Eswar Kumar Kilari

Influence of nicorandil on the pharmacodynamics and pharmacokinetics of gliclazide in rats and rabbits

Chronic diabetes precipitates ischaemic heart disease (IHD) and many other disorders. IHD inturn is shown in the form of angina initially. According to EUROPA study, the incidence of angina is high in type II diabetics. Gliclazide, a second generation sulphonylurea derivative is widely used in the treatment of type-II diabetes and is known to release insulin by K+ channel inhibition. Nicorandil, a newer antianginal drug widely used now a days acts by opening potassium channels in the cardiac muscle cell and also by releasing nitric oxide. However its action on pancreatic cell K+ channel is not known. Since there is possibility for drug interaction leading to decreased activity of gliclazide the present study was conducted to evaluate the effect of the combination.Studies in normal and alloxan induced diabetic rats were conducted with oral doses of 2 mg/kg bd. wt. of gliclazide, 1.8 mg/kg bd. wt. of nicorandil and their combination with adequate washout periods in between treatments. Studies in normal rabbits were conducted with 5.6 mg/1.5 kg bd. wt. of gliclazide, 1.4 mg/1.5 kg bd. wt. of nicorandil and their combination given orally. Blood samples were collected in rats from retro orbital puncture at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h and by marginal ear vein puncture in rabbits at 0, 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 h. All the blood samples were analysed for glucose by GOD/POD method. The blood samples of rabbits were analysed by HPLC for gliclazide.Gliclazide produced hypoglycaemic/antidiabetic activity in normal and diabetic rats with peak activity at 1 h and 8 h and hypoglycaemic activity in normal rabbits at 3 h, while nicorandil alone produced significant hyperglycaemia at 4 h and reduced the effect of gliclazide with no significant change in pharmacokinetics when administered in combination. The interaction observed appears to be pharmacodynamic at the receptor level as expected.

Antidiabetic effect of α-mangostin and its protective role in sexual dysfunction of streptozotocin induced diabetic male rats

Sexual dysfunction is one of the diabetic complications in males. The present study aimed to evaluate the antidiabetic effect of α-mangostin and its protective role in sexual dysfunction of streptozotocin (STZ) induced diabetic male rats. Male Wistar rats were divided as control, diabetic control, diabetic rats administered with 25, 50 mg/kg body weight (bw) of α-mangostin and 1 mg/kg bw of gliclazide. The α-mangostin was administered once daily for a period of 55 days. On day 55 animals were sacrificed, serum was analyzed for testosterone levels, and sperm was collected from the epididymis and sperm parameters analyzed. Testis and epididymis were examined for antioxidant enzymes like superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) levels, lipidperoxidation products, and histopathological alterations. In diabetic rats, sperm count, motile sperms, viable sperms, and hypo-osmotic swelling tail coiled sperms were significantly decreased while sperm malformations increased when compared with normal rats. Serum testosterone levels and testicular 3β and 17 β-hydroxysteroid dehydrogenase levels were significantly decreased in diabetic rats. Significant reduction in testicular and epididymal SOD, catalase, GPx levels, and elevation in lipid peroxidation products were observed. However, α-mangostin treatment showed noteworthy recovery in all parameters towards the control levels. It may therefore be suggested that α-mangostin showed a protective effect against sexual dysfunction in STZ induced diabetic rats.

Influence of antioxidant (L- ascorbic acid) on tolbutamide induced hypoglycaemia/antihyperglycaemia in normal and diabetic rats

BackgroundDiabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia. Increased oxidative stress and decreased antioxidant levels are the leading cause of diabetes and diabetic complications. So it is felt that supplementation of antioxidants may be useful in controlling the glucose levels and to postpone the occurrence of diabetic complications. The objective of our study is to find the influence of antioxidant supplementation (L-ascorbic acid) on tolbutamide activity in normal and diabetic rats.MethodsL- ascorbic acid/tolbutamide/L-ascorbic acid + tolbutamide were administered orally to 3 different groups of albino rats of either sex in normal and diabetic condition. Blood samples were collected from retro-orbital puncture at different time intervals and were analyzed for blood glucose by GOD-POD method. Diabetes was induced by alloxan 100 mg/kg body weight administered by I.P route.ResultsL-ascorbic acid/ tolbutamide produced hypoglycaemic activity in a dose dependant manner in normal and diabetic condition. In the presence of L-ascorbic acid, tolbuatmide produced early onset of action and maintained for longer period compared to tolbutamide matching control.ConclusionSupplementation of antioxidants like L-ascorbic acid was found to improve tolbutamide response in normal and diabetic rats.

