ABSTRACTObjective: To evaluate the efficacy of Zincovit (ZVT) tablets with grape seed extract (GSE) in patients with Type 2 diabetes mellitus by testing thehypothesis of a greater reduction in plasma glucose levels (fasting blood sugar [FBS] and post-prandial blood sugar [PPBS]) from baseline and after45 days of therapy as compared to standard comparator.Methods: This was a randomized, open-label, comparative (2-arm), prospective 45 days study. Treatment consisted of 2 arms: Antidiabetic drugplus non-pharmacological measure alone or ZVT tablets with GSE plus non-pharmacological measures. A total of 30 patients (15 in each arm) wereincluded in the study.Results: ZVT tablet did not alter the FBS, PPBS, and HbA1c level in diabetic patients compared to diabetic patients treated with placebo. No changeswere seen in any of the safety parameters when given for 45 days.Conclusion: ZVT tablets do not possess antidiabetic activity in spite of good safety profile in our study design. This could be due to several limitationsof the study such as inadequate sample size, short duration of the study, and wrong selection of the patients. A long-term, double-blind, placebocontrolled study in a large sample of population measuring glycemic parameters, and cardiovascular outcomes could give a clear picture of the antidiabeticeffectof ZVT with GSE tablets.Keywords: Diabetes mellitus, Zincovit tablets, Grape seed extract, Antioxidant, Safety parameters

Bairy K, Laxminarayana

Rao, Yeshwanth

Vidyasagar, Sudha

English

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Vol 9, Issue 2, 2016Online - 2455-3891 Print - 0974-2441A 45-DAY RANDOMIZED, OPEN-LABEL, COMPARATOR STUDY TO EVALUATE THE SAFETY AND EFFICACY OF ZINCOVIT TABLETS WITH GRAPE SEED EXTRACT (NUTRITIONAL FOOD SUPPLEMENT) IN PATIENTS WITH TYPE 2 DIABETES MELLITUSYESHWANTH RAO1, SUDHA VIDYASAGAR2, LAXMINARAYANA BAIRY K1*1Department of Pharmacology, Melaka Manipal Medical College, Manipal University, Manipal - 576 104, Karnataka, India. 2Department of Medicine, Kasturba Medical College, Manipal University, Manipal - 576 104, Karnataka, India. Email: klbairy@yahoo.comReceived: 23 December 2015, Revised and Accepted: 02 January 2016ABSTRACTObjective: To evaluate the efficacy of Zincovit (ZVT) tablets with grape seed extract (GSE) in patients with Type 2 diabetes mellitus by testing the hypothesis of a greater reduction in plasma glucose levels (fasting blood sugar [FBS] and post-prandial blood sugar [PPBS]) from baseline and after 45 days of therapy as compared to standard comparator.Methods: This was a randomized, open-label, comparative (2-arm), prospective 45 days study. Treatment consisted of 2 arms: Antidiabetic drug plus non-pharmacological measure alone or ZVT tablets with GSE plus non-pharmacological measures. A total of 30 patients (15 in each arm) were included in the study.Results: ZVT tablet did not alter the FBS, PPBS, and HbA1c level in diabetic patients compared to diabetic patients treated with placebo. No changes were seen in any of the safety parameters when given for 45 days.Conclusion: ZVT tablets do not possess antidiabetic activity in spite of good safety profile in our study design. This could be due to several limitations of the study such as inadequate sample size, short duration of the study, and wrong selection of the patients. A long-term, double-blind, placebo controlled study in a large sample of population measuring glycemic parameters, and cardiovascular outcomes could give a clear picture of the anti-diabetic effect of ZVT with GSE tablets.Keywords: Diabetes mellitus, Zincovit tablets, Grape seed