ACTIVO-I Study Report A Retrospective Prescription Event Monitoring for Safety and Efficacy of Bioactives in the Management of Overweight and Obesity

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1 96 Clinical Study Indian Medical Gazette MARCH 2014 ACTIVO-I Study Report A Retrospective Prescription Event Monitoring for Safety and Efficacy of Bioactives in the Management of Overweight and Obesity Deepak Kharat, Consultant Ashwin Clinic, Pune. Abstract Objective: The study was conducted on the combination of bioactive ingredients [Bioactives; Hoodia Gordonii, Hydroxycitric Acid (the active ingredient in Garcinia cambogia), Green tea extract, Ginger extract and Piperine] to estimate its safety and efficacy in decreasing the body weight (BW), body mass index (BMI) and waist circumference (WC) after treatment. Design and methods: The study was retrospective prescription event monitoring study. Total 99 overweight and obese patients (52 males and 47 females; mean age ± years) were enrolled in the study. Subjects were administered one capsule of Bioactives orally one hour before lunch and dinner daily for 90 days. All subjects were given standard advice regarding healthy food choices in their diet and physical activity. However, subjects were not advised to restrict dietary calorie intake. Clinical examination, BW, BMI and WC were estimated in all subjects at baseline and at the end of 30, 60 and 90 days. Observations: Bioactives was found to be significantly effective in decreasing BW by 4.36%, 7.12 % and 10.25% at 30, 60 and 90 days respectively and these results were statistically significant (p = 0.002, p < and p < respectively). BMI was also reduced with Bioactives by 5.11%, 9.83% and 11.88% at 30, 60 and 90 days respectively and results were statistically significant (p <0.0001, p < and p < respectively). Bioactives was found to be significantly effective in decreasing WC by 3.28%, 5.29% and 7.31% at 30, 60 and 90 days respectively and these results were statistically significant (p = , p < and p < respectively). Bioactives can be rated as good to very good based on results observed on 66% patients. Side effect or adverse event was not reported in any case. Conclusion: Bioactives appears to be significantly effective in decreasing the BW, BMI and WC within 30, 60 and 90 days in overweight and obese patients. Bioactives has excellent tolerability as adverse event was not reported in any case. Keywords bioactives, body weight, body mass index and waist circumference Introduction Obesity is increasingly recognized as public health burden, because it is associated with an increased risk for many diseases, including the metabolic syndrome, viz. hypertension, insulin resistance or type 2 diabetes mellitus, atherosclerosis and coronary heart disease 1. Over the last two decades, numerous strategies, both non-pharmacological and pharmacological, have been developed in order to achieve long-term body-weight reduction and improve risk. Various drugs such as orlistat, sibutramine etc. have been evaluated for their effect on the body weight. Pooled data from clinical trials suggest that people given orlistat in addition to lifestyle modifications, such as diet and exercise, lose body weight significantly than those not taking the drug over the course of a year. Address for correspondence: Dr Deepak Kharat, M.D. (Medicine), F.C.G.P. (ONCO), Consultant, Ashwin Clinic, Survey No. 673/B4, Denalaxmi Housing Society, Bibvewadi, Pune , India. kh_deepak@hotmail.com

