indeed, the carboxyl-terminal of mortalin seems to serve a specific function in neurodegenerative disorders and oxidative stress. McMaster University researchers have recently discovered a novel protein that is

Lubarda.indd 68 2013-02-01 1:18 PM

The Journal of IHP


3

related to the carboxyl-terminal of mortalin, and this protein is under investigation for its possible roles in neurodegeneration.

Catecholamine-regulated protein 40 (CRP40): A novel molecular chaperone

The Catecholamine-Regulated Protein 40 is a novel heat-shock like protein that was discovered and characterized by Drs. Mishra and Gabriele of McMaster University (Hamilton, Canada) (Gabriele 2009, Nair 2001). CRP40 is a splice variant of mortalin, showing significant homology to mortalin’s carboxyl-terminus. Specifically, the sequence between exons 10-17 is identical to mortalin, with a promoter region at intron 9 (Gabriele 2009). Interestingly, this carboxyl-terminus homology means that the above discussed PD-related mortalin mutations would affect CRP40 function as well. Like mortalin, CRP40 belongs to the Hsp70 family, as evidenced by the following characteristics: 1) CRP40 exhibits the characteristic and conserved heat-shock motif; 2) expression of CRP40 is inducible by elevated temperature; and 3) the organellar localization motif, which allows Hsp70s to translocate between organelles, is conserved (Gabriele 2009, Nair 2001). Although the full mechanistic functions of CRP40 have not yet been elucidated, evidence suggests that it may play a role as a molecular chaperone, not unlike mortalin. Further study is required to determine how CRP40 functions in protein folding and proteostasis as related to neurodegenerative conditions.

One major distinction between CRP40 and mortalin lies in their localization. While mortalin is expressed in all cells, CRP40 is found exclusively in the CNS and in specific blood cells (Ross 1995). This pattern of expression makes CRP40 of particular interest to research in neurological disorders, especially neurodegeneration, as CRP40 may serve a more specific function in CNS disorders.

CRP40 may have similar roles to mortalin as a chaperone protein, but CRP40 also displays some functions in neuroprotection. Thus far, studies have shown that upregulation of CRP40 in the presence of excess DA can actually be inhibited by treatment of cells with antioxidants, suggesting that CRP40 is a reactant protein to the oxidative stress caused by the natural oxidation of DA (Nair 2001). Further, heat-shocked cells that were subsequently treated with CRP40 protein showed decreased denaturation and aggregation of

proteins in comparison to untreated cells — a finding that highlights CRP40 as a heat-shock protein and molecular chaperone (Gabriele 2009, Nair 2001).

Unlike other members of the Hsp70 family, CRP40 contains the tyrosine and aspartate residues necessary for DA binding (Gabriele 2009, Nair 2001). Staining studies show that CRP40 colocalizes in neuronal cells with DA and Tyrosine Hydroxylase (TH), the rate-limiting molecule in DA synthesis (Gabriele 2009, Goto 2001, Nair 2001). This protein actually displays covalent interactions with the catecholamine neurotransmitters, but does not interrelate with serotonin or other amines (Nair 2001, Ross 1993, Ross 1995). In fact, CRP40 expression is inducible by presence of excess DA, which makes it an interesting target for research related to the neurodegenerative disorders with dopaminergic components, like SCZ and PD (Nair 2001).

Recent reports have revealed the importance of CRP40 to these dopaminergic degenerative conditions. Gabriele et al. (2005) conducted a study using human post-mortem SCZ samples obtained from the Stanley Foundation Neuropathology Consortium. Results showed that CRP40 is dysregulated in the affected brain regions and suggest its involvement in the pathogenesis of SCZ. In fact, there was a significant decrease in the protein expression of CRP40 in patients with SCZ (Gabriele 2005). Similarly, in studies using human post-mortem PD brain samples, Mortalin/CRP40 were found to be dysregulated in PD-specific brain regions (Jin 2006, Shi 2008). Specifically, there is a quantitative decrease in Mortalin/CRP40 expression with progression of the disease (Shi 2008). These reports present important evidence that CRP40 may act as a potential biomarker for neurological disorders. Future studies will be conducted to determine whether CRP40 and its dysregulation in neurological disorders may be exploited for early disease-detection and monitoring of disease progression.

Since the discovery of CRP40, new findings and evidence have converged to reveal its involvement in neurodegenerative disease pathology. Specifically, CRP40 seems to have great significance to CNS disorders involving DA. As well, CRP40 may be involved in the crucial process of proteostasis that is impaired in neurodegenerative diseases. The Gabriele group is moving forward with this important research and has engaged in studies of both basic and clinical sciences in order to elucidate potential breakthroughs of CRP40 in the realm of neurodegenerative disorders. ■

Lubarda.indd 69 13-02-04 3:01 PM


References

Burbulla LF, Schelling C, Kato H, Rapaport D, Woitalla D, Schiesling C, Schulte C, Sharma M, Illig T, Bauer P, Jung S, Nordheim A, Schöls L, Riess O, Krüger R. Dissecting the role of the mitochondrial chaperone Mortalin in Parkinson’s disease: functional impact of disease-related variants on mitochondrial homeostasis. Hum Mol Genet. 2010;19(22):4437-4452.

Caughey B, Lansbury PT. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003;26:267-298.

Choi J, Forster MJ, McDonald SR, Weintraub ST, Carroll CA, Gracy RW. Proteomic identification of specific oxidized proteins in ApoE-knockout mice: relevance to Alzheimer’s disease. Free Radic Biol Med. 2004;36(9):1155-1162.

Deocaris CC, Kaul SC, Wadhwa R. From proliferative to neurological role of an Hsp70 stress chaperone, mortalin. Biogerontol. 2008;9(6):391-403.

Ellis RJ. Molecular chaperones: assisting assembly in addition to folding. Trends Biochem Sci. 2006;31(7):395-401.

Forman MS, Trojanowski JQ, Lee VM. Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med. 2004;10(10):1055-1063.

Gabriele JP, Chong VZ, Pontoriero GF, Mishra RK. Decreased expression of a 40-kDa catecholamine-regulated protein in the ventral striatum of schizophrenic brain specimens from the Stanley Foundation Neuropathology Consortium. Schizophr Res. 2005;74(1):111-119.

Gabriele N, Pontoriero GF, Thomas N, Shethwala SK, Pristupa ZB, Gabriele JP. Knockdown of mortalin within the medial prefrontal cortex impairs normal sensorimotor gating. Synapse. 2010;64(11):808-813.

Gabriele J, Pontoriero GF, Thomas N, Thomson CA, Skoblenick K, Pristupa ZB, Mishra RK. Cloning, characterization, and functional studies of a human 40-kDa catecholamine-regulated protein: implications in central nervous system disorders. Cell Stress Chaperon. 2009;14(6):555-567.

Goto A, Doering L, Nair VD, Mishra RK. Immunohistochemical localization of a 40-kDa catecholamine regulated protein in the nigrostriatal pathway. Brain Res. 2001;900(2):314-319.

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Kaul SC, Wadhwa R, Matsuda Y, Hensler PJ, Pereira-Smith OM, Komatsu Y, Mitsui Y. Mouse and human chromosomal assignments of mortalin, a novel member of the murine hsp70 family of proteins. FEBS Lett. 1995;361(2-3):269-272.

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METAGENICS PHYTOMULTI PhytoMulti by Metagenics is a robust multivitamin fortified with over 20 phytonutrient extracts, including lutein, greet tea extract, and resveratrol. As such, PhytoMulti is an ideal product for use in adults in order to optimize vitamin and mineral status, in lieu of poor dietary intake or increased physiological requirements, but also provides a broad spectrum of plant nutrients in order to mimic the many health effects of a plant-based diet. The USDA MyPlate recommendations include between 9-10 servings of fruits and vegetables per day, but less than 10% of adults achieve this target (Murphy 2011). The Mediterranean dietary pattern is an example of a well-researched diet that is very high in phytonutrients. The Mediterranean diet is associated with markedly lower risk of several chronic diseases, including cardiovascular disease and diabetes (Eustruch 2006, Interact Consortium 2011, Nordmann 2011), and a high fruit and vegetable diet has been shown to reduce risk of cancer (Block 1992), in large part due to high amounts of combined phytonutrients. Phytonutrients have been shown to confer beneficial health effects through numerous mechanisms, including modulation of signal transduction pathways, antioxidant properties, and through hormonal effects. PhytoMulti contains over 20 of these plant substances, including: lutein, zeaxanthin, acacia nilotica, and extracts of artichoke leaf, grape seed extract, green coffee, green tea, citrus bioflavonoids, resveratrol, prune skin, watercress, rosemary, pomegranate, lycopene, cinnamon, bitter melon, and blueberry. Multivitamin supplementation has been shown to benefit a variety of physical and cognitive parameters particularly in children, pregnant women or women who may become pregnant, individuals under increased stress, individuals with poor absorption, and the elderly. In pregnancy, supplementation with a folic acid containing multivitamin has been shown to reduce risk of complications such as placental abruption, preeclampsia, in addition to decreasing risk of congenital defects including neural tube defects, anencephaly, myelomeningocele, meningocele, oral facial cleft, structural heart defects, limb defects, urinary tract anomaly, and hydrocephalus when used prior to conception and during the first trimester (Wilson 2007). Periconceptional multivitamin use in lean women has been shown to decrease the risk of small-for-gestational-age (SGA) under the 5th percentile by up to 46% compared to non-users (OR=0.54, 95% CI), and has been associated with a 71% reduction in preeclampsia risk (OR=0.29, 95% CI) in lean women, users versus non-users (Catov 2007; Bodnar 2006). Periconceptional multivitamin use has also been associated with reduced risk of several pediatric cancers, including leukemia (OR=0.61) (39% reduced risk); pediatric brain tumors (OR=0.73) (27% reduced risk); and neuroblastoma (OR=0.53) (47% reduced risk) in a recent meta-analysis (Goh 2007).