extract, Antioxidant, Safety parameters.INTRODUCTIONDiabetes mellitus is a metabolic disorder characterized by derangements in carbohydrate, protein, and fat metabolism caused by complete or relative insufficiency of insulin secretion and insulin action. The pharmaceutical drugs are either too expensive or have undesirable side effects. Treatment with sulfonylureas and biguanides are also associated with side effects [1]. In recent years, much attention has been focused on the role of oxidative stress, and it has been reported that oxidative stress may constitute the key and common event in the pathogenesis of secondary diabetic complications. Free radicals are continuously produced in the body as a result of normal metabolic processes and interaction with environmental stimuli. Oxidative stress results from an imbalance between radical-generating and radical-scavenging systems that have increased free radical production or reduced activity of antioxidant defenses or both. Implication of oxidative stress in the pathogenesis of diabetes mellitus is suggested not only by oxygen free-radical-generation but also due to non-enzymatic protein glycosylation, auto-oxidation of glucose, impaired glutathione metabolism, alteration in antioxidant enzymes, and formation of lipid peroxides [1-4]. In addition to reduced glutathione (GSH), there are other defense mechanisms against free radicals such as the enzymes superoxide dismutase (SOD), GSH peroxidase, and catalase, whose activities contribute to eliminate superoxide, hydrogen peroxide, and hydroxyl radicals. Diabetes is associated with lower levels of endogenous antioxidants such as Vitamins A, C, E, lycopine, and lipoic acid. Total serum antioxidant capacity is reduced, and antioxidant effect of serum albumin and high density lipoprotein is impaired in people with diabetes. It is uncertain, however, whether depleted levels of these endogenous antioxidants and free radical scavengers are a cause or an effect of oxidative stress [5,6]. Conflicting results are available about the activity of various antioxidant enzymes. Cytosolic Cu2+/Zn2+ SOD (SOD 1) and mitochondrial Mn2+ SOD (SOD 2) are lower in human diabetic neutrophils. Renal SOD 1 and glutathione peroxidase is found to be increased in diabetic rat kidneys. SOD 2 shows no change. Glutathione oxidase activity is higher in the renal cortex of diabetic mice than non-diabetic controls. The exact contribution of antioxidant enzymes to oxidative stress in diabetes is not fully understood. Many of the complications of diabetes mellitus, including retinopathy and atherosclerotic vascular disease, the leading cause of mortality in diabetes mellitus, have been linked to oxidative stress, and antioxidants have been considered as treatments. Oxidative stress is increased in experimental models of streptozotocin (STZ)-induced diabetes mellitus [7,8].Zincovit tablet (ZVT) is an advanced formula of high concentration of vitamins, minerals, and grape seed extract (GSE). ZVT releases a stream of antioxidant benefits. In diabetes mellitus, oxygen free radicals (OFRs) are generated by stimulating H2O2 in-vitro, as well as in-vivo, in pancreatic ß-cells. OFR-scavenging enzymes can respond to conditions of oxidative stress with a compensatory mechanism that increases the enzyme activity in diabetic rats [1]. The antioxidant of flavonoids present in the ZVT with GSE acts as strong superoxide radicals and singlet oxygen quencher STZ-induced experimental diabetes is a valuable model for induction of Type 1 diabetes. Few studies such as the one done by Irina et al. regarding antioxidant effects of GSE suggest