2 Indian Medical Gazette MARCH However, orlistat is notorious for its gastrointestinal side effects, which can include steatorrhea (oily, loose stools). A long term study indicate that during the first year of treatment, the proportion of patients experiencing at least one gastrointestinal event with orlistat or placebo was 91% vs. 65%, respectively. Pharmacoepidemiological studies seem to indicate that attrition rates in clinical practice are higher (64% 77%) with orlistat and the major causes of cessation of treatment are high cost and side effects. Orlistat is a potential cause of acute kidney injury 2,3,4,5,6. Sibutramine is an oral anorexiant. Until 2010 it was marketed and prescribed as an adjunct in the treatment of obesity along with diet and exercise. It has been associated with increased cardiovascular events and strokes and has been withdrawn from the market in several countries. Rimonabant has already been withdrawn from the market 7, 8. Role of Bioactives in Management of Overweight and Obesity With an alarming rise in the prevalence of obesity and metabolic syndrome; the use of Bioactives, such as dietary supplements, to promote weight loss has been increasing e.g. Garcinia cambogia, Hoodia Gordonii, green tea, piperine, ginger, etc. In vitro and in vivo studies showed that (-)-hydroxycitric acid (HCA) the principal acid of the Indian fruit Garcinia cambogia decreases body weight gain. Hoodia Gordonii is an edible cactus known for its appetite suppressing property. Epigallocatechin Gallate (EGCG), the most abundant catechin in green tea, has received the most attention as a potential anti-obesogenic agent. Piperine is an active component of black pepper that can effectively suppress lipid peroxidation. Evidence from the animal literature supports the use of ginger as a functional dietary agent for weight management and prevention of metabolic disorders 1, 9,10,11,12. In the current scenario of deficiency of safe antiobesity drugs, the combination of bioactive ingredients (Hoodia Gordonii, Garcinia cambogia, green tea, piperine, and ginger) may be a safe and effective approach to manage overweight and obesity. This retrospective prescription event monitoring study was conducted on the combination of bioactive ingredients to estimate its safety and efficacy in decreasing the body weight (BW), body mass index (BMI) and waist circumference (WC) after treatment. Study design Materials and Methods The study was retrospective prescription event monitoring study. All therapeutic decisions were taken by attending physician. Total 99 overweight and obese patients (52 males and 47 females) were enrolled in the study. Patients were not suffering from any psychological disorders, metabolic syndrome or hypocalcemia. Data of each subject was documented in a prescription event monitoring form. Intervention Subjects were administered one capsule of Bioactives (combination of bioactive ingredients) orally one hour before lunch and dinner daily for 90 days. The duration of observation was 90 days. All adverse events reported or observed during the study were documented by the attending Table 1 The composition of Bioactives Each serving veg. capsule contains: Garcinia Cambogia Extract (Standardized to contain 60 % HCA) Hoodia Gordonii Powder Green Tea Extract Ginger Extract Piperine 275 mg 200 mg 65 mg 35 mg 11 mg physician. The test medication was Bioactives (marketed by Emcure Uth Healthcare Ltd. Pune, India) and its composition is shown in Table 1. All subjects were given standard advice regarding healthy food choices in their diet and physical activity. However, subjects were not advised to restrict dietary calorie intake. Clinical examination, BW, BMI and WC were estimated in all subjects at baseline and at the end of 30, 60 and 90 days. Any adverse effect reported was recorded in the prescription event monitoring form. All subjects had consumed one capsule of Bioactives orally daily one hour before lunch and dinner. Statistics The proportions of data were analyzed by Fisher s exact test and statistical significance between time points was calculated by student s T test. Efficacy was estimated by decrease in BW, BMI and WC after treatment. Side effects/ adverse events if any were reported.

98 Indian Medical Gazette MARCH 2014 Table 2 Subject demographics Number of subjects screened 99 Sex (M/F) Study population 52 males and 47 females Age (years; mean ± SD) 45.45 ± 10.

26 The demographics of subjects are presented in Table 2. Fig. 1 The effect of Bioactives in reduction of body weight Fig.

3 98 Indian Medical Gazette MARCH 2014 Table 2 Subject demographics Number of subjects screened 99 Sex (M/F) Study population 52 males and 47 females Age (years; mean ± SD) ± Diagnosis Baseline body weight (Kg; mean ± SD) Baseline body mass index (mean ± SD) Baseline waist circumference (cm; mean ± SD) Overweight and obese ± ± ± 8.26 The demographics of subjects are presented in Table 2. Fig. 1 The effect of Bioactives in reduction of body weight Fig. 2 The effect of Bioactives in reduction of body mass index Observations Total 99 subjects were enrolled in the study with mean age ± years. All subjects, were either overweight or obese. Table 3 shows that Bioactives was found to be significantly effective in decreasing BW by 4.36%, 7.12 % and 10.25% at 30, 60 and 90 days respectively and these results were statistically significant (p = 0.002, p < and p < respectively). BMI was also reduced with Bioactives by 5.11%, 9.83% and 11.88% at 30, 60 and 90 days respectively and results were statistically significant (p <0.0001, p < and p < respectively). Bioactives was found to be significantly effective in decreasing WC by 3.28%, 5.29% and 7.31% at 30, 60 and 90 days respectively and these results were statistically significant (p = , p < and p < respectively). Results are depicted in Fig. 1, Fig. 2 and Fig. 3. Parameter Body weight (Kg) (n = 99) Body mass index (n = 99) Waist circumference (n = 99) Baseline Table 3 The effect of Bioactives on clinical parameters At 30 days p value R (%) At 60 days p value R (%) At 90 days p value R (%) ± ± % ± 8.45 < % ± 8.79 < % ± ± 2.59 < % ± 4.57 < % ± 2.94 < % ± ± % ± 8.26 < % ± 9.32 < % R (%) = Reduction as compared to baseline, SD = Standard deviation.

