Theracurmin Review - Dr. Michael Murray

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Clinical Application of “Curcumin”, a Multi-Functional Substance predefined dose-limiting toxicity was observed in the first 3 patients, the Phase II clinical trial was continued at a daily dose of 8 g for all 21 patients. No notable adverse events related to concomitant curcumin were reported, and the median compliance was as high as 100% (range: 79%-100%). In all patients, the median survival and one-year survival rate were 161 days (95% confidence interval: 109-223 days) and 19% results considering a dismal prognosis of this disease after getting refractory to gemcitabine, despite the relatively small sample size. curcumin’s low bioavailability still compromised its clinical application. A number of studies have cited extremely low blood curcumin concentrations (Table 1), indicating that curcumin bioavailability needs to be improved to exert significant Table 1 Subject healthy volunteers patients with precancerous lesions patients with colorectal cancer healthy volunteers patients with colorectal cancer healthy volunteers patients with pancreatic cancer Previously reported blood curcumin concentrations Dose of curcumin 2 g/day 8 g/day 3.6 g/day 12 g/day 3.6 g/day 8 g/day 8 g/day Sample size II) New clinical trials using THERACURMIN ® In Japan and abroad, efforts are now being made to improve the bioavailability of curcumin by developing new formulations using various drug delivery systems (liposomes, nanoparticles, and phospholipids) as well as derivatives with higher activity. In one pharmacokinetic study, maximum blood concentration (Cmax) in 6 healthy volunteers after ingestion of THERACURMIN ® at a dose of 150 mg was 189 ± 48 ng/mL (mean ± standard error), which was higher than that observed with conventional curcumin at a daily dose of 8 g. The same 6 subjects also received THERACURMIN ® at a dose of 210 mg after a 2-week period, resulting in a Cmax of 275 ± 67 ng/ mL. These results further demonstrate the markedly improved bioavailability of THERACURMIN ® compared with curcumin and dose-dependently increased blood curcumin concentration up to 210 mg in human 3) . In light of these f indings, THERACURMIN ® is expected to provide more reliable effects with higher blood curcumin concentrations, and a new clinical trial using THERACURMIN ® is now underway to test its 8 2 3 3(1) *1 Blood curcumin concentration detectable in only 1 patient 3 6 5 Plasma curcumin level (mean±SE) 6 ± 5 ng/ml 651 ± 688 ng/ml 4 ± 0.2 ng/ml 57 ng/ml*1 below 1 ng/ml 2300 ± 260 ng/ml 134 ± 70 ng/ml Reference 26 27 28 29 30 31 25 curcumin on arterial stiffness William Osler once stated, “a man is as old as his arteries”. Accordingly, stiffness of the central arteries such as the aorta (arterial stiffness) increases with aging and is an independent risk factor for cardiovascular disease. In the past, little attention was paid to the potential effects of habitual exercise and eating habits on arterial stiffness, because the increase in arterial stiffness was traditionally considered an irrevocable phenomenon of aging. However, since the discovery of the link between habitual aerobic exercise and decreased arterial stiffness, increasing focus has been situated on the importance of exercise in decreasing arterial stiffness. A similar relationship has been identified between diet and arterial stiffness. In this section, we review the relationship between exercise and diet with arterial stiffness, as well as touch on the latest findings regarding the relationship between arterial stiffness and curcumin in particular. I) Exercise and arterial stiffness Arterial stiffness is a risk factor for cardiovascular and cerebrovascular diseases that increases with age. To counter these risks, increased physical activity and habitual exercise in daily life may help prevent or inhibit this stiffness, thereby slowing the development of cardiovascular and cerebrovascular diseases in middle-aged and older people. Indeed, arterial stiffness has been shown to be lower in middle-aged and older people who exercised regularly such as by jogging, walking, or cycling than in those who did not 32) . Similar findings were found in those with high levels of physical activity in their daily lives 33) or in those who took up relatively shortterm aerobic exercise regimens (over 2 to 3 months) 32,34,35) , all findings which support the notion that habitual aerobic aerobic exercise-induced decreases in arterial stiffness have also been noted in both the young and elderly as well as in the obese 32,34-37) . Regarding the mechanism for these effects, we previously reported the involvement of endothelin-1, which is produced by vascular endothelial cells and has a