1 www.ihpmagazine.com | June/July 2014 clinic profile PM42684014 | 60 BLOOR STREET WEST SUITE 1106 | TORONTO ONTARIO, M4W 3B8 | $14.95 WWW.IHPMAGAZINE.COM SEPTEMBER 2014 FOOD AND NHP LABELLING By Christopher Habib, ND HealthCare 365 Bringing Patient Relationship Management (PRM) to Ontario Off Label Application of Common Prescription Medications for Integrative Cancer Management By Jacob Schor, ND, FABNO Continuing Education MAGNOLIA EXTRACT AND CANCER By Maria Shapoval, ND, and Vivian Liang, HBSc (Cand) SUPPLEMENTATION IN PREGNANCY By Jordan Robertson, ND, et al.
Transcript
1 www.ihpmagazine.com | June/July 2014
clinic profile
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WWW.IHPMAGAZINE.COM SEPTEMBER 2014
FOOD AND NHP LABELLINGBy Christopher Habib, ND
HealthCare 365 Bringing Patient Relationship
Management (PRM) to Ontario
Off Label Application of Common Prescription Medications for Integrative Cancer Management
By Jacob Schor, ND, FABNO
Continuing Education
MAGNOLIA EXTRACT AND CANCERBy Maria Shapoval, ND, and Vivian Liang, HBSc (Cand)
SUPPLEMENTATION IN PREGNANCYBy Jordan Robertson, ND, et al.
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4 www.ihpmagazine.com | September 2014
from the publisher
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Sanjiv founded Nature’s Source Natural Dispensary in 1998, and soon after started IHP Magazine in order to pull together all of his experience in the health and wellness industry, as well as to create a way to help connect resources and information to experts working in the field. Sanjiv has a background in organic chemistry and biochemistry, and also conducted research in the pharmaceutical industry. Nature's Source works closely with medical doctors, naturopathic doctors, chiropractors, homeopathic practitioners, personal trainers and nutritionists to take care of people searching for preventative health strategies and illness recovery solutions. Nature's Source offers a wide selection of supplement brands and specialty products, including professional lines, sports nutrition, homeopathics, and natural health and beauty products. All products are high-quality, evidence-based, and tested by third-parties for compliance. For more information, please visit www.natures-source.com.
Back to BasicsI would like to share an experience with you I most recently had. My son and I were invited to a hockey camp hosted by an NHL player from a Caribbean background. While taking pictures a gentlemen approaches me with a thick accent and begins to tell me the story of two his boys who now play in the NHL and what they went through to get to there. At first I didn’t think much of this conversation, yet I slowly found myself mesmerized. He described a story of poverty… Of taking transit hours to get his children to a game, without money in his pocket to take transit home, hoping the bus driver would allow them to get home without paying the fare. As he continued his story, I was overwhelmed… A simple, hard working, modest man, with very little, devoted to finding a way to let his children play the game they love, sitting back 20 years later proudly telling the story of his two sons in the NHL. I have invited this inspirational man to come speak to the our staff… You can not help but be inspired in this mans presence!
As I look around we are scrambling to stay on top of technology when what really matters is human connection. There is no email, twitter, face book, web site or what ever may exist that can replace that. I was truly honored to have met such a humble and wonderful man and to have heard of his family’s journey. We all need to pay attention to how many people around us are on a journey, be it personal, health or wealth! Stay in touch… a voice goes a long way.
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contents
This Issue: September 2014 • Vol. 7 • No. 4
Cover StoryHealthCare 365Bringing Patient Relationship Management (PRM) to Ontario
The Journal of IHPPeer-reviewed articles on clinically revelant topics
4 Publisher’s Letter
11 Research News
22 Industry News
26 Calendar
30 Product Profiles
47 Editor’s Letter
49 Peer Review Board
51 Editorial Board
73 Continuing Education
Coming Next Issue
Metformin in Cancer management
Cognitive decline – integrative management
Physiology of menopause
Departments
Cover Photograph by Robyn Russell
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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)
This study aimed to better define the relationship between sun exposure and serum 25-hydroxyvitamin D (25(OH)D) concentration. It was called the Quantitative Assessment of Solar UV Exposure for Vitamin D Synthesis in Australian Adults (AusD) Study. Cross-sectional data were collected from 1,002 participants aged 18-75 years in 4 Australian sites spanning 24° of latitude. Participants completed the following: 1) questionnaires on sun exposure, dietary vitamin D intake, and vitamin D supplementation; 2) 10 days of personal ultraviolet radiation dosimetry; 3) a sun exposure and physical activity diary; and 4) clinical measurements and blood collection for 25(OH)D determination. A multiple regression model described 40% of the variance in 25(OH)D concentration; modifiable behavioral factors contributed 52% of the explained variance, and environmental and demographic or constitutional variables contributed 38% and 10%, respectively. The amount of skin exposed was the single strongest contributor to the explained variance (27%), followed by location (20%), season (17%), personal ultraviolet radiation exposure (8%), vitamin D supplementation (7%), body mass index (weight (kg)/height (m)(2)) (4%), and physical activity (4%). The authors conclude that modifiable behavioral factors strongly influence serum 25(OH)D concentrations in Australian adults. Am J Epidemiol. 2014. PMID: 24573539.
Multivitamin supplementation for perceived stress
This study was a double-blind placebo-controlled study of 138 adults (aged 20 to 50 years) who were administered a multivitamin containing B-vitamins versus placebo over a 16-week period. Salivary cortisol measurements were taken at waking, 15-min, 30-min and at bedtime, at baseline, 8-weeks and 16-weeks. Perceived Stress (PSS) was measured at baseline, 8-weeks and 16-weeks, while blood serum measures of B6, B12 and homocysteine (HCy) as well as red cell folate (B9) were also collected at these time points. A significant interaction was found between treatment group and study visit for the Cortisol Awakening Response (CAR). Compared to placebo, at 16-weeks multivitamin supplementation was found to be associated with a near-significant trend towards an increased CAR. No significant differences in PSS were found between groups, with PSS increasing in both groups across the course of the study. Red cell folate was found to be significantly correlated with the CAR response at 16-weeks while HCy levels were not found to be associated with the CAR response, although HCy significantly correlated with waking cortisol levels at 8-weeks. The authors conclude that a possible interpretation of the elevation in CAR associated with multivitamin supplementation is that this represents an adaptive response to everyday demands in healthy participants. Nutrients. 2013. PMID: 24284609.
Daily vitamin D supplementation in preterm infants
This study compared the effect of 800 vs 400 IU of daily oral vitamin D3 on the prevalence of vitamin D deficiency at 40 weeks postmentrual age in preterm infants of 28 to 34 weeks gestation. The trial was randomized and double-blind. Eligible infants were allocated to receive either 800 or 400 IU of vitamin D3 per day (n = 48 in both groups). Primary outcome was serum 25-hydroxyvitamin D deficiency, measured as levels <20 ng/mL at 40 weeks. The results showed that prevalence of deficiency in the 800-IU group was significantly lower than in the 400-IU group at 40 weeks (38.1% vs. 66.7%; relative risk: 0.57; 95% confidence interval: 0.37-0.88) and at 3 months' corrected age (12.5% vs. 35%; relative risk: 0.36; 95% confidence interval: 0.14-0.90). One infant (2.4%) in the 800-IU group had vitamin D excess (100-150 ng/mL). Bone mineral content and bone mineral density were not different between the 2 groups. The authors conclude that daily supplementation with 800 IU of vitamin D reduces the prevalence of deficiency at 40 weeks and at 3 months in preterm infants without showing any improvement in bone mineralization. However, there is a possibility that this dose may occasionally result in vitamin D excess. Pediatrics. 2014. PMID: 24515510.
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research news
Intravenous vitamin C during percutaenous coronary intervention
This study was to explore whether antioxidant vitamin C infusion before the procedure was able to affect the incidence of periprocedural myocardial injury (PMI) in patients undergoing PCI. In this prospective single-centre randomized study, 532 patients were randomized into 2 groups: the vitamin C group, which received a 3-g vitamin C infusion within 6 hours before PCI, and a control group, which received normal saline. The primary end point was the troponin I-defined PMI, and the second end point was the creatine kinase (CK)-MB-defined PMI. Separate analyses using both end points were performed. PMI was defined as an elevation of cardiac biomarker values (CK-MB or troponin I) > 5 times the upper limit of normal (ULN), alone or associated with chest pain or ST-segment or T-wave changes. The results showed that after PCI, the incidence of PMI was reduced, whether defined by troponin or by CK-MB, compared with the control group. Logistic multivariate analysis showed that preprocedure use of vitamin C is an independent predictor of PMI either defined by troponin I (OR 0.56) or by CK-MB (OR 0.37). The authors conclude that in patients undergoing elective PCI, preprocedure intravenous treatment with vitamin C is associated with less myocardial injury. Can J Cardiol. 2014. PMID: 24365194.
Omega-3 fatty acids for depression after myocardial infarction
This study examined the effects of supplementation of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on prevalence and severity of depression were evaluated in patients after a myocardial infarction. A cross-sectional evaluation (posttest-only design) within the prospective, randomized, controlled, multicenter OMEGA trial was performed in patients after myocardial infarction at 12 months' follow-up (N = 2,081; age, mean = 64 years; men, 76.7%; women, 21.8%). Patients received supplementation with ethyl esters 90 (460-mg EPA and 380-mg DHA) or placebo for 12 months. Depression was assessed with the Beck Depression Inventory-II (BDI-II); a BDI-II cutoff score of ≥ 14 was used as diagnosis of depression. The results showed that no effects of EPA/DHA supplementation on depressive symptoms according to BDI-II score (mean [SD]) could be demonstrated: EPA/DHA (n = 1,046), 7.1 (6.9); placebo (n = 1,035), 7.1 (7.0); P = .7. The post hoc analyses of depressed patients with and without antidepressants revealed a tendency toward an antidepressant effect in patients with EPA/DHA supplementation as monotherapy: EPA/DHA (n = 125), 19.4 (5.8); placebo (n = 113), 19.9 (5.1); P = .07. However, in depressed patients with EPA/DHA supplementation as adjunctive to conventional antidepressants, a clinically relevant antidepressant effect was demonstrated: EPA/DHA (n = 33), 20.9 (7.1); placebo (n = 29), 24.9 (8.5); P < .05. J Clin Psychiatry. 2013. PMID: 24330904.
Vitamin D does not improve muscle strength in adults
This study tested whether vitamin D supplementation increases muscle strength and power compared with placebo. It was a randomized, double-blind, placebo-controlled trial. Two hundred fifty-one healthy adult males and females aged 18-50 years with non-Western immigrant background performed the baseline test and 86% returned to the follow-up test. The intervention was sixteen weeks of daily supplementation with 25 μg (1000 IU) vitamin D3, 10 μg (400 IU) vitaminD3, or placebo. The results showed that Percentage change in jump height did not differ between those receiving vitamin D (25 or 10 μg vitaminD3) and those receiving placebo (mean difference -1.4%, 95% confidence interval: -4.9% to 2.2%, P=.44). No significant effect was detected in the subgroup randomized to 25 μg vitamin D or in other preplanned subgroup analyses nor were there any significant differences in handgrip strength or the chair-rising test. Mean serum 25-hydroxyvitamin D3 concentration increased from 27 to 52 nmol/L and from 27 to 43 nmol/L in the 25 and 10 μg supplementation groups, respectively, whereas serum 25-hydroxyvitamin D3 did not change in the placebo group. The authors conclude daily supplementation with 25 or 10 μg vitamin D3 for 16 weeks did not improve muscle strength or power measured by the jump test, handgrip test, or chair-rising test in this population with low baseline vitamin D status. J Clin Endocrinol Metab. 2014. PMID: 24248184.
Probiotics decrease inflammation in type 2 diabetics and in those with liver disease
This study examined 72 patients with T2D and NAFLD. All patients divided by us on the way of therapy into 2 groups. The main group (n = 45) received oral antidiabetic therapy and multiprobiotic "Symbiter" within 30 days. Patients of comparison group (n = 27) received only hypoglycemic drugs. Also in each group they identified patients with normal and elevated level of transaminases. They observed 1.5-2 times increasing of cytokines in patients with NAFLD and elevated transaminase levels compared to patients with normal transaminase levels. They noted statistically significant reduction of proinflammatory cytokines in plasma, after 30 days of therapy, in patients with elevated levels of transaminases. In particular, the level of IL-6 decreased on 30.9% (P < 0.001), IL-8 - 19.9% (P = 0.001), TNF-alpha - 13.4% (P < 0.001), IL-1beta - 17.9% (P < 0.001) and IFN-gamma on 18.7% (P < 0.001) respectively. In patients with normal levels transaminases and NAFLD were significantly decreased only TNF-alpha on 15.1% (P = 0.003) and IL-8 on 15.2% (P = 0.017). Significant changes in cytokines levels in patients of comparative group was not observed. Probiotics can be recommended for use in patients with different stages of NAFLD and T2D as an adjunct to standard treatment regimens because it decreases manifestations of low-grade systemic inflammatory response. Lik Sprava. 2013. PMID: 24605611.
Multivitamin for cataract and age-related macular degeneration: RCT
This study tested whether long-term multivitamin supplementation affects the incidence of cataract or age-related macular degeneration (AMD) in a large cohort of men. It was a randomized, double-blind, placebo-controlled trial. The participatns were 14,641 US male physicians aged ≥ 50 years. They received a daily multivitamin or placebo. Incident cataract and visually significant AMD responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-reports confirmed by medical record review. The results showed that during an average of 11.2 years of treatment and follow-up, a total of 1817 cases of cataract and 281 cases of visually significant AMD were confirmed. There were 872 cataracts in the multivitamin group and 945 cataracts in the placebo group (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.83-0.99; P = 0.04). For visually significant AMD, there were 152 cases in the multivitamin group and 129 cases in the placebo group (HR, 1.19; 95% CI, 0.94-1.50; P = 0.15). The authors conclude that the randomized trial data from a large cohort of middle-aged and older US male physicians indicate that long-term daily multivitamin use modestly and significantly decreased the risk of cataract but had no significant effect on visually significant AMD. Ophthalmology. 2014. PMID: 24268861.
Hepatotoxicity induced by supplements
A new review article was recently published describing the dangers of supplements. Details of the abstract are shared below, but caution is advised to the reader regarding making sweeping generalizations about an entire industry: The regulation of herbal and dietary supplements varies across the globe and in some locations such as the United States, the regulatory laws are likely outdated. Many recent regulatory approaches in Europe do not require testing for premarket safety. The true incidence of hepatotoxicity from herbal and dietary supplements is unknown. The presentation is most often with a hepatocellular enzyme pattern, and the outcomes can be severe, leading to transplantation in some circumstances. The diagnosis of hepatotoxicity due to herbal and dietary supplements is made in the same way as for drugs. However, patients often must be coaxed into revealing a history of use. No causality assessment approach is perfectly suited for hepatotoxicity from herbal and dietary supplements, but the Roussel Uclaf Causality Assessment Method is most used. The authors conclude future endeavors must focus on defining epidemiology, establishing an accepted nomenclature, and identifying culprit ingredients, predisposing host factors, and useful biomarkers for injury. Semin Liver Dis. 2014. PMID: 24879982.
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research news
Long-term multivitamin supplementation and cognitive function
This study evaluated whether long-term multivitamin supplementation affects cognitive health in later life. The design was a randomized, double-blind, placebo-controlled trial. Up to 4 repeated cognitive assessments by telephone interview were completed over 12 years. Patients were 5947 male physicians aged 65 years or older. They took a daily multivitamin or placebo. The measurement was a global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary end point was a verbal memory score combining 4 tests of verbal memory, which is a strong predictor of Alzheimer disease. The results showed no difference was found in mean cognitive change over time between the multivitamin and placebo groups or in the mean level of cognition at any of the 4 assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was -0.01 SU when treatment was compared with placebo. Similarly, cognitive performance did not differ between the multivitamin and placebo groups on the secondary outcome, verbal memory. The authors conclude that the dose of vitamins may be too low or the population may be too well-nourished to benefit from a multivitamin. In male physicians aged 65 years or older, long-term use of a daily multivitamin did not provide cognitive benefits. Ann Intern Med. 2013. PMID: 24490265
High fat diet improves body composition, inflammation, and vascular function
Inflammation, insulin resistance and vascular dysfunction characterize obesity and predict development of cardiovascular disease (CVD). Although women experience CVD events at an older age, vascular dysfunction is evident 10years prior to coronary artery disease. Questions remain whether replacing SFA entirely with MUFA or PUFA is the optimal approach for cardiometabolic benefits. This study tested the hypotheses that: a) body composition, inflammation and vascular function would improve with a high fat diet (HFD) when type of fat is balanced as 1/3 SFA, 1/3 MUFA and 1/3 PUFA; and b) body composition, inflammation and vascular function would improve more when balanced HFD is supplemented with 18C fatty acids, in proportion to the degree of 18C unsaturation. Obese premenopausal women were stabilized on balanced HFD and randomized to consume 9g/d of encapsulated stearate (18:0), oleate (18:1), linoleate (18:2) or placebo. The results showed significant improvements occurred in fat oxidation rate (up 6%), body composition (%fat: down 2.5±2.1%; %lean: up 2.5±2.1%), inflammation (down IL-1α, IL-1β, 1L-12, Il-17, IFNγ, TNFα, TNFβ) and vascular function (down BP, down PAI-1, up tPA activity). When compared to HFD+placebo, HFD+stearate had the greatest effect on reducing IFNγ (down 74%) and HFD+linoleate had the greatest effect on reducing PAI-1 (down 31%). Metabolism. 2014. PMID: 24559846.
Lipoic acid and pyridoxine for multiple outcomes in diabetic nephropathy
This study was designed to investigate the effects of combined administration of lipoic acid and pyridoxine on albuminuria, oxidative stress, blood pressure, serum advanced glycation end-products, nitric oxide (NO), and endothelin-1 in patients with diabetic nephropathy. Thirty-four patients were randomly assigned to either a supplement group or a placebo group. The patients in the supplement group received 800 mg lipoic acid and 80 mg pyridoxine daily for 12 weeks, whereas the placebo group received corresponding placebos. Urinary albumin, serum malondialdehyde (MDA), and systolic blood pressure decreased significantly in the supplement group compared to the placebo group (p < 0.05). Serum NO increased in the supplement group compared to the placebo group (p < 0.05). Serum pentosidine and carboxymethyl lysine decreased significantly in the supplement group at the end of week 12 compared to baseline (p < 0.05). No statistically significant differences were observed between the two groups in mean changes of serum endothelin-1, glucose, and diastolic blood pressure. The authors conclude that combined administration of lipoic acid and pyridoxine improves albuminuria in patients with diabetic nephropathy by reducing oxidative stress, advanced glycation end-products, and systolic blood pressure. Int J Vitam Nutr Res. 2013. PMID: 24491880.
011-016.IHP Research.indd 16 2014-08-26 10:07 AM
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ACES + Zn® Carlson ACES + Zn is a blend of antioxidants, each naturally sourced to provide you with high quality nutrition to support good health. Free radicals can be found everywhere from air pollution, pesticides, tobacco smoke and even innate metabolic processes in our body (1). When produced in excess, free radicals can promote oxidative stress which damages DNA, proteins and other molecules in our body. ACES + Zn provides not only the antioxidants found in Carlson ACES®; vitamins A as beta-carotene, vitamin C as calcium ascorbate and vitamin E as alpha-tocopherol, but also the essential minerals selenium and zinc which support the body’s production of other antioxidants. Together, the nutrients supplied in Carlson ACES + Zn help your body to neutralize free radicals and reduce the damaging effects from these molecules.
As provitamin A, beta-carotene is a fat-soluble vitamin that not only helps maintain adequate levels of vitamin A, but also serves as an antioxidant in the body to support good health (2). Beta-carotene acts as an antioxidant in two ways. First, inactivating singlet oxygen molecules that otherwise can react, and thus damage cellular materials such as DNA and proteins. Additionally, beta-carotene acts as a free radical scavenger, inactivating reactive oxygen species (ROS) in the body (3). This function may help protect against various health conditions. For example, in conjunction with other antioxidant nutrients, beta-carotene is thought to help prevent the oxidation of LDL-cholesterol, thus supporting a healthy cardiovascular system (2).
Vitamin C (ascorbic acid) is a water-soluble antioxidant nutrient that is important for the maintenance of good health. Ascorbic acid also acts as a free radical scavenger in our body (4). The antioxidant function of vitamin C may help protect against free-radical damage in our eyes to support eye health and may aid in the prevention of LDL-cholesterol oxidation to support a healthy cardiovascular system (5,6,7). In addition to these important health benefits, the antioxidant role of vitamin C may also be important in immune function. Evidence suggests that vitamin C is concentrated in neutrophils, a type of white blood cell important for immunity. These neutrophils can produce, and often leak, damaging ROS molecules. The presence of vitamin C may help protect the areas surrounding the neutrophils from intracellular oxidative damage (3). Finally, vitamin C not only directly neutralizes free radicals to help maintain good health, but it also increases vitamin E function by reducing it back to its antioxidant form (4). Therefore, vitamin C plays both a direct and supportive antioxidant role in the body, critical for maintaining good overall health.
Vitamin E (as alpha-tocopherol) is a fat-soluble antioxidant nutrient in the body. Vitamin E acts as a chain-breaking antioxidant that prevents free-radical reactions from occurring (3). In particular, vitamin E protects polyunsaturated fatty acids (PUFAs), embedded in our cell membranes, from oxidative damage (3). In fact, Carlson uses naturally-sourced vitamin E (as alpha-tocopherol) as an antioxidant in our fish oils to reduce the oxidation of the omega-3 fatty acids and maintain the integrity of the product. Clinically, the protection of lipids from oxidative damage may provide a cardiovascular benefit to humans. Many studies show a correlation between increased vitamin E levels and improved cardiovascular health. It is thought that vitamin E, with vitamin C and beta-carotene, acts as an antioxidant to prevent the oxidation of the LDL-cholesterol (2). Therefore, vitamin E is an important antioxidant nutrient that may support overall cardiovascular health.