Indian Medical Gazette MARCH 2014 99 Fig. 3 The effect of Bioactives in reduction of waist circumference Bioactives can be rated as good to very good based on results observed on 66% patients.

4 Indian Medical Gazette MARCH Fig. 3 The effect of Bioactives in reduction of waist circumference Bioactives can be rated as good to very good based on results observed on 66% patients. Side effects or adverse events e.g. muscle cramps, weakness, morning sickness were not reported in any case. Thus, Bioactives was very well tolerated. Discussion In a placebo controlled study conducted by Preuss et al., 60 human volunteers were given a 2,000 kcal diet/day, participated in a 30 min walking exercise program 5 days/ week. Subjects were given an oral dose of placebo or Garcinia cambogia-derived (-)-hydroxycitric acid (HCA) (providing 2,800 mg HCA) in three equally divided doses min before meals. Garcinia cambogia-derived (-)- hydroxycitric acid (HCA) is a safe, natural supplement for weight management. Body weight and BMI were reduced by 5.4% and 5.2% respectively. Other parameters were also improved as there was significant decrease in food intake, total cholesterol, LDL, triglycerides and serum leptin levels and there was significant increase in levels of HDL and urinary fat metabolites. Thus, Garcinia cambogiaderived (-)-hydroxycitric acid (HCA) is a safe, natural supplement for weight management 13. Clinical studies indicate that Hoodia gordonii appears to be beneficial in reducing food intake, body weight, craving for carbohydrates and providing a mild energizing effect in overweight and obesity 9. In a randomized, controlled and prospective trial conducted by Basu A et al., 35 subjects with obesity and metabolic syndrome were recruited and were randomly assigned to the control (4 cups water/day), green tea (4 cups/day), or green tea extract (2 capsules and 4 cups water/d) group for 8 weeks. The tea and extract groups had similar dosing of epigallocatechin-3-gallate (EGCG), the active compound in green tea. Green tea beverage and green tea extracts caused a significant decrease in BW and BMI versus controls at 8 weeks. Green tea beverage showed a decreasing trend in LDL-cholesterol and LDL/ high-density lipoprotein (HDL) versus controls. Green tea beverage consumption or extract supplementation for 8 weeks significantly decreased BW (- 2.5 ± 0.7, p <0.01; ± 0.6, p <0.05 respectively) and BMI (- 0.9 ± 0.3, p <0.01; ± 0.2, p <0.05) 14. In a randomized, double blind, placebo-controlled, 8 week trial conducted by Gleicher N et al., 86 overweight subjects were enrolled. The efficacy on metabolic changes produced by consumption of a dietary supplement (combination of bioactive ingredients e.g. epigallocatechin gallate, piperine, etc.) versus a placebo was assessed. The dietary supplement consumption was associated with a significant decrease in insulin resistance, assessed by homeostasis model assessment (p <0.001), leptin/ adiponectin ratio (p <0.04), respiratory quotient (p <0.008) and LDL-cholesterol levels (p <0.01). Statistically significant differences were recorded between the two groups in relation to urinary norepinephrine levels (p <0.001). Leptin, ghrelin, C-reactive protein decreased and resting energy expenditure increased significantly in the supplemented group (p <0.05, 0.03, 0.02 and 0,02 respectively), but not in the placebo group; adiponectin decreased significantly in the placebo group (p <0.001) but not in the supplemented group, although no statistical significance between the groups was elicited. The resting energy expenditure/free fat mass significantly increased in both groups. There was a trend towards reduction in BMI, fat mass in the supplemented group. The combination of bioactive ingredients (epigallocatechin gallate, piperine, etc.) appears to be useful for the treatment of obesity-related inflammatory metabolic dysfunctions 11. In a randomized crossover study conducted by Mansour et al., 10 men, age 39.1 ± 3.3 yrs and body mass index (BMI) 27.2 ± 0.3 kg/m 2 participated. Subjects consumed a breakfast meal with or without 2 g ginger powder dissolved in a hot water beverage. Visual analog scales ratings showed lower hunger (p =0.002), lower prospective food intake