vasoconstrictive effect and a stimulatory effect on vascular smooth muscle proliferation 38) . In middle-aged and older people who received exercise therapy for 3 months, acute administration of an endothelin receptor antagonist decreased arterial stiffness before exercise therapy but had no effect on stiffness after exercise therapy, when both the plasma endothelin-1 concentration and arterial stiffness had already decreased 38) habitual aerobic exercise may decrease arterial stiffness by decreasing the production of or sensitivity to endothelin-1. II) Diet and arterial stiffness Various studies have shown that not only habitual exercise, but also eating habits can decrease arterial stiffness. In one study in obese individuals, diet improvement with calorie restriction over 3 months resulted in a mean weight decrease of approximately 8 kg as well as a decrease in arterial stiffness 39) . In addition, many studies have reported how certain diets may affect arterial stiffness 40) . For example, one demonstrated that salt intake substantially affects arterial stiffness as well as blood pressure 41,42) . A cross-sectional study showed that a decrease in salt intake results in not only a decrease in blood pressure but also in arterial stiffness, independent of blood 48
Clinical Application of “Curcumin”, a Multi-Functional Substance pressure 41) . In a longitudinal study in postmenopausal women with hypertension, arterial stiffness was decreased after 3 months on a low-salt diet 42) . Interestingly, the decrease in stiffness was more pronounced following a change in diet than that achieved with habitual exercise 42) . Besides salt reduction, fish consumption has also been reported to help reduce arterial stiffness, as increased consumption has been associated with decreased arterial stiffness 43) , suggesting that the polyunsaturated fatty acids in fish oil, abundant in blue-skin fish such as mackerel, saury, and sardine, may be involved in decreasing arterial stiffness. In addition, a number of studies have shown a decrease in arterial stiffness due to vitamins (vitamin C and vitamin E), garlic powder, and milkderived lactotripeptides. III) Curcumin and arterial stiffness We recently evaluated the effects of continuous use of curcumin on arterial stiffness. In postmenopausal middleaged and older women, arterial stiffness decreased after use of THERACURMIN ® over a period of two months (unpublished exercise over the same period. These findings suggest that curcumin may be an alternative therapy to decrease arterial stiffness in patients who cannot or will not continue exercise. We also evaluated the effects of combining habitual aerobic exercise and THERACURMIN ® on arterial stiffness, finding that arterial stiffness decreased more markedly with combination therapy than with either alone (unpublished data). 6. Conclusion Japan’s rapidly aging society is experiencing increased social demand for healthy longevity. Meeting this demand via development of new highly functional food-derived substances and medicinal seeds from foods will require organically combining nutritional, pharmaceutical, and medical sciences using new methodologies and technologies. Studies to date have evaluated the interactions between pharmaceutical products and foods or their safety on an individual rather than comprehensive basis. As reviewed in this article, many studies ranging from basic studies to clinical studies have been conducted on curcumin and its clinical applications in treating various diseases. Given its range of effects, curcumin alone may be useful in treating and preventing a number of diseases, but fully establishing its potential will require further studies and clinical application. Acknowledgments We would like to express our deep gratitude to <strong>Dr</strong>s. Koji Hasegawa, Hiroki Sasaki, Yoshihiko Otsuka, and Tadashi Hashimoto, who provided useful comments. This work was supported in part by research grants from the Japan Society for the Promotion of Sciences (JSPS) and the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. IV) To improve arterial stiffness We demonstrated that the arterial stiffness is decreased by curcumin (Fig. 5). Furthermore, we suggest that maximizing the effects of curcumin against arterial stiffness can best be achieved by combining habitual exercise and eating habits. Such a combination of exercise and diet with curcumin may represent a remarkably effective non-pharmacological therapy. The authors declare no financial or other conflicts of interest in the writing of this paper. Fig. 5. Curcumin improves artificial stiffness. 49
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Theracurmin Review - Dr. Michael Murray

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