Nutraceuticals and DMD November 2016 Researchers in Australia have recently published a well referenced, accessible review of the published evidence for the use of supplements or nutraceuticals to help fill the void in treatment options for DMD patients. The publication is accessible here - Nutraceuticals and their potential to treat Duchenne muscular dystrophy: separating the credible from conjecture (Woodman et al, Nutrients, 2016, 8, 713) This is an area of particular interest to Duchenne UK - we are currently funding a project on Soybeans (Haelan) at the University of Sheffield, led by Professor Steve Winder. Read more about that project here. Our Research Director has reviewed the publication and has provided the following summary: One study reports that in the United States up to 80% of caregivers give complementary and alternative medicine alongside conventional treatments so it is vital to understand which of the array of available treatments has been shown to be potentially useful. There is no universally approved definition of a nutraceutical or food supplement but the UK food supplements regulation (2003) offers this definition “A concentrated source of a vitamin, mineral or other substance with a nutritional or physiological effect, alone, or in combination, sold in dose form”. Alternatively, the Canadian definition of a nutraceutical is also a good guide “a compound within a food that can be isolated and puriﬁed and sold that has the potential to beneﬁt health and treat chronic disease”. The authors sound a note of caution in that the supplement industry is not regulated to the same extent as the pharmaceutical industry and manufacturers of supplements do not have to comply to the same quality standards in manufacturing their product. In Europe, the majority of food supplements are covered by food law, but where they have a medicinal effect or make a medicinal claim (i.e. to prevent, treat or cure any disease or medical condition), they must be licensed under medicines legislation, which, in the UK is the responsibility of the MHRA. Medicines law is not harmonised across the EU and what may be freely sold in one EU Member State as a food may be classified as medicinal in another EU Member State. The review focuses on a number of nutraceuticals: Coenzyme Q10 (CoQ10) Melatonin Traditional Chinese medicine Soybeans Curcumin Resveratrol Beetroot juice L-Arginine Vitamin D Green tea Taurine Duchenne UK is currently conducting an experiment on one of the products in the list, Soybeans. Genistein and Bowman Birk Inhibitor (BBI) are both compounds found in soy beans and preliminary studies in mice have shown that they have the potential to modulate the immune response and chronic inflammation in DMD. Duchenne UK is currently funding a project at the University of Sheffield, led by Professor Steve Winder, that is building on these initial studies to look at a range of doses of Genistein and BBI and compare them with the effect of Haelan which is a soy based supplement used by some DMD patients. Results from this project will be available late 2017. Many nutraceuticals are thought to have anti-inflammatory and or anti-oxidant effects and the review focusses on substances that are thought to work in these ways. Oxidative stress is the result of an imbalance between reactive oxygen species and antioxidants in the body, this imbalance results in cell death and tissue degeneration. Nutraceuticals such as Coenzyme Q10, melatonin, traditional Chinese medicine and green tea are thought to have antioxidant properties and so could be useful for treating muscles damaged by oxidative stress, as in DMD. The review concludes that there is evidence that Coenzyme Q10 could be a valuable addition to helping preserve muscle strength and function when used alongside conventional treatments. For melatonin the picture is more mixed. Whilst there was evidence of an anti-oxidant effect in a small study of 10 DMD patients, there was no quantitative measure of effect on muscle function. Additionally, there is no long term safety data available for the use of melatonin in children and adolescents. The reviewers conclude that, until further studies are reported that determine whether melatonin is therapeutically useful for DMD, supplementation is not advised. The section of the review devoted to Chinese herbal supplements is alarming. The reviewers found evidence that many of the imported Chinese herbal supplements could be contaminated with pesticides that are not legal in Western countries, or be contaminated with heavy metals such as lead, mercury, cadmium and thallium. Regular users of Chinese herbal medicines may have an increased risk of developing cancers/diseases of the kidneys and other organs of the urinary tract and heavy metal poisoning. Accordingly, the reviewers recommend that DMD patients do not supplement with Chinese herbal medicines. A double-blind, randomized, placebo-controlled clinical trial is currently ongoing in Germany to assess the effect of green tea extract in 40 patients with DMD. The results are expected in 2018 and so there will soon be robust evidence on which to base advice for the use of green tea extract for patients with DMD. Muscle inflammation is the result of a coordinated process involving many cell types starting within 2 hours of muscle injury. Inflammation, resulting from chronic muscle injury, plays a key role in the pathology of dystrophic muscle in DMD and so compounds with anti-inflammatory properties are potential therapeutic agents. The review considers the evidence for the anti-inflammatory properties of soy beans, curcumin, resveratrol, beetroot juice, L-arginine, taurine and Vitamin D. Genistein and Bowman Birk Inhibitor (BBI) are both compounds found in soy beans and preliminary studies in mice have shown that they have the potential to modulate the immune response and chronic inflammation in DMD. Duchenne UK is currently funding a project at the University of Sheffield, led by Professor Steve Winder, that is building on these initial studies to look at a range of doses of genistein and BBI and compare them with the effect of Haelan which is a soy based supplement used by some DMD patients. Results from this project will be available late 2017. Curcumin has not yet been tested for DMD but is available as a supplement due to its anti-cancer properties. Curcumin is rapidly metabolized in the liver and intestine and high levels of curcumin cannot, currently, be maintained in blood or skeletal muscle. The reviewers conclude that curcumin may be useful for DMD but further studies are needed to evaluate its toxicity, dose and to optimize a delivery method. Resveratrol is found in grapes and has been called the ‘fountain of youth’ as a result of its ability to increase the lifespan of yeast, worms, flies and mice. However, as with curcumin, the bioavailability is very low and more pre-clinical studies are needed to assess whether treatment with resveratrol offers any potential benefit for DMD. An extensive body of pre-clinical and clinical data show that increasing nitric oxide (NO) availability is beneficial for dystrophic muscle. NO attenuates the vasoconstriction that results from exercised skeletal muscle which optimizes blood flow and reduces necrosis and inflammation. Beetroot juice and L-arginine are both supplements that are thought to increase available NO as a result of their sodium nitrate content. Two small clinical studies have been conducted to investigate the effect of a single dose of sodium nitrate (beetroot juice) in patients with Becker muscular dystrophy. It is unclear whether the effect on muscle ischemia observed in these short studies would be sustained in a longer term study with chronic administration. Several pre-clinical studies have reported beneficial effects of L-arginine for DMD. Interestingly, in a small open label clinical study where L-arginine was given in combination with metformin for 16 weeks, the motor function measure and 2 minute walking distance time improved in 4 of the 5 patients with DMD. The research team that carried out this small study have since undertaken a larger placebo controlled study of the effects of a combination of metformin with L-citrulline and it is anticipated that the results will be published in 2017. Duchenne UK is actively involved in the ongoing discussion around the potential therapeutic benefit of L-arginine and L-citrulline for DMD and is currently supporting a pre-clinical project investigating the effects of these drugs singly and in combination. There are some encouraging mouse studies with taurine although the safety profile in humans is quite limited. The reviewers conclude that more research is needed before supplementation can be recommended. Vitamin D is a key dietary component for bone health in all people. Long term corticosteroid use is detrimental to bone health and it is estimated that around 78% of DMD patients are vitamin D deficient. Data from Duchenne Connect, an online patient registry where patients self-report data, revealed that vitamin D supplementation signiﬁcantly increased the probability of walking at age 12. Other long term clinical studies also support the recommendation that patients with DMD should supplement their diet with Vitamin D and calcium to maintain bone health and prevent fracture-associated loss of ambulation.