Monograph
September 2014 | www.ihpmagazine.com 19
research news
Vitamin C and E for anxiety and depression in diabetics
Anxiety, stress, and depression are common features that are found in diabetic patients. Hyperglycemia leads to increased oxidative stress which diminishes the antioxidant defense system. Oxidative stress is a potential cause of depression and anxiety disorders. In this randomized single-blind study, evaluation of the effects of two antioxidants (vitamin C and vitamin E) was done on stress, depression and anxiety levels in 45 diabetic patients for six weeks. The patients were randomly divided in three groups of vitamin E (400 IU day(-1)), vitamin C (1000 mg day(-1)) and placebo. DASS-21 (Depression Anxiety Stress Scales 21-item) questionnaire items were read to each patient and completed by the main investigator of this study before and after six weeks of supplementation. The scores of depression, anxiety and stress were evaluated separately based on the DASS questionnaire. The results showed a significant decrease in anxiety level (p = 0.005) in vitamin C group compared to other groups but there were no significant differences between groups in terms of changes in stress and depression scores. The authors conclude that short-term supplementation of vitamin C is safe and beneficial for reducing anxiety levels in diabetic patients through alleviating oxidative damage. Pak J Biol Sci. 2013. PMID: 24511708.
Vitamin E and memantine for functional decline in Alzheimer disease: RCT
This study aimed to determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. It was a double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD. Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). The results showed over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units, less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. The authors conclude that among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. JAMA. 2014. PMID: 24381967.
Antioxidant therapy in hemodialysis: RCT
This study tested the hypothesis that oral antioxidant therapy over 6 months would decrease selected biomarkers of acute-phase inflammation and oxidative stress and im-prove erythropoietic response in prevalent maintenance hemodialysis therapy (MHD) patients. In total, 353 patients were enrolled in a prospective, placebo-controlled, double-blind clinical trial and randomly assigned to receive a combination of mixed tocopherols (666 IU/d) plus α-lipoic acid (ALA; 600 mg/d) or matching placebos for 6 months; 238 patients completed the study. High-sensitivity C-reactive protein (hsCRP) and IL-6 concentration were measured as biomarkers of systemic inflammation, and F2 isoprostanes and isofurans were measured as biomarkers of oxidative stress. The groups did not significantly differ at baseline. At 3 and 6 months, the treatment had no significant effect on plasma hsCRP, IL-6, F2 isopros-tane, or isofuran concentrations and did not improve the erythropoietic response. No major adverse events were related to the study drug, and both groups had similar mor-tality and hospitalization rates during the study. The authors conclude that the adminis-tration of mixed tocopherols and ALA was generally safe and well tolerated, but did not influence biomarkers of inflammation and oxidative stress or the erythropoietic response. J Am Soc Nephrol. 2014. PMID: 24371300.
011-016.IHP Research.indd 19 2014-08-26 10:07 AM
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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)
BiologyThe element silicon frequently exists as a compound with oxygen, silicon dioxide or silica (Si2O); in solution, silica exists as a hydrated form called orthosilicic acid (OSA) (Jurkic 2013). Choline-stabilized orthosilicic acid (ch-OSA) is, as the name suggests, a uniquely effective and stable complex of choline and OSA in water solution. ch-OSA has been shown to promote formation of type I collagen, a component of bone and connec-tive tissue (Spector 2008), and silicon is present at 1-10 ppm in hair (Wickett 2007).
Clinical Trials: BoneA randomized double blind, placebo controlled trial found that supplementation with ch-OSA is able to improve markers of bone formation in women with osteopenia (Spector 2008). A total of 184 women with lumbar T scores below -1.5 received either1000 mg calcium and 800 IU vitamin D3, along with one of three different ch-OSA doses (3, 6 and 12 mg Si) or placebo. In the 136 women who completed the study, there was a trend for ch-OSA to confer additional benefit to calcium plus vitamin D3 treatment, especially for markers of bone formation, which included: osteocalcin, bone specific alkaline phosphatase, procollagen type I N-terminal propeptide (P1NP). The addition of ch-OSA showed significant benefit on formation of type I collagen formation after 12 months of treatment for the 6 and 12 mg Si doses, compared to placebo. There was no significant change in lumbar spine bone mineral density (BMD). However, subgroup analysis showed a significant improvement in BMD at the femoral neck for women who had baseline T-score <-1 at baseline. There were no ch-OSA related adverse events observed and biochemical safety parameters remained within the normal range.
A study in the standard animal model for post-menopausal bone loss showed similar results, with ch-OSA resulting in increased bone mineral content in femoral and lumbar locations, as well as decreased bone resorption (Calomme 2006).
Hair, Skin and NailsIn a randomized, double blind, placebo controlled trial, supplementation with ch-OSA was shown to improve hair tensile strength, elasticity, and thickness (Wickett 2007). A total of 48 women with fine hair were given 10mg silicon as ch-OSA daily, or a placebo for nine months. Researchers found that the elastic gradient decreased in both groups, but the change was signifi-cantly smaller in the ch-OSA group (-4.52%) compared to placebo group (-11.9%). Similarly, break load changed significantly in the placebo group (-10.8%) but not in the ch-OSA supplemented group (-2.20%). Notably, the cross sectional area or “thickness” of the hair shaft increased significantly after 9 months in the ch-OSA supplemented subjects only.
In a second RCT, 50 women with photodamaged facial skin were randomized to receive either 10mg silicon as ch-OSA or placebo daily for 20 weeks (Barel 2005). Skin roughness (microrelief ) param-eters increased in the placebo group but decreased in the ch-OSA group, and this change was significant between the two groups. The difference between longitudinal and lateral shear propagation
times increased in the placebo group, but decreased in the ch-OSA group suggesting decreased skin elasticity in the placebo group and increased skin elasticity in the ch-OSA group. Finally, visual analog scale scores for nail and hair brittleness were significantly lower in the ch-OSA group compared to baseline scores.
Recommended adult dose: Drops: Mix 5 drops in a glass of juice twice a day (morning and evening) and drink immediately or as directed by a health care practitioner.
Capsules: 2 capsules daily or as directed by a health care practitioner
Medicinal ingredients:Silicon (ch-OSA): 1 drop of BioSil™ is equivalent to 1 mg of silicon.
ReferencesBarel A, Calomme M, Timchenko A, De Paepe K, Demeester N, Rogiers V, Clarys P, Vanden Berghe D. Effect of oral intake of choline-stabilized orthosilicic acid on skin, nails and hair in women with photodamaged skin. Arch Dermatol Res. 2005 Oct;297(4):147-53.
Calomme M, Geusens P, Demeester N, Behets GJ, D’Haese P, Sindambiwe JB, Van Hoof V, Vanden Berghe D. Partial preven-tion of long-term femoral bone loss in aged ovariectomized rats supplemented with choline-stabilized orthosilicic acid. Calcif Tissue Int. 2006 Apr;78(4):227-32.
Jurkić LM, Cepanec I, Pavelić SK, Pavelić K. Biological and therapeutic effects of ortho-silicic acid and some ortho-silicic acid-releasing compounds: New perspectives for therapy. Nutr Metab (Lond). 2013 Jan 8;10(1):2.
Lassus A. Colloidal silicic acid for oral and topical treatment of aged skin, fragile hair and brittle nails in females. J Int Med Res. 1993 Jul-Aug;21(4):209-15.
Spector TD, Calomme MR, Anderson SH, Clement G, Bevan L, Demeester N, Swaminathan R, Jugdaohsingh R, Berghe DA, Powell JJ. Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo- controlled trial. BMC Musculoskelet Disord. 2008 Jun 11;9:85.
Wickett RR, Kossmann E, Barel A, Demeester N, Clarys P, Vanden Berghe D, Calomme M. Effect of oral intake of choline-stabilized orthosilicic acid on hair tensile strength and morphology in wom-en with fine hair. Arch Dermatol Res. 2007 Dec;299(10):499-505.
BioSil by Preferred Nutrition is a nutritional supplement that supports the healthy growth and maintenance of skin, hair and nails. It has also been shown to help in the formation of cartilage and bone, for the maintenance of healthy joints.
BioSil contains silicon as choline-stabilized orthosilicic acid (ch-OSA); one drop of BioSil contains the equivalent of 1mg silicon and 20mg of choline as ch-OSA.
BioSil
22 www.ihpmagazine.com | September 2014
industry news
Canadian Study Identifies New Approach To Improving Care For Type 2 DiabetesA Canadian study has identified a new strategy for improving the care of patients living with Type 2 Diabetes (T2D) by empowering them to manage their own insulin therapy. The START study (Self-Titration with Apidra® to Reach Target), the first research of its kind, found that T2D patients adjusting their own insulin doses can control the disease and achieve blood sugar targets just as safely and effectively as patients whose treatment is being conventionally managed by their physicians. “This is a significant finding because it offers a new approach to addressing a long-standing gap in the care of T2D patients,” says Dr. Stewart Harris, lead investigator of the study and professor of family medicine at Western University in London, Ontario. “Many family doctors feel they lack the skills to manage what can be complex and challenging issues. In the past 10 years, family doctors have become more comfortable initiating insulin therapy, but continue to be reluctant to move to the next step and so they delay intensifying insulin,” Dr. Harris explains. The START study, a Canadian ‘real world’ study that involved more than 300 patients and 47 primary care physician sites nationally, found that patients managing their own treatment were less afraid and more aggressive about increasing insulin than the physician-managed group. Based on the results, the study identifies a strategy to overcome the T2D care gap. It centers on engaging patients in making decisions about their own treatment and gives family physicians greater confidence to move to the next step by adding mealtime insulin when appropriate. This study provides a simple and easy protocol for family physicians and their patients to manage insulin therapy and thus achieve blood sugar goals. “Our approach demystifies insulin intensification, and it can be adopted anywhere. It has the potential to change physician practices and improve care for millions of people,” notes Dr. Harris. The START study was initiated by investigators at Western University, McGill University, McMaster University, and the Winnipeg Regional Health Authority. Sanofi Canada, which has a long history of innovation and discovery in the field of diabetes, sponsored the study.
Health Canada Approves HPV Test for First-Line Primary Screening of Cervical CancerRoche announced that Health Canada approved the cobas® 4800 HPV (Human Papillomavirus) Test for use as a first-line primary screening test for cervical cancer in women 25 and older. Roche has also launched the fully automated CINtec® PLUS test to improve the detection and early intervention of pre-cancerous cervical disease. The Health Canada approved CINtec®PLUS cytology test helps identify women with high-grade pre-cancerous cervical lesions who need immediate colposcopy. Roche's portfolio of cervical cancer screening products provides the most comprehensive strategies for cervical cancer prevention and treatment. "We are very pleased that Health Canada has approved the cobas® 4800 HPV test for use as a first-line primary screening test to identify women at increased risk for the development of cervical cancer", said Ian Parfrement, President & General Manager, Roche Diagnostics Canada. "We will partner with healthcare professionals and authorities to redefine and adapt current practice guidelines to encourage clinicians to incorporate these new tests in their patient protocols. If caught early, cervical cancer is one of the most preventable and curable cancers with a survival rate of more than 90% and with our Cervical Cancer Screening solution we will certainly improve patient care and people's health." The cobas® 4800 HPV Test provides both pooled high-risk HPV DNA results and individual detection of HPV 16 and HPV 18, the two types responsible for about 70 percent of cervical cancer. Health Canada's decision to approve the expanded use for the cobas® 4800 HPV Test was based on results from the landmark ATHENA trial, which enrolled more than 47,000 women. The study demonstrated that one in four women who are HPV 16 positive will have cervical disease within three years and that nearly 1 in 7 women with normal Pap cytology who were HPV 16 positive actually had high-grade cervical disease that was missed by cytology.
Aeterna Zentaris Implements Global Resources Optimization ProgramAeterna Zentaris Inc. announced the roll-out of a global resources optimization program as the Company pursues its strategy of transitioning into a commercially operating specialty biopharmaceutical company. Initiated earlier this year, the program's goal is to streamline R&D activities and increase commercial operations and flexibility. With the implementation of the global resources optimization program, the Company expects to have approximately 65 employees by year-end, as compared to 90 employees at the beginning of 2014. Due to the nature of certain proceedings, the Company intends to provide an estimate of the anticipated global restructuring charges and future cost savings as and when the financial and accounting implications of the global resources optimization program become better defined. David Dodd, Chairman, CEO of Aeterna Zentaris commented, "These difficult but prudent and necessary decisions ensue from our recent in-depth review of all of the Company's activities, mainly of our drug discovery activities in order to streamline our operations, optimize our resources and R&D productivity, reduce our operating cash burn and more appropriately, align our financial resources with our strategic goal of transitioning into a commercially operating specialty biopharmaceutical company. Through this global resources optimization program, we expect to become more efficient and better focused on the potential launch of MACRILENTM for the evaluation of adult growth hormone deficiency, on the required patient recruitment to secure a first interim analysis for our current Phase 3 ZoptEC trial in endometrial cancer, as well as on the future development of some of our promising Erk inhibitor compounds. As for commercial activities, we have started building our core business team based at our new global commercial hub in Charleston, South Carolina, thus increasing efforts on potential in-licensing, acquisition and co-promotion agreements for revenue-generating marketed products."
019-025.IHP IndustryNews.indd 22 2014-08-26 9:23 AM
September 2014 | www.ihpmagazine.com 23
industry news
Canadians Want End-of-Life Care Brought Out of the ShadowsWhile Canadians have diverse views on end-of-life care issues, there is a strong desire across the country for more palliative care services to help ensure a “good death,” the Canadian Medical Association (CMA) said today. This is the principal finding in the CMA’s final report from its National Dialogue on End-of-Life Care tour between February and late May 2014. “This cross-country effort was not about telling Canadians about CMA’s position, it was about listening to Canadians about what their health care system could do to help ensure not only a long, healthy life but also a good death,” said CMA President, Dr. Louis Hugo Francescutti. Fewer than 30% of the Canadians who will die in 2014 will have access to palliative care. The report makes a number of conclusions based on the consultation including: All Canadians should discuss end-of-life wishes with their families or other loved ones, all Canadians should prepare advance care directives that are appropriate and binding for the jurisdiction in which they live, a national palliative care strategy is needed, all Canadians should have access to appropriate palliative care services, medical students, residents and practicing physicians need more education and training about palliative care approaches and greater knowledge about advance care directives, should Canada change laws to allow physician-assisted dying, strict protocols and safeguards are required to protect vulnerable individuals and populations. The national dialogue focused on three main issues: advance care directives, palliative care, and physician-assisted dying. Beyond seeking input from Canadians on their views about the status of end-of-life care in Canada, the National Dialogue also sought to establish a common set of definitions and terminology to inform and frame discussion on end-of-life care issues. The Dialogue also included an educational element that described the current legal and legislative situation in Canada and abroad.
Nutritional Professionals may order therapeutic diets in hospitalsA landmark federal ruling that all qualified nutrition professionals and not just Registered Dietitians, may order therapeutic diets in hospitals, has leveled the playing field between nutrition professionals and Registered Dietitians. The U.S. Department of Health and Human Services’ Centers for Medicare and Medicaid (CMS) ruled that: “all patient diets, including therapeutic diets, must be ordered by a practitioner responsible for the care of the patient, or by a qualified dietitian or qualified nutrition professional as authorized by the medical staff and in accordance with State law.” The ruling adopts the Board for Certification of Nutrition Specialists’ (BCNS) formal recommendation to CMS that qualified nutrition professionals obtain any privileges granted to Registered Dietitians. The ruling goes on to state: “We agree with commenters that the regulatory language should be inclusive of all qualified nutrition professionals. We do not agree with commenters who requested that we use the term “registered dietitian” or define “qualified dietitian” as an individual specifically registered with the Commission on Dietetic Registration. We agree that a more flexible approach would be the best way to ensure that patients benefit from the improved quality of care that these professionals can bring to hospital food and dietetic services.” “This ruling has vast implications for the nutrition profession,” said BCNS President Sidney Stohs, PhD, CNS, FACN, ATS. “It embraces the right of a variety of highly qualified nutrition professionals, such as Certified Nutrition Specialists, to practice in hospitals, and rejects the assertion that Registered Dietitians should have an exclusive right to provide medical nutrition therapy.” “Most importantly,” said Dr. Stohs, “this ruling is a victory for patients, giving hospitals flexibility in determining which type of nutrition provider will best serve its patients’ health.” The Board for Certification of Nutrition Specialists (BCNS) is the foremost credentialing body for advanced nutrition professionals. Its Certified Nutrition Specialist® certifying program is accredited by the National Commission for Certifying Agencies (NCCA), the preeminent standard of excellence for certifying bodies, and is featured in the U.S. Department of Labor’s Definition of the Nutritionist Profession. The BCNS’ Center for Nutrition Advocacy is the leading advocate ensuring public access to a range of nutrition professionals.
Canadian Team Reaches Next Milestone in Addressing Medical-Isotope CrisisAt the Society of Nuclear Medicine and Molecular Imaging’s annual conference, a Canadian team with members from TRIUMF, the BC Cancer Agency, the Centre for Probe Development & Commercialization, and Lawson Health Research Institute announced that they have dramatically advanced technology for addressing the medical-isotope crisis. The key medical isotope, technetium-99m (Tc-99m), can now be produced in meaningful quantities on the world’s most popular cyclotrons, many of which are already installed across Canada and around the world. Patients, doctors, and hospitals have been concerned about a supply shortage of the workhorse medical isotopes used in cardiac tests and cancer scans as the world moves away from uranium-based nuclear reactors to create these exotic, short-lived, life-saving compounds. The Canadian team has demonstrated the successful production of Tc-99m on a standard cyclotron manufactured by GE Healthcare, confirming that this alternative technology can be used by roughly half of the world’s already-installed cyclotrons. Speaking for the consortium, Dr. Frank Prato of the Lawson Health Research Institute said, “This achievement is based on the efforts of the entire team and showcases our progress; we have a technology that can be applied in jurisdictions across Canada and around the world to produce this important isotope.” Next steps in deploying this technology for Canadian patients will include regulatory approval and working with provincial governments to make the choices required to diversify the supply chain and strengthen healthcare systems. The Canadian team is working to license its proprietary technology and to be positioned to market and supply the essential ingredients to cyclotrons around the world to enable their Tc-99m production.
019-025.IHP IndustryNews.indd 23 2014-08-26 9:23 AM
24 www.ihpmagazine.com | September 2014
industry news
Atrium Innovations Names Peter Luther President and Chief Executive OfficerAtrium Innovations Inc., a globally recognized leader in the development, manufacturing and commercialization of innovative, science-based natural health products, announced today that Peter Luther, former President of Johnson & Johnson Consumer Healthcare, has been named President and Chief Executive Officer of Atrium, effective at the end of June. He succeeds Pierre Fitzgibbon, who, as previously announced, will leave the Company by mutual agreement with the Board of Directors. The Company also announced that Jacques Bougie, former President and CEO of Alcan Inc., W. Brian Edwards, founder and former CEO of BCE Emergis, and Mr. Luther will join Atrium's Board of Directors. Mr. Bougie will serve as Chairman of the Board and be based in Montreal, Québec. Mr. Luther, 49, has 25 years of experience in the consumer packaged goods and healthcare industries. Since 1987, he has worked for Johnson & Johnson and has served as President of several of the company's large divisions over the past 10+ years. His most recent role was President of the Consumer Healthcare business. In this role, Mr. Luther drove over $2.0 billion in annual retail sales in 2013 across 17 of the world's most iconic brands, including Listerine®, Band-Aid® and Neosporin®. On behalf of Atrium's owners - the Permira Funds, Fonds de solidarité FTQ and Caisse de dépôt et placement du Québec - John Coyle, Partner at Permira, said, "We are thrilled to have attracted an executive of Peter's caliber to lead Atrium and capitalize on the Company's numerous growth opportunities. His leadership skills, deep appreciation of industry regulation, keen focus on innovation, and proven track record of growing consumer brands make him a perfect fit for Atrium as the Company moves forward on its path to becoming a branded, global leader in the health products space. We look forward to working closely with Peter and the entire senior management team as they continue to grow this outstanding Company."
Wellness Not the Focus of Health Benefit PlansOnly 36% of health benefit plan sponsors regularly receive an analysis of claims data. 79% of health benefit plan sponsors look to benefit plan providers for guidance in developing plans. Compelling new data in the 2014 edition of The Sanofi Canada Healthcare Survey indicates that workplace health benefit plan sponsors (employers) are ill-equipped to develop strategic health benefit plans to respond to the future needs of employees. One out of two employees (53% of survey respondents) reports having at least one chronic disease as Baby Boomers remain the largest age group in the workforce. These needs are vastly different from younger Gen Y employees entering the workforce and looking for different, more flexible plans. Health benefit plans are important to employees. While health benefits are important to all generations of plan members, with four in five (78%) reporting that the health benefit plan is an important factor when choosing a job (76% among Gen X and Gen Y, 80% among Boomers), only half (52%) of plan sponsors indicate that keeping employees healthy and productive is a main purpose of offering their health benefit plan. "It is important that healthcare plan sponsors and plan providers* design healthcare benefit plans that respond to the needs of their employee populations," says David Willows, VP, Strategic Market Solutions at Greenshields Canada. "The goal of the plan should be to keep employees well, so that those involved (sponsor, provider and employee) do not find themselves with greater health costs and lost productivity." Survey data reveals that there appears to be a few problems in the communications between health benefit plan sponsors and providers. The first issue is that only one-third (36%) report regularly receiving an analysis of claims data from their plan providers (insurance company or advisor) to better understand the use of their plan. A further 20% report receiving this type of information occasionally. The second issue is that, of those who do receive this type of data, just half (49%) use it to develop targeted improvements to their plans.
Prenatal maternal stress predicts asthma and autism traits in childrenA new study finds a link between prenatal maternal stress (PNMS) and the development of symptoms of asthma and autism in children. A team of scientists from The Douglas Mental Health University Institute and from McGill University has been studying women who were pregnant during the January 1998 Quebec ice storm since June of that year and observing effects of their stress on their children's development (Project Ice Storm).The team examined the degree to which the mothers' objective degree of hardship from the storm and their subjective degree of distress explained differences among the women's children in asthma-like symptoms and in autism-like traits. Results reported in the journal Psychiatry Research show that the greater the mothers' objective hardship from the ice storm (such as more days without electricity), and the greater the mothers' distress about the ice storm 5 months later, the more severe their children's autistic-like traits at 6½ years of age. The team emphasizes that the children in Project Ice Storm are not autistic; the results describe normal variations among children. These traits include difficulty making friends, being clumsy, speaking in odd ways, etc. The effect of the mothers' ice storm stress was especially strong when the ice storm happened in the first trimester of pregnancy. Interestingly, the children with the most severe symptoms had mothers who had had high levels of hardship from the ice storm but low levels of distress. In May, the team reported in the journal Biomedical Research International that girls whose mothers had had high levels of distress after the ice storm were more likely to have experienced wheezing, to have been diagnosed with asthma by a doctor, and to have been prescribed asthma medication before the age of 12. There was no effect in boys, and there was no effect of the mothers' objective hardship. These results demonstrate the power of a stressor in pregnancy to influence both the physical development and the mental health of the unborn child. Project Ice Storm continues to follow the children's development, including brain MRI scans at the age of 16 years starting in September. ■
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aanp
I have had the privilege of attending ten consecutive AANP conventions… A feat I thought was most impressive, until Dr Traub informed me this was his 23rd consecutive…
What makes the annual AANP convention, the largest convention of ND’s in the world, a happening that brings people back year after year?