In patients under high levels of psychological stress, use of a multivitamin has been shown improve perceived levels of stress and psychometric parameters. Gruenwald et al (2002) found that use of a multivitamin for 6 months resulted in a 40.7% overall improvement in self rated stress levels using a psychological-neurological questionnaire to assess “psycho-organic, central vegetative, and somatic discomforts.” Other outcomes included a 29% decrease in frequency of infections and 91% decrease in gastrointestinal discomfort. Schlebusch et al (2000) found similar benefit on various psychometric parameters in a 30 day trial (1997), and Harris found that multivitamin supplementation can improve measures of mood, stress, and alertness in older men (2011). Importantly, supplementation with a spectrum of B vitamins has also been shown to reduce ratings of workplace stress (Stough 2011). Several trials have shown increased cognitive performance in children taking a multivitamin supplement. Benton et al (1988) found a significant increase in non-verbal intelligence in children taking a multi versus those taking placebo after 8 months’ intervention. In a 14 month study of 608 children, Vazir et al (2006) found a significant increase in attention-concentration increment scores in those supplemented with a micronutrient-fortified beverage versus those receiving placebo. Additional benefits demonstrated in children include a reduced mean duration (5.0 versus 7.5 days, supplement versus placebo) of several common childhood illnesses including such as fever, cough and cold, diarrhea, and ear infections (Sarma 2006). In the elderly, multivitamin supplementation has been shown to significantly improve status of such nutrients as vitamin D, vitamin B6, vitamin B12, folate, vitamin C, vitamin E, zinc, and selenium (McKay 2000; Girodon 1997). In addition, supplementation has also been found to significantly reduce rates of infection in the elderly, as found a trial in 81 subjects given various supplemental combinations of micronutrients and followed over a 2 year period (Girodon 1997).

PhytoMulti: Active Ingredients* (per 1 tablet) Ingredient Dose Unit Vitamin A as retinyl acetate 2500 IU Vitamin A as carotenoids 2500 IU Vitamin E d-alpha tocopherol 50 IU Vitamin C ascorbic acid 60 mg Vitamin D3 cholecalciferol 500 IU Vitamin K phytonadione 60 mcg Thiamine mononitrate 12.50 mg Riboflavin 7.50 mg Niacin 6.25 mg Niacinamide 18.75 mg Pantothenic acid 37.5 mg Vitamin B6 pyridoxine HCl 12.50 mg Calcium L-Mefolinate 400 mcg Vitamin B12 cyanocobalamin 120 mcg Biotin 250 mg Magnesium citrate 20 mg Chromium polynicotinate 100 mcg Copper citrate 500 mcg Iodine potassium iodide 75 mcg Manganese citrate 250 mcg Molybdenum aspartate 25 mcg Selenium aspartate 50 mcg Zinc citrate 7.50 mg * In addition to extracts of over 20 phytonutrients.

References Benton D, Roberts G. Lancet. 1988 Jan 23;1(8578):140-3. Block G, et al. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutrition

and cancer 1992;18(1):1-29. Bodnar LM, Tang G, Ness RB, Harger G, Roberts JM. Am J Epidemiol. 2006 Sep 1;164(5):470-7. Epub

2006 Jun 13. Catov JM, Bodnar LM, Ness RB, Markovic N, Roberts JM. Am J Epidemiol. 2007 Aug 1;166(3):296-303.

Epub 2007 May 11. Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Fertil Steril. 2008 Mar;89(3):668-76. Epub 2007

Jul 10. Eustruch R, Martínez-González MA, Corella D, et al. Ann Intern Med. 2006 Jul 4;145(1):1-11 Girodon F, Lombard M, Galan P, Brunet-Lecomte P, Monget AL, Arnaud J, Preziosi P, Hercberg S. Ann

Nutr Metab. 1997;41(2):98-107. Goh YI, Bollano E, Einarson TR, Koren G. Clin Pharmacol Ther. 2007 May;81(5):685-91. Epub 2007 Feb

21. Grieger JA, Nowson CA, Jarman HF, Malon R, Ackland LM. Eur J Clin Nutr. 2007 Nov 28. Gruenwald J, Graubaum HJ, Harde A. Adv Ther. 2002 May-Jun;19(3):141-50. Harris E, Kirk J, Rowsell R, Vitetta L, Sali A, Scholey AB, Pipingas A. Hum Psychopharmacol. 2011

Dec;26(8):560-7. InterAct Consortium. Diabetes Care. 2011 Sep;34(9):1913-8. McKay DL, Perrone G, Rasmussen H, Dallal G, Hartman W, Cao G, Prior RL, Roubenoff R, Blumberg JB.

J Am Coll Nutr. 2000 Oct;19(5):613-21. Murphy MM, et al. Journal of the American Dietetic Association 2011:in press. Nilsen RM, Vollset SE, Rasmussen SA, Ueland PM, Daltveit AK. Am J Epidemiol. 2008 Apr

1;167(7):867-74. Epub 2008 Jan 10. Nordmann AJ, Suter-Zimmermann K, Bucher HC, et al. Am J Med. 2011 Sep;124(9):841-51.e2. Ribeiro ML, Arçari DP, Squassoni AC, Pedrazzoli J Jr. Mech Ageing Dev. 2007 Oct;128(10):577-80. Epub

2007 Aug 15. Sarma KV, Udaykumar P, Balakrishna N, Vijayaraghavan K, Sivakumar B. Nutrition. 2006 Jan;22(1

Suppl):S8-14. Schlebusch L, Bosch BA, Polglase G, Kleinschmidt I, Pillay BJ, Cassimjee MH. S Afr Med J. 2000

Dec;90(12):1216-23. Stough C, Scholey A, Lloyd J, Spong J, Myers S, Downey LA. Hum Psychopharmacol. 2011

Oct;26(7):470-6. Tanvetyanon T, Bepler G. Cancer. 2008 Jul 1;113(1):150-7. Vazir S, Nagalla B, Thangiah V, Kamasamudram V, Bhattiprolu S. Nutrition. 2006 Jan;22(1 Suppl):S26-

32. Wilson RD, et al. J Obstet Gynaecol Can. 2007 Dec;29(12):1003.


The Journal of IHP – Continuing Education


Colin MacLeod, NDKinesis Health Associates164-166 Ochterloney St.Dartmouth, Nova Scotia, Canada

NAC at high oral or intravenous doses is the gold standard treatment for acetaminophen toxicity. NAC antidotes acetaminophen poisoning by repleting glutathione stores and as a result mitigates liver damage. NAC exerts its therapeutic action through glutathione repletion, as well as glutamate modulation and mucous thinning in treating other health conditions. Recently data has surfaced supporting NAC as an effective treatment for a variety of health conditions, including non-acetaminophen-induced acute liver failure, COPD, flu prevention, idiopathic pulmonary fibrosis, acute renal failure due to contrast media, schizophrenia, bipolar disorder, autism, grooming disorders, obsessive compulsive disorder, addiction and angina. Adverse effects of NAC by the oral route are mild at low doses and exclusively gastrointestinal, while IV NAC can lead to anaphylactic reactions, including pruritus, rash, tachycardia, hypotension, bronchospasm and syncope. Care should be taken with concomitant treatment with nitrates and NAC, due to NAC’s potentiating effect on nitrates. It is evident from the published data that NAC is a safe and valuable clinical tool, useful for treating a wide variety of health conditions.

N-acetyl-cysteineA Versatile Intervention

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.

IntroductionAlthough widely accepted as the primary antidote

to acetaminophen overdose and as a mucolytic agent, N-acetyl-cysteine (NAC) has a variety of clinical applications, some of which have only recently come to light. Cysteine is a non-essential amino acid that is found mostly in animal products. NAC is essentially cysteine with an acetyl group attached. This acetyl group limits digestive degradation and promotes absorption. NAC powder has a white colour and dissolves clear to slightly purple in water. NAC has a sulphur-like odour and unpleasant taste which makes high oral doses challenging to administer.

Standard DosingNAC is commonly available without prescription

in 500mg or 600mg capsules. NAC is also available at 200mg/ml solution for oral and intravenous use in the treatment of acetaminophen overdose and as a mucolytic in pulmonary conditions with excessive mucous. Dosing of NAC is condition specific

and has been best established in the treatment of acetaminophen toxicity.

In the treatment of acetaminophen toxicity in adults, the oral dose of NAC is 1,330 mg/kg (93,100 mg in 70 kg individual) in 18 doses spread over three days: a loading dose of 140 mg/kg followed by 17 doses of 70 mg/kg every four hours (Prescott 2005). The intravenous dose is 300 mg/kg (21,000 mg in 70 kg individual) divided into three separate IV bag drips over 21 hours: a loading dose of 150 mg/kg in 5% dextrose is given over a 15-minute period, followed by 50 mg/kg in four hours and 100 mg/kg in 16 hours, for a total dose of 300 mg/kg in 20 and one quarter hours (Prescott 2005). The intravenous route is used in Canada, Europe and Australia, whereas the oral route is used in the United States.