that the treatment of STZ-induced diabetic rats with GSE lowered the protein’s oxidant damage in rat’s plasma and liver tissues [1,9]. The antioxidant activity of phenols is due to their redox properties that allow them to act as reducing agents by donating hydrogen, quenching singlet oxygen, or acting as metal chelators. It has been reported that various proteins, including hemoglobin, albumin, collagen, low-density lipoprotein (LDL), or crystalline proteins undergo non-enzymatic glycation in diabetes. The rate of glycation is proportional Research ArticleAsian J Pharm Clin Res, Vol 9, Issue 2, 2016, 220-222 Rao et al. 221METHODSTrial designThis was a randomized, open-label, comparative (2-arms), prospective 45 days study. Treatment consisted of 2 arms: Antidiabetic drug plus non-pharmacological measure alone or ZVT with GSE plus non-pharmacological measures. Patients who met entry criteria were randomized after screening to one of the two treatment arms in a 1:1 ratio. The study was approved by the Institutional Ethics Committee (IEC), and all included patients gave their written informed consent prior to entry into the study, and the study was performed in accordance with the ethical principles consistent with good clinical practice and international harmonization guidelines. Patients were evaluated at day 0 and day 45.EndpointsThe primary endpoint of the study was comparative assessment percentage change from baseline (day 0) in fasting blood sugar (FBS) and post-prandial blood sugar (PPBS) to 45 days in both the groups. Secondary endpoints included safety assessment by doing routine hematological and biochemical investigations. Patients were also observed for any adverse signs and symptoms.Inclusion criteriaOutpatients and inpatients (both males and females) with Type 2 diabetes mellitus between the age of 18 and 75 years. Patients with fasting glucose levels above 125 mg/dl and below 250 mg/dl, and or post-prandial glucose levels above 200 mg/dl and below 350 mg/dl will be included. Patients who are eligible and able to participate in the study must consent to do so after the details of the study are explained to them (written informed consent).Exclusion criteriaPatients with Type 1 diabetes mellitus, with known allergy to zinc, with severe comorbid conditions such as renal impairment, hepatic impairment, Stage IV congestive cardiac failure, carcinoma, immunosuppression, refusal to give written informed consent voluntarily, alcohol or drug abuse, pregnancy or lactation or pediatric age group, and any other medical condition that in the opinion of the investigator, may be an unacceptable additional risk to the patient.Safety assessmentsSafety assessments included recording of treatment-emergent adverse events (adverse events that started or worsened during randomized treatment), hematological and biochemical measurements, and physical examination.Patient characteristicsA total of 30 patients (15 in each arm) were included in the study and all the 30 patients completed the study. Both males and females were included in the study. Patients were selected carefully as per the inclusion/exclusion criteria, and the comorbid conditions were minimal/clinically not significant/well under control.RESULTSEfficacyTable 1 shows the pre-treatment and post-treatment values of FBS, PPBS, and HbA1c values. ZVT tablet did not alter the FBS, PPBS, and HbA1c level in diabetic patients compared to diabetic patients treated with placebo. Results were analyzed using the non-parametric unpaired t-test (Mann–Whitney test).SafetyOverall ZVT tablets were very well-tolerated over 45 days. Occasional