A big part is the comradery… Attending an AANP convention is a once- a- year opportunity to engage in a reunion of hundreds of ND colleagues, and simultaneously introduce a new generation of ND’s to the profession. As we all know, wonderful things happen when you get several hundred ND’s to descend on a facility at the same time.
An equally important aspect is the ever- improving line- up of world- class speakers and lectures… My favorites include the annual nutrition update (hosted by Dr Alan Gaby) and the annual botanical medicine update (hosted by Dr Paul Saunders). I am also a keen attender of the research track – It has been exciting to see the progression of the research track at the AANP – from modest case reports and review articles, to a point where 70%+ of the presentations are ND’s conducting controlled, clinical trials.
It’s also a stage where “ND hero’s” can be found at every turn… I recall being disappointed as a student at CCNM with a handful of courses, so I would go to the library looking for things to read to reaffirm my career choice as an ND. I would read Alt Med Rev by the hours… People like Allan Miller, Tori Hudson, Paris Kidd, Lynn Patrick, Alan Gaby, and so on… Attend an AANP sometime… They are all there. And nothing puts a bigger smile on an authors face then when you tell them how much you enjoyed so and so paper they wrote!
Not to mention, it is where the most cutting edge of new happenings in the world of integrative medicine are unveiled. Industry saves the launch of the newest and best for the stage of the AANP. Dr Lise Alschuler, winner of the AANP doctor of the year award for 2014, has championed an incredible online resource for ND’s, partnering with some amazing talent to do so, including Dr Tori Hudson and Dr Gaetano Morello. Important improvements in integrative diagnostic assessment, cutting- edge new nutraceutical and herbal preparations, and the latest and greatest in medical devices are all on display.
The annual AANP convention symbolizes family. Each year I am blown away by the immense Canadian presence at this
premier event. And our American hosts do an impeccable job of making the event feel like home. I implore every ND across Canada to at the very least add attending an AANP convention to the bucket list. Better yet, book yourself from now to attend in 2015. You will be welcomed, entertained, loved, educated, advanced, educated some more, loved some more, then be sent on your way back home. You will return home invigorated to apply what you have learned in practice. You will likely find yourself a regular attendee before you know it. ■
AANP 2014By Philip Rouchotas, MSc, ND
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26 www.ihpmagazine.com | September 2014
calendar
SEPTEMBER
September Date TBAIVT Therapy CourseOrganized by: OANDToronto, ONFor more information, visit http://www.oand.ca
September 7-9Conflict Management and NegotiationOrganized by: CMAOttawa, ONFor more information, visit http://cma.ca/pmi
September 10-12Engaging OthersOrganized by: CMAOttawa, ONFor more information, visit http://cma.ca/pmi
September 10Treatment of postmenopausal hot flashes and sleep disturbancesOrganized by: Restorative MedicineOnline TeleconferenceFor more information, visit http://restorativemedicine.org/cme-webinars/
September 11Case Management and Treatments for Lyme DiseaseOrganized by: SeroyalOnline TeleconferenceFor more information, visit http://www.seroyal.com
September 11-13MAPS Fall 2014: Standard of Care CME ConferenceOrganized by: MAPSOrlando, FLFor more information, visit http://www.medmaps.org
September 24Pre and Post Natal Nutrition and Raising “Super Babies”Organized by: SeroyalOnline TeleconferenceFor more information, visit http://www.seroyal.com
September 27Integrative medicine for children’s mental healthOrganized by CSOMCalgary, Mount Royal UniversityFor more information, visit www.csom.ca
September 27-28Chinese Scalp Acupuncture CourseOrganized by: AimedicineToronto, ONFor more information, visit http://www.aimedicine.ca
September 28Integrative medicine for children’s mental healthOrganized by CSOMVancouver, SFU Harbour CentreFor more information, visit www.csom.ca
September 27-28Advanced Workshop: Biotherapeutic DrainageOrganized by: SeroyalToronto, ONFor more information, visit http://www.seroyal.com
OCTOBER
October 1A closer look at estrogens, breast health, and other therapeuticsOrganized by: Restorative MedicineOnline TeleconferenceFor more information, visit http://restorativemedicine.org/cme-webinars/
October 2-3OAND Business SymposiumOrganized by: OANDToronto, ONFor more information, visit http://www.oand.ca
October 3-5Evolution of Disease and Biotherapeutic Drainage for Individualized MedicineOrganized by: SeroyalVancouver, BCFor more information, visit http://www.seroyal.com
October 9-12AARM’s Annual ConferenceOrganized by: Restorative MedicineOnline TeleconferenceFor more information, visit http://restorativemedicine.org
October 11-122014 ILANP Conference: Integrative and Nutritional Approaches to GI HealthOrganized by: AANPFormat UnspecifiedFor more information, visit http://www.naturopathic.org
October 18Biotherapeutic Drainage and UNDA CompoundsOrganized by: SeroyalSeattle, WAFor more information, visit http://www.seroyal.com
October 18Nutrition for Doc’s- Part IIOrganized by CSOMOttawa, Saint Paul UniversityFor more information, visit www.csom.ca
October 19The Advantage of Phytotherapy: A simple, efficient therapyOrganized by: SeroyalSeattle, WAFor more information, visit http://www.seroyal.com
October 20-22Dollars and Sense: Leadership in Delivery of Cost-effective HealthcareOrganized by: CMAToronto, ONFor more information, visit http://cma.ca/pmi
October 23-25Management Dynamics: Getting the Job DoneOrganized by: CMAToronto, ONFor more information, visit http://cma.ca/pmi
IHP Calendar.indd 26 2014-08-26 9:35 AM
September 2014 | www.ihpmagazine.com 27
calendar
October 25Integrative medicine for treatment of depressionOrganized by CSOMToronto, Dalla Lana School of Public HealthFor more information, visit www.csom.ca
October 25-26Improve Clinical Outcomes and Elevate Your PracticeOrganized by: SeroyalCalgary, ABFor more information, visit http://www.seroyal.com
October 26-27Clinical Homeopathy Training ProgramOrganized by: CEDHToronto, ONFor more information, visit http://www.cedhusa.org
October 26-27Science and Connection: Integrative Health and Medicine ConferenceOrganized by: Scripps’ and ABIHMSan Diego, CAFor more information, visit http://www.scripps.org/events
October 30Individualized Nutrition: Mechanisms of EpigeneticsOrganized by: SeroyalOnline TeleconferenceFor more information, visit http://www.seroyal.com
NOVEMBER
November 5Stress Management and Adrenal ExhaustionOrganized by: Seroyal Online Teleconference For more information, visit http://www.seroyal.com
November 6-8Nurse Practitioners’ ConferenceOrganized by: NPAOHamilton, ONFor more information, visit http://www.npao.org
November 7-8IN-CAM Research SymposiumOrganized by: IN-CAMCalgary, ABFor more information, visit http://www.incamresearch.ca
November 8Nutrition for Doc’s- Part IOrganized by CSOMToronto, University of TorontoFor more information, visit www.csom.ca
November 8-9Individualized Nutrition for Women’s Health: Beyond Bio-identical HormonesOrganized by: SeroyalToronto, ONFor more information, visit http://www.seroyal.com
November 13How to Build Your Practice Using Biotherapeutic DrainageOrganized by: SeroyalOnline TeleconferenceFor more information, visit http://www.seroyal.com
November 21-23OAND ConventionOrganized by: OANDToronto, ONFor more information, visit www.oand.ca
November 23-24Clinical Homeopathy Training ProgramOrganized by: CEDHToronto, ONFor more information, visit http://www.cedhusa.org
November 23-24Developing and Leading System ImprovementOrganized by: CMAVancouver, BCFor more information, visit http://cma.ca/pmi
November 23-25Physician as a CoachOrganized by: CMAVancouver, BCFor more information, visit www. cma.ca/pmi
November 25-26Quality Measurement for Leadership and LearningOrganized by: CMAVancouver, BCFor more information, visit http://cma.ca/pmi
November 25-27Talent Management: Developing Physician LeadersOrganized by: CMAVancouver, BCFor more information, visit http://cma.ca/pmi
November 26Metabolic SyndromeOrganized by: SeroyalOnline TeleconferenceFor more information, visit http://www.seroyal.com
November 29Nutrition for Doc’s- Part IOrganized by CSOMVancouver, SFU Harbour CentreFor more information, visit www.csom.ca
November 2014 through June 2015Clinical homeopathy training course for physicians and allied healthcare professionalsOrganized by The Centre for Education and Development of Homeopathy (CEDH)Toronto, OntarioFor more information, visitwww.cedhusa.org/ca/toronto or call 1-866-550-2334.
DECEMBER
December 6-7Clinical Application of Biotherapeutic Drainage using UNDA CompoundsOrganized by: SeroyalToronto, ONFor more information, visit http://www.seroyal.com
IHP Calendar.indd 27 2014-08-27 12:42 PM
The information contained herein is for informational purposes only and does not establish a doctor-patient relationship. Please be sure to consult your physician before taking this or any other product. Consult your physician for any health problems.
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Figure 2. In subjects who received MicroActive® Curcumin as a single dose equivalent to 250 mg curcumin, Tmax for MicroActive® Curcumin was 2 hours followed by sustained release for over 9 hours. Cmax for MicroActive® Curcumin was 30-fold greater than for curcumin (250 mg dose of total curcuminoids). AUC for MicroActive® Curcumin was 8.6-fold greater than curcumin.
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Figure 1. In a human study, subjects received a single dose of either MicroActive® Resveratrol or an equivalent dose of 500 mg pure (98%) resveratrol (control). Peak plasma concentrations, AUC and duration in plasma were superior to control, and sustained release was evident over the 24-hour period.
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The information contained herein is for informational purposes only and does not establish a doctor-patient relationship. Please be sure to consult your physician before taking this or any other product. Consult your physician for any health problems.
ResCu-SR™
What Is It?ResCu-SR™ offers a unique combination of highly bioavailable, sustained-release resveratrol and curcumin to support longevity, and overall health.
Uses For ResCu-SR™
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ResCu-SR™ was developed using a proprietary MicroActive® delivery technology that renders a soluble, sustained-release resveratrol (MicroActive® resveratrol) and a soluble micronized curcumin (MicroActive® curcumin). Superior solubility and absorption performance have been confirmed in dissolution studies and pharmacokinetic trials of both compounds. The MicroActive® technology is a patented delivery system that improves solubility, reduces particle size, improves absorption and provides sustained-release of polyphenols. In a human pilot study, peak plasma resveratrol and area under the curve (AUC) values were 250% greater with MicroActive® Resveratrol compared to an equivalent dose of 98% pure resveratrol. Superior plasma concentrations remained after a 9-hour period (Figure 1). In a separate human trial, peak plasma curcumin levels were 4 to 60-fold greater with MicroActive® Curcumin compared to an equivalent dose of a standard 95% curcumin preparation (Figure 2). Superior plasma concentrations remained after a 9-hour period.
What Is The Source?Resveratrol is synthetic. Curcuminoids are derived from Curcuma longa (turmeric) extract (root).
Are There Any Potential Drug Interactions?Resveratrol and curcuminoids may be contraindicated with blood thinning medications. Consult your physician for more information.
Are There Any Potential Side Effects Or Precautions?If pregnant or lactating, consult your physician before taking this product. It is recommended to use resveratrol cautiously in patients with hormonal disorders and those using estrogen therapy, as resveratrol may act as either an estrogen agonist or estrogen antagonist. Turmeric can cause nausea or diarrhea in some individuals. It is not recommended for individuals with biliary obstruction. Consult your physician for more information.
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Figure 2. In a human pilot study, a single dose of MicroActive® Curcumin increased plasma curcumin to levels exceeding those achieved with a standard 95% curcumin by 4 to 60-fold over a 9-hour period.
RecommendationsPure Encapsulations recommends 1–2 capsules daily, with meals.
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30 www.ihpmagazine.com | September 2014
product pro� les
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ealth
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’s Hea
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PASCOLEUCYN
PASCOLEUCYN® is a homeopathic remedy that increases the body’s natural defenses. It relieves symptoms due to colds and � u such as headaches, stu� y nose, sore throat, cough and fever. A prophylactic intake of PASCOLEUCYN® can give your patients broad protection against colds and � u. Recommend the ampoules once or twice per season for general defense, and the drops when others around your patient are starting to get sick. For complete dosing suggestions for all ages, visit www.pascoe.ca. Made in Germany and quality assured, with 60 years of con� dence.
Curcumin Active from AOR
Curcumin Active contains Optimized Curcumin, the most bioavailable curcumin on the market with bioavailability increases of over 100-fold. Curcumin Active provides curcumin’s plethora of bene� ts including relieving in� ammation and joint pain in a low dose of 1 to 2 capsules a day. Optimized Curcumin is exclusively available in Canada from AOR.
Cysto Renew - Bladder Support Formula
Cysto Renew™, developed by Dr. Geo Espinosa, is a unique combination of ingredients including Lemon Balm and Rhodiola designed to help calm the bladder and support healthy functioning of the urinary tract system. Each ingredient contributes to the health of the bladder glycosaminoglycan layer, nitric oxide production, healthy stress response, and normal mast cell production that helps promote a healthy functioning bladder and normal urine frequency.
NEW Easy-to-Swallow Fish Oil from Progressive
Each OmegEssential® JEWELS mini so� gel has 50% more EPA than most regular strength so� gels and it’s only half the size!
EGCG SAP
Epigallocatechin gallate (EGCG) is a powerful natural antioxidant, and the major chemoprotective agent in green tea. Combined with anthocyanidins and lycopene, this standardized synergistic blend of antioxidants is supported by a wealth of scienti� c literature. A potent and popular choice of healthcare practitioners for combating oxidative stress; EGCG is designed to address the underlying process behind a myriad of chronic and degenerative conditions, including cancer and cardiovascular disease.
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product profiles
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Sport
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ition
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’s Hea
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Biotherapeutic Drainage™ Liver and Kidney Support
Biotherapeutic Drainage™ Liver and Kidney Support restores the liver and kidneys’ toxin elimination abilities using key therapies from UNDA Numbered Compounds and phytoembryotherapy support from GENESTRA BRANDS Black Currant Bud.
Mag-Matrix Liquid
Mag-Matrix Liquid™ is a unique blend of highly absorbable magnesium sources- magnesium glycinate, malate and citrate. Sweetened with xylitol and a subtle but pleasing natural lemon flavour.
Pure Tranquility Liquid
Pure Tranquility Liquid offers calming support combining inhibitory neurotransmitters GABA and glycine, along with L-theanine to support relaxation and stress reduction. Delivered in a convenient pleasant tasting liquid allowing for variability in dosing, Pure Tranquility Liquid enhances alpha wave production in the brain thereby promoting relaxation and relief of moderate occasional stress.
proteins+Natural Chocolate Peanut Butter
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PASCOFLAIR
PASCOFLAIR® is a unique preparation containing 425mg of Passionflower extract which works within 30 minutes to calm the brain and improve sleep onset due to stress. Studies also have shown passionflower has anxiolytic effects equal to diazepam, oxazepam, and mexazolam with a better safety profile than these medications. Extracts from passionflower have also shown promise in the treatment of opiate, benzodiazepine, and nicotine withdrawal in mice and humans. PASCOFLAIR® won the 2009 “Apotheken-Award” for Natural Medicine – an honor chosen by German pharmacists each year for the best in natural medicine.
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32 www.ihpmagazine.com | September 2014
product pro� les
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Grape Seed SAP
� e proanthocyanidins from grape seed extract (GSE) demonstrate anti-in� ammatory mechanisms and exhibit cytotoxic behaviour towards human breast, lung and gastric adenocarcinoma cells. With superior free-radical scavenging ability to Vitamins C, E, and beta-carotene, GSE is a powerful antioxidant, which may protect organs and tissues from the toxic e� ects of pharmaceutical drugs and environmental stressors, while preventing the development of atherosclerotic plaques.
St Francis Herb Farm Introduces Encapsulated Herbal Extracts
St Francis is launching a new line of encapsulated high potency dried herbal extracts. Encapsulated for convenience and concentrated e� ectiveness they provide all the bene� ts of liquid tinctures eliminating the need for large liquid or even capsules doses. � e capsules feature a typical 5:1 concentration, meaning that every mg of encapsulated herb is 5 times more potent than the same amount in the raw herb form. Products include; Ashwagandha, Astragalus, Dandelion, Ginger, Hawthorn, Lemon Balm, Milk � istle, Olive Leaf, Passion Flower, Rhodiola, Valerian, Echinace and Fenugreek/Blessed � istle. Now available in bottle sizes of 60 Vegicaps representing a convenient one month supply.
Passi� ora Plex
Passi� ora Plex is an UNDA brand liquid-based homeopathic preparation intended for the relief of restless sleep and insomnia. � is formulation combines extracts of Pasi� ora incarnata (passion� ower) and other key ingredients.
Carlson ACES+Zn
Carlson ACES+Zinc provides natural antioxidants to help protect the body from the harmful e� ects of free radicals.
Curcummatrix
Curcummatrix™ o� ers a patented technology speci� cally designed to increase the bioavailability. Curcummatrix™ o� ers a solubility in duodenal conditions 7.5 times greater than the same amount of native curcumin.
Progressive OmegEssential® JEWELS is a high potency blend of cold water, wild caught, purified fish oil along with a family of strategic support nutrients. Fish Oils for the Maintenance of Good Health
As a source of omega-3 fatty acids, namely EPA and DHA, fish oils aid in the maintenance of good health, help support cognitive health/brain function and cardiovascular health (NHPD Monograph: Fish Oil). Fontani, et al (2005) conducted a study to evaluate the effect of omega-3 supplementation on cognitive performance in 33 normal healthy men and women (aged 22 – 51 years) during a 35-day period. Tests involving different types of attention were used, along with the Profile of Mood States (POMS). Results showed a mood profile with increased vigour and reduced anger, anxiety and depression states after omega-3. Furthermore, findings indicated that omega-3 supplementation is associated with an improvement of attentional and physiological functions, particularly those involved in complex cortical processing. Higher consumption of fish and omega-3 fatty acids has been associated with a lower risk of coronary heart disease (CHD). Hu, et al (2002) examined the association between fish and omega-3 fatty acid consumption and risk of CHD in women. Dietary consumption and follow-up data from 84,688 female nurses (aged 34 to 59 years) free from cardiovascular disease and cancer were compared from validated questionnaires. The outcomes indicated that women who consumed more fish and fish oil (omega-3 fatty acids) significantly reduced their risk of heart disease (particularly CHD deaths) by 30%, compared to women who rarely ate fish. Similarly, a prospective, nested case-control analysis was performed among apparently healthy men, who had no evidence of prior heart disease by Albert, et al (2002) to address the hypothesis that long-chain omega-3 fatty acids found in fish are associated with a reduced risk of sudden death from cardiac causes. The fatty-acid composition of whole blood in 184 men was compared with the previously collected blood of 94 men, in whom sudden death occurred as the first manifestation of cardiovascular disease. The study reported that men who consumed long-chain omega-3 fatty acids had a significantly reduced risk of sudden death. Dosage
Indication: Fish Oil Supplement. Helps support cardiovascular health, brain function and healthy mood balance. Adults (≥ 19 years) Dosage
Take 2 softgels with breakfast and 2 softgels with dinner for a total of 4 softgels per day. Interactions
Omega-3 fatty acids may increase the risk of bleeding when taken with anticoagulants, aspirin, ginkgo biloba or ginseng (Mason, 2001). Therefore, medical supervision is required. Based on human studies, fish oils may lower blood pressure when taken in certain doses and have additive effects in patients treated with anti-hypertensives (Prisco, et al, 1998). Use with caution. Quality Assurance
Parameter 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.
September 2014 | www.ihpmagazine.com 35
cover story
HealthCare
Bringing Patient Relationship Management (PRM) to OntarioBy Philip Rouchotas, MSc, ND Photography by Robyn Russell
365
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cover story
n 2010, some of the most well respected individuals working in health care came together to revolutionize how care was delivered in Canada.
Today, HealthCare 365 has grown to include three practice areas - a family practice looking at ways to improve primary care, a Naturopath clinic, and RMT - as well as numerous partners in the community. Each area of focus has been integrated with the driving force behind the organization - technology enabled care coordination by nurses and nurse practitioners working to fill in the systemic gaps of the healthcare system.
Dr. Paul Walker (MD., Ph.D, F.R.C.S.C), Dr. Vera Kohut (BSc., MD., CCFP, FCFP), and Skip Schwartz (Architect, OAA, RAIC), started HealthCare 365 as a beta clinic to determine the main causes for the systemic gaps in patient care and the institutionalized shortcomings of the public health system. With industry leading technology and business professionals working alongside a diverse medical team coming from both public and private health care, problem areas were identified and the team went to work.
I
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What they - and many other industry leaders have discovered - are three trends within the health care system that are in desperate need of attention: ❱ Chronic disease is the new number one cause of death and
disability worldwide. This is a historic paradigm shift, mainly because until this point in history, injuries, infectious disease, and other incident-based medical events have been the focus of our healthcare institutions. But today, for the first time, chronic disease is the new leader in both death and healthcare spending, and our institutions are not properly equipped to address this new challenge.
❱ More individuals are presenting with multiple chronic conditions, which require an expanding network of providers, appointments and tests to diagnose, and the need to prescribe and amend complex care plans on a continuous basis. These challenges are compounded for the majority of our existing workforce, who are part of the “sandwich generation”, forced to take care of themselves, their parents, and their children. The result is an overwhelming, confusing management struggle that inevitably falls on their shoulders.