Liver damage is prevented most effectively when treatment is administered orally (Smilkstein 1988) or intravenously (Whyte 2007) within eight hours of the acetaminophen overdose. However, treatment should not be denied up to 24 hours after poisoning as there

073-078.IHP_ContinuingEducation-issue 31-v2.indd 73 2013-02-01 3:32 PM


is still life-saving potential (Prescott 2005). Most conditions experimentally treated with NAC have used considerably smaller doses than that used for acetaminophen toxicity. Limited data exists on the efficacy and safety of nebulized NAC.

PharmacokineticsWhen 600mg of NAC was administered orally to

healthy human volunteers, 6.4-10% was absorbed into the bloodstream intact (Borgström 1986). In an animal model, it has been found that low oral bio-availability is due, in part, to de-acetylation and conversion to other sulphur-containing compounds within the digestive tract, but that a significant amount of NAC reaches the blood as other-sulphur containing compounds (Cotgreave 1987).

The half-life of NAC in healthy adults has been reported differently by different investigators, including 2.27 hours (Borgström 1986) and 5.7 hours (Prescott 1989) for the intravenous route, and 3.7 hours for the oral route (Nolin 2010). The newborn half-life of NAC has been reported to be between 7.8 and 15.2 hours when administered intravenously, but depends largely on weight and gestational age (Ahola 1999). The half-life of NAC is significantly longer when given orally to patients with end-stage renal disease (Nolin 2010), or chronic liver disease (Jones 1997).

Pregnant women with acetaminophen poisoning should be treated with a standard high-dose oral NAC protocol due to its life-saving potential for the mother and fetus (Riggs 1989). If NAC is given to a pregnant woman in high oral or intravenous doses placental transfer will occur (Horowitz 1997). Minimal data exists on the safety and efficacy of IV NAC in pregnant women for treatment of acetaminophen toxicity.

Mechanism of ActionNAC is believed to act through three

major mechanisms: providing glutamate for neurotransmission, providing cysteine for the synthesis of glutathione, and cleaving disulphide bonds present in mucous.

Glutathione, the most ubiquitous endogenous antioxidant is composed of three major amino acids: glutamate, glycine and cysteine. Of its three components, cysteine supply is the rate limiting step in glutathione production (Lu 2012, Radtke 2012). Some of the therapeutic effects of NAC have been attributed to its ability to provide glutathione, including in pulmonary conditions

and hepatic injury. NAC does not seem to increase plasma glutathione in healthy human controls but will increase plasma glutathione in humans who have depressed glutathione stores from oral acetaminophen dosing (Burgunder 1989).

The activity of NAC in psychiatric conditions has been postulated to be due to its ability to provide glutamate for neurotransmission and in restoring brain glutathione. Altered glutamate status has been reported to be an important factor in psychiatric conditions with an addictive or compulsive component (Dean 2011). NAC’s structure also includes a free sulphhydryl (-SH) group which is thought to act on the relatively weak disulphide bonds within mucous to break it into smaller, less viscous segments which can be more easily cleared.

Clinical Indications

Acetaminophen ToxicityNAC has been used for over 30 years as an antidote

to acetaminophen toxicity (Scalley 1978). NAC’s remarkable efficacy as an acetaminophen antidote can be seen in observational evidence where a delay of NAC administration of even a few hours can be the difference between full recovery and liver failure (Smilkstein 1988). NAC’s ability to replete glutathione is the mechanism by which it antidotes acetaminophen toxicity.

Non-Acetaminophen-Induced Acute Hepatic FailureNAC has proven to be helpful in increasing survival

in hepatitis- and drug-induced liver failure at high oral (Mumtaz 2009, Sotelo 2009) and intravenous (Kortsalioudaki 2008, Lee 2009) doses similar to those used in acetaminophen toxicity. Kortsalioudaki found that intravenous NAC administered to children with non-acetominophen acute liver failure resulted in shorter length of hospital stay, higher incidence of native liver recovery without transplantation, and better survival after transplantation (2008). Much smaller oral doses of 600mg/day have been associated with no change in duration of hospitalization compared to controls (Gunduz 2003).

High-dose NAC is a promising treatment in drug- or hepatitis-induced acute hepatic failure. Although no firm dosing schedule can be identified, an oral or intravenous protocol similar to that used in acetaminophen toxicity should be considered due to the increased survival evidenced in four human trials (Mumtaz 2009, Sotelo 2009, Kortsalioudaki 2008, Gunduz 2003).




Chronic Obstructive Pulmonary DiseaseSeveral studies have been performed on the

effectiveness of NAC for Chronic Obstructive Pulmonary Disease (COPD) using oral doses of 600-1200mg/day. Some studies (Hansen 1994, Pela 1999, Stav 2009, Völkl 1992, Zuin 2005) though not all (Black 2004, Decramer 2005, Lukas 2005, Schermer 2009) found that use of NAC in addition to conventional treatments is more effective in the management of COPD related symptoms compared to conventional treatment alone. In addition, several trials report improvements in specific measurements of lung function, including FEV1, inspiratory capacity (IC), and functional residual capacity (FRC) (Decramer 2005, Pela 1999, Stav 2009).

It should be noted that although many of the trials utilize FEV1 as the primary measure of effectiveness, failure to show benefit on this outcome should not be strictly interpreted as a failure of treatment success. Stav et al point out that although FEV1 is used to classify disease severity and is a good predictor of COPD mortality, it is a “poor predictor of clinical symptoms, exercise tolerance, and response to bronchodilators in COPD” (2009). Furthermore, COPD is characterized by “disease changes at the level of small airways, which is not usually expressed by the measurement of FEV1… IC [inspiratory capacity], however, is a lung volume measure that has been found to correlate well with patient dyspnea and exercise tolerance (2009). For instance, reduced IC during exercise correlated well with dynamic hyperinflation (Stav 2009). Some trials have shown small but significant improvements in FEV1 associated with NAC treatment (Pela 1999, Völkl 1992, Zuin 2005), while others have not (Decramer 2005).

The BRONCUS trial was a large (N=523), high quality trial showing no effect of 600mg NAC compared with placebo on the maximal forced expiratory volume in one second (FEV1) and prevention of COPD exacerbations (primary outcomes) when given over a three year period (Decramer 2005). However, a significant reduction in the functional residual capacity (FRC), the volume remaining in the lungs at the end of passive expiration, was seen in the NAC group on secondary analysis: FRC decreased from 4·46L to 4·09L in patients assigned to NAC, p<0.0001 (Decramer 2005). Other trials have also noted improvements in other measures of lung function associated with air trapping, including IC and FVC (Stav 2009). Considering its negligible adverse effects, low cost, and data showing benefit on measures of lung function associated with air trapping, NAC deserves to be considered as an adjunctive treatment option in COPD at oral doses of 600-1200mg/day.

Flu PreventionOne large (N=262), high-quality trial has been

performed on the effect of NAC on influenza. Elderly patients were treated prophylactically for six months during flu season with oral NAC at 600mg twice daily or placebo. Although influenza infection rates were not different between treatment and placebo groups, influenza-like episodes, symptom severity and length of time confined to bed in the NAC group were significantly lower. The NAC group was also found to have a significant immune stimulation as compared to baseline and compared to the placebo group, as measured through anergy (De Flora 1997).

Idiopathic Pulmonary FibrosisIdiopathic Pulmonary Fibrosis (IPF) is a condition

of unknown etiology which is characterized by scarring of the lungs and most commonly affects people 50-70 years of age. One randomized, double-blind placebo-controlled trial (N=182) administered NAC orally at 600mg three times daily as an add-on to standard treatment in patients with IPF. The NAC group had significantly slowed deterioration of lung vital capacity (VC) and diffusion capacity compared to the placebo group (Demedts 2005). Conversely, data on nebulized NAC suggests that it does not improve outcomes in IPF (Bando 2010, Tomioka 2005) and may even lead to acute exacerbations (Bando 2010). On considering these trials, oral NAC at 600mg three times daily should be considered as an add-on to standard medical treatment for IPF.

Renal Protection from X-ray Contrast MediaContrast media used during radiographic examination

can cause nephropathy and acute renal failure. Risk factors for contrast-induced nephropathy include compromised kidney function, diabetes and reduced intravascular volume. Numerous clinical trials have been conducted over the past decade on prevention of acute renal failure with most using oral doses of 600mg NAC twice daily on the day before and the day of contrast media administration. As a whole the results have been mixed with some studies showing benefit from NAC (Briguori 2011, Koc 2012, Sar 2010) and others showing no effect (Anderson 2011, Gurm 2012, Jaffery 2012).

As is the case with COPD, the evidence is equivocal, but the intervention has negligible adverse effects and the cost is low. With this in mind, oral NAC at 600mg twice daily on the day before and the day of contrast media administration should be considered for patients with compromised kidney function as an add-on to standard treatment for prevention of acute kidney failure.



Nitrate-treated AnginaSulfhydryls seem to be fundamental to nitrate-

induced vasodilation (Mehra 1994). Data also suggests that in angina patients receiving nitrates, NAC given orally may lead to a significant decrease in ischemic effects as assessed by ECG (Boesgaard 1991), myocardial infarction rates (Ardissino 1997), angina symptoms and death rates (Ardissino 1997). Oral dosages in this setting have ranged from 1800-2400 mg per day in divided doses (Ardissino 1997, Boesgaard 1991). NAC given intravenously may lead to a decreased tolerance to nitrates (Boesgaard 1992, Pizzulli 1997) and a decreased rate of myocardial infarction (Horowitz 1988) in nitrate-treated angina patients. However, not all trials have shown that NAC is of benefit, when given orally (Hogan 1990) or intravenously (Parker 1987).