side effects observed in a couple of patients were nausea, abdominal pain, headache, diarrhea, and constipation (Table 2). The intensity of these adverse effects was mild in nature. There were no other significant changes in the laboratory parameters at the end of the treatment in both the groups. Table 2 shows the pre-treatment and post-treatment values of liver function test, renal function test lipid profile, blood glucose, electrolyte balance, and hematological parameters. There is no change in any of the safety parameters when given for 45 days.DISCUSSIONThere are several published reports indicating the beneficial effects of complementary and ayurvedic medicine in the treatment of Type 2 diabetes mellitus. Chromium and possibly Gymnema appears to improve glycemic control. In the indigenous Indian system of medicine (Ayurveda), a mention was made on a good number of plants for the cure of diabetes or “madhumeha” and some of them have been experimentally evaluated and the active principles were isolated [12-15].In the present study, ZVT tablets at a dose of 1-2 tablets per day half an hour before food as an add-on therapy (with the standard background antidiabetic medications) over a 45-day period was found to statistically non-inferior (p>0.05) to the existing standard antidiabetic medications in lowering the FBS, PPBS, and HbA1c levels. As per the current literature, oral administration of ZVT tablet with GSE to normal and diabetic rats for 45 days significantly reduced the levels of blood glucose in a dose-dependent manner among diabetic treated rats when compared to diabetic control rats [16]. In our study, there is no beneficial effect in diabetes patients. This could be due to several limitations of the study such as inadequate sample size, short duration of the study, and wrong selection of the patients. Studies investigating diabetes management should be of at least 4 month’s duration. Furthermore, diabetic studies must focus on cardiovascular outcomes also apart from glycemic control. This is also one of the serious limitations of our study. This is important because better glycemic control might not always lead to real-world clinical benefits [17]. However, in spite of all these negative results literature clearly confirms the antioxidant effect of ZVT tablets. The antioxidative effect of flavonoids present in the ZVT with GSE acts as strong superoxide radicals and singlet oxygen quencher [16]. Therefore, ZVT with GSE supplementation may be beneficial in controlling the blood glucose level as an add-on drug in Type 2 diabetic patients.Table 1: Comparison of diabetic parameters before and after the administration of study drug/placebo in the diabetic patientsVariable #Pre-treatment values (mean±SEM) (n=15)95% CI ‡Post-treatment values (mean±SEM) (n=15)95% CIControl Drug Control Drug Control Drug Control DrugFBS (mg/dl) 94.37±3.04 104.4±4.9 87.19-101.6 93.39-115.4 99.38±2.43 103.9±3.2 93.64-105 196.74-111PPBS (mg/dl) 110±8.3 114.2±5.3 90.35-129.7 102.3-126.1 114.75±7.5 106.5±4.6 96.9-132.5 96-116.92HbA1c 5.43±0.14 5.7±0.12 5.09-5.76 5.49-6.04 5.59±0.03 5.62±0.03 5.52-5.66 5.44-5.8#p>0.05 between the pre-treatment values of the control and drug groups indicating that both groups are similar to each other. Statistical analysis carried out by Mann–Whitney test (non-parametric unpaired t-test), ‡p>0.05 between the post-treatment values of the control and drug groups indicating that there is no difference between the drug and the placebo on the measured parameters. Statistical analysis carried out by Mann–Whitney test (non-parametric unpaired t-test), SEM: Standard