❱ Providers are trained and compensated for diagnosing disease and prescribing care plans. They work within the boundaries set by institutions designed to address medical
events. They are not trained, compensated or given resources to deliver disease management. This results in a growing mismatch between patients’ emerging needs and providers’ traditional abilities.
Upon identifying these problem areas, the HealthCare 365 team spent the next four years on development and testing a system that would supplement the existing system while bringing invaluable change to both health provider and patient. Dr. Vera Kohut, MD, the Medical Director at HealthCare 365, explains that “everyone in health care talks about Patient Relationship Management (PRM) systems, everyone agrees they are desperately required, and incredibly superior to current strategies, yet no one is doing anything about implementing them! That is what got me very excited to join the HealthCare 365 team.”
HealthCare 365 has engineered a robust, best-practice PRM technology platform that fully integrates the health data and care plans of patients across all of their health providers. Unlike many health apps and technology initiatives which place the patient or client as the user, this platform is used by nurse care coordinators and administrative team members to effectively manage everything pertaining to patients’ care
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cover story
plans. In addition to eliminating the risk for clients to stop using a product, it enhances the level of care and degree of integration by connecting with GPs, specialists, naturopaths, social workers, PSWs, and any one else involved in the delivery of care and well-being of a patient.
Not only has HealthCare 365 pioneered a best practice health management platform - the first of its kind in Canada - it has also taken an integrated approach both within its clinical structure, and in the broader health community with which it operates.
Early in the development phase, the team realized that communicating with everyone involved in a patient’s care, from the family doctor to PSWs or physiotherapists, provided valuable updates and touch points for the care team in the coordination process. As a result, HealthCare 365 mandated an integrated approach that included all providers in the circle of care. Not only does the service prompt the nurse care coordinators to reach out proactively to each health provider, it also ensures that all pertinent information is shared within the circle of care. This feature safeguards against human error and gaps in the system wherein patient information inevitably gets lost or missed, but also provides a new layer of communication between parties that would not be in contact without the program.
The integrated approach has also been incorporated into the clinic, which has evolved considerably since its beginnings in 2010. There are two family doctors, a nurse practitioner, nurse care coordinators, as well as a Naturopath and RMT. Dr Elizabeth Stavros, ND, beams with excitement to be a member of this esteemed team. “They really are incredible to work with - Dr Kohut has become an important mentor. We collaborate on the care of many patients, and I think the team is starting to see the importance of naturopathic care in a number of difficult chronic illness cases” describes Dr Stavros. “Dr. Kohut’s knowledge is
“everyone in health care talks about Patient Relationship Management (PRM) systems, everyone agrees they are desperately required, and incredibly superior to current strategies, yet no one is doing anything about implementing them! That is what got me very excited to join the HealthCare 365 team.”
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cover story
The HealthCare 365 team:
Clinical Leaders:Dr Vera Kohut, MD, CCFP, FCFP, Medical DirectorDr Roman Elinson, MD, CCFP, PhysicianDr Elizabeth Stavros, ND, Naturopathic DoctorTanya Radforth, BScN, PHCNP, Director of Care CoordinationMichelle Colenutt, RPN, Senior Care Coordinator
Management TeamSkip Schwartz, Architect, OAA, RAIC, Chief Executive OfficerDr Paul Walker, MD, PhD, FRCSC, Chief Medical OfficerAndrew Clarfield, MBA, Vice President of OperationsRhonda Saks, Manager- Business OperationsRyan Borenstein, BComm, Manager- OperationsMatt King, BA, Manager- Accounts and Projects
amazing - I am so grateful to be able to learn from such a talented team”.
HealthCare 365 believes that eliminating the gaps that exist in our health care system with regard to patient care results in a freer exchange of information and an elevated level of patient care through provider communication. The team believes that this revolutionary concept in health is the future of health care in Canada - for all Canadians.
IHP is grateful to the HealthCare 365 team for allowing us to showcase their vision to you. I arrived at the facility with limited to zero knowledge of what PRM or care coordination meant, yet left feeling I had a good understanding. The importance of such work within the Canadian healthcare landscape is obvious. Seeing the team at work, the success they are achieving, and the improved outcomes delivered to patients, I am left frustrated that the program is confined to the clinic in downtown Toronto. We wish the team much success... Gather your pilot data, and start banging on, better yet banging down, Health Canada doors! ■
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SUPERCRITICAL CO2 TRIGLYCERIDE
866.856.9954 • douglaslabs.ca
“There’s growing evidence that the natural triglyceride form or reesterfied form of the omega 3 fatty acids has the greatest absorption.
It also significantly increases the Omega-3 index.” Dr. Martin P. Gallagher
QÜELL Fish Oil is Supercritical CO2 extracted oils in triglyc-eride form, manufactured in Germany exclusively for Douglas Laboratories. QÜELL Fish Oil is unique among other fish oils for its’ critical extraction, purity, bioavailability and concentrations. Critical ExtractionSupercritical CO2 advanced technology is the superior protec-tion against oxidation. The extraction method of fish oil uses less heat and no chemical solvents when compared to molecu-lar distillation, resulting in fewer unwanted isomer formations and “cleaner” oil. Critical PuritySupercritical fluid extraction uses CO2 (carbon dioxide) instead of oxygen to gently extract the fatty acids, which also protects them from microorganisms that can’t survive without oxygen. No chemical preservatives, solvents, or undesirable compounds are found in QÜELL Fish Oils. Heavy metal and contaminant levels measure significantly lower than the standard. Critical BioavailabilityRecent scientific data shows the triglyceride form of fish oil is better absorbed when compared to ethyl esters. Recent data have demonstrated that omega-3 fatty acids delivered in a tri-glyceride form may result in greater plasma levels and a higher omega-3 index compared with omega-3 fatty acids delivered in the form of ethyl esters.
Critical ConcentrationMany fish oils contain only about 30% omega-3 fatty acids, of which roughly 18% is EPA and 12% DHA. The remaining 70% is a varying mixture of other components. In other words, regular fish oil contains less than a third of the desired active ingredients and more than two thirds of “other” components. These other components may include cholesterol, omega-6 fatty acids, saturated fatty acids, oxidation products and con-taminants. Highly concentrated fish oil, like QÜELL, provide at least 75% active ingredients, leaving less room for nonessential compounds.
Environmental ImpactQÜELL uses wild fish such as anchovies, sardines and mackerel that are recognized as not being endangered species. The pro-duction process produces no toxic impurities or solvents and all waste and waste water are recycled or transformed into energy.
No fishy smellThe QÜELL fish oils are naturally free of odor and taste due to the supercritical CO2 purification process, which allows for a pleasant experience when consuming fish oil.
Omega-3 supplementationThe benefits of omega-3 fatty acids continue to emerge and numerous health organizations around the world recommend increasing the daily intake of EPA and DHA. Data continues to accumulate that supports EPA and DHA in cardiovascular health as well as many other areas, including neurological health, vision health, and joint health. The omega-3 fatty acid EPA is the direct precursor for the prostaglandins, which are involved in helping to maintain the body’s normal inflammatory processes. DHA plays a major role in the structural integrity of neuronal membranes. DHA is essential for neurological and visual development and is vital throughout pregnancy to sup-port fetal brain growth and formation of the retina and visual cortex. As the most abundant fatty acid in the brain, adequate amounts of DHA are needed throughout infancy and adult-hood for ongoing optimal function. Low levels of DHA may adversely influence behavior and mental performance, and have been correlated with changes in disposition, memory, visual and other neurological parameters. For more information, please visit douglaslabs.ca.
By Christopher Habib, NDPhotography by Robyn Russell
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clinic profile
This IHP clinic profile is focused on Dr. Elizabeth Stavros, ND. Prior to becoming an ND, she worked in corporate marketing for 6 years. Dr. Stavros was
motivated to change career paths and become an ND after her own health concerns were unaddressed by the conventional medical system. As a result, she visited an ND who helped to resolve her health challenges in a short amount of time using herbs. Surprised by how well naturopathic medicine worked, Dr. Stavros thought: “Why isn’t this approach to health care common knowledge?” and that was the day her life pivoted. She realized that she wanted to bridge the healthcare gap between what patients were seeking and what conventional medicine was providing. It was difficult for her to make the decision to leave corporate marketing, but she felt that naturopathic medicine was something profound and worthy of changing careers for.
Dr. Stavros was recommended to the CEO of HealthCare365 a year ago. The team at HealthCare365 is highly integrated (their full story is also described in this issue). They are in constant communication about the patients that they share. The clinic’s primary focus is on prevention and wellness, which
fits perfectly with the philosophy of naturopathic medicine. In addition to treating disease, the team at HealthCare365 seeks to prevent health conditions that patients are predisposed to before they manifest. This means the inclusion of genetic testing as needed to make prevention more targeted. Prior to making treatment decisions, Dr. Stavros learns about a patient on multiple levels and explores their goals. Based on this information, she orders personalized labs, including hormone testing and chemistry panels, to grasp what is happening internally and to help guide treatment.
Dr. Stavros provides a detailed explanation of potential causes and remedies for the concerns that led the patient to treatment. She then provides suggestions for personalized supplement options, dietary recommendations and lifestyle modifications to enhance health and wellbeing from the inside out.
Dr. Stavros was an extremely successful student, reaching her required clinic numbers within a matter of months. Since starting up practice is a challenge for every practitioner, her advice to new practitioners is: “Find your niche and market yourself appropriately.” Ultimately, she believes what makes a
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clinic profile
Elizabeth Stavros, [email protected]: 416-642-9160www.healthcare365.orgwww.doctorstavros.com
practice successful is whether patients achieve their health goals. Her largest source of referrals is from current satisfied patients and word-of-mouth referrals. Dr. Stavros also does a lot of speaking engagements at various downtown businesses and this too has been a successful source of referrals.
Dr. Stavros practices using evidence-based medicine, including empirically based modalities like Traditional Chinese Medicine (TCM). She relies on a variety of herbs and tinctures, largely based on TCM methodology. Dr. Stavros’ has done additional training in Mind-Body Medicine at Harvard University and her approach emphasizes the dynamic interplay between brain and body. She utilizes holistic treatment modalities to address each person’s unique challenges. The patient demographic and areas of specialty for Dr. Stavros include women’s health, hormonal concerns, and oncology. By empowering patients to make positive changes to their health and emotional well-being, Dr. Stavros assists in lasting growth and healing.
Dr. Stavros is a firm believer in integrative medicine. She believes it makes sense to work on a medical team to promote coordination of patient care. Dr. Stavros says that communication is executed almost seamlessly at HealthCare365. She will see patients of the other practitioners, then engage in consults with the patients directly. After the consults, she will inform the team of the patient’s treatment plan and progress. “Integrative medicine is the way of the future. Working hand-in-hand with a medical team is rewarding and helps patients achieve optimal health outcomes.” She uses data and facts to guide her suggestions; listens carefully to patients, spends many hours researching, and works hard to master as much of the integrative medicine field as possible. Dr. Stavros donates a portion of her time & clinic proceeds to a charity that she co-founded called Meet Your Meat, which connects consumers with farmers who raise animals ethically. We at IHP would like to congratulate Dr. Stavros on her success and thank her for sharing her story with us. ■
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46 www.ihpmagazine.com | June/July 2014
1
2
3
CE
A review of preclinical studiesBy Maria Shapoval, ND and Vivian Liang, HBSc, (cand).
Magnolia extract (honokiol) and cancer
p61
The Journal Of
Food and NHP Labellingp66Clarifying TerminologyBy Christopher Habib, ND
Clinical recommendations By Daniyal Abdali, Dania Aslam, Verdah Bismah, Olivia Cook, Anna Liu, Laila Nasser, Jordan Robertson, ND, Marlie Valencia
Maternal supplementation of fish oil, vitamin D, probiotics and phosphatidylcholine in improving long term infant health
p53
off-label application of common prescription meds for integrative cancer managementBy Jacob Schor, ND, FABNO
Interesting drugs p73
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editor’s letter
Gearing up for FallThe annual AANP convention, held this year at the beautiful Biltmore resort in Arizona, serves as the wake- up call that “busy season” is upon us… With fall comes the most key conferences of the year, a pick up in practice as patients return from summer holidays, and, of course, lots to do in the garden!
We are excited to present the Healthcare 365 team as the issue’s cover story, and their gifted ND, Elizabeth Stavros, as the issue’s clinic profile. The concept of a “healthcare administrative assistant”, someone who coordinates a patients healthcare experience across visits with family physicians, specialists, and even hospitals, has worked successfully in many countries around the world. Healthcare 365 is attempting to introduce the concept of Patient Relationship Management (PRM) to Ontario.
Our contributors to the issue have once again provided important content sure to immediately impact how you deliver care to your patient base. The CE article is provided by first- time IHP contributor, yet internationally renown ND, FABNO, Dr Jacob Schor, reviewing common RX medications that may have a role in integrative cancer management. Jordan Robertson, ND, and her team of McMaster students provide an important article reviewing the role of several natural health products in pregnancy and their role in impacting disease risk of the resulting offspring. Maria Shapoval, ND, and Vivian Liang review preclinical evidence of an emerging medicine; magnolia (honokiol) for inte-grative cancer management. Chris Habib, ND, attempts to decipher language used by food and natural health product manufacturers in an article reviewing labeling terminology.
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peer review
Andrea Maxim, NDHealing Journey Naturopathic Clinic25 Caithness St. W.Caledonia, Ontario N3W [email protected]
Aoife Earls, MSc, ND Trafalgar Ridge Chiropractic and Acupuncture2387 Trafalgar Road, Unit 7AOakville, Ontario L6H [email protected]
Ashley Weber, HBSc, NDUpper Beach Health and Wellness1937 Gerrard St E.Toronto, [email protected]
Berchman Wong, ND Adjust Your Health5809 Macleod Tr SW, Suite 218Calgary, Alberta T2H [email protected]
Betty Rozendaal, BES, MA, NDThornhill Naturopathic Health Clinic12A Centre StreetThornhill, Ontario L4J [email protected]
Susan Coulter, BSc, NDRoots of Health2-497 Laurier AveMilton, Ontario 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, Nova Scotia B3K [email protected]
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editorial board
Jason Boxtart, NDDr. Boxtart has served on the Board of Directors of the Canadian Association of Naturopathic Doctors for six years, three of those years as the Chairman of the Board. In that position he chaired both the Canadian Naturopathic Coordinating Council and the Canadian Naturopathic Foundation. He received the Dr. Verna Hunt Award for his service to the profession. He held Adjunct Faculty of Medicine positions with the University of Northern British Columbia in the Norther Medical Program for nine years, working with new students in the Medical Program, introducing them to medical sociology and Naturopathic Medicine. Dr. Boxtart has been in private practice with his wife Dr. Cher Boomhower since 2002, co-founders of the Northern Centre for Integrative Medicine. NCIM is a multidisciplinary practice in northern BC. His practice focus is chronic musculoskeletal pain and integrative oncology. Dr. Boxtart is currently the Team Leader for British Columbia for the Pure Norths’ Energy Foundation. Pure North is a unique health care organization, providing primary prevention medical services to vulnerable populations throughout western Canada.
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.
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.
IHP Editorial Board Members
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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 was the first Canadian Naturopathic Physician to qualify with a fellowship from the American Board of Naturopathic Oncology in 2007. He and his wife, Dr. Karen Parmar launched the Integrated Health Clinic in 2000 and have since facilitated its growth to become one of the largest integrated health care facilities in Canada. Dr. Parmar was a consulting naturopathic physician at the Lions Gate Hospital cancer clinic from 2008 to 2012. He has established collaborative relationships with many oncologists and other practitioners, ensuring patients are provided a truly integrative and evidence-guided treatment. Dr. Parmar is also active in writing and lecturing in the fields of clinical hyperthermia, the tumour microenvironment, and integrative oncology. He continues to serve as a board member for the Oncology Association of Naturopathic Physicians, a position he has held since 2008. He is licensed by the College of Naturopathic Physicians of B.C.
Kristy Prouse, MD, 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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The Journal of IHP
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Maternal supplementation of fish oil, vitamin D, probiotics and phosphatidylcholine in improving long term infant healthClinical recommendationsBy Daniyal Abdali1, Dania Aslam1, Verdah Bismah1, Olivia Cook2, Anna Liu2, Laila Nasser1, Jordan Robertson2, 3, Marlie Valencia2
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Fish oilFish oil contains eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are essential omega-3 long chain polyunsaturated fatty acids (n3-LCPUFA) (Cleland 2006). During pregnancy, only DHA is uptaken by the placenta and passed onto the fetus (Innis 2005). It is well-established that maternal supplementation of fish oil increases birth weight and gestational length, thus reducing the rate of preterm births (Salvig 2011, Szajewska 2006). Recently, there is evidence that DHA also increases cognitive functioning and reduces the prevalence of allergies later in life (Dunstan 2003a, Judge 2007, Larque 2006).
Multiple randomized controlled trials (RCTs) suggest that maternal DHA supplementation during pregnancy improves the cognitive performance of infants later in life (Dunstan 2008, Helland 2003, Judge 2007). Animal studies propose a mechanism of action for DHA involving the hippocampus. DHA incorporates itself into the brain as membrane phospholipids (Janssen 2013, Su 2010). During in-utero brain development, DHA increases neurite outgrowth, synaptogenesis, neurogenesis, and neuronal differentiation to develop learning memory (Innis 2008, Su 2010). Although multiple RCTs support the cognitive benefits of maternal DHA supplementation, others fail to demonstrate significant impact (Helland 2001, Helland 2008, Makrides 2010, Van Goor 2011).
Figure 1: hypothesized effects of DHA on preventing allergy. DHA reduces antigen presentation as well as decreases levels of Interleukin (IL)-13 and IL-4, decreasing T Helper (TH) 2 response (Dunstan 2003b, Dunstan 2004a, Dunstan 2004b, Hughes 1996, Krauss-Etshmann 2008). Another hypothesis involves the DHA-mediated decrease of IL-5, IL-1, and Interferon (IFN)-γ, ultimately decreasing the inflammatory response.
DHA has also become increasingly studied in the prevention of allergy, including atopic dermatitis, asthma and allergic rhinitis (Dunstan 2003a). Omega-3 LCPUFA suppresses eicosanoids, ultimately decreasing the inflammatory response (Dunstan 2008, Kremmyda 2011). The exact biological mechanism of n-3 LCPUFA on the immune response is unknown, although numerous hypotheses have been made (see Figure 1). Clinical trials have demonstrated strong evidence supporting the use of DHA to reduce allergy in infants (Dunstan 2003a,
IntroductionMaternal nutrition is an evolving area of prenatal care and is critical in ensuring babies are born healthy and at term (Health Canada 2002). Nutrient supplementation can reduce the risk of adverse effects on the fetus, which include miscarriage, congenital anomalies, cancer and chronic health conditions (Black 2001, Goh 2006, Goh 2007, Ladipo 2000). Ethical considerations limit clinical studies examining maternal supplementation, as interventions pose a potential risk to both mother and fetus (Foulkes 2011). Thus, the safety of interventions must be well-established prior to study recruitment (Foulkes 2011).
The importance of taking nutritional supplements during pregnancy is well-recognized in reducing the incidence of congenital anomalies (De-Regil 2010). Deaths due to congenital anomalies have decreased from 3.1 to 1.1 per 1,000 live births from 1981 to 2007 in Canada, which is a statistically significant decrease (Health Canada 2002, Health Canada 2013). This decline can be attributed to better prenatal care and supplementation with folic acid and prenatal multivitamins (Goh 2006, Health Canada 2013). The decline in infant mortality has shifted the focus of prenatal care to improving long term health and chronic conditions, which have become increasingly prevalent (Health Canada 2002). These conditions include allergies, asthma and mental illness (Asher 2006, Masoli 2004, Mental Health Commission of Canada 2010, Public Health Agency of Canada 2011). Evidence indicates that supplementation during pregnancy can reduce these chronic health conditions. Fish oil, vitamin D, probiotics, and phosphatidylcholine are four emerging nutritional supplements in this field. The objective of this article is to explore the physiological effectiveness, biochemical mechanism, and clinical recommendations of the aforementioned supplements in improving long term health outcomes of the infant.
1 | Bachelor of Health Sciences Candidate, McMaster University
2 | Bachelor of Health Sciences Graduate,
McMaster University
3 | Doctor of Naturopathic Medicine
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Krauss-Etshmann 2008). Klemens, Beman and Mozurkewich (2011) completed a systematic review of five RCTs and concluded that DHA supplementation during pregnancy reduced the prevalence of both childhood asthma and positive egg skin prick tests, however the meta-analysis did not find consistent findings in terms of food allergy and atopy.
In conclusion, current evidence is conflicted on the benefits of fish oil for improving cognitive development and reducing allergy. However, given the potential benefits as well as the safety of fish oil intake, clinical recommendations for improving cognitive development and allergy can be made (Lo 2012). For cognitive development, a dosage of DHA ranging from 0.3 g/day to 2.2 g/day has been shown to be effective (Dunstan 2008, Helland 2003, Judge 2007). For allergy, a DHA dosage of 0.12 g/day to 1.1g/day can be administered (Kremmyda 2011). Administration of fish oil should start during the second or third trimester, as it is a critical time for brain development (Rogers 2013). Reviewed RCTs have administered fish oil starting from the second trimester (Dunstan 2003a, Dunstan 2003b, Dunstan 2004a, Dunstan 2004b, Dunstan 2008, Helland 2001, Helland 2003, Helland 2008, Judge 2007, Makrides 2010, Van Goor 2011).
Vitamin DThe role of vitamin D in bone growth, both in utero and after birth, has been well assessed (Abrams 2007, Mahon 2010). Studies are now examining the role of vitamin D in utero in the maturation of the immune system, which may have implications in the development of asthma, wheezing, allergenic rhinitis, and type I diabetes (T1D) (Erkkola 2009).