Considerable care must be taken when giving NAC to nitrate-treated patients orally (Ardissino 1997) or intravenously (Horowitz 1988) due to NACs ability to potentiate associated hypotension and headaches. If prescribed, oral NAC should be started at a low dose (600mg three (Ardissino 1997) or four times daily (Boesgaard 1991)) with careful monitoring of blood pressure and headache occurrence. No clear recommendation can be given for intravenous dosing.

SchizophreniaThree trials have examined NAC in patients with

schizophrenia (Berk 2008, Carmeli 2012, Lavoie 2008). One double-blind, placebo-controlled trial (N= 140) using oral NAC at 1,000mg twice daily showed statistically significant improvements in those treated with NAC across several standardized schizophrenia measurement scales, and akathisia (restless leg syndrome) also improved significantly compared to placebo (Berk 2008). The mechanism by which NAC treats schizophrenia is thought to be through brain glutamate/ NMDA receptor modulation and reduction of oxidative stress (Dean 2011).

Lavoie et al conducted a randomized, double-blind, cross-over trial comparing 2g NAC to placebo for a period of 60 days to investigate N-methyl-D-aspartate (NMDA) receptor function, characteristically low in schizophrenia (2008). Mismatch negativity (MMN) is an auditory evoked potential (AEP) component related to NMDA receptor function that is impaired in patients with schizophrenia (Lavoie 2008). In this study, treatment with NAC significantly improved MMN generation compared with placebo (p=0.025),

suggesting improved NMDA receptor activity, but the study was not continued for long enough to observe changes in clinical severity as reported by the same group in Berk 2008 (above) (Lavoie 2008).

Lastly, a recent proof-of-concept study found that NAC was able to significantly increase multivariate phase synchronization (MPS) on EEG testing compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions in patients with schizophrenia (Carmeli 2012). Authors suggested that this may be an early marker of clinically important treatment effects.

Bipolar DisorderTwo small double-blind, placebo-controlled trials

(N=75, N=17) in patients diagnosed with bipolar disorder showed very encouraging improvement in measures of symptom severity, functioning and quality of life with oral NAC at 1,000mg twice daily as an add-on to conventional therapy (Berk 2008, Magalhães 2011A). Improvements were evident by eight weeks (Beck 2008). In a sub-analysis of the study by Berk 2008, six of seven participants with bipolar II in the NAC group experienced a full remission of depressive and manic symptoms, compared to only two of seven in the placebo group (p=0.031) (Magalhaes 2011B). In an analysis of the effect of adjunctive NAC treatment on depressive symptoms in bipolar patients, Magalhaes et al reported “very large effect sizes in favor of NAC … for depressive symptoms and functional outcomes .... Eight of the ten participants on NAC had a treatment response at endpoint; the same was true for only one of the seven participants allocated to placebo” (2011A).

A report of a larger cohort (N=149) from the two-month open label phase following an RCT showed similar results, which were described by the authors as a “robust decrement in depression scores” associated with NAC treatment (Berk 2011). Adverse effects were non-significant in all three trials.

AutismA small (N=33), 12-week double-blind randomized

placebo-controlled trial treated autistic patients (3.2-10.7 years of age) with oral NAC in an escalating dose schedule reaching a maximum of 900mg three times daily. Compared with the placebo group, the NAC group had significant improvements on the Aberrant Behaviour Checklist irritability subscale. Adverse effects were mild and exclusively gastrointestinal (Hardan 2012).




Grooming DisordersThere are several case reports and small trials of

oral NAC in the treatment of addiction, compulsive disorder and excessive grooming disorders. It has been suggested that the mechanism of action may involve changes to glutamate levels in the brain (Dean 2011).

One small (N=50) randomized, double-blind trial compared NAC 1,200mg or 2,400mg per day to placebo in the treatment of trichotillomania (compulsive hair pulling). Significant improvements were noticed after nine weeks of treatment in hair pulling with 56% of participants in a NAC treated group reporting “much or very much improved” whereas 16% in placebo group reported the same level of improvement (Grant 2009). Another two cases of trichotillomania showed encouraging improvement when treated with oral NAC at 1,200 mg/day for three and six months, respectively (Rodrigues-Barata 2012).

In the case of nail biting, three patients showedcomplete abstinence of nail-biting after oral NAC at 1,000mg bid for four to seven months (Berk 2009). Encouraging improvement was also seen in one case of trichotillomania, one case of nail biting with trichotillomania and one case of skin picking when treated with oral NAC at 1,800-2,400mg/day (Odlaug 2007).

Obsessive Compulsive DisorderA small (N=36) randomized, double-blind trial

compared 600-2,400mg/day NAC and placebo orally for 12 weeks in patients with obsessive compulsive disorder who were refractory to SSRI treatment. The patients in the NAC group had a 52.6% rate of “full response”, while the patients taking placebo had a 15% rate of “full response”. Full response was defined as a 35% or greater reduction on the Yale-Brown Obsessive Compulsive Scale. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score was also significantly improved in the NAC group as a whole (p<0.001) (Afshar 2012).

Addiction Two small (N=13) (N=15) placebo-controlled trials

(LaRowe 2006, 2007) and one small (N=23) open-label trial (Mardikian 2006) have shown significant reductions in cocaine craving and usage with oral doses of NAC at 1200-3600mg/day.

Another small (N=116), eight-week double-blind randomized placebo-controlled trial targeted promoting cannabis abstinence in adolescents. Participants were given 1200mg NAC twice daily or placebo orally, along with brief weekly counselling sessions and a small cash-based reward system. When

adjusted for cannabis use at baseline, the NAC group had significantly higher odds than the placebo group of negative urine cannabinoid tests during treatment, OR 2.4 (95% CI 1.1-5.2) (Gray 2012).

An open-label trial followed by a double blind placebo-controlled trial investigated the effect of oral NAC at 1,800mg/day on pathological gambling. Significant improvements were seen in the Yale-Brown Obsessive Compulsive Scale Modified for Pathological Gambling in the NAC group compared to the placebo group in both sections of the study (Grant 2007).

Although individually these case studies and clinical trials modestly support NAC use, the totality of evidence supports oral NAC at 1,200-3,600mg/day as a viable treatment option in addiction (specifically cocaine, cannabis and gambling), excessive grooming behaviours (specifically trichotillomania, skin picking and nail biting) and obsessive compulsive disorder.

Adverse Effects and ToxicityA safety analysis of high-dose NAC examined its

effects on 503 patients with acetaminophen toxicity. The oral route caused nausea and vomiting in 23% of patients and anaphylactic reactions in 2%. The IV route caused anaphylactic reactions in 9% of patients and nausea and vomiting in 6% of patients. The anaphylactic reactions were, in decreasing order of occurrence, pruritus, tachycardia, flushing, urticaria, non-urticarial rash, hypotension, bronchospasm and syncope (Bebarta 2010).

One retrospective study of 187 patients with acetaminophen toxicity treated with intravenous NAC found only seven adverse reactions, six being cutaneous and one being life-threatening, but not clearly caused by NAC (Kao 2003). Massive accidental intravenous overdoses have been reported to cause kidney failure (Mullins 2011), severe brain injury (Heard 2011) and death (Bailey 2004, Elms 2011).

Oral and intravenous NAC are considered to be of equal efficacy in treating acetaminophen poisoning (Kanter 2006). The intravenous route is not recommended for patients prone to anaphylaxis or at high risk for bronchospasm, such as asthmatics. The oral route is not recommended for patients with nausea or vomiting severe enough to render oral treatment ineffective (Kanter 2006). Oral doses of 600mg twice daily were associated with an insignificant adverse effect profile compared to placebo in a 262 person trial (De Flora 1997).



References

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Ahola T, Fellman V, Laaksonen R, et. al. Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants. Eur J Clin Pharmacol. 1999 Nov;55(9):645-50.

Anderson S, Park Z, Patel R. Intravenous N-acetylcysteine in the prevention of contrast media-induced nephropathy. Ann Pharmacother. 2011 Jan;45(1):101-7.

Ardissino D, Merlini PA, Savonitto S, et. al. Effect of transdermal nitroglycerin or N-acetylcysteine, or both, in the long-term treatment of unstable angina pectoris. J Am Coll Cardiol. 1997 Apr;29(5):941-7.

Bailey B, Blais R, Letarte A. Status epilepticus after a massive intravenous N-acetylcysteine overdose leading to intracranial hypertension and death. Ann Emerg Med. 2004 Oct;44(4):401-6.

Bando M, Hosono T, Mato N, et. al. Long-term efficacy of inhaled N-acetylcysteine in patients with idiopathic pulmonary fibrosis. Intern Med. 2010;49(21):2289-96.

Bebarta VS, Kao L, Froberg B, et. al. A multicenter comparison of the safety of oral versus intravenous acetylcysteine for treatment of acetaminophen overdose. Clin Toxicol (Phila). 2010 Jun;48(5):424-30.

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Boesgaard S, Aldershvile J, Pedersen F, Pietersen A, Madsen JK, Grande P. Continuous oral N-acetylcysteine treatment and development of nitrate tolerance in patients with stable angina pectoris. J Cardiovasc Pharmacol. 1991 Jun;17(6):889-93.

Boesgaard S, Aldershvile J, Poulsen HE. Preventive administration of intravenous N-acetylcysteine and development of tolerance to isosorbide dinitrate in patients with angina pectoris. Circulation. 1992 Jan;85(1):143-9.

Borgström L, Kågedal B, Paulsen O. Pharmacokinetics of N-acetylcysteine in man. Eur J Clin Pharmacol. 1986;31(2):217-22.

Briguori C, Quintavalle C, De Micco F, Condorelli G. Nephrotoxicity of contrast media and protective effects of acetylcysteine. Arch Toxicol. 2011 Mar;85(3):165-73.