5 100 Indian Medical Gazette MARCH 2014 (p =0.004) and greater fullness (p =0.064) with ginger consumption versus control. Enhanced thermogenesis and reduced feelings of hunger with ginger consumption, suggest a potential role of ginger in weight management 12. Above-mentioned results are mostly in relation to the effect of individual ingredients; however this study is first ever study that was conducted on the combination of bioactive ingredients (Bioactives; Garcinia cambogia, Hoodia gordonii, green tea, piperine and ginger). In this study, Bioactives resulted in significant decrease in the BW, BMI and WC in overweight and obese patients. Results appear to be superior to that observed in previously conducted studies. Superior effect might be due to synergistic effect of combination of bioactive ingredients. Additionally, advice on healthy food choices and physical activity may have contributed in positive effect. However, results have to be further assessed through double blind and randomized study in more number of subjects to confirm synergistic effect of this formulation (Bioactives). Side effect or adverse event was not reported in any case; that indicates excellent safety profile and tolerability with this formulation. The limitation of the study was the design as it was uncontrolled retrospective prescription event monitoring study. Other parameters viz. body fat area, etc. were not assessed during the study. In the current scenario of deficiency of safe antiobesity drugs, the combination of bioactive ingredients (Hoodia Gordonii, Garcinia cambogia, green tea, piperine, and ginger) appears to be a safe and effective approach to manage overweight and obesity. Summary This study shows that Bioactives (Obicure capsule) appears to be significantly effective in decreasing the body weight, body mass index and waist circumference within 30, 60 and 90 days in overweight and obese patients. Bioactives has excellent tolerability as adverse event was not reported in any case. Acknowledgements The author of study wishes to thank Emcure Uth Healthcare for providing technical assistance. The author also wishes to thank Dr. Himanshu Tayade for his support in writing manuscript of the study. References 1. Boschmann M., Thielecke F. The effects of epigallocatechin-3-gallate on thermogenesis and fat oxidation in obese men: a pilot study. J Am Coll Nutr. 26(4):389S-395S, Padwal R., Li S.K., Lau D.C. Long-term pharmacocapsule for obesity and overweight. Cochrane Database Syst Rev (3): CD Torgerson J.S., Hauptman J., Boldrin M.N. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 27(1): , Belinda S. Drew, Andrew F. Dixon, John B. Dixon. Obesity management: Update on orlistat. Vasc Health Risk Manag. 3(6): Obesity management: Update on orlistat, Vray M., Joubert J.M., Eschwège, et al. Results from the observational study EPIGRAM: management of excess weight in general practice and follow-up of patients treated with orlistat. Therapie. 60(1):17-24, Weir M.A., Beyea M.M., Gomes T., et al. Orlistat and acute kidney injury: an analysis of 953 patients. Arch Intern Med. 171(7): , Accessed on 14th March Accessed on 14th March Ilze Vermaak, Josias H. Hamman, Alvaro M. Viljoen. Hoodia Gordonii. An Up-to-Date Review of a Commercially Important Anti-Obesity Plant. Planta Med. 77(11): , Kohsuke Hayamizu, Yuri Ishii, Izuru Kaneko, et al. Effects of garcinia cambogia (Hydroxycitric Acid) on visceral fat accumulation: a double-blind, randomized,

6 Indian Medical Gazette MARCH placebo-controlled trial. Current Therapeutic Research. 64(8): , Rondanelli M., Opizzi A., Perna S., et al. Improvement in insulin resistance and favourable changes in plasma inflammatory adipokines after weight loss associated with two months consumption of a combination of bioactive food ingredients in overweight subjects. Endocrine. Dec 28, Mansour M.S., Ni Y.M., Roberts A.L. et al. Ginger consumption enhances the thermic effect of food and promotes feelings of satiety without affecting metabolic and hormonal parameters in overweight men: a pilot study. Metabolism. 61(10): , Preuss H.G., Rao C.V., Garis R., et al. An overview of the safety and efficacy of a novel, natural (-)- hydroxycitric acid extract (HCA-SX) for weight management. J Med. 35(1-6):33-48, Basu A., Sanchez K., Leyva M.J., et al. Green tea supplementation affects body weight, lipids, and lipid peroxidation in obese subjects with metabolic syndrome. J Am Coll Nutr. 29(1):31-40, 2010.

International Journal of Pharma and Bio Sciences COMPARISON OF EFFICACY AND SAFETY OF RIMONABANT WITH ORLISTAT IN OBESE AND OVERWEIGHT PATIENTS

International Journal of Pharma and Bio Sciences RESEARCH ARTICLE PHARMACOLOGY COMPARISON OF EFFICACY AND SAFETY OF RIMONABANT WITH ORLISTAT IN OBESE AND OVERWEIGHT PATIENTS Corresponding Author DR.JAIN