error of mean, FBS: Fasting blood sugar, PPBS: Post-prandial blood sugar, CI: Confidence of intervalto the concentration of blood glucose [10,11]. Therefore, ZVT with GSE supplementation may be beneficial in controlling the blood glucose level. Hence, this study.Asian J Pharm Clin Res, Vol 9, Issue 2, 2016, 220-222 Rao et al. 222CONCLUSIONSFrom the present study, we need to conclude that ZVT tablets do not possess antidiabetic activity in spite of good safety profile. However, the long-term, double-blind, placebo controlled study in a large sample of population measuring glycemic parameters, and cardiovascular outcomes could give a clear picture of the antidiabetic effect of ZVT with GSE tablets.ACKNOWLEDGMENTSThe authors are grateful to Apex Laboratories Pvt Ltd, Chennai and Manipal University, Manipal for the support to carry out this project.REFERENCES1. Chis IC, Ungureanu MI, Marton A, Simedrea R, Muresan A, Postescu ID, et al. Antioxidant effects of a grape seed extract in a rat model of diabetes mellitus. Diab Vasc Dis Res 2009;6:200-4.2. Farvid MS, Jalali M, Siassi F, Hosseini M. Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in Type 2 diabetes. Diabetes Care 2005;28:2458-64.3. Giardino I, Edelstein D, Brownlee M. BCL-2 expression or antioxidants prevent hyperglycemia-induced formation of intracellular advanced glycation end products in bovine endothelial cells. J Clin Invest 1996;97(6):1422-8.4. Rajasekaran S, Sivagnanam K, Subramanian S. Antioxidant effect of Aloe vera gel extract in streptozotocin-induced diabetes in rats. Pharmacol Rep 2005;57:90-6.5. Shirwaikar A, Rajendran K, Punitha IS. Antidiabetic activity of alcoholic stem extract of Coscinium fenestratum in streptozotocin-nicotinamide induced Type 2 diabetic rats. J Ethnopharmacol 2005;97:369-74.6. Sachdewa A, Khemani LD. Effect of Hibiscus rosa sinensis Linn. ethanol flower extract on blood glucose and lipid profile in streptozotocin induced diabetes in rats. J Ethnopharmacol 2003;89:61-6.7. Eidi A, Eidi M, Esmaeili E. Antidiabetic effect of garlic (Allium sativum L.) in normal and streptozotocin-induced diabetic rats. Phytomedicine 2006;13(9-10):624-9.8. Agrawal N, Singh SK, Singh N, Kalra S, Srivastava G. Oxidative stress and diabetes. Internet J Geriatr Gerontol 2010;6(1):31.9. Pari L, Latha M. Effect of Cassia auriculata flowers on blood sugar levels, serum and tissue lipids in streptozotocin diabetic rats. Singapore Med J 2002;43:617-21.10. Venkateswaran S, Pari L. Effect of Coccinia indica leaves on antioxidant status in streptozotocin-induced diabetic rats. J Ethnopharmacol 2003;84(2-3):163-8.11. Kaleem M, Asif M, Ahmed QU, Bano B. Antidiabetic and antioxidant activity of Annona squamosa extract in streptozotocin-induced diabetic rats. Singapore Med J 2006;47:670-5.12. Chopra RN, Nayar SL, Chopra IC: Glossary of Indian Medicinal Plants. New Delhi: CSIR; 1956. p. 66-7.13. Al-Awadi FM, Gumaa KA. Studies on the activity of individual plants of an antidiabetic plant mixture. Acta Diabetol Lat 1987;24:37-41.14. Ivorra MD, Payá M, Villar A. A review of natural products and plants as potential antidiabetic drugs. J Ethnopharmacol 1989;27:243-75.15. Alarcon-Aguilara FJ, Roman-Ramos R, Perez-Gutierrez S, Aguilar-Contreras A, Contreras-Weber CC, Flores-Saenz JL. Study of the anti-hyperglycemic effect of plants used as antidiabetics. J Ethnopharmacol 1998;61:101-10.16. Satyam SM, Bairy LK, Pirasanthan R. Influence of grape seed extract and zinc containing multivitamin-mineral nutritional food supplement on lipid profile in normal and diet-induced hypercholesterolemic rats. J Clin Diagn Res 