Burgunder JM, Varriale A, Lauterburg BH. Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration. Eur J Clin Pharmacol. 1989;36(2):127-31.

Carmeli C, Knyazeva MG, Cuénod M, Do KQ. Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial. PLoS One. 2012;7(2):e29341.

Cotgreave IA, Berggren M, Jones TW, Dawson J, Moldéus P. Gastrointestinal metabolism of N-acetylcysteine in the rat, including an assay for sulfite in biological systems. Biopharm Drug Dispos. 1987 Jul-Aug;8(4):377-86.

Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011 Mar;36(2):78-86.

Decramer M, Rutten-van Mölken M, Dekhuijzen PN, et. al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005 Apr 30-May 6;365(9470):1552-60.

De Flora S, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J. 1997 Jul;10(7):1535-41.

Demedts M, Behr J, Buhl R, et. al.. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2005 Nov 24;353(21):2229-42.

Elms AR, Owen KP, Albertson TE, Sutter ME. Fatal myocardial infarction associated with intravenous N-acetylcysteine error. Int J Emerg Med. 2011 Aug 30;4(1):54.

Grant JE, Kim SW, Odlaug BL. N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry. 2007 Sep 15;62(6):652-7.

Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2009 Jul;66(7):756-63.

Gray KM, Carpenter MJ, Baker NL, et. al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry. 2012 Aug 1;169(8):805-12.

Gunduz H, Karabay O, Tamer A, Ozaras R, Mert A, Tabak OF. N-acetyl cysteine therapy in acute viral hepatitis. World J Gastroenterol. 2003 Dec;9(12):2698-700.

Gurm HS, Smith DE, Berwanger O, et. al. Contemporary use and effectiveness of N-acetylcysteine in preventing contrast-induced nephropathy among patients undergoing percutaneous coronary intervention. JACC Cardiovasc Interv. 2012 Jan;5(1):98-104.

Hansen NC, Skriver A, Brorsen-Riis L, et al. Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis. Respir Med. 1994 Aug;88(7):531-5.

Hardan AY, Fung LK, Libove RA, et. al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012 Jun 1;71(11):956-61.

Heard K, Schaeffer TH. Massive acetylcysteine overdose associated with cerebral edema and seizures. Clin Toxicol (Phila). 2011 Jun;49(5):423-5.

ConclusionNAC, the standard treatment for acetaminophen toxicity, has several relatively unknown clinical uses, including treatment of acute liver failure, COPD, flu prevention, idiopathic pulmonary fibrosis, acute renal failure due to

contrast media, schizophrenia, bipolar disorder, autism, grooming disorders, obsessive compulsive disorder, addiction and angina. Care should be taken to avoid adverse effects associated with nitrate potentiation in angina treatment. ■




Hogan JC, Lewis MJ, Henderson AH. Chronic administration of N-acetylcysteine fails to prevent nitrate tolerance in patients with stable angina pectoris. Br J Clin Pharmacol. 1990 Oct;30(4):573-7.

Horowitz RS, Dart RC, Jarvie DR, Bearer CF, Gupta U. Placental transfer of N-acetylcysteine following human maternal acetaminophen toxicity. J Toxicol Clin Toxicol. 1997;35(5):447-51.

Horowitz JD, Henry CA, Syrjanen ML, et. al. Nitroglycerine/N-acetylcysteine in the management of unstable angina pectoris. Eur Heart J. 1988 Jan;9 Suppl A:95-100.

Jaffery Z, Verma A, White CJ, et. al. A randomized trial of intravenous n-acetylcysteine to prevent contrast induced nephropathy in acute coronary syndromes. Catheter Cardiovasc Interv. 2012 May 1;79(6):921-6.

Jones AL, Jarvie DR, Simpson D, et. al. Pharmacokinetics of N-acetylcysteine are altered in patients with chronic liver disease. Aliment Pharmacol Ther. 1997 Aug;11(4):787-91.

Kanter MZ. Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning. Am J Health Syst Pharm. 2006 Oct 1;63(19):1821-7.

Kao LW, Kirk MA, Furbee RB, Mehta NH, Skinner JR, Brizendine EJ. What is the rate of adverse events after oral N-acetylcysteine administered by the intravenous route to patients with suspected acetaminophen poisoning? Ann Emerg Med. 2003 Dec;42(6):741-50.

Koc F, Ozdemir K, Kaya MG, et. al. Intravenous N-acetylcysteine plus high-dose hydration versus high-dose hydration and standard hydration for the prevention of contrast-induced nephropathy: CASIS--a multicenter prospective controlled trial. Int J Cardiol. 2012 Mar 22;155(3):418-23.

Kortsalioudaki C, Taylor RM, Cheeseman P, et. al. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver Transpl. 2008 Jan;14(1):25-30.

Larowe SD, Mardikian P, Malcolm R, et. al. Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict. 2006 Jan-Feb;15(1):105-10.

LaRowe SD, Myrick H, Hedden S, et. al. Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry. 2007 Jul;164(7):1115-7.

Lavoie S, Murray MM, Deppen P, et. al. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology. 2008 Aug;33(9):2187-99.

Lee W, Hynan L, Rossaro L, et. al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009 Sep;137(3):856-64, 864.e1.

Lu SC. Glutathione synthesis. Biochim Biophys Acta. 2012 Sep 17. Epub ahead of print.

Lukas R, Schärling B, Schultze-Werninghaus G, Gillissen A. [Antioxidant treatment with N-acetylcysteine and vitamin C in patients with chronic bronchitis]. Dtsch Med Wochenschr. 2005 Mar 18;130(11):563-7.

Magalhães PV, Dean OM, Bush AI, et. al. N-acetylcysteine for major depressive episodes in bipolar disorder. Rev Bras Psiquiatr. 2011 Dec;33(4):374-8.A

Magalhães PV, Dean OM, Bush AI, et. al. N-acetyl cysteine add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial. J Affect Disord. 2011 Mar;129(1-3):317-20.B

Mardikian PN, LaRowe SD, Hedden S, Kalivas PW, Malcolm RJ. An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Mar 30;31(2):389-94.

Mehra A, Shotan A, Ostrzega E, et. al. Potentiation of isosorbide dinitrate effects with N-acetylcysteine in patients with chronic heart failure. Circulation. 1994 Jun;89(6):2595-600.

Mumtaz K, Azam Z, Hamid S, et. al. Role of N-acetylcysteine in adults with non-acetaminophen-induced acute liver failure in a center

without the facility of liver transplantation. Hepatol Int. 2009 Aug 29.

Mullins ME, Vitkovitsky IV. Hemolysis and hemolytic uremic syndrome following five-fold N-acetylcysteine overdose. Clin Toxicol (Phila). 2011 Oct;49(8):755-9.

Nolin TD, Ouseph R, Himmelfarb J, et. al. Multiple-dose pharmacokinetics and pharmacodynamics of N-acetylcysteine in patients with end-stage renal disease. Clin J Am Soc Nephrol. 2010 Sep;5(9):1588-94.

Odlaug BL, Grant JE. N-acetyl cysteine in the treatment of grooming disorders. J Clin Psychopharmacol. 2007 Apr;27(2):227-9.

Parker JO, Farrell B, Lahey KA, Rose BF. Nitrate tolerance: the lack of effect of N-acetylcysteine. Circulation. 1987 Sep;76(3):572-6.

Pela R, Calcagni AM, Subiaco S, et. al. N-acetylcysteine reduces the exacerbation rate in patients with moderate to severe COPD. Respiration. 1999 Nov-Dec;66(6):495-500.

Pizzulli L, Hagendorff A, Zirbes M, et. al. N-acetylcysteine attenuates nitroglycerin tolerance in patients with angina pectoris and normal left ventricular function. Am J Cardiol. 1997 Jan 1;79(1):28-33.

Prescott L. Oral or intravenous N-acetylcysteine for acetaminophen poisoning? Ann Emerg Med. 2005 Apr;45(4):409-13.

Prescott LF, Donovan JW, Jarvie DR, Proudfoot AT. The disposition and kinetics of intravenous N-acetylcysteine in patients with paracetamol overdosage. Eur J Clin Pharmacol. 1989;37(5):501-6.

Radtke KK, Coles LD, Mishra U, et. al. Interaction of N-acetylcysteine and cysteine in human plasma. J Pharm Sci. 2012 Dec;101(12):4653-9.

Riggs BS, Bronstein AC, Kulig K, et. al. Acute acetaminophen overdose during pregnancy. Obstet Gynecol. 1989 Aug;74(2):247-53.

Rodrigues-Barata AR, Tosti A, Rodríguez-Pichardo A, Camacho-Martínez F. N-acetylcysteine in the Treatment of Trichotillomania. Int J Trichology. 2012 Jul;4(3):176-8.

Sar F, Saler T, Ecebay A, et. al. The efficacy of n-acetylcysteine in preventing contrast-induced nephropathy in type 2 diabetic patients without nephropathy. J Nephrol. 2010 Jul-Aug;23(4):478-82.

Scalley RD, Conner CS. Acetaminophen poisoning: a case report of the use of acetylcysteine. Am J Hosp Pharm. 1978 Aug;35(8):964-7.

Schermer T, Chavannes N, Dekhuijzen R, et. al. Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis. Respir Med. 2009 Apr;103(4):542-51.

Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988 Dec 15;319(24):1557-62.

Sotelo N, de los Angeles Durazo M, Gonzalez A, Dhanakotti N. Early treatment with N-acetylcysteine in children with acute liver failure secondary to hepatitis A. Ann Hepatol. 2009 Oct-Dec;8(4):353-8.