Vitamin D must first be metabolized into its active form, 25-hydroxyvitamin D3 [1,25(OH)2D3] before it can bind nuclear hormone receptors to regulate gene transcription and consequently, the immune system (Principi 2012, Zella 2003). Inadequate 25-hydroxyvitamin D3 levels at birth or in the first few months of life, due to insufficient vitamin D intake by the mother, may make the offspring more susceptible to respiratory disease (Principi 2012). A large-scale trial demonstrated that high maternal intake of vitamin D during pregnancy, defined as 280 IU per day, was inversely proportional to the development of asthma and allergic rhinitis (Erkkola 2009). Other trials have reported similar findings in that increased maternal consumption of vitamin D decreases the risk of recurrent wheezing in infants, and that insufficient maternal vitamin D increases the susceptibility of infants to respiratory tract infections (Camargo 2007, Karatekin 2007, Roth 2010). The hypothesized mechanism preventing respiratory diseases includes a regulatory T-cell(Treg)-mediated anti-inflammatory cytokine profile, as outlined in Figure 2 (Principi 2012, Wintergerst 2007). However, several studies have shown that low 25-hydroxyvitamin D3 levels have no association with the incidence of asthma and wheeze (Camargo 2011, Pike 2013).
Large-scale trials have shown that vitamin D supplementation in early life also reduces incidence of T1D (Wolden-Kirk 2012). T1D is believed to be mediated by the upregulation of the TH1 type immune response (Roep 2003). 25-hydroxyvitamin D3 is hypothesized to reduce the prevalence of T1D by increasing TH2 dominance, which helps to balance levels of TH1 and TH2 within the body (Figure 3). However, further evidence on the correlation between maternal vitamin D consumption and T1D in infants is required (Erkkola 2009, Marjamäki 2010).
There is conflicting evidence on the correlation between vitamin D deficiency and respiratory disease (Marjamäki 2010, Principi 2012, Rothers 2011). However, given the potential benefits of supplementation shown in large-scale trials and the safety of supplementation, a clinical recommendation of 280 IU can be made (Erkkola 2009). Evidence on the correlation between vitamin D and T1D alone is not strong enough for a clinical recommendation. Administration of 2000 IU/day of vitamin D during the third trimester of pregnancy is generally recommended for skeletal development (Camargo 2007, Mahon 2010, Principi 2012). The lowest risk of disease in the child must be maintained by administration of 2000 IU/day (Principi 2012). Due to the majority of the western world having decreased sun exposure due to more sedentary lifestyles, vitamin D supplements are nevertheless recommended (Camargo 2007).
Figure 2. Asthma, Wheezing, Allergy: 1,25(OH)2D3 reduces inflammation in the lungs by 1. inhibiting the expression of interleukin-12 (IL-12), 2. inhibiting dendritic cell (DC) expression of IL-4, and 3. promoting the induction of CD4+CD25+Foxp3+Tregs (Roep 2003, Sandhu 2010). Downstream, these effects decrease the peripheral blood TH1 and TH2 profile, thereby inhibiting the influx of inflammatory cytokines (IL-4 and IL-13) in the lungs and increasing secretion of IL-10 by CD4+CD25+Foxp3+ Tregs and DCs. Ultimately, these mechanisms decrease inflammation within the lungs (Sandhu 2010).
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This makes supplementation necessary, as vitamin D deficiency is also common during pregnancy (Johnson 2011). The safety of this recommendation of vitamin D is clear, with lowest adverse effects being 10000 IU/day (Hollis 2004). Since the general recommended dose of vitamin D (2000 IU) exceeds the dosage for respiratory disease prevention, a recommendation of 2000 IU/day of vitamin D may result in both immune and skeletal benefits in the fetus.
ProbioticsProbiotics are live microorganisms that confer health benefits to the host when administered in adequate amounts (FAO/WHO, 2001). These organisms are non-pathogenic and non-toxigenic (Macfarlane, 1999). Probiotics are typically consumed as live cultures that are added into fermented foods such as yogurt and dietary supplements (Bertelsen 2014). Maternal intake of probiotics is thought to protect against allergic diseases in
children, such as atopic dermatitis (Bertelsen 2014).Meta-analyses on the effect of maternal probiotic
supplementation for preventing atopic dermatitis in infants have reported the need for more definitive observational and mechanistic studies. Pelucchi et al (2012) and Doege (2012) reported a reduced risk of atopic dermatitis in infants after maternal probiotic supplementation. However, evidence is conflicted on whether probiotic strain is important for reducing risk of atopic dermatitis in infants. Although Pelucchi (2012) reported this effect regardless of probiotic strain, Doege and many other individual studies reported this effect for Lactobacillus alone (Dotterud 2010, Kalliomäki 2001, Kukkonen 2007, Wickens 2008). Nevertheless, other studies using this strain did not show reduced risk of atopic dermatitis (Huurre 2008, Kopp 2008, Kuitunen 2009, Rautava 2006, Soh 2009). Therefore, although there is evidence supporting the use of probiotics in reducing atopic dermatitis in infants, evidence for the use of specific probiotic strains remains inconclusive.
A few hypotheses suggest mechanisms by which probiotic supplementation may reduce atopic dermatitis and other inflammatory conditions:
I. Certain strains of lactobacillus and L.reuteri bacteria produce high amounts of H2O2 and reuterin respectively, which have antimicrobial effects (Erickson 2000, Fons 2000, Talarico 1989)
II. Probiotics may induce a TH1 response by increasing the production of IFN-γ, and IL-12. This TH1 response down-regulates the TH2 response, thus reducing immunoglobulin E and eosinophilic cells, which are involved in the inflammatory response associated with atopic dermatitis (Berger 2000, Romagnani 2000, Vaarala 2003).
Although the effect of taking probiotics during pregnancy to reduce atopic dermatitis in infants is inconclusive, studies have not shown any negative effects of supplementation. Since the safety of administration is established, probiotic supplementation during pregnancy is recommended. Although the timing and dosage of maternal probiotic supplementation remains inconclusive at this time (Kuitunen 2009, Huurre 2008, Kopp 2008, Abrahamsson 2007), supplementation four to six weeks before birth and one month to two years following birth is thought to reduce atopic dermatitis in infants (Dotterud 2010, Kalliomäki 2001, Kocourková 2007, Kukkonen 2007, Niers 2009, Wickens 2008).
A large-scale trial demonstrated that high maternal intake of vitamin D during pregnancy, defined as 280 IU per day,
was inversely proportional to the development of asthma and allergic rhinitis.
Figure 3. Type 1 Diabetes: 1,25(OH)2D3 effects DCs by inhibiting the surface expression of major histocompatibility complex II, co-stimulatory molecules, as well as production of the cytokines IL-12 and IL-23 (Wolden-Kirk 2012). Thus, DCs are created with less antigen-presenting capacity but, more importantly, this induces a shift in T-cell differentiation from a TH1 towards a TH2 and Tregs phenotype (Wolden-Kirk 2012).
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PhosphatidylcholineCholine is a conditionally essential nutrient. Although produced by the body, under certain circumstances, choline becomes essential to consume via external sources (Zeisel 2013). Diets lacking in milk, meat, eggs and other choline-rich foods, which are primarily seen in vegans, need additional choline via supplementation. Supplementation is also essential to a significant portion of women who have a single nucleotide polymorphism that prevents them from synthesizing choline (Ziesel 2011). Additionally, pregnant women have an increased need for choline because large amounts of choline are delivered to the fetus across the placenta (Zeisel 2013). Although pregnant women show increased choline synthesis, supplementation still remains necessary for optimal fetal development (Zeisel 2006).
Choline is an essential nutrient critical for fetal brain development (Zeisel 2006). Emerging evidence has shown that choline supplementation reduces the incidence of schizophrenia in infants (Ross 2013). Animal studies have also shown that phosphatidylcholine reduces neural tube defects, as well as improves cognition and memory of offspring later in life (Mehedint 2010, Zeisel 2006, Zeisel 2011). Although both human and animal trials have been conducted, larger clinical studies are needed (Mehendit 2010, Ross 2013, Zeisel 2011). Choline acts as an upstream methyl donor for DNA, RNA and proteins. Lack of choline can lead to hypomethylation of DNA which can alter gene expression, leading to neural tube defects (Zeisel 2006, Zeisel 2011). Choline and folate metabolism intersect at a common pathway for methyl-group donation, and it is reasonable to hypothesize that methylation reactions shared between the two may influence neural tube closure (Zeisel 2006). In addition, choline allows for the formation of acetylcholine in the fetus, resulting in greater transmission of impulses that enhances cognitive functioning (Meck 2003).
In order to maintain the dietary choline requirement throughout pregnancy, pregnant women should take 450 mg/day to ensure healthy fetal development. This value was determined through extrapolation of data obtained from adult rat tissues to an estimation of human fetal weight (Institute of Medicine 1998).
ConclusionThis review has found evidence supporting maternal supplementation for improving long term infant health and preventing chronic conditions based on literature assessing physiological effectiveness and biochemical mechanisms. With the rise of chronic conditions, the focus of prenatal care has shifted to preventative medicine (Health Canada 2002). The reviewed clinical studies examining maternal supplementation have shown possible benefits and no harm. Thus, pregnant women may benefit from taking these supplements within the recommended dosage as preventative treatments.
Though there are studies with conflicting conclusions, this may be attributed to the limitations that arise from studying supplementation during pregnancy. These limitations include the coexistence of micronutrient deficiencies and unstandardized diets that vary by age, season, year, ethnic group, and culture (Black 2001). Future research on the effects of supplementation would benefit from standardizing the method of delivery, length of supplementation, physiological outcome measures, as well as the age of testing between studies, in order to facilitate a stronger comparison of study results. Nonetheless, current research is sufficient to make clinical recommendations given the possible benefits and low risks of these supplements (see Table 1). In conclusion, fish oil, vitamin D, probiotics, and phosphatidylcholine should be administered within the recommended dosage as a preventative treatment for chronic conditions including allergy, asthma and mental illness. ■
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Table 1: Clinical Recommendations for Pregnant Women
Supplement Dosage
Phosphatidylcholine 450 mg/d
Fish Oil 0.3 to 2.2 g DHA/day
Vitamin D 0.5 mg/d (2000IU/d)
Probiotics Inconclusive
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Su HM. Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance. The Journal of Nutritional Biochemistry. 2010;21(5):364–73.
Szajewska H, Horvath A, Koletzko B. Effect of n-3 long-chain polyunsaturated fatty acid supplementation of women with low-risk pregnancies on pregnancy outcomes and growth measures at birth: a meta-analysis of randomized controlled trials. The American Journal of Clinical Nutrition. 2006;83(6):1337–1344.
Talarico TL, Dobrogosz WJ. Chemical characterization of an antimicrobial substance produced by lactobacillus reuteri. Antimicrobial Agents and Chemotherapy. 1989;33(5):674–679.
Van Goor SA, Dijck-Brouwer DA, Erwich JJ, Schaafsma A, Hadders-Algra M. The influence of supplemental docosahexaenoic and arachidonic acids during pregnancy and lactation on neurodevelopment at eighteen months. Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2011;84(5-6):139–46.
Vaarala O. Immunological effects of probiotics with special reference to lactobacilli. Clinical and Experimental Allergy. 2003;33(12):1634-1640.
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Vivian Liang, HBSc (candidate)University of Toronto Scarborough1265 Military TrailToronto ON M1C [email protected]
Magnolia extract (honokiol) and cancerA review of preclinical studies
By Maria Shapoval, ND and Vivian Liang, ND
AbstractHonokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)- 4-prop-2-enyl-phenol) is a natural lignan traditionally extracted from the bark and cones belonging to the genus Magnolia. Derivatives of honokiol have been used in therapies in Chinese, Korean, and Japanese traditional medicine, while Magnolia officinalis has been frequently used to treat gastrointestinal disorders. Recently, honokiol has been observed to have neuroprotective and anticancer effects. The anticancer effects appear to be due to honokiol’s ability to target cell signaling pathways that regulate apoptosis, growth and proliferation. Preclinical studies report positive impact on skin, breast, brain and several other cancer types, whether alone or synergistically with chemotherapy or radiation. This review will focus on the preclinical research of honokiol it applies to oncology.
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IntroductionHonokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)- 4-prop-2-enyl-phenol) is a natural lignan traditionally extracted from the bark and cones belonging to the genus Magnolia. Derivatives of honokiol have been used in Chinese, Korean, and Japanese traditional medicine (Lee 2011), while Magnolia officinalis has been frequently used to treat gastrointestinal disorders (Chan 2008). Recently, honokiol has been observed to have neuroprotective and anticancer effects. Previous studies have shown that honokiol has anti-tumorigenic (Crane 2008), anti-angiogenic (Bai 2003), antioxidant, antithrombic, anxiolytic (Arora 2012) and anticarcinogenic (Chilampalli 2011) properties. The anti-cancer properties of honokiol are related to its ability to induce apoptosis in malignant cells, where apoptotic pathways have been altered to promote immortality (Wyllie 1980). Honokiol has demonstrated anti-cancer effects by targeting cell signaling pathways that regulate apoptosis, growth, and proliferation. Honokiol can induce apoptosis via G0-G1 phase cell cycle arrests, mediate apoptotic signaling cascades and inhibit pro-survival mechanisms (Lee 2011). This paper is the first of a two-part series that will review the preclinical research on honokiol first in cancer models, and secondly in neurological conditions.
Mechanisms of Action Honokiol induces apoptosis via G0-G1 cell cycle arrest
Many chemotherapeutic agents attempt to suppress the growth of cancer cells by causing disruptions to the cell cycle. Honokiol-treated prostate cancer cell lines have demonstrated an enrichment of the G0-G1 fraction (an increase in the percentage
of cells at the G0-G1 stage) accompanied by a decrease in S phase and G2-M phase cells, in a concentration-dependent manner (Hahm 2007, Wang 2004). The accumulation of cells in G0/G1 phase is accompanied by an observed decrease in levels of cyclins and Cdks, factors necessary for sequential cell cycle progression (Hahm 2007). For instance, honokiol-treated cells exhibit decreased phosphorylation of retinoblastoma (RB) by Cdk4/cyclin D1 complex, suggesting honokiol-mediated cell arrest at G1 phase(Hahm 2007). It has been established that phosphorylated RB promotes the progression of the cell from the early G1 phase through the R point (“the point of no return”) to late G1 phase (Goodrich 1991). Honokiol has been shown to increase the accumulation of cells in the G0/G1 phase and decrease overall cell survival with increasing concentrations of honokiol (Park 2009). These observations suggest honokiol effectively induces cell cycle arrest, consequently inducing apoptosis among malignant cell populations.
Honokiol induces apoptosis via modulating expression of proteins that regulate the apoptotic pathway In cancerous cells, the tumor suppressor protein p53 is frequently downregulated to prevent apoptosis from occurring despite mutations in DNA. Consequently, the downregulation of p53 is an important contributor to the proliferation of many cancers (Lowe 1994). There is evidence that honokiol encourages the expression of the p53, thus activating downstream target genes to induce cell cycle arrest and apoptosis.
Honokiol also upregulates parallel pathways leading to apoptosis. For instance, honokiol has been shown to stimulate apoptosis in the colorectal cell line RKO through increased activation of the p53-independent pathway (Wang 2004). In honokiol-treated RKO cells, there was a significant degradation of chromosomal DNA in a concentration-dependent manner. RKO cells treated with 80-100μΜ honokiol resulted in significantly more fragmented DNA (DNA ladders) compared control cells, which showed non-degraded, high molecular weight DNA.
Honokiol has exhibited pro-apoptotic effects in human prostate cancer cell lines LNCAP and PC3 (Hahm 2008). Honokiol induces phosphorylation of p53, induction of p21, and decrease phosphorylation of retinoblastoma (Rb), allowing E2F-mediated gene transcription. The pro-apoptotic protein, p53 is an important regulator of the cell cycle that can arrest the cell cycle or initiate apoptosis in response to DNA damage(Lowe 1994). Under normal circumstances, p53 prevents the progression of the cell from G1 phase to S phase if DNA damage is beyond repair and induces apoptosis of the mutated cell. Honokiol activates intracellular apoptotic pathways leading to the degradation of proteins responsible for
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chromatin condensation, DNA fragmentation, cell shrinkage, and membrane blebbing (Kerr 1972, Luthi 2007). These observations suggest honokiol is capable of activating apoptotic cascades for a variety of cancers.
Anti-proliferative effect of honokiol via inhibition of EGFR-PI3K-Akt pathwayIt is known that over-activation of the PI3K pathway, regulated by external growth factors (EGFs), contributes to the competitive nature and metastatic competence of cancers (Hennessy 2005). External growth factor receptors (EGFR) are activated when a growth factor binds to it, activating downstream signaling cascades such as the PI3K signaling pathway and activation of STAT3 (Zandi 2007). There is evidence that honokiol inhibits the EGFR signaling pathway, indicated by inhibition of downstream signaling molecules(Leeman-Neill 2010). Increased phosphorylation and activation of EGFR by growth factors leads to downstream signaling targeting DNA synthesis and cell growth. Treatment with honokiol resulted in a dose-dependent suppression of cellular-Src (c-Src) and EGFR protein levels, and induced cell cycle arrest and apoptosis in MDA-MB-321 human breast cancer cells (Park 2009). In addition, two honokiol-treated HNSCC cell lines, 1483 and Cal-33, exhibited a significant increase in apoptotic cells by 7.4 fold (Leeman-Neill 2010). C-Src phosphorylates EGFR, which mediates proliferative and pro-angiogenic effects through downstream signaling cascades, therefore a decrease in c-Src protein levels would result in an inhibition of cancer cell growth (Zandi 2007). This suggests honokiol has anti-proliferative effects by regulating the c-Src/EGFR-mediated signaling pathway. Subsequently, decreased phosphorylation and activation of downstream kinases that initiate gene transcription, including PBK/Akt, can be attributed to treatment with honokiol. Under normal conditions, PBK/Akt promote cell survival by phosphorylating transcription factors as well as regulators in the apoptotic signaling cascade(Nicholson 2002). Similarly, the aggressiveness of cancer can be attributed to the increased activation
of Akt (Lee 2009). Inactivation of Akt by honokiol is observed to result in a decreased overall survival rate of cancer cells due to disinhibition of antiapoptotic mechanisms. As a result, downstream signaling molecules such as mTOR and NF-κβ that promote cell proliferation are downregulated (Wullschleger 2006).
Therapeutic applications of Honokiol in cancerHonokiol has been tested against several cancer cell lines and has demonstrated significant inhibitory results. In the case of skin cancer, 3mg of topical honokiol application resulted in 80% in tumor size and 62% in malignant progression from papilloma to carcinoma, induced by UVB-radiation (Arora 2012). This was thought to be accomplished by the inhibition of pro-inflammatory cytokines, as well as cyclooxygenase-2 and prostaglandin E2. This study suggests a potential application as a sunscreens or other topical application in high risk individuals. Whether it facilitates recovery from sun burns and/or yields post-exposure protection remains to be explored. Aside, a small randomized double-blind placebo controlled study (n=40) applied 1% honokiol twice daily for 56 days yield a positive trend in wrinkle reduction (p=0.058) with no significant adverse effects, while the 5% of honokiol patch-test produced irritation (n=3) (Bernard 2012).
In the case of breast cancer, honokiol demonstrated a dose-dependent inhibition of cancer cell growth irrespective of hormone receptor (HR), HER-2 or p-53 status (Arora 2012). While in the case of intracerebral gliosarcoma, honokiol was able to cross the blood-brain barrier and reduce tumor volume. Other cancer types demonstrating positive results include: leukemia, multiple myeloma, malignant melanoma (Kaushik 2012), and lung, ovarian, prostate, colorectal, gastric, renal (Li 2014) and pancreatic cancers. Honokiol inhibited prostate cancer cell growth and down regulated the androgen receptor, which is involved in the transition toward androgen-independence (Hahm 2014). Given honokiol’s mild 5α-reductase inhibiting properties, it may
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offer some protection against prostate cancer development (Bernard 2012, Hudak 2006).
Interactions There is evidence demonstrating that honokiol has synergistic effects with some chemotherapeutic drugs. For instance, honokiol has been shown to significantly improve the anticancer activity of erlotinib (Tarceva ®), an FDA approved tyrosine kinase inhibitor which is used in the treatment of head and neck squamous cell carcinoma (HNSCC) as well as lung cancer (Leeman-Neill 2010). A recent study indicated that erlotinib had some marginal success in increasing overall survival in patients with non-small cell lung cancer (Ellis 2014). Erlotinib acts on the family of EGFRs to prevent cancer cell growth and proliferation. Honokiol is observed to enhance the anti-growth activities of erlotinib in vitro. Empirical data indicate that combing honokiol with erlotinib yielded a 77% growth inhibition compared to erlotinib alone, which yielded 52% growth inhibition (Leeman-Neill 2010). In the same study, honokiol is additionally observed to enhance the activity of cetuximab (Erbitux ®), used in treatment for 1483 HNSCC cells. Analogous to erlotinib, honokiol increases the effectiveness of cetuximab, a growth inhibitor. Used in combination with honokiol, cetuximab slowed the growth of HNSCC cells by 46.8% compared to using cetuximab alone. In addition, synergism of honokiol with doxorubicin and daunorubicin has enhanced their effects against multidrug-resistant breast cancer cell line MCF-7/ADR and acute promyelocytic leukemia cell line HL-60, respectively (Tian 2013). Honokiol decreases expression of P-glycoprotein (P-gp) by inhibiting the transcription of the target gene. P-gp is the main cause to the phenomenon of multidrug resistance cancers (Kartner 1983). As a result, honokiol synergistically enhances the cytotoxicity of doxorubicin and daunorubicin. When combined with radiation therapy, honokiol promoted tumor reduction in the case of lung cancer. The combination resulted in a 78% reduction in tumor size compared to 42% with radiation alone (Arora 2012).
SafetyThe empirical application of honokiol to humans is limited as most of the data are preclinical, reducing our scope of knowledge related to side effects. To our knowledge, there has only been one study that directly considered the toxicity of honokiol. Honokiol was administered to Sprague-Dawley rats once a day for 14 days through IV injection with a dose rage of 20-80mg/Kg body weight and no significant differences were noted with respect to body weight, hematological values, and tissue pathologies between the honokiol-treated group and the vehicle treated group (Wang 2011). These observations are suggestive of a good safety profile, however more research is required for characterization of an accurate toxicity profile of honokiol in humans. The ability of honokiol to effectively cross the blood-brain barrier suggest that it may be valuable for its anticancer effects in the central nervous system. A preliminary study indicates that a high dose of honokiol (100μΜ) applied directly to fetal cortical neurons can cause neuronal death (Fukuyama 2002). In addition, honokiol is a known potent arterial thrombosis inhibitor (Hu 2005). Patients with recognized histories of coagulopathy or clotting disorders should use honokiol with caution.