2014;8:HC12-5.17. Nahas R, Moher M. Complementary and alternative medicine for the treatment of Type 2 diabetes. Can Fam Physician 2009;55:591-6.Table 2: Comparison of safety parameters (hematological/biochemical) before and after the administration of study drug/placebo in diabetic patientsVariable #Pre-treatment values (mean±SEM) (n=15)95% CI ‡Post-treatment values (mean±SEM) (n=15)95% CIControl Drug Control Drug Control Drug Control DrugALT (IU/l) 27.7±4 22.6±4 14.41-41.11 15.7-29.5 26.5±3.7 23.9±3.32 16.84-36.16 17.39-29.4AST (IU/l) 24.5±2.72 22.4±1.6 15.5-33.9 18.4-25.5 23.8±2.5 21.8±1.62 16.8-30.9 18.8-24.7TC (mg/dl) 181±15.12 171.6±14.79 156.9-206.1 143.1-199 195.25±20.8 163.7±10.6 166.9-225.6 144.8-181.6TG (mg/dl) 126±32.9 129.2±16.2 81.5-172.5 99.5-159.9 138.75±32.2 115.7±15.42 80.2-196.28 87.8-144.6HDL (mg/dl) 51.25±12 48.9±4.67 32.7-97.7 39.3-56.4 50.71±11.3 50.23±5.09 31.29-69.21 41.29-58.3LDL (mg/dl) 104±12.2 97.5±13.29 96.2-122.8 73.4-121.6 117.75±20.5 92.7±9.25 85.62-149.9 76.79-108.6TC/HC 3.84±0.89 3.63±0.29 2.6-5.4 3.1-4.2 4.4±0.78 3.3±0.32 2.4-6.3 2.7-3.9Urea (mg/dl) 23.25±2.59 25±4.79 11.9-35.5 17.17-33.8 22.5±2.72 23.5±2.8 13.83-31.17 18.16-27.8Creat (mg/dl) 0.87±0.05 0.83±0.09 0.54-1.19 0.62-1.03 0.87±0.16 0.82±0.12 0.37-1.38 0.55-1.09Na (mmol/l) 136.14±1.7 136.92±0.39 132.2-139.78 135.9-138.7 141.25±1.32 37.1±0.92 139-143.43 135.32-138.4K (mmol/l) 4.12±0.35 4.4±0.14 3.6-4.6 4.16-4.71 4.38±0.24 4.31±0.13 3.9-4.7 4.1-4.53Hb (g/dl) 12.25±0.59 12.6±0.3 10.7-13.7 12.1-13.2 12.5±0.15 12.6±0.41 11.01-14 11.9-13.3HCT (%) 36.9±1.36 38.5±0.86 33.9-40.4 36.7-40.2 38.13±1.66 38.23±1.11 34.44-42 36.3-40.24PLC (103/μl) 248.8±8.9 250.6±18.7 209.8-288.6 217.5-283.9 259.5±14.72 252.2±17 212.65-306.3 213.7-290.7TWBC (103/μl) 8.25±0.54 6.9±0.58 6.1-10.4 5.9-7.9 7.9±1.02 7.5±0.51 5.9-9.9 6.6-8.36N (%) 51.9±3.25 51.12±2.2 44.8-59.2 45.3-56.6 49.85±3.84 51.63±2.18 37.64-62.06 46.69-56.57L (%) 36.13±3.45 35.87±2.7 30.5-41.6 29.8-41.8 39.37±4.3 36.12±2.36 25.65-53.09 30.78-41.5M (%) 6.4±1.3 87.5±0.3 4.38-8.67 6.75-8.3 6.4±0.4 6.6±0.34 5.1-7.8 6.4-7.3E (%) 6.13±1.72 4.8±0.86 1.8-10.4 3.3-6.3 6.1±1.72 5.2±0.84 3.03-9.3 3.64-6.87B (%) 0.4±0.03 0.67±0.09* 0.23-0.56 0.51-0.84 0.5±0.04 0.62±0.12 0.34-0.65 0.39-0.85ESR 31.7±7.98 24.3±3.23 17.35-46.07 16.9-31.1 40.25±7.04 25±4.17 17.85-62.65 15.57-34.43#p>0.05 between the pre-treatment values of the control and drug groups indicating that both groups are similar to each other. Statistical analysis carried out by Mann–Whitney test (non-parametric unpaired t-test), ‡p>0.05 between the post-treatment values of the control and drug groups indicating that there is no difference between the drug and the placebo on the measured parameters. Statistical analysis carried out by Mann–Whitney test (non-parametric unpaired t-test), ESR: Erythrocyte sedimentation rate, TWBC: Total white blood cell, Hb: Hemoglobin, ALT: Alanine aminotransferase, AST: Aspartate transaminase, TC: Total cholesterol, TG: Triglyceride, HDL: High density lipoprotein, LDL: Low density lipoprotein, SEM: Standard error of mean, CI: Confidence of interval

A 45-DAY RANDOMIZED, OPEN-LABEL, COMPARATOR STUDY TO EVALUATE THE SAFETY AND EFFICACY OF ZINCOVIT TABLETS WITH GRAPE SEED EXTRACT (NUTRITIONAL FOOD  SUPPLEMENT) IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

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A 45-DAY RANDOMIZED, OPEN-LABEL, COMPARATOR STUDY TO EVALUATE THE SAFETY AND EFFICACY OF ZINCOVIT TABLETS WITH GRAPE SEED EXTRACT (NUTRITIONAL FOOD SUPPLEMENT) IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

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