Stav D, Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study. Chest. 2009 Aug;136(2):381-6.

Tomioka H, Kuwata Y, Imanaka K, et. al. A pilot study of aerosolized N-acetylcysteine for idiopathic pulmonary fibrosis. Respirology. 2005 Sep;10(4):449-55.

Völkl KP, Schneider B. Therapy of respiratory tract diseases with N-acetylcysteine. An open therapeutic observation study of 2,512 patients. Fortschr Med. 1992 Jun 30;110(18):346-50.

Whyte IM, Francis B, Dawson AH. Safety and efficacy of intravenous N-acetylcysteine for acetaminophen overdose: analysis of the Hunter Area Toxicology Service (HATS) database. Curr Med Res Opin. 2007 Oct;23(10):2359-68.

Zuin R, Palamidese A, Negrin R, Catozzo L, Scarda A, Balbinot M. High-dose N-acetylcysteine in patients with exacerbations of chronic obstructive pulmonary disease. Clin Drug Investig. 2005;25(6):401-8.



1. Cysteine is a non-essential amino acid found mostly in animal products; this acetyl group on NAC limits digestive degradation and promotes absorption. Which of the following is true about NAC?a) NAC powder has a yellow colour and dissolves as an orange-red color in water. b) NAC has a sulphur-like odour and unpleasant taste which makes administration of high oral doses challenging. c) NAC has a thick, viscous consistency when mixed in solution with sterile water, necessitating the use of a filter for IV administration.d) All of the above.

2. NAC is available as a 200mg/ml solution for oral and intravenous use in the treatment of acetaminophen overdose and as a mucolytic in pulmonary conditions with excessive mucous.a) Trueb) False

3. In Canada, NAC is administered by the intravenous route in the treatment of acetaminophen overdose. Which best reflects the dosing schedule used?a) 150 mg/kg (~10g) in 5% dextrose infused over 21 hours: a loading dose of 75 mg/kg given first over 15min, followed by 25 mg/kg over 4h, and 50 mg/kg over 16h.b) 3000 mg/kg (~210g) in 5% dextrose infused over 21 hours: a loading dose of 1500 mg/kg given first over 15min, followed by 500 mg/kg over 4h, and 1000 mg/kg over 16h.c) 300 mg/kg (~21g) in 5% dextrose infused over 21 hours: a loading dose of 150 mg/kg given first over 15min, followed by 50 mg/kg over 4h, and 100 mg/kg over 16h.d) Any of the above can be utilized in this emergency situation.

4. NAC is thought to act in a number of ways. These include:a) providing substrate for the synthesis of glutathione, the most ubiquitous antioxidant in the body;b) acting as a precursor to glutamate, a neurotransmitter in the brain;c) cleaving disulphide bonds present in mucus;d) all of the above.

5. In patients with COPD, NAC acts as a mucolytic and has been shown to increase measures of lung function associated with air trapping such as functional residual capacity (FRC) and

forced vital capacity (FVC).a) Trueb) False

6. NAC may be useful in the treatment of angina due to its potential to enhance the vasodilating effects of nitrates. In this population, NAC has been shown to decrease the development of tolerance to nitrates and reduce the incidence of myocardial infarction. Which dose of NAC is associated with these effects?a) 600mg dailyb) 1200mg dailyc) 2400mg dailyd) 4000mg daily

7. Due to nitrate potentiation by NAC, blood pressure including orthostatic BP should be carefully monitored when combining these two agents.a) Trueb) False

8. NAC is thought to modulate brain glutamate/ NMDA receptoractivity in patients with schizophrenia, bipolar, and in addiction. Which of the following outcomes have been demonstrated in these settings?a) improvement in several standardized schizophrenia measurement scalesb) full remission of depressive and manic symptoms in a subset of patientsc) reduction in cocaine cravingsd) all of the above

9. The dose of NAC most commonly utilized in psychiatry is which of the following?a) 600-1200mg dailyb) 1200-2400mg dailyc) 2400-3600mg dailyd) none of the above

10. The most common adverse effects of oral NAC appear to be:a) nausea and vomiting in 23% of patients & anaphylaxis in 2%b) osmotic diarrhea in 20% of patientsc) strong body odour in patients taking high dosagesd) all of the above

Questions

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Saw palmetto (Serenoa repens)Standardized (lipophillic) Serenoa extract has been found to be a potent inhibitor of 5 -reductase, resulting in decreased tissue DHT. An open-label, dose response study was conducted on 42 healthy males to determine the effect of a combination of carotenoid astaxanthin and saw palmetto berry lipid extract on DHT and testosterone levels (Angwafor 2008). The men were divided into two groups: one group received 800 mg/day of the combination supplement and the other group received 2000 mg/day of the supplement for 14 days. ANOVA-RM showed significant within-group increases in serum total testeosterone and significant 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 testeosterone or the decrease of DHT; therefore both doses were effective (Angwafor 2008).

Another study tested liposterolic extract of Serenoa repens (LSESr) and beta-sitosterol in the treatment of males (23-64 years of age) with mild to moderate AGA. Six of 10 (60%) subjects were rated as improved at the final visit, thus establishing the effectiveness of 5 -reductase inhibitors against AGA (Prager 2002). Chronic inflammation of the hair follicle is considered to be a contributing factor for AGA. A study by Chittur et al sought to determine whether blockade of inflammation using LSESr and two anti-inflammatory agents (carnitine and thioctic acid) could alter the expression of molecular markers of inflammation (Chittur 2009). It was found that the combination suppressed lipopolysaccharide-activated gene expression of chemokines associated with pathways involved in inflammation and apoptosis.The study concluded that 5-alpha reductase inhibitors in combination with blockade of inflammatory processes could represent a new two-pronged approach in the treatment of AGA.

Fenugreek SeedsFenugreek seeds contain 5% to 30% protein, steroid saponins, sterols, flavonoids and alkaloids (notably trigonelline and choline). Steroid saponins bind and eliminate extra cholesterol and hormones in the body; DHT is made from testosterone, which is in turn is made from cholesterol. Therefore, when excess cholesterol is eliminated, less DHT can be made (Stark 1993). In a study of 20 adults who consumed 12.5g and 18.0g of germinated fenugreek seed powder for one month, higher levels of consumption resulted in a significant reduction in total cholesterol and low-density lipoprotein (LDL) levels (Sowmya 1999).

Flax lignansFlax 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 2009). Flaxseed interventions reduced total and LDL cholesterol by 0.10 mmol/L (95% CI: -0.20, 0.00 mmol/L) and 0.08 mmol/L (95% CI: -0.16, 0.00 mmol/L), respectively. Significant reductions 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).

VitaminsIn a Polish study of 46 women who had symptoms of diffuse alopecia, calcium pantothenate was orally administered twice a day in doses of 100 mg for four to five months, and vitamin B6 was injected every day for 20 to 30 days and repeated again after six months (Brzezi ska-Wcisło 2001). It was determined that vitamin B6 administered parenterally for a few weeks induces improvement in the hair condition in a subset of women and reduces hair loss.

Recommended adult dose: One capsule per day

ReferencesAngwafor F III, Anderson ML. An open label, dose response study to determine the e�ect of a dietary supplement on dihydrotesto sterone, testosterone and estradiol levels in healthy males. J Int Soc Sports Nutr 2008;5:12.

Brzezi ska-Wcis ło L. Evaluation of vitamin B6 and calcium pantothenate e�ectiveness on hair growth from clinical and trichographic as pects for treatment of di�use alopecia in women. Wiad Lek 2001;54:11-8.

Chittur S, Parr B, Marcovici G. Inhibition of in�ammatory gene expression in keratinocytes using a composition containing carni tine, thioctic acid and saw palmetto extract. Evid Based Complement Alternat Med 2009.

Pan A, Yu D, Demark-Wahnefried W, Franco OH, Lin X. Meta-analysis of the e�ects of �axseed 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 e�ectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia. J Altern Complement Med 2002;8:143-52.

Serenoa repens monograph. Alternative Medicine Review 1998;3:227-9.

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

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

Stark A, Madar Z. The e�ect 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.

PRODUCT MONOGRAPHBio-FenBio-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 of fenugreek seeds, saw palmetto berries and flax lignans, as well as specific vitamins. Each ingredient is known to possess inhibitors of the enzyme 5 -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- -reductase catalyzes the enzymatic conversion of testosterone to dihydrotestosterone, which binds to the receptor five-fold more avidly than the parent compound (Sinclair 1998).

Medicinal Ingredients Dose Per Capsule

Fenugreek (Trigonella foenum graecum) seed extract 4:1

260 mg

Saw palmetto berry extract containing 45% free fatty acids

160 mg

Flax lignans, standardized to 20% secoisolariciresinol diglucoside (SDG)

100 mg

D-calcium pantothenate (Vitamin B5) 10.40 mg

Niacinamide (Vitamin B3) 10.25 mg

Pyridoxine HCl (Vitamin B6) 2 mg

Riboflavin (Vitamin B2) 1.58 mg

Folic acid 0.095 mg

Biotin 400 mcg

Non-Medicinal Ingredients

Inert microcrystalline cellulose and vegetable-based magnesium stearate in a veggie-based capsule

activfuel+

References

Bautista-Hernández VM, et al J Int Med Res. 2008 Nov-Dec;36(6):1220-6.

Bosco C, et al. Int J Sports Med. 1997 Jul;18(5):369-72.