ConclusionPreclinical studies demonstrate the potential therapeutic activity of honokiol in the treatment of cancer, primarily through pro-apoptotic pathways. Whether alone or synergistically with radiation or chemotherapy, honokiol offers a new option in cancer care that should be further explored in clinical trials. Given the traditional use of Magnolia officinalis in Traditional Chinese Medicine, it is likely already employed in clinical practice, although to date no case reports have been published exploring its application in patients with cancer. Part II of this article will continue our review of Magnolia with a focus on its effects in neurological conditions, including stroke, pain, depression and anxiety. ■
Honokiol has exhibited pro-apoptotic effects in human prostate cancer cell lines LNCAP and PC3
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AbstractThe terminology applied to food and nutritional dietary supplements has been an area of controversy and confusion for consumers and health care practitioners alike. The average consumer does not necessarily understand the full scope of label claims such as ‘organic’ and ‘all-natural � avouring’. Some label claims are regulated by the government, while others are additional assurances made by reputable companies going above and beyond. The most worrisome label claims take advantage of marketing hype. In this article, we will review some of the terminology that is commonly used by manufacturers and attempt to clarify what some of the more confusing terms really mean, in the hopes that practitioners can appropriately educate their patients. We will focus largely on the descriptions and processes of organic labelling. The term organic denotes a production process that aims to increase the quality and durability of the environment and ensures the humane treatment of animals. It also entails that no GMOs are used and the inclusion of only permitted substances. We will also brie� y discuss Natural Product Numbers, the terms Non-GMO Vegetable Capsule, all-natural � avouring, and the use of third party testing.
IntroductionThe different type of terminology applied to food and nutritional dietary supplements has been an area of controversy and confusion for consumers and health care practitioners alike. For instance, what does it mean exactly if a product is labelled as organic? Some of the terminology used is regulated by branches of the federal government (such as Health Canada), while other claims are provided as additions by the manufacturers. Some of these additional claims found on supplement labels often include the guarantee that no ingredients not found on the label are in the supplement. Some companies will qualify this statement by saying that their products contain none of the following, for example: wheat, gluten, yeast, sugar, starch, nuts, peanuts, sesame seeds, sulphites, mustard, dairy, soy, eggs, fish, shellfish, preservatives, artificial colour or flavour, or any animal by-product. These types of guarantees are made by the companies directly and they are not required to do this by law, since the list of ingredients by itself should be sufficient for identifying what is actually found in the supplement. For products regulated as foods in Canada, there is a legal requirement to label any priority allergens within the product, or that have come into contact with the product (Food Allergen Labelling 2014). While for products that are regulated as natural health products or NHPs, there is no formal requirement. However, if Health Canada becomes aware of a priority allergen within or that has come into contact with a product, then it will work with the manufacturer to have this identified on the product label. Otherwise, these claims are generally made for the benefit of the conscientious consumer, or perhaps to reiterate the message that the company marketing the product is diligent about the purity of its products. In this article, we will review some of the terminology that is commonly used by manufacturers and attempt to clarify what some of the more confusing terms really mean, in the hopes that practitioners can appropriately educate their patients. We will focus largely on the descriptions and processes of organic labelling, but we will also discuss Natural Product Numbers, the term “all-natural flavouring”, and the use of third party testing.
OrganicThe term ‘organic’ is probably one of the most confusing terms that have ever been used in
the natural health industry, perhaps because of its historical lack of regulation. The Canada Organic Regime was the Government of Canada’s response to requests by the organic sector and consumers to develop regulations for organic products. The resulting federal Organic Products Regulation defines specific requirements for organic products to be labelled as organic or to have the Canada Organic logo. These regulations only came into effect in 2009 (CFIA Fact Sheet 2014).
In the strictest sense, a product is organic when it complies with the Canadian Organic Standards. There are General Principles and Management Standards (CGSB-32.310) as well as a Permitted Substances List (CGSB-32.311). A product must comply with both to be considered organic. This includes guarantees by the farmer and seed supplier that at no point in the process are genetically modified organisms (GMOs) used. There are also guidelines of what constitutes organic soil amendments and organic pesticides and herbicides. According to the Organic Production Systems General Principles and Management Standards, several practices must be followed:
• Management methods are selected in order to restore and sustain ecological stability.
• Soil fertility is maintained and enhanced by promoting optimal biological activity and conservation of soil resources.
• Weeds, pests and diseases are managed using biological and mechanical control methods and cultural practices.
• Crop selection and rotation are important for managing nutrient cycling, recycling of plant and animal residues, water management, augmentation of beneficial insects to encourage a balanced predator-prey relationship, and the promotion of biological diversity, and ecologically based pest management.
• Livestock are provided with living conditions and space allowances appropriate to their behavioural requirements and organically produced feed.
Organic production aims to increase the quality and durability of the environment and ensures the humane treatment of animals. There is an extensive list of prohibited
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substances, methods, and ingredients. In addition to GMOs, other categories of prohibited substances include synthetic pesticides, synthetic growth regulators, synthetic processing substances, food additives, processing aids, synthetic drugs, and nanotechnology. Organic practices cannot guarantee that organic products are entirely free of residues or substances prohibited by the organic standard because of exposure from the atmosphere or from sources beyond the control of the operator, but the practices are designed to ensure the smallest amount of residues. Thus, the term organic perhaps speaks more to a certified process, rather than a final product (Organic Production System General Principles Managements and Standards 2014).
There is a standard process to obtain organic certification in Canada. The Canadian Food Inspection Agency (CFIA) is the institution responsible for monitoring and enforcing the regulations and from an organization perspective, the CFIA reports to the Minister of Health. The CFIA designates Conformity Verification Bodies. The Conformity Verification Bodies then accredit various Certification Bodies. The Certification Bodies are the ones responsible for verifying the correct application of the Canadian Organic Standards. There are currently approximately 20 of these accredited Certification Bodies, the main Canadian Organic Certifier is Pro-Cert (and they have thousands of clients in Canada and the United States). Verification officers are employed by the Certification Bodies and conduct on-site inspections of farms and facilities where organic producers are conducting their operations. The Certification Bodies have the power to suspend or cancel organic certification if necessary. To ensure the Certification Bodies are functioning appropriately, they are audited by the Conformity Verification Bodies, who are in-turn audited by the CFIA (CFIA Fact Sheet 2014).
The regulations are designed to protect consumers against false organic claims and to govern the organic logo. Foods making organic claims must also comply with the regulations on labelling and advertising (CFIA Organic Claims 2014). The regulations also apply to internationally imported organic products, for which there are equivalency arrangements made so that appropriate products also follow Canadian regulations. The regulations have defined the label ‘organic’ to indicate that at
least 95% of the contents are organic. Labels should not state that products are ‘100% organic’ or ‘certified organic’ or ‘made with organic ingredients’, as these may be misleading for consumers (anything over 95% can be called organic and technically anything labelled organic must be certified anyways). The regulations are quite specific about what is allowed and what is considered a possible misrepresentation.
When it comes to supplements and natural health products in particular, the Natural Health Product Regulations also apply. These regulations came into effect in 2004 and they are enforced by the Natural Health Products Directorate (NHPD), the regulating authority for products being sold in Canada. Their role is to ensure natural health products that are being sold are safe, effective, and of high-quality (NHPD 2014). Prior to the Organic Products Regulation, the NHPD had its own set of requirements for labelling a product as ‘organic’. Some of these requirements were flexible and various types of terminology were permitted. However, the most current position of the NHPD is that they do not certify or verify products as organic (in other words, they themselves are neither a Certification Body nor a Conformity Verification Body). The NHPD dictates that any food ingredients in natural health products should comply with the Organic Products Regulation. If a product is labelled as ‘organic’, it must be certified by an accredited agency and as such must have been produced in accordance with the production, processing, packaging, storage, and distribution provisions of the Organic Products Standards (NHPD Quality of Natural Health Products Guide 2014).
Natural Product Numbers (NPNs): This means that a product is licensed by Health Canada and has been found to be safe, effective and of high quality for the recommended conditions of use as stated on the product label. NPNs are eight-digit numbers. Homeopathic products have corresponding Homeopathic Medicine Numbers (DIN-HM). All Canadian manufacturers, packagers, labellers, and importers of natural health products must have site licenses. To get a license, they must maintain proper distribution records, have proper procedures for product recalls and for the handling, storage and delivery of their products, and demonstrate that they meet Good Manufacturing Practice requirements. Good Manufacturing Practices are meant to
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ensure proper standards and practices for the testing, manufacture, storage, handling and distribution of natural health products are met. Health Canada provides an additional guidance document for this purpose (Drugs and Health Products 2014). The NHP Regulations also require product license holders to monitor all adverse reactions related to their product. License holders must report serious adverse reactions to Health Canada within 15 days after the day on which they become aware of the reaction. The licensee is also required to annually prepare and maintain a summary report, which includes a critical analysis of all adverse reactions associated with each of the licensee’s natural health products. Although each annual report does not have to be submitted to Health Canada, it must be prepared and maintained by the licensee as part of their pharmacovigilance records. If Health Canada requests a specific annual summary report, it must be submitted to Health Canada within 30 days.
The safety and efficacy of products and their health claims must be supported by proper evidence. The key in properly utilizing information from a product that has an NPN is to follow the recommended conditions of use. In other words, it is easier to say a product is used for “the maintenance of bones and joints” than it is to say that a product is used “in the treatment of arthritis”. In general but not always, the stronger the claim, the more evidence is required to make it. This means that if a product
has strong claims, the consumer can be certain these claims have been well-validated. One reason why recommended conditions of use on a product label might appear more general in nature is because that may be the only way they would be approved for sale, based on the evidence provided by the licensee. Also, Section 3 of the Food and Drugs Act prohibits the sale and advertising to the general public of products that treat, prevent, or cure the conditions listed on Schedule A. Health Canada’s licensing requirements for natural health products apply to companies that manufacture, package, label, or imports products for sale in Canada, but they do not apply to health care practitioners who compound products on an individual basis for their patients, or to retailers.
Non-GMO Vegetable Capsule: This label claim is fairly straight-forward. Non-GMO indicates the capsule is free of any genetically modified organisms. The capsule is also appropriate for vegans and vegetarians. Usually these capsules are made of polysaccharides, which are a source of fiber and help bind and form the capsule. Note that if the product is already labelled as organic, the additional label of ‘Non-GMO’ is redundant (CFIA Organic Claims 2014).
All-Natural Flavouring or Natural Flavours: These terms have gotten some bad press and perhaps rightly so. Natural flavour is an umbrella term that in the simplest terms means that the source of what is adding taste comes from a plant or animal. The ingredients are created and
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processed in a lab environment and could contain any number of unhealthy or harmful components. Consumers would be better served if ingredients were listed in full, as severe allergies can be triggered by items that are not listed clearly (Food Labelling for the Industry 2014).
Independently Tested: ‘Independently tested’ means that a manufacturer is hiring another company to verify its purity and label claims. For example, Pure Check is a quality assurance program used by the company Ascenta, through which every lot of product is third party tested by an independent lab for quality, purity, and label claims (Pure Check 2014). The results are posted online, providing full transparency. Every lot of product is tested and posted online. Pure Check tests for Mercury, Arsenic, Dioxin-like PCBs, Lead, PCBs, Dioxins and furans, Cadmium, Oxidation by-products (Peroxide, Anisidine). Other types of third party testing are fairly similar.
ConclusionIt is unfortunate that food and natural health product labelling is so confusing. Luckily, many companies do an excellent job of having clear labels and following regulations. The bulk of this article focused on the term organic, including what it means exactly and how the certification is obtained. We identified that supplements that are labelled organic must follow the Organics Products Regulations and comply with the Canadian Organic Standards. Overall, the term organic denotes a production process that aims to increase the quality and durability of the environment and ensures the humane treatment of animals. It also entails that no GMOs are used and the inclusion of only permitted substances. Organic is the first label claim that is federally regulated that we discussed. The other labelling item that is federally regulated is NPNs. As we identified, NPNs mean that products have been assessed by Health Canada to be safe, effective and of high quality for the recommended conditions of use as stated on the product labels. Overall, health care practitioners should strive to find products that have NPNs, are labelled organic, have third-party testing, and list their ingredients in full.
References
Canadian Food Inspection Agency. “CFIA Fact Sheet: Organic Products in Canada”. Accessed June 30, 2014. Accessible at: http://www.inspection.gc.ca/food/organic-products/fact-sheet/eng/1389651477171/1389651725636
Canadian Food Inspection Agency. “CFIA Organic Claims”. Accessed June 30, 2014. Accessible at: http://www.inspection.gc.ca/food/labelling/food-labelling-for-industry/organic-claims/eng/1389725994094/1389726052482?chap=0
Health Canada. “Drugs and Health Products”. Accessed June 30, 2014. Accessible at: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/gmp-bpf-eng.php
Health Canada. “Food Allergen Labelling.” Accessed June 30, 2014. Accessible at: http://www.hc-sc.gc.ca/fn-an/label-etiquet/allergen/index-eng.php
Health Canada. “Food Labelling for the Industry”. Accessed June 30, 2014. Accessible at: http://www.inspection.gc.ca/food/labelling/food-labelling-for-industry/eng/1383607266489/1383607344939
Health Canada. “Labelling Guidance Document: Organic Products”. Accessed June 30, 2014. Accessible at: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/labelling-etiquetage-eng.php#a5_5
Health Canada. “NHPD”. Accessed June 30, 2014. Accessible at: http://www.hc-sc.gc.ca/ahc-asc/branch-dirgen/hpfb-dgpsa/nhpd-dpsn/index-eng.php
Health Canada. “NHPD Quality of Natural Health Products Guide”. Accessed June 30, 2014. Accessible at: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/eq-paq-eng.php
National Standard of Canada. “Organic Production System General Principles Managements and Standards” Accessed June 30, 2014. Accessible at: http://www.pro-cert.org/images/documents/standards/CANCGSB-32.310-2006%20ENG%20Reprinted%20in%20August%202011.pdf
Public Works and Government Services Canada. “General Principles and Management Standards”. Accessed June 30, 2014. Accessible at: http://www.tpsgc-pwgsc.gc.ca/ongc-cgsb/programme-program/normes-standards/internet/bio-org/principes-principles-eng.html#a1
Pure Check. “Pure Check”. Accessed June 30, 2014. Accessible at: http://www.purecheck.net/index.html
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Curcumin Active is not just curcumin or turmeric. While 95% standardized curcumin products are far better therapeutically than turmeric, curcumin is still renowned for being poorly absorbed, with large doses of up to 8 grams being needed to achieve therapeutic benefits (Cheng et al., 2001; Lao et al., 2006). Although there are many different “high‐bioavailability” curcumin products now available to the natural health industry, many of them have outrageous and unfounded bioavailability claims. The results of the clinical studies behind the bioavailability and effectiveness of AOR’s Optimized Curcumin may also seem extreme; however, they are 100% valid and show the most promising results by far.
Although Optimized Curcumin demonstrated a 65‐fold increase in bioavailability as determined by its CMax compared to regular curcumin, the AUC (area under the curve) actually showed more than a 100‐fold increase (Gota et al., 2010). Just one capsule of Curcumin Active delivers a therapeutically effective dose of curcumin, the equivalent of over 13g of a regular 95% curcumin extract. This would require taking 30 capsules of regular 95% curcumin extract, or more than 100 capsules of 750mg turmeric root extract!
Bioavailability Mechanism AOR’s Optimized Curcumin consists of Solid Lipid Particles™ (SLP) which are tiny nano‐sized (1 billionth of a meter) particles that have a protective layer providing a phenomenal increase in stability, potency and effectiveness. Unlike regular curcumin, SLP™ particles
have increased stability in varying pH conditions, are absorbed rapidly through the intestinal lining, and are protected from phase II detoxification. Unlike other so‐called bioavailable curcumins, AOR’s Optimized Curcumin then exists as free curcumin, not glucuronidated curcumin which does not pass through the blood‐brain barrier. Finally, the tiny size of the nanoparticle allows it to be taken up into the body’s cells quickly to be put to use. This means that Optimized Curcumin delivers all of the health benefits of curcumin much more efficiently than any other product.
Therapeutic Potentials Clinical studies show that curcumin is highly effective for improving joint mobility and for reducing stiffness, swelling and pain. Curcumin’s main mechanism of action as an anti‐inflammatory is through modulating the notorious NF‐κB signaling. Curcumin is also a potent antioxidant and anti‐microbial, and is cardioprotective. Additionally, recent studies have found that curcumin may be beneficial in HIV (Gandapu et al., 2011), chronic liver disease (Bischt et al., 2011), and even MS (Xie et al., 2011). The abundance of research points towards curcumin’s therapeutic potential in cancer, where it has been found to inhibit TNF‐α, angiogenesis, metastasis, encourage cancer cell apoptosis and shrink tumors in some patients, help prevent relapse, and it has been used as an adjunct therapy with radiation and certain forms of chemotherapy. Curcumin has been seen as a very promising compound in the treatment and prevention of Alzheimer’s disease, based on in vitro work, but bioavailability problems have prevented clinical application (Belkacemi et al. 2011). The incredible increase in bioavailability of Optimized Curcumin compared to normal curcumin has made it possible to study the effect of curcumin on Alzheimer’s disease in vivo, and a human study using the equivalent of 400‐600mg of Optimized Curcumin on Alzheimer’s patients is underway (Belkacemi et al., 2011). A new study led by Dr. DiSilvestro at the University of Ohio found increased clearance of serum beta‐amyloid in healthy subjects after only 1 month at a low dose of 80mg of Optimized Curcumin. Imagine the potential results of longer‐term supplementation and in people with known diseases!
Curcumin Active is Safe & Effective Curcumin is therapeutically beneficial in many degenerative diseases. AOR’s Optimized Curcumin has a phenomenal safety profile in both healthy individuals as well as in fragile populations such as cancer patients, and regular curcumin has shown no toxicity with up to 12 grams (Cheng et al., 2001; Lao et al., 2006; Gota et al., 2010; DiSilvestro et al., 2012). Curcumin Active by AOR delivers a high dose of Optimized Curcumin, the most bioavailable curcumin on the market that is efficient in relieving pain and inflammation and protective against inflammatory‐based conditions.
References: Begum AN et al. J Pharmacol Exp Ther. 2008 Jul;326(1):196‐208. Belkacemi A et al. Expet Rev Mol Med. 2011 Nov; 13(e34):1‐15. Bisht S et al. Lab Invest. 2011 Sep;91(9):1383‐95. Buhrmann C et al. J Biol Chem. 2011 Aug 12;286(32):28556‐66. Cheng AL et al. Anticancer Res. 2001 Jul‐Aug;21(4B):2895‐900. Dadhaniya P et al. Food Chem Toxicol. 2011 Aug;49(8):1834‐42. DiSilvestro RA et al. Nutr J. 2012 Sep 26;11:79. Frautschy, SA. 38th Annual Meeting of the Society of Neuroscience, Washington DC, November 15, 2008. Frautschy, SA et al. 39th Annual Meeting of the Society of Neuroscience , Chicago, IL October 2009. Frautschy, SA et al. 39th Annual Meeting of the Society of Neuroscience , Chicago, IL October 2009. Gandapu U et al. PLoS One. 2011 6(8):e23388. Gota VS et al. J Agric Food Chem. 2010 Feb 24;58(4):2095‐9. Lao CD et al. BMC Complement Altern Med. 2006 Mar 17;6:10. Mito S et al. Biol Pharm Bull. 2011 34(7):974‐9. Xie L et al. Int Immunopharmacol. 2011 Mar;11(3):323‐30. Yekollu SK et al. Diabetes. 2011 Nov;60(11):2928‐38.
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Non‐medicinal ingredients: ascorbyl palmitate, microcrystalline cellulose, soy lecithin, stearic acid, maltodextrin, silicon dioxide. Capsule: hypromellose. *LONGVIDA® is a registered trademark of Verdure Sciences Inc. International patent pending.
Adult Dosage: Take 1 to 2 capsules daily, or as directed by a qualified health care practitioner. Caution: Consult a health care practitioner prior to use if you are pregnant, taking antiplatelet medication or blood thinners, or if you have gallstones, a bile duct obstruction, stomach ulcers or excess stomach acid. Consult a health care practitioner if symptoms persist or worsen.
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successful completion of the questions at the end of this paper has been approved for continuing education by the bddt-n; 1.0 credit pharmacology and by the cnpbc; one ce hour.
AbstractThis article reviews the non-label use of several common drugs for prevention of cancer recurrence. Some of these drugs may be outside naturopathic scopes of practice. Nevertheless this information could benefit our patients if we use this information to lobby other providers to prescribe these drugs. Whether or not we chose to use these drugs in practice, it is important to understand the potential these drugs may have and conversely where benefits remain unproven or doubtful. Four drugs will be reviewed, metformin, aspirin, statins and beta-blockers. The status of these drugs shifts often. While earlier promising results from statins are not holding up, and the benefits of aspirin in preventing breast cancer recurrence have recently been questioned, the news on metformin continues to be positive. Let’s look at these drugs one at a time.
Interesting drugsoff- label application of common prescription meds for integrative cancer managementBy Jacob Schor
Jacob Schor, ND, FABNODenver Naturopathic Clinic1181 S. Parker Rd #101Denver CO 80231303 337-4884www.DenverNaturopathic.com
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MetforminMetformin, originally derived from the plant Galega officinalis, has been used for millennia to treat diabetes symptoms (Bailey 2004). Metformin is now one of the most commonly prescribed drugs in the world with over 120 million prescriptions a year (Ben Sahra 2010). Metformin was approved to treat type-2 diabetes in Great Britain in 1958 and in the US in 1995. Metformin is also used to treat polycystic ovarian syndrome (Diamanti-Kandarakis 2010).
The idea that metformin might act as an anti-cancer agent arose only a decade ago when it was realized that metformin regulated AMP-activated protein kinase (AMPK) an action that might control cancer cell proliferation.
Josie Evans and colleagues from Scotland were the first to report that diabetics who took metformin were less likely to develop cancer. Evans analyzed data from 314,127 people of whom 11,876 were newly diagnosed with type-2 diabetes and of these, 923 were eventually diagnosed with cancer. Compared with a control group of diabetics who had not taken
metformin, using metformin reduced the odds of getting cancer by 21% (Evans 2005).