Duncan MJ, et al. J Sports Med Phys Fitness. 2012 Jun;52(3):280-5.

el-Sayed MS, et al. Comp Biochem Physiol A Physiol. 1997 Nov;118(3):789-803.

Howatson G, et al. J Int Soc Sports Nutr. 2012 May 8;9(1):20.

Fulgoni VL, et al. Am J Clin Nutr. 2008 May;87(5):1554S-1557S.

Laurent D, et al. J Clin Endocrinol Metab. 2000 Jun;85(6):2170-5.

Lemon PW, et al. Can J Appl Physiol. 1997 Oct;22(5):494-503.

Paddon-Jones D, et al. Am J Clin Nutr. 2008 May;87(5):1558S-1561S.

Shimomura Y, et al. Int J Sport Nutr Exerc Metab. 2010 Jun;20(3):236-44.

activfuel+ is a sports nutrition supplement designed specifically for pre- and during- exercise consumption. This new formula from Genuine Health complements proteins+ and Vegan proteins+ powders and bars, which are appropriate options to assist with the third stage of performance, recovery, and help repair and build muscles. activfuel+ is designed to provide energy, improve mental motivation and physical performance, improve endurance and stamina, improve recovery time, and increase immune function in conjunction with exercise of any intensity.

Build & PrepareWhey protein isolate is a complete source of protein & helps meet the higher protein requirement associated with physical activity (Fulgoni 2008). Exercise increases protein requirements 1) up to 25% to maintain existing muscle mass, and 2) up to 50% to gain muscle mass (Lemon 1997). Dietary protein increases thermogenesis and helps regulate 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 after six months (Paddon Jones 2008).

Branched chain amino acids (leucine, isoleucine, valine) are anabolic and promote muscle synthesis. In addition, research has shown that BCAAs decrease muscle protein breakdown (catabolism) during exercise; improve motivation and performance by decreasing the mental perception of fatigue; improve reaction time during performance; lower levels of the stress hormone cortisol during recovery; reduce the typical delayed onset muscle soreness (DOMS) associated with exercise; reduce muscle fatigue associated with exercise (Howatson 2012, Shimomura 2010).

Fuelactivfuel+ provides a balanced source of low glycemic carbohydrates from brown rice, agave, and beet root, to replenish glycogen stores and improve endurance exercise performance, and enhance recovery with improved subsequent exercise performance (el-Sayed 1997). In addition, kola nut provides a modest dose of caffeine (100mg), a proven ergogenic aid that can increase fat utilization, delay depletion of glycogen stores, increase reaction time and mental performance, and increase time to exhaustion (Duncan 2012, Laurent 2000). Despite the performance enhancement properties of caffeine, some individuals remain sensitive to even small doses, and therefore Genuine Health offers a caffeine-free version of the activfuel+ formula.

Speed & StrengthTaurine is one of the most abundant amino acids in muscle tissue. Supplementation helps offset exercise induced depletion and diminished performance. According to a study published in 2009, taurine was effective in decreasing lactate accumulation, which limits the ongoing production of energy in the muscle cells and contributes to DOMS.

Rehydrate & Replenish ingredients replace electrolytes lost during exercise, while Go the Distance ingredients improve endurance. Creatine increases lean body mass, strength, and total workload capacity; in particular, creatine improves strength, power and performance in repetitive bouts of brief, highly intense physical activity (e.g. sprints, jumping, resistance training) (Bosco 1997).

Directions: mix one scoop (20.9g) of activfuel+ in one to one and a half cups (250-375mL to taste) of pure water or juice. Take once daily before and/or during your physical activity, or as 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 oxygen concentration during exercise (Bautista-Hernández 2008).

Ingredient Dose

Whey protein isolate (bovine milk) 5.6g

L-leucein 333mg

L-isoleucine 333mg

L-valine 333mg

Oryza sativa: whole grain sprouted brown rice dry syrup 6.0g

Beta vulgaris: organic red beet root 1.5g

Agave tequilana: inulin from agave 1.0g

Taurine 500mg

Kola acuminata: Kola nut seed extract (standardized to 10% naturally occurring caffeine) in caffeinated version only

500mg

Cocos nucifera: coconut water freeze dried powder 500mg

Sodium (chloride) 50mg

Potassium (chloride) 15mg

Creatine monohydrate 1.0g

Malus domestica: organic apple peel (Appleboost®) 300mg

Rhodiola rosea root extract (3% rosavin; 10:1=1000mg) 100mg

Magnesium (aspartate) 80mg

Vitamin B1 (thiamine hydrochloride) 10mg

Table 1. activfuel+ formula

Action

Build & Prepare

Fuel

Speed & Strength

Rehydrate &Replenish

Go the Distance

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

Figure 1. Targeted Dosing, according to Body Weight and Exercise Intensity

>200lb

150 - 200lb

100 - 150 lb

Light (30min) Medium (30-60min) Heavy (60-90min) Endurance (>90min)

Green=1 svg; Yellow = 2svg; Red= 3svg


For more information visit: www.nfh.ca © NFH Nutritional Fundamentals for Health 2012

Bio-Q10 SAPPRODUCT MONOGRAPH

WHAT IS COENZYME Q10?Coenzyme Q10 (CoQ10) is a quinone compound synthesized in the human body and has properties similar to those of vitamins.(1, 2) Coenzyme Q10 occurs widely in living organisms, and because of its ubiquitous distribution in nature it is also known as ubiquinone. Structurally, CoQ10 (C59H90O4) is a benzoquinone ring compound, has 10 isoprenoid units in the side chain, and occurs naturally in the trans configuration. CoQ10 is present in all human tissues, highly concentrated in the mitochondria as an endogenous cofactor in the mitochondrial energy production.(2, 3) Another important function of CoQ10 is as an antioxidant.(1) Many chronic diseases are associated with dysfunctional energy metabolism, and CoQ10 supplementation has been widely tested and used in the treatment of cardiac, neurologic, oncologic, as well as other disorders.(3)

Used in most countries, CoQ10 supplementation targets improving cellular bioenergies, counteracting oxidative stress and slowing down some aging-related pathologies.(2, 4)

ENERGY PRODUCTION AND ANTIOXIDANT PROPERTIESPresent in all human tissues, ~50% of CoQ10 is localized in the mitochondrial membrane.(5) CoQ10, a cofactor in the mitochondrial electron transport chain (ETC), is essential for ATP production and therefore plays a fundamental role in cellular bioenergies. CoQ10 mainly functions in the ETC as a mobile redox agent shuttling electrons and protons; however, the redox functions of CoQ10 exist outside of the mitochondria. CoQ10 in its reduced form, ubiquinol, is a powerful antioxidant. As an antioxidant, CoQ10 prevents lipid peroxidation (3) and can recycle and regenerate other antioxidants such as tocopherol and ascorbate.(5)

ABSORPTION AND TRANSPORTCoQ10 is a lipophilic substance (or fat-soluble nutrient) and is therefore absorbed in the gastrointestinal tract by the same method as lipids, such as vitamin E.(2) Being hydrophobic and of large molecular weight, the absorption of dietary CoQ10 is enhanced in the presence of lipids or fatty meals. Secretions from the pancreas and bile acid facilitate emulsification and micelle formation that is necessary for the absorption of CoQ10 in the small intestine.

In a study examining the absorption rates of CoQ10, 60 subjects were divided into 4 groups and administered 100 mg of CoQ10 daily. Group 1 took Bio-Q10 in a soft capsule, Group 2 Bio-Q10 in a hard capsule, Group 3 CoQ10 (ubiquinone) in a soft capsule and Group 4 CoQ10 (ubiquinone) in a hard capsule. After 3 weeks, the highest absorption rate was seen in group 1 (1624 ng/mL), followed by group 2 (985 ng/mL), then group 3 (1066 ng/mL) and then group 4 (737 ng/mL).(6)

In an animal study, researchers divided rats in to 6 groups and administered 100 mg/kg of regular ubiquinone with one of four emulsifiers (sorbitan stearate, polysorbate 80, glycerin esters or fatty acid, or propylene glycol state), ubiquinol or Bio-Q10. Three hours later, the plasma concentration was measured. In the four groups who received the emulsified ubiquinone, levels ranged between 0.75–1.25 g/ml; the ubiquinol group was 3.0 g/ml, and the Bio-Q10 group measured at 3.2 g/ml. This demonstrates that the absorption of the Bio-Q10 was comparable to ubiquinol and between 2.5–4.25 times that of the emulsified ubiquinone.(7)

CoQ10 is packaged into chylomicrons and transported via the lymphatics to the circulation.

Being mostly carried by VLDL/LDL particles, plasma CoQ10 concentrations are highly dependent on plasma lipoproteins. In the human circulatory system, about 95% of CoQ10 in circulation exists in its reduced form as ubiquinol. CoQ10 is most concentrated in tissues with high energy requirements such as the heart, brain, liver, muscles and kidney. Studies show that with chronic dosing, there appears to be a dose-dependent relationship between supplementation and CoQ10 tissue levels for oil-based, powder-based and solubilized formulations of CoQ10.(2)

UBIQUINONE VS. UBIQUINOLCoQ10 is found in the body in two forms: ubiquinone and ubiquinol. Ubiquinone is an oxidized form of CoQ10 that is used to create energy. Ubiquinol is the reduced form of CoQ10 that is used to provide antioxidant protection. Both of these forms are needed and used by the body, and it is the location in the body which will determine which form CoQ10 will take. For energy production inside cells, ubiquinone is used and outside cells for antioxidant function, ubiquinol is the form the body uses. Ubiquinone and ubiquinol form a redox pair, which means the body can easily convert from one form to the other. Ubiquinol taken in supplement form is unstable and is converted back to ubiquinone before it is absorbed. Oil-based ubiquinol does, however, have improved bioavailability over powdered ubiquinone with absorption.(6)

SAFETY AND CONTRAINDICATIONSCoQ10 has an excellent safety record. The observed safe level risk assessment method reveals strong evidence of safety at intakes up to 1200 mg/day.(1) Adverse effects with CoQ10 supplementation are rare, with <1% of the patient population reporting GI discomfort.(3) There may be potential interactions with warfarin (Coumadin), and due to CoQ10’s potential hypoglycemic and hypotensive effects, discuss adjunctive use of CoQ10

with other medications with a health care provider.(3) There is not enough scientific evidence to support the safe use of CoQ10 during pregnancy or lactation.(3) Statins, which are potent inhibitors of cholesterol biosynthesis, also inhibit CoQ10 synthesis and thus lower its endogenous levels in the body.(8) Even brief exposure to statin therapy causes a marked decrease in blood CoQ10 concentration leading to exercise intolerance, myalgia (heart pain) and myoglobinuria. However, these conditions are reversed with CoQ10 supplementation.(8)

CARDIOVASCULAR INDICATIONSNumerous clinical trials supplementing with 100–300 mg/day of CoQ10 have found improvements in several clinical parameters related to chronic heart failure (CHF), including frequency of hospitalization, dyspnea, fatigue, and edema.(3, 4, 9) A clinical trial of 23 patients with CHF supplementing oral CoQ10 (100 mg t.i.d.) resulted in improved functional capacity, endothelial function, and left ventricular contractility without any side effects.(10) Similarly, CoQ10 supplementation may offer myocardial protection during cardiac surgery and improve postoperative cardiac function, as well as reduce myocardial structural damage.(11) A review of clinical trials using CoQ10 at various doses for hypertension, typically as adjuvant therapy, found a mean decrease in systolic and diastolic blood pressure of 16 and 10 mmHg, respectively.(12) Additionally, preliminary human studies of patients within three days after a heart attack given CoQ10 orally reported reductions in deaths, abnormal heart rhythms, and second heart attacks.(9) CoQ10 supplementation may also benefit cardiomyopathy (dilated, hypertrophic), angina from clogged heart arteries, and atherosclerosis.(9)

NEUROLOGIC AND METABOLIC INDICATIONSIn Parkinson’s disease, CoQ10 may be used for slowing of functional decline. A clinical trial of 80 patients supplementing 1200 mg/day of CoQ10 experienced 44% less functional decline.(13) Furthermore, CoQ10 also has demonstrated positive trends in improving metabolism and physical endurance and reducing symptoms associated with selected mitochondrial diseases.(3, 9) In early Alzheimer’s disease, evidence from human research suggests that CoQ10 supplementation may slow down, but not cure, dementia in patients.(9) In migraine studies, patients taking 150–300 mg/day of CoQ10 experienced a significant decrease in frequency (≥50%) of migraine attacks, and it was concluded that the number to treat was three.(3) Preliminary studies also show potential benefits of CoQ10 supplementation with Friedreich’s ataxia, as well as Huntington’s disease.(3, 9)

OTHER DISORDERSDue to CoQ10’s hypoglycemic and hypotensive effects, CoQ10 supplementation has been studied in patients with type 2 diabetes.(14) A recent study supplementing 200 mg/day of CoQ10 for 12 weeks observed improved blood pressure and glycemic control in type 2 diabetes patients; however, these results were not associated with a reduction in oxidative stress. Since CoQ10 is vital in energy production, the effects of CoQ10 supplementation on exercise performance in athletes and normal healthy adults have been studied; however, results are variable.(9)

Preliminary studies in periodontitis (gum disease) have also observed improvements in bleeding, swelling and pain with oral or topical application of CoQ10.(9)

CoQ10 can also have an impact on fertility. A study performed on human seminal fluid found that seminal CoQ10 concentrations have a direct correlation with seminal parameters including count and motility. Changes in CoQ10 levels were associated with conditions involved in male infertility, including asthenozoospermia and varicocele. In two separate studies looking at idiopathic asthenozoospermia, researchers found that CoQ10 in the ubiquinol and ubiquinone forms were significantly increased in both sperm cells and seminal plasma after treatment. Researchers concluded that patients with lower baseline levels of motility and CoQ10 levels had the highest probability to be responders to treatment and that exogenous supplementation of CoQ10 can be effective for improving idiopathic asthenozoospermia.(15)

REFERENCES1. Hathcock J.N. and A. Shao. “Risk assessment for coenzyme Q10 (Ubiquinone)”. Regulatory Toxicology and Pharmacology 45, No. 3

(2006): 282–88.2. Bhagavan, H.N. and R.K. Chopra. “Coenzyme Q10: absorption, tissue uptake, metabolism and pharmacokinetics”. Free Radical

Research 40, No. 5 (2006): 445–453.3. Bonakdar, R.A. and E. Guarneri. “Coenzyme Q10”. American Family Physician 72, No. 6 (2005): 1065–1070.4. Littarru, G.P. and L. Tiano. “Clinical aspects of coenzyme Q10: an update”. Current Opinion in Clinical Nutrition and Metabolic Care 8,

No. 6 (2005): 641–646.5. Ernster, L. and G. Dallner. “Biochemical, physiological and medical aspects of ubiquinone function”. Biochimica et Biophysica Acta 127,

No. 1 (1995): 195–204. 6. An absorbability study on CoQ10-containing products. Mitsubishi Gas Chemical Company, Inc. Unpublished paper.7. An availability study of BioQ10SA in rate, 2010. Mitsubishi Gas and Chemical Company, Inc. Unpublished paper.8. Rundek, T., A. Naini, R. Sacco, et al. “Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular

disease and stroke”. Archives of Neurology 61, No. 6 (2004): 889–892.9. http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-coenzymeq10.html10. Belardinelli, R., A. Muçaj, F. Lacalaprice, et al. “Coenzyme Q10 and exercise training in chronic heart failure”. European Heart Journal 27,

No. 22 (2006): 2675–2681.11. Rosenfeldt, F., S. Marasco, W. Lyon, et al. “Coenzyme Q10 therapy before cardiac surgery improves mitochondrial function and in vitro

contractility of myocardial tissue”. The Journal of Thoracic and Cardiovascular Surgery 129, No. 1 (2005): 25–32.12. Rosenfeldt, F., D. Hilton, S. Pepe, and H. Krum. “Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart

failure”. Biofactors 18, No. 1–4 (2003): 91–100.13. Shults, C.W., D. Oakes, K. Kieburtz, et al. “Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional

decline”. Archives of Neurology 59, No. 10 (2002): 1541–1550.14. Hodgson, J.M., G.F. Watts, D.A. Playford, et al. “Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in

subjects with type 2 diabetes”. European Journal of Clinical Nutrition 56, No. 11 (2002): 1137–1142.15. Balercia, G., A. Mancini, F. Paggi, et al. “Coenzyme Q10 and male infertility”. Journal of Endocrinological Investigations 32, No. 7 (2009):

626–32.

IHP 2013-01 (Bio-Q10 SAP).indd 2 2013-01-15 15:09:18


Bio-Q10 SAPScience-based soy-emulsified coenzyme Q10 for optimal absorption

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Coenzyme Q10 is produced by the human body and is necessary for the basic functioning of healthy living cells. It has 2 main physiological roles: energy production and antioxidant protection. Without CoQ10, the chain of cellular energy is broken and without energy, cellular life ceases. CoQ10 levels decrease with age and are even lower in patients with chronic diseases. Prescription drugs, including statins, may also lower CoQ10 levels, yet they can be increased by supplementing with CoQ10. Bio‑Q10 has the ability to be absorbed 2.5–4.25 times more efficiently than the standard ubiquinone form of CoQ10.

ACTIVE INGREDIENTSEach vegetable capsule contains:

Bio‑Q10 (Coenzyme Q10) (Ubiquinone‑10 from Japan) (Bacterial fermentation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 mg

Contains no: Preservatives, artificial flavor or color, sugar, dairy, starch, wheat, gluten, yeast, citrus, corn or egg.Bio-Q10 SAP does contain soy.Bio-Q10 SAP contains 60 vegetable capsules per bottle.

ADULT DOSAGEAdults: Take 1 capsule two to three times daily or as directed by your health care practitioner.

INDICATIONS ɶ Bio‑Q10 provides protection against cardiovascular disease. ɶ Bio‑Q10 has the ability to transfer electrons and therefore acts as an

antioxidant. ɶ Bio‑Q10 can help prevent deficiency from statins medications. ɶ Bio‑Q10 can help treat idiopathic asthenozoospermia, which can

contribute to infertility. ɶ Bio‑Q10 may be helpful in slowing decline in Parkinson’s patients. ɶ Bio‑Q10 may help lower blood pressure and improve glycemic control in

patients with type 2 diabetes.

HIGH-BIOAVAILABILITY FORM OF UBIQUINONENFH’s Bio-Q10 SAP is manufactured by blending a unique emulsifier—a specific soy protein—with CoQ10. The protein is ideal for blending with CoQ10, as it has both a hydrophobic and hydrophilic component. The water‑insoluble components are dispersed with the emulsifier in water and are then absorbed well in the small intestine. Bio‑Q10 has the ability to be absorbed 2.5–4.25 times more efficiently than the standard ubiquinone form of CoQ10.

PURITY AND STABILITYThird‑party testing is performed on the finished product to ensure Bio-Q10 SAP is free of heavy metals, pesticides, volatile organics and other impurities.

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IHP Magazine - February/March 2013

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