A report followed that diabetics taking metformin had a lower rate of cancer mortality than patients who had taken insulin or sulfonylureas. Cancer mortality was 3.5% for metformin users, 4.9% for patients who used sulfonylurea and 5.8% for subjects who used insulin. Insulin use increased cancer-related mortality by 90% over metformin (Bowker 2006).
In 2009 Ana Gonzalez-Angulo looked back at 155 diabetic breast cancer patients treated between 1990 and 2007. Twenty-four percent of the patients getting metformin had no detectable tumor after standard chemotherapy, compared with only 8 percent of similar patients not using metformin.
In a study of 8,000 patients with type-2 diabetes, cancer was diagnosed in 7.3% of the metformin users and 11.6% of the nonusers with median times to cancer diagnosis of 3.5 and 2.6 years following their initial diagnosis of diabetes respectively (Libby 2009).
During this same time period, cell
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studies were published that reported metformin has a strong antiproliferative effect on a range of cancer cell lines including breast, colon, ovary, pancreas, lung, and prostate cancer (Ben Sahra 2010).
The number of studies published on metformin and the clinical trials in progress has increased rapidly. A June 1, 2014 search on clinicaltrials.gov using the term ‘metformin and cancer’ produces a list of 206 clinical trials.
Out of the many interesting papers, here are a few that deserve mention:• Metformin and ovarian cancer. Progression-free survival at
5 years was 51% for diabetic patients who used metformin compared with 23% for the non-diabetic patients and 8% for diabetic patients not using metformin. Overall survival at five years was 63%, 37%, and 23% respectively for the diabetic patients who used metformin, the non-diabetic patients, and the diabetic patients who did not use metformin (Romero 2012).
• Endometrial cancer. A recent retrospective cohort compared 1495 women, about a quarter of who were diabetic and of the diabetics, 54% used metformin. The non-metformin users had 1.8 times worse recurrence free survival and 2.3 times worse overall survival (Ko 2014).
• Pancreatic cancer risk meta-analysis including13 studies comprising 10 cohort studies and three case-control studies. Use of metformin was associated with a significant lower risk of pancreatic cancer (RR 0.63, 95% CI 0.46-0.86) (Wang 2014 ).
• Progression of non-invasive bladder cancer. Diabetics not taking metformin had 45% higher risk of disease recurrence (HR 1.45, 95% CI 1.09-1.94), more than double the risk of progression (HR 2.38, 95% CI 1.40-4.06). Diabetics who took metformin had half the risk of disease recurrence (HR 0.50, 95% CI 0.27-0.94) (Rieken 2013).
Most of the human papers published to date have been retrospective, looking at diabetics, they do not yet answer a key question: will metformin offer benefit to our non-diabetic cancer patients? (Quinn 2013)
Prognosis: The prospect that metformin may become an adjunctive cancer therapy continues to look good. Its safety profile is good. One concern is that metformin blocks vitamin B-12 absorption (de Jager 2010), though this effect is overcome by calcium supplementation (Bauman 2000) or direct replacement of vitamin B12 through sublingual or intramuscular administration. With respect to dosing, the prospective clinical trials currently underway use doses of metformin that range from 1000-2000 mg per day.
Aspirin: That aspirin might reduce deaths from cancer was first noticed in the 1970s (Kaiser 2012), but let’s not try to cover the whole history but instead just mention several recent papers:
In a meta-analysis that combined data from eight trials, which used aspirin as an intervention against cardiovascular disease,
aspirin users had 21% fewer deaths due to cancer. This benefit only became apparent after five years. The effect was more pronounced for gastrointestinal cancers, which fell by 54% (Rothwell 2011).
A second meta-analysis combined data from 34 trials, a total of 69,224 participants. Aspirin use reduced cancer deaths by 15%. The longer participants took aspirin, the greater the benefit. Taking aspirin for three or more years reduced cancer risk by 25% in women and 23% in men. Taking aspirin five years or more reduced cancer death risk by 37% (Rothwell 2012).
Harvard epidemiologist Michelle Holmes reported regular aspirin use associated with significantly lower risk of breast cancer recurrence and death. This prospective observational study used data from 4,164 women diagnosed with breast cancer between 1976 and 2002. Women who reported taking aspirin two to five times a week had a 64% lower risk of dying and women taking aspirin 6 to 7 days a week had a 71% lower risk compared to those not taking aspirin. Taking aspirin two to five times a week reduced risk of metastasis by 60%. Taking aspirin six to seven times a week reduced risk by 43% (Holmes 2010).
The Iowa Women’s Health Study reported a similar 47% reduction in risk of breast-cancer death for women with breast cancer using aspirin compared to nonusers (Blair 2007). Oddly, the Life After Cancer Epidemiology (LACE) cohort reported no association with aspirin use and cancer recurrence, but a 44% lower recurrence for current NSAID intake (Kwan 2007). A New York based cohort reported a non-significant 18% reduction between pre-diagnostic aspirin use with breast cancer death (Li 2012). Harvard reported recently that there was no benefit from aspirin use in breast cancer recurrence in a cohort of 27,426 Swedish women (Holmes 2014). No definitive explanation has been given for this range of results.
A 2012 study reported that aspirin use reduced risk of death from prostate cancer among men who had been treated via radiotherapy and prostatectomy. In this study, 193 of 5,995 men treated died of prostate cancer, and aspirin use was associated with 57% lower prostate cancer specific mortality (Choe 2012).
In over 900 patients with colorectal cancer, taking aspirin improved survival in patients with tumors containing a PIK3CA gene mutation. Five-year survival for those taking aspirin was 97% compared to 74% for those not taking aspirin, reducing cancer related death by 82% (Liao 2012). This mutation may be present in about 17% of colorectal cancers (Palomba 2012).
While not all papers are positive, they still provide a strong argument for breast or prostate cancer patients to start taking aspirin and for colon cancer patients to either take aspirin or to be tested for this PIK3CA gene. Mechanisms for the possible role of aspirin in cancer prevention include anti-inflammatory effects via COX-1/ COX-2 inhibition (Barron 2014), and modification of the tumour microenvironment via antiplatelet effects (Su 2014). Aspirin may also possess anti-metastatic effects; in a recent cohort study, prediagnostic aspirin use was protective against lymph node positive breast cancer RR 0.89; 95% CI 0.81-0.97 (Barron 2014).
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StatinsOver the last few years, statins have been promoted as useful for cancer, in particular breast cancer, but more recently this idea has been discredited.
In November 2012 and then in April 2013, two studies were published suggesting statin use had a significant effect on cancer. The first was a report that people in Denmark who took statins had a 15% lower risk of dying from cancer (Nielsen 2012). The second report showed that statin use was associated with a 66% reduction in the risk of dying from breast cancer. Murtola had examined statin use and breast cancer mortality among all 31,114 women diagnosed with breast cancer in Finland between 1995-2003. Breast cancer death rate among statin users was 7.5% while among non-statin users it was 21%. Women with localized disease who took statins were 67% less likely to die than nonusers. Among those with metastatic disease, statin use was associated with a 48% decreased risk of death (Murtola 2013).
Other in vitro and animal experiments published about the same time, reported statins increased breast cancer apoptosis (Koyuturk 2006), prevented carcinogenesis (Kubatka 2011), and inhibited tumor growth (Campbell 2006), including growth of triple negative breast cancer cells (Park 2013).
These data looked promising but since then, larger trials have not confirmed benefit, so the idea has lost momentum.
A meta-analysis combined 24 studies involving more than 2.4 million participants, including 76,759 breast cancer cases and found no significant benefit (Undela 2012).
Another paper analyzed data drawn from 22 randomized, controlled trials which included a total of 66,582 patients receiving statin therapy for LDL lowering and 66,604 receiving placebo for five years. Five years of statin therapy had no effect on the risk of cancer-related death (RR 1.00, 95% CI 0.93–1.08) (Emberson 2012).
Another study, compared 565 breast cancer cases with 2,260 controls and found no significant differences in breast cancer risk between women who took statins and those who did not (Chan 2014).
A German study following a group of 6,213 breast cancer patients actually (Nickels 2013) found a trend in statin users toward increased risk of non-breast cancer mortality (HR 1.49, 95% CI 0.88-2.52) and increased overall mortality (HR 1.21, 95% CI 0.87-1.69). No effect was seen on breast cancer mortality (Nickels 2013).
Another study using data from the Women’s Health Initiative, including 154,587 women with 7,430 confirmed breast cancer cases, reported no relationship between statins and breast cancer, with a similar rate (0.42%) of breast cancer among users and controls (Desai 2013).
While we may wish some of the early results to hold true, a broad review by Santa-Maria et al recently concluded that to date there is not a “strong relationship between statin use and reduced breast cancer incidence” (Santa-Maria 2013). Bonovas writing in March 2014 concludes that “As of today, the accumulated epidemiological evidence does not support the hypothesis that statin use affects the risk of developing breast cancer when taken at low doses for managing hypercholesterolemia. However, current evidence cannot exclude an increased risk of breast cancer with statin use in subsets of individuals, for example, the elderly” (Bonovas 2014).
This increased risk just mentioned was observed in a case-control study of women in the Seattle-Puget Sound area in which women who used statins for 10 plus years had nearly double the risk of breast cancer compared to women who had never used statins (McDougall 2013).
The initial data from the Nielsen and Murtola studies were exciting, but as time passes we must hesitate to believe their results. If true, we should be prescribing statins to women as breast cancer treatment. Yet, if the Puget Sound results are true, we should tell women to stop taking statins.
β-BlockersFive years ago, Paul Fitzgerald hypothesized that norepinephrine (NE) was an etiologic factor in some cancers (Fitzgerald 2009). A year later he asked whether drugs such as β-blockers, which interfere with NE signaling, could block cancer (Fitzgerald 2010). Recent evidence suggests that he is correct; β-blocker use is associated with lower recurrence, progression, and mortality from breast cancer and melanoma (Fitzgerald 2012).
In an analysis of 466 breast cancer patients, use of β-blockers was associated with a 57% reduced risk of metastasis and a 71% reduction in breast cancer mortality after 10 years (Powe 2010).
In data from 1,779 women who were part of the LACE cohort, β-blocker use was associated with non-significantly lower hazard of recurrence and cause-specific mortality (Ganz 2011).
Women who took propranolol in the year prior to their breast cancer diagnosis were significantly less likely to present with T4 tumors (OR 0.24, 95%CI 0.07 to 0.85) or with advanced N2/N3/M1 disease (OR 0.20, 95% CI 0.04 to 0.88) compared with matched nonusers. While propranolol use was significantly associated with lower breast cancer-specific mortality, no benefit was seen in women using atenolol (Barron 2011).
In another study of triple negative breast cancer (TNBC), β-blocker use associated with a 70% reduction in disease relapse, although there was no impact on overall survival (Melhem-Bertrandt 2011).
A 2012 study reported that aspirin use reduced risk of death from prostate cancer among men who had been treated via
radiotherapy and prostatectomy.
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In a group of 800 women treated for early TNBC, at five years after diagnosis, 14% of the women taking β-blockers relapsed compared to nearly 28% of the women not taking β-blockers. When the statisticians were done with the data, adjusting for all the other factors that might have influenced these patients’ outcomes, the results were even better. Using β-blockers reduced risk of metastasis by 68% and risk of dying by 58% (Botteri 2013).
There is also a strong association between β-blocker use and reduced risk of death from malignant melanoma. For almost five years, 4,179 Danish patients diagnosed with malignant melanoma were followed. Those who received β-blockers were on average older and sicker, yet their risk of dying from melanoma was 15% lower and dying from any cause 19% lower than for non-users (Lemeshow 2011).
β-blocker use is also associated with reduced progression in thick malignant melanoma, (greater than 1 mm in depth). Patients with thick melanoma who had taken β-blockers for one or more years had a 36% reduced risk of progression. No deaths occurred among the 30 β-blocker treated patients while 24 the 91 untreated patients died (De Giorgi 2011).
Stress encourages ovarian cancer progression through activation of the Src pathway and it has been demonstrated that depression, Src activation and survival times of women with ovarian cancer may be correlated. As final proof of principle, the authors used patient data from the FDA’s Adverse Event Reporting System to show use of β-blockers, which block Src activation, reduced death rates of people with cancer. Use of β-blockers reduced death by 17%, with a 14.6% decrease in mortality in patients with ovarian or cervical cancer (Guillermo 2013).
Not all data are consistent; a Danish study from June 2014 found no benefit using β-blockers or other blood pressure reducing drugs in breast cancer. These drugs made things worse. In data from 18,733 women diagnosed with non-metastatic breast cancer, researchers had compared 10-year-recurrence rate with use of β-blockers, ACE inhibitors, and angiotensin receptor blockers. In the raw data, use of any β-blocker was associated with a 9% reduction in recurrence but when the data was analyzed taking into account other risk factors, β-blocker use actually appeared to increase risk by about 30% (adjusted HR 1.3, 95% CI 1.1 to 1.5). Two particular β-blocking drugs, metoprolol and sotalol actually increased recurrence rates by 50% and 100% (Sørensen 2013).
Perhaps we have not been asking the right questions in these studies. In August 2013 scientists at MD Anderson pointed out that, “… all published studies so far are retrospective and most do not take into account the specific β-blocker used or address which is most likely to benefit cancer patients. The published epidemiological studies are correlative and have not examined the adrenergic receptor status of the tumors” (Nagaraja 2013). Thus perhaps only specific β-blocker drugs will provide benefit in tumors that express the right β-receptors or β-receptor subtype. It may matter which specific drugs are used.
Benefit may also vary according to when the drugs were used. Two recent papers suggest these drugs do not help when used after treatment. Recently, post-diagnostic β-blocker use was identified in 25% of 1,184 prostate cancer-specific deaths and 26% of 3,531 matched controls providing no evidence that these drugs reduced cancer specific death in users (Cardwell 2014). The same researcher a year earlier, found no benefit from β-blockers in breast cancer. Just under 19% of 1,435 women who died of breast cancer were using β-blockers after diagnosis while just over 19% of 5,697 matched controls who died were not, suggesting very little evidence of an association (Cardwell 2013).
Few of us are enthusiastic to prescribe β-blockers. What is important about these studies is that they affirm our intuitive belief that stress reduction will aid cancer patients. In addition to their effects on blood pressure, β-adrenergic blockers exert anxiolytic effects; in fact, atenolol and propranolol are used in the treatment of anxiety and post traumatic stress disorder (Emilien 1998, Shahzad 2014, Vaiva 2003). Thus, it is possible that β-blockers may exert beneficial effects on risk of relapse and/ or mortality via modulation of epinephrine/ norepinephrine activity as part of the stress response. In addition, these studies may provide a rough estimate of the magnitude of effect that stress reduction might have.
Another type of blood pressure medication is of recent interest in cancer treatment, the angiotensin inhibitors. In animal models of breast and prostate cancer the angiotensin inhibitor losartan improved the delivery of chemotherapy drugs and oxygen throughout tumors by increasing blood flow; combining losartan with standard chemotherapy drugs delayed the growth of tumors and extended survival. A clinical trial using losartan during treatment of pancreatic cancer is underway (ClinicalTrials.gov Identifier: NCT01821729). Efforts that increase promote vasodilation and increase blood flow to the tumor during chemotherapy, including stress reduction, relaxation, and specific pharmacotherapy, may in fact be worth the effort (Chauhan 2013).
ConclusionWhile our readers will want a clear bottom line, conclusions remain indistinct. The statins have the weakest supporting evidence. Metformin has perhaps the strongest argument in favor, followed by aspirin. Both are relatively safe to use and, though probably wishful thinking, this writer takes comfort in their association with chemicals of natural origin. The blood pressure lowering drugs, while intriguing, feel more removed from the typical naturopathic scope of practice and remain to this reviewer more an argument for stress reduction than a call for a prescription.
Kaplan-Meier estimates of survival outcomes. The three groups are: ovarian cancer patients with type II diabetes taking metformin (n=16); ovarian cancer patients without type II diabetes (n=297); and ovarian cancer patients with type II diabetes not taking metformin(n=28). P values are from the log-rank test. (A) Progression-free survival; (B) overall survival. ■
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ReferencesBailey CJ, Day C: Metformin: its botanical background. Pract Diab Int 2004, 21:115-117.
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Barron TI, Flahavan EM, Sharp L, Bennett K, Visvanathan K. Recent Prediagnostic Aspirin Use, Lymph Node Involvement, and 5-Year Mortality in Women with Stage I-III Breast Cancer: A Nationwide Population-Based Cohort Study. Cancer Res. 2014 Aug 1;74(15):4065-77.
Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000 Sep;23(9):1227-31.
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Blair CK, Sweeney C, Anderson KE, Folsom AR: NSAID use and survival after breast cancer diagnosis in post-menopausal women. Breast Cancer Res Treat 2007, 101(2):191–197.
Bonovas S, Lytras T, Sitaras NM. Statin use and breast cancer: do we need more evidence and what should this be? Expert Opin Drug Saf. 2014 Mar;13(3):271-5.
Botteri E, Munzone E, Rotmensz N, Cipolla C, De Giorgi V, Santillo B, Zanelotti A, Adamoli L, Colleoni M, Viale G, Goldhirsch A, Gandini S. Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women. Breast Cancer Res Treat. 2013 Aug;140(3):567-75.
Bowker SL1, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who usesulfonylureas or insulin. Diabetes Care. 2006 Feb;29(2):254-8.
Campbell MJ, Esserman LJ, Zhou Y, Shoemaker M, Lobo M, Borman E, Baehner F, Kumar AS, et al. Breast cancer growth prevention by statins. Cancer Res. 2006 Sep 1;66(17):8707-14.
Cardwell CR, Coleman HG, Murray LJ, Entschladen F, Powe DG. Beta-blocker usage and breast cancer survival: a nested case-control study within a UK Clinical Practice Research Datalink cohort. Int J Epidemiol. 2013 Dec;42(6):1852-61.
Cardwell CR, Coleman HG, Murray LJ, O’Sullivan JM, Powe DG. Beta-blocker usage and prostate cancer survival: A nested case-control study in the UK Clinical Practice Research Datalink cohort. Cancer Epidemiol. 2014 Jun;38(3):279-85.
Chan TF, Wu CH, Lin CL, Yang CY. Statin use and the risk of breast cancer: a population-based case-control study. Expert Opin Drug Saf. 2014 Mar;13(3):287-93.
Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, Popović Z, Huang P, Bawendi MG, Boucher Y, Jain RK. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun. 2013;4:2516.
Choe KS, Cowan JE, Chan JM, Carroll PR, D’Amico AV, Liauw SL. Aspirin use and the risk of prostate cancer mortality in men treated with prostatectomy or radiotherapy. J Clin Oncol. 2012 Oct 1;30(28):3540-4.
de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial.BMJ. 2010 May 20;340:c2181.
Desai P, Chlebowski R, Cauley JA, Manson JE, Wu C, Martin LW, Jay A, et al. Prospective analysis of association between statin use and breast cancer risk in the women’s health initiative. Cancer Epidemiol Biomarkers Prev. 2013 Oct;22(10):1868-76.
Diamanti-Kandarakis E, Economou F, Palimeri S, Christakou C: Metformin in polycystic ovary syndrome. Ann N Y Acad Sci 2010 1205:192-198.
De Giorgi V, Grazzini M, Gandini S, et al. Treatment with β-blockers and reduced disease progression in patients with thick melanoma. Arch Intern Med. 2011;171(8):779–781.
Emberson JR, Kearney PM, Blackwell L, et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One 2012;7:e29849-e29849
Emilien G, Maloteaux JM. Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists. Eur J Clin Pharmacol. 1998 Feb;53(6):389-404.
Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;330:1304–5.
Fitzgerald PJ. Is norepinephrine an etiological factor in some types of cancer? Int J Cancer. 2009;124(2):257–263.
Fitzgerald PJ. Testing whether drugs that weaken norepinephrine signaling prevent or treat various types of cancer. Clin Epidemiol.2010;2:1–3.
Fitzgerald PJ. Beta blockers, norepinephrine, and cancer: an epidemiological viewpoint.Clin Epidemiol. 2012;4:151-6.
Ganz PA, Habel LA, Weltzien EK, Caan BJ, Cole SW. Examining the influence of beta blockers and ACE inhibitors on the risk for breast cancer recurrence: results from the LACE cohort. Breast Cancer Res Treat. 2011;129(2):549–556.
Guillermo A-P, Allen JK, Cruz A, et al. Src activation by b-adrenoreceptors is a key switch for tumour metastasis. Nat Commun. 2013;4:1403.
Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE. Aspirin intake and survival after breast cancer. J Clin Oncol. 2010 Mar 20;28(9):1467-72.
Holmes MD, Olsson H, Pawitan Y, Holm J, Lundholm C, Andersson TM, Adami HO, Askling J, Smedby KE. Aspirin intake and breast cancer survival - a nation-wide study using prospectively recorded data in Sweden. BMC Cancer. 2014 Jun 2;14(1):391
Kaiser J. Will an Aspirin a Day Keep Cancer Away? Science 21 September 2012: 1471-1473.
Ko EM, Walter P, Jackson A, Clark L, Franasiak J, Bolac C, Havrilesky LJ, Secord AA, Moore DT, Gehrig PA, Bae-Jump V. Metformin is associated with improved survival in endometrial cancer. Gynecol Oncol. 2014 Feb;132(2):438-42.
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The Journal of IHP – Continuing Education
Koyuturk M, Ersoz M, Altiok N. Simvastatin induces apoptosis in human breast cancer cells: p53 and estrogen receptor independent pathway requiring signalling through JNK. Cancer Lett. 2007 Jun 8;250(2):220-8.
Kubatka P, Zihlavniková K, Kajo K, Péc M, Stollárová N, Bojková B, Kassayová M, Orendás P. Antineoplastic effects of simvastatin in experimental breast cancer. Klin Onkol. 2011;24(1):41-5.
Kwan ML, Habel LA, Slattery ML, Caan B: NSAIDs and breast cancer recurrence in a prospective cohort study. Cancer Causes Control 2007, 18(6):613–620.
Lemeshow S, Sorensen HT, Phillips G, et al. β-Blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol Biomarkers Prev. 2011;20(10):2273–2279.
Li Y, Brasky TM, Nie J, Ambrosone CB, McCann SE, Shields PG, Trevisan M, Edge SB, Freudenheim JL: Use of nonsteroidal anti-inflammatory drugs and survival following breast cancer diagnosis. Cancer Epidemiol Biomarkers Prev 2012, 21(1):239– 242.
Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, Imamura Y, Qian ZR, Baba Y, Shima K, Sun R, Nosho K, Meyerhardt JA, Giovannucci E, Fuchs CS, Chan AT, Ogino S. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012 Oct 25;367(17):1596-606.
Libby G1, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009 Sep;32(9):1620-5.
McDougall JA, Malone KE, Daling JR, Cushing-Haugen KL, Porter PL, Li CI. Long-term statin use and risk of ductal and lobular breast canceramong women 55 to 74 years of age. Cancer Epidemiol Biomarkers Prev. 2013 Sep;22(9):1529-37.
Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol. 2011;29(19):2645–2652.
Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E. Statins and Breast Cancer mortality. Annual Meeting April 7, 2013. American Association for Cancer Research
Nagaraja AS, Sadaoui NC, Lutgendorf SK, Ramondetta LM, Sood AK. β-blockers: a new role in cancer chemotherapy? Expert Opin Investig Drugs. 2013 Aug 7.
Nickels S, Vrieling A, Seibold P, Heinz J, Obi N, Flesch-Janys D, Chang-Claude. Mortality and recurrence risk in relation to the use of lipid-lowering drugs in a prospective breast cancer patient cohort. J.PLoS One. 2013 Sep 25;8(9):e75088.
Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012 Nov 8;367(19):1792-802.
Palomba G, Colombino M, Contu A, Massidda B, Baldino G, Pazzola A, Ionta M, Capelli F, Trova V, Sedda T, Sanna G, Tanda F, Budroni M. Prevalence of KRAS, BRAF, and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia. J Transl Med. 2012 Aug 29;10:178.
Park YH, Jung HH, Ahn JS, Im YH. Statin induces inhibition of triple negative breast cancer (TNBC) cells via PI3K pathway. Biochem Biophys Res Commun. 2013 Sep 20;439(2):275-9.
Powe DG, Voss MJ, Zanker KS, et al. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget. 2010;1(7):628–638.
Quinn BJ, Kitagawa H, Memmott RM, Gills JJ, Dennis PA. Repositioning metformin for cancer prevention and treatment. Trends Endocrinol Metab. 2013 Sep;24(9):469-80.
Rieken M, Xylinas E, Kluth L, Crivelli JJ, Chrystal J, Faison T, Lotan Y, Karakiewicz PI,Fajkovic H, Babjuk M, Kautzky-Willer A, Bachmann A, Scherr DS, Shariat SF. Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer. BJU Int. 2013 Dec;112(8):1105-12.
Romero IL, McCormick A, McEwen KA, Park S, Karrison T, Yamada SD, Pannain S, Lengyel E. Relationship of type II diabetes and metformin use to ovarian cancerprogression, survival, and chemosensitivity. Obstet Gynecol. 2012 Jan;119(1):61-7.
Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011 Jan 1;377(9759):31-41.
Rothwell PM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, Tognoni G, Lee R, Belch JF, Wilson M, Mehta Z, Meade TW. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. 2012 Apr 28;379(9826):1602-12.
Santa-Maria CA, Stearns V. Statins and Breast Cancer: Future Directions in Chemoprevention. Curr Breast Cancer Rep. 2013 Sep 1;5(3):161-169.
Shahzad N, Ahmad J, Khan W, Al-Ghamdi SS, Ain MR, Ibrahim IA, Akhtar M, Khanam R. Interactions of atenolol with alprazolam/escitalopram on anxiety, depression and oxidative stress. Pharmacol Biochem Behav. 2014 Feb;117:79-84.
Sørensen GV, Ganz PA, Cole SW, Pedersen LA, Sørensen HT, Cronin-Fenton DP, Garne JP, et al. Use of β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and risk of breast cancer recurrence: a Danish nationwide prospective cohort study. J Clin Oncol. 2013 Jun 20;31(18):2265-72.
Su BB, Chen JH, Shi H, Chen QQ, Wan J. Med Hypotheses. 2014 Aug;83(2):148-50.
Undela K, Srikanth V, Bansal D. Statin use and risk of breast cancer: a meta-analysis of observational studies. Breast Cancer Res Treat. 2012 Aug;135(1):261-9.
Vaiva G, Ducrocq F, Jezequel K, Averland B, Lestavel P, Brunet A, Marmar CR.Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol Psychiatry. 2003 Nov 1;54(9):947-9. Erratum in: Biol Psychiatry. 2003 Dec 15;54(12):1471.
Wang Z, Lai ST, Xie L, Zhao JD, Ma NY, Zhu J, Ren ZG, Jiang GL. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2014 Apr 18. pii: S0168-8227(14)00190-9.
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1. Prescription medications that have been studied for off-label use for their anticancer effects include:
a) metforminb) ACE inhibitorsc) beta blockersd) a and c only
2. Which of the following is true about the first study documenting decreased risk of developing cancer among patients receiving metformin?
a) the study was conducted by Josie Evansb) the study showed a 50% decreased risk of cancer after 10 years of metformin usec) the study showed strongest effects on breast cancer chemopreventiond) none of the above
3. In another study, insulin use was associated with increased risk of cancer related mortality. The effect size was:
a) 20% increaseb) 50% increasec) 68% increased) 90% increase
4. According to the paper, metformin has been studies for which of the following cancers?
a) lung cancerb) ovarian cancerc) lymphomasd) all of the above
5. Most of the research to date on metformin relates to use by patients who have diabetes. It remains to be seen whether the same chemopreventive effects will hold true among non-diabetic patients.
a) trueb) false
6. Which of the following is true about the effects of aspirin on cancer development and progression?
a) aspirin may have anti-platelet effect that favourably modify the tumour microenvironmentb) aspirin may have anti-inflammatory effects via COX-1 and COX-2 inhibitionc) aspirin may have anti-metastatic effectsd) all of the above
7. In November 2012 and then in April 2013, two studies were published suggesting statin use had a significant effect on cancer, however since then the evidence has been disappointing, with a meta-analysis of 22 studies showing that statin use for LDL-lowering had no significant effect on cancer risk.
a) trueb) false
8. Recently, as case control study of women living in the Puget Sound area showed that 10 year statin use was associated with double the risk of breast cancer, raising some concern about the real effects of statins.
a) trueb) false
9. Beta blocker use has been associated with reduced risk of several cancer types, including which of the following?
a) melanomab) invasive bladder cancerc) multiple myelomad) all of the above
10. A proposed mechanism of action for the effect of beta blockers on cancer is modulation of the stress response and the epinephrine/ norepinephrine system.
Size of Practice (# of Doctors): ❒ 0-5 ❒ 5-10 ❒ 10 & up Years of Practice: ❒ 0-5 ❒ 5-10 ❒ 10 & up
Questions
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GREENS+ ORIGINAL Greens + by Genuine Health is a nourishing superfood blend containing 23 plant-based ingredients such as lecithin, spirulina, barley grass, wheat grass, chlorella, eight strains of probiotics, and herbs such as Siberian ginseng and milk thistle to help support key areas such as stress management and liver function. As such, Greens+ is an ideal product for improving energy and vitality, balance pH, and providing antioxidants to support good health. Greens+ formula has been the subject of extensive research, investigating its effect on a variety of endpoints including in vivo antioxidant capacity, pH and alkalinity, energy, osteoporosis, and cancer cell growth (Boon 2004, Rao 2008, Rao 2011). Research at the University of Toronto has shown that greens+ demonstrates potent antioxidant and cell protective effects in vitro and in vivo (Guthrie 2011, International Journal of Molecular Science, Rao 2011). The greens+ formula was found to contain key phytonutrients such as quercetin, apigenin, kaempferol, and luteolin. The formula was able to inhibit lipid peroxidation, which may present a role in chronic diseases including cardiovascular, neurological, and psychiatric illness. In a human clinical trial, subjects supplemented with greens+ for one month experienced significant increases in their in vivo antioxidant capacity, a reduction in oxidative cellular damage to fats and proteins, and an increase in the key antioxidant enzyme, glutathione peroxidase (Rao 2011). This study underscores the bioavailability of nutrients in this formula as well as its therapeutic effect in the human body. Interestingly, the ingredient lecithin may account for up to 12-15% of the total antioxidant capacity of the greens+ formula. A randomized, double blind, placebo controlled trial conducted in over 100 subjects at the University of Toronto found that supplementation with greens+ was effective in increasing energy and vitality, with significant improvements compared to placebo (p=0.018) (Boon 2004). There were also trends toward improved mental health, well-being and overall health associated with use of greens+. The greens+ formula has been demonstrated to influence bone metabolism (Rao 2008). In an in vitro study, exposure of osteoblast-like cells, SaOS-2 cells, to various concentrations of total free polyphenolic from greens+ extracts resulted in increased osteoblast number, and stimulated mineralized bone nodule formation (Rao 2008). These results indicate that greens+ may promote maturation of osetoprogenitors and exert beneficial effects on bone formation. Authors states, “we speculate that it may be a good alternative to drugs for the prevention of osteoporosis” (Rao 2008). A second mechanism of its effect on bone is modulation of the Potential Renal Acid Load (PRAL); PRAL analysis evaluates an agent’s potential for promoting acid or alkaline formation in vivo. In general, foods such as fruits and vegetables are alkaline forming, while meats and grains are acid forming. With chronic over-consumption of “acidic” foods, calcium is released from bone to buffer the acid produced (Remer 2011, Shi 2012) . Greens+ has been shown to promote an alkaline state, and may offsetting the negative effects of meat and grain
consumption by reducing calcium release and helping preserve bone mass. Finally, greens+ also contains eight strains of Lactobacillus and Bifidobacertium probiotic species to ensure healthy digestion and immune function. These species have been shown to improve irritable bowel syndrome, reduce upper respiratory tract infections, and may have a role in maintaining healthy immune tolerance (Rerksuppaphol 2012, Yoon 2014). Greens+ is one of the most thoroughly research nutraceutical blends of its kind, with confirmed benefits on several important areas of health demonstrated by laboratory studies and human clinical research. Recommended use: To increase your energy and well-being. Adult dosage: Mix 3 tsp (8.5g) in 1 cup (250mL) of pure water or juice. Shake well. If you are a new user of greens+, begin with 1 tsp daily and gradually increase to 3 tsp daily over a 3 week period. Do not take on empty stomach. Consult a health care practitioner for use beyond 3 months. Caution: Not to be taken by children, during pregnancy, while breastfeeding, by those on medication or with chronic health problems unless under the recommendation of a health care practitioner. Consult a health care practitioner prior to use if you have nausea, fever, vomiting, bloody diarrhea or severe abdominal pain. Do not use if you have gastrointestinal blockage or an immune-compromised condition (e.g. AIDS, lymphoma, patients undergoing long-term corticosteroid treatment). Discontinue use and consult a health care practitioner if symptoms of digestive upset occur, persist or worsen beyond 3 days. Use with caution if allergic to bee products. Keep refrigerated after opening. References Boon H, Clitheroe J, Forte T. Effects of greens+: a randomized, controlled trial. Can J Diet Pract Res. 2004 Summer;65(2):66-71. Rao LG, Balachandran B, Rao AV. Polyphenol extract of Greens+™ nutritional supplement stimulates bone formation in cultures of human osteoblast-like SaOS-2 cells. J Diet Suppl. 2008;5(3):264-82. Rao V, Balachandran B, Shen H, Logan A, Rao L. In vitro and in vivo antioxidant properties of the plant-based supplement greens+™. Int J Mol Sci. 2011;12(8):4896-908. Remer T, Manz F, Alexy U, Schoenau E, Wudy SA, Shi L. Long-term high urinary potential renal acid load and low nitrogen excretion predict reduced diaphyseal bone mass and bone size in children. J Clin Endocrinol Metab. 2011 Sep;96(9):2861-8. Rerksuppaphol S, Rerksuppaphol L. Randomized controlled trial of probiotics to reduce common cold in schoolchildren. Pediatr Int. 2012 Oct;54(5):682-7. Shi L, Libuda L, Schönau E, Frassetto L, Remer T. Long term higher urinary calcium excretion within the normal physiologic range predicts impaired bone status of the proximal radius in healthy children with higher potential renal acid load. Bone. 2012 May;50(5):1026-31. Vaghef-Mehrabany E, Alipour B, Homayouni-Rad A, Sharif SK, Asghari-Jafarabadi M, Zavvari S. Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis. Nutrition. 2014 Apr;30(4):430-5. Yoon JS, Sohn W, Lee OY, Lee SP, Lee KN, Jun DW, Lee HL, Yoon BC, Choi HS, Chung WS, Seo JG. Effect of multispecies probiotics on irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Gastroenterol Hepatol. 2014 Jan;29(1):52-9.
Greens+ Formula Ingredients per 8.5g Dose Unit Lecithin (97% oil free; soybean; 26% phosphatidylcholine)
Shiitake is a medicinal mushroom that helps regulate and support healthy immune function in conditions varying from bacterial infections to certain cancers. Shiitake may also be used to support the cardiovascular system by regulating homocysteine and cholesterol levels.
IMMUNE BENEFITSIn a study exploring the antibacterial effect of a bioprocessed polysaccharide (BPP) isolated from Lentinus edodes against murine salmonellosis, BPP did not demonstrate bactericidal properties in vitro, but did stimulate the uptake of the bacteria into RAW 264.7 murine macrophage cells. This was demonstrated by an increase in colony-forming unit counts of the contents of the macrophages incubated with salmonella.[1] These results suggest that the activity of BPP functions by improving Th1 immunity by activating macrophages to help fight bacterial infection.[1]
In a human clinical trial, researchers explored the use of oral administration of the active substance (1-6,1-3)-beta-glucan (Lentinex) from Lentinus edodes in healthy elderly patients.[2] In the double-blind, crossover, placebo-controlled trial, 42 subjects were allocated to either control or treatment group receiving 2.5 mg/d Lentinex or placebo for 6 weeks.[2] After a washout period of 4 weeks, groups were reversed. There was no difference noted between placebo and treatment group in the safety blood variables, which included CBC, liver, and kidney function.[2] The treatment groups given Lentinex had a significant increase in the number of circulating B-cells compared to control.[2]
In a study of the specific polysaccharide L-II isolated and purified from the fruiting body of Lentinus edodes and its effects on the cellular immune response of sarcoma 180–bearing mice,[3] researchers included four study arms and administered the mice one of three doses of the polysaccharide L-II (1, 5, and 10 mg/kgbw), or control, for 10 days.[3] Tumor weight, relative thymus and spleen weight, phagocytosis, and macrophage proliferation were studied.[3] In all three treatment groups, a significant increase in spleen and thymus weight were noted, as well as a significant increase in phagocytosis and macrophage activity and a decrease in tumor formation.[3] The control group saw an increase in the concentration of both TNF-alpha and IFN-gamma, which was not observed in the treatment groups.[3] Researchers concluded that the antitumor activity of the polysaccharide L-II on mice transplanted sarcoma 180 was mediated by immunomodulation inducing both the macrophage and T-cell–dependent immune responses.[3]
HOMOCYSTEINE AND CARDIOVASCULAR HEALTHElevated homocysteine has been associated with neuronal degenerative diseases and cardiovascular concerns.[4] In a study exploring the effect of Lentinus edodes on hyperhomocysteinemia, hyperhomocysteinemia was induced in mice by the administration of a folate- and vitamin B12–deficient diet (DFV).[4] Mice were spilt into five groups and received either 5, 10 or 20% L-edodes flour or eritadine (10 mg/kg) or DFV (control group) for two weeks.[4] The DFV group experienced a significant increase in homocysteine.[4] The increased homocysteine serum levels were reduced in all the treatment groups in a dose-dependent manner.[4] The mRNA expression of DNA methyl transferases DNMT1 and DNMT3a were both reduced in the DFV group, but those levels were recovered in all four treatment groups.[4] The results of this study suggest that L. edodes components including eritenine may have beneficial effects on hyperhomocysteniemia by regulating DNA methylation-related genes in mice.[4]
Eritenine has also been shown to reduce cholesterol levels.[5] In a mouse study exploring this effect, researchers divided mice into six groups.[5] One group was fed a normal diet, second group was fed a high-fat diet, and the third group a high-fat diet with eritadenine (10 mg/kgbw) and the other three groups a high-fat diet with 5, 10 or 20% L. edodes for four weeks.[5] Mice across all groups had similar weight gain.[5] Levels of total serum cholesterol (T-CHO), low-density lipoprotein (LDL), and triglyceride (TG) were increased in the high-fat diet group compared to the normal controls; high-density lipoprotein (HDL) was unaffected.[5] Mice in the treatment groups of L. edodes had reductions in a dose-dependent manner of the T-CHO, LDL and TG levels.[5] The mRNA expression of cholesterol 7-α-hydroxylase 1 (CYP7A1) was reduced in the hypercholesterolemic mice, but was increased with supplementation of both L. edodes at each dose, and by eritadenine supplementation.[5] It was also observed that the liver tissues showed reduced lipid accumulation in all
four treatment groups, and there was suppression of atherosclerotic plaque development due to the high-fat diet in the four treatment groups as well.[5] Results of this study indicate that a high-fat diet may increase serum T-CHO, LDL, and TG levels by inhibiting the livers expression of CYP7A1, and that L. edodes may help regulate lipid metabolism by regulating the expression of this gene in the liver.[5]
SHIITAKE AND CHEMOTHERAPYIn a pilot study, researchers explored the safety and efficacy of Lentinula edodes mycelia (LEM) extract in patients undergoing postoperative adjuvant chemotherapy for breast cancer or gastrointestinal cancer.[6] Study participants underwent their first round of chemotherapy with no supportive therapy, and their second round with the concomitant administration of LEM.[6] Researchers monitored adverse events, quality of life (QOL) score, lymphocyte subpopulations, lymphocyte activity, and serum immune indices during the study.[6] During the first course of chemotherapy, no changes in QOL or immune parameters where noted. Following the second course of combined therapy, there were improvements noted in QOL, NK-cell activity, and immune function, with no adverse effects noted.[6] Researchers concluded that a large-scale investigation is important to confirm these results, but that the data suggests the concomitant use of LEM with chemotherapy is safe and improved that immune function and quality of life of patients undergoing chemotherapy.[6]
SHIITAKE AND CANCERResearchers examined the antitumor effect of oral supplementation of LEM extract on mice that had been inoculated subcutaneously with B16 melanoma.[7] Ingestion of LEM extract significantly inhibited tumor growth, which was not observed in the nude mice, suggesting a T-cell–dependent mechanism.[7] Ingestion of the LEM extract led to a significant restoration of H-2Kb-restricted and melanoma reactive T cells in both the spleen and draining lymph nodes of melanoma-bearing mice.[7] Analysis via flow cytometry showed that the percentage of Foxp3+ CD4+ T cells increased in the spleen and draining lymph nodes in the melanoma-bearing mice, but reduced significantly with the LEM extract treatment.[7] Results of this study indicate that oral supplementation of LEM extract restores the immune responses of class i–restricted and melanoma-reactive CD8+ T cells in melanoma-bearing mice likely via mitigation of regulatory T cells–mediated immunosuppression.[7]
In a second study, researchers tested the antitumor effect and mechanism of oral ingestion of LEM following inoculation of murine colon carcinoma colon-26 (C26) cells into the subserosal space of the cecum of mice.[8] The primary site of the immune response in this model is the gut-associated lymphoid tissue (GALT).[8] GALT is known to be a site for immunological tolerance–inducing for several dietary antigens.[8] Supplementation with LEM extract suppressed the growth of i.c. C26 inoculated cells in a T cell–dependent manner and restored the T cell response of the mesenteric lymph nodes and the spleen.[8] Ingestion of LEM showed only a marginal effect on Tregs, but significantly reduced the plasma levels of TGF-beta and IL-6, both of which were increased in the i.c. C26 inoculated mice.[8] Researchers summarized that oral supplementation with LEM extract can restore antitumor T-cell responses of mice, even when the antitumor immune response is initiated in the GALT. This may have relevant implications for the anticancer immunotherapy of human colon cancer.[8]
REFERENCES1. Kim, S.P., et al. “A polysaccharide isolated from the liquid culture of Lentinus edodes (shiitake) mushroom mycelia containing
black rice bran protects mice against Salmonellosis through upregulation of the Th1 immune reaction”. Journal of Agricultural and Food Chemistry Vol. 62, No. 11 (2014): 2384–2391.
2. Gaullier, J.M., et al. “Supplementation with a soluble β-glucan exported from Shiitake medicinal mushroom, Lentinus edodes (Berk.) singer mycelium: a crossover, placebo-controlled study in healthy elderly”. International Journal of Medicinal Mushrooms Vol. 13, No. 4 (2011): 319–326.
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Shiitake SAP is a hot water–extracted medicinal mushroom. Shitake, also known as Lentinula edodes, is an edible mushroom that grows predominantly in Asia. Shiitake is the second most commonly consumed type of mushroom, but it also has several medicinal functions. Shiitake SAP can be used to help support healthy immune function and cardiovascular health, and is an excellent source of antioxidants. Further studies show that shiitake may help support the immune system in the management of various cancers, and may improve quality of life for patients undergoing chemotherapy.
ACTIVE INGREDIENTSEach vegetable capsule contains:
Contains no: Preservatives, artificial flavour or colour, sugar, dairy, starch, wheat, gluten, yeast, soy, corn, citrus, or eggs.
DOSAGEAdults: Take 1 capsule daily with food or as directed by your health-care practitioner.
INDICATION ɶ Shiitake SAP can be used to help support healthy immune
function. ɶ Shiitake SAP is a source of antioxidants. ɶ Shiitake SAP may help lower homocysteine levels and support
healthy cholesterol levels. ɶ Shiitake SAP may help quality of life and immune function for
patients undergoing chemotherapy.
SAFETY AND SIDE EFFECTSThere have been no reported side effects from consumption of shiitake mushroom. Consult a health-care practitioner prior to use if you suffer from an immune system disorder (e.g. Crohn’s disease, myasthenia gravis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, HIV/AIDS, etc.), if you are taking immunosuppressants, or if you have diabetes.
PURITY, CLEANLINESS, AND STABILITYThird-party testing is performed on the finished product to ensure Shiitake SAP is free of heavy metals, volatile organics, and other impurities.
Scientific Advisory Panel (SAP):adding nutraceutical research to achieve optimum health
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