Polydatin alleviates alcohol-induced acute liver injury in mice: Relevance of matrix metalloproteinases (MMPs) and hepatic antioxidants

BACKGROUND Alcohol, a most commonly consumed beverage, is the foremost cause of liver injury throughout the world. Polydatin, a stilbenoid glucoside, was known to possess antioxidant and anti-inflammatory properties and is being investigated for use in various disorders. PURPOSE The present study was intended at investigating the hepatoprotective efficacy of polydatin against acute-alcohol induced liver injury model in mice. STUDY DESIGN C57BL/6 mice were fed with five doses of 50% ethyl alcohol (10ml/kg body weight) to induce acute liver injury. Effect of polydatin against alcohol induced hepatic injury was investigated by giving 50 or 100mg/kg polydatin, orally, for 8 days. METHODS Serum markers of liver injury, morphology, histology and fibrosis of liver tissue, levels of enzymatic and non-enzymatic antioxidants and the mitochondrial respiratory enzyme activities in liver tissue were investigated. The activities and the protein expression of matrix metalloproteinases (MMP-2 and -9), the expression of NF-κB in the liver tissue were also studied. RESULTS Polydatin pre-treatment significantly alleviated the alcohol induced hepatic injury by reducing the serum liver injury markers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), attenuating oxidative stress and restoring antioxidant balance in the hepatic tissue. Simultaneously, polydatin pre-treatment also prevented alcohol induced mitochondrial damage and refurbished the matrix metalloproteinases levels of the hepatic tissue. CONCLUSION The findings of the present study suggest that polydatin may have a potential benefit in preventing alcohol-induced acute hepatic injury.

Biological and phytopharmacological descriptions of Litchi chinensis

Plants remain a vital source of drugs and at present, much emphasis is given to nutraceuticals. Herbal medicines have been the basis of treatment and cure for various diseases and physiological conditions in the traditional methods practiced such as ayurveda and homeopathy. Litchi chinensis belongs to the Sapindaceae family and is well-known in the Indian traditional system for its traditional uses. The parts of the plant used are leaves, flowers, fruits, seed, pulp, and pericarp. All parts of the plant are rich sources of phytochemicals––epicatechin; procyanidin A2 and procyanidin B2; leucocyanidin; cyanidin glycoside, malvidin glycoside, and saponins; butylated hydroxytoluene; isolariciresinol; kaempferol; rutin; and stigmasterol. In the present review, we explore the lychees description, traditional medicinal uses, and phytoconstituents, and investigate the pharmacological activities in various parts of the lychee to show its importance in ethanopharmacology. This is so that this review can serve as a ready-to-use material for further research on the plant.

Phyllanthus niruri leaves aqueous extract improves kidney functions, ameliorates kidney oxidative stress, inflammation, fibrosis and apoptosis and enhances kidney cell proliferation in adult male rats with diabetes mellitus

ETHNOPHARMACOLOGICAL RELEVANCE Phylanthus niruri has been used to treat ailments related to the urogenital organs. In this study, this herb was hypothesized to help to ameliorate kidney disease in diabetes mellitus (DM). AIMS To investigate P. niruri leaves aqueous extract (PN) effects on kidney functions, histopathological changes and levels of oxidative stress, inflammation, fibrosis, apoptosis and proliferation in DM. METHODS PN was orally administered to streptozotocin-nicotinamide-induced male diabetic rats for 28 days. At the end of the treatment, fasting blood glucose (FBG) and kidney functions were measured. Kidney somatic index, histopathological changes and levels of RAGE, Nrf2, oxidative stress markers (TBARS, SOD, CAT and GPx), inflammatory markers (NFkβ-p65, Ikk-β, TNF-α, IL-1β and IL-6), apoptosis markers (caspase-3, caspase-9 and Bax), fibrosis markers (TGF-β1, VEGF and FGF-1) and proliferative markers (PCNA and Ki-67) were determined by biochemical assays, qPCR, Western blotting, immunohistochemistry or immunofluorescence. RESULTS Administration of PN helps to maintain near normal FBG, creatinine clearance (CCr), blood urea nitrogen (BUN), BUN/Cr ratio, serum electrolytes, uric acid and urine protein levels in DM. Decreased RAGE, TBARS and increased Nrf2, SOD-1, CAT and GPx-1 were observed in PN-treated diabetic rat kidneys. Expression of inflammatory, fibrosis and apoptosis markers in the kidney reduced but expression of proliferative markers increased following PN treatment. Lesser histopathological changes were observed in the kidney of PN-treated diabetic rats. CONCLUSION PN helps to preserve near normal kidney function and prevents histopathological changes via ameliorating oxidative stress, inflammation, fibrosis and apoptosis while enhancing proliferation of the kidney in DM.

Anti-Inflammatory, Anti-Apoptotic and Pro-Proliferative Effects of Vitis Vinifera Seed Ethanolic Extract in the Liver of Streptozotocin-Nicotinamide-Induced Diabetes in Male Rats

OBJECTIVES Consumption of Vitis vinifera seed has been reported to ameliorate liver pathology in diabetes mellitus; however, the mechanisms underlying its effects remain unknown. In this study, the anti-inflammatory, anti-apoptotic and pro-proliferative effects of the ethanolic seed extract of V. vinifera (VVSEE) in the liver in cases of diabetes were identified. METHODS Adult male rats with streptozotocin-nicotinamide-induced diabetes were given 50, 100 or 200 mg/kg body weight VVSEE orally for 28 days. At the end of the treatment, body weights were determined, and the blood was collected for analyses of fasting blood glucose, insulin and liver enzyme levels. Following sacrifice, livers were harvested and their wet weights and glycogen contents were measured. Histologic appearances of the livers were observed under light microscopy, and the expression and distribution of inflammatory, apoptosis and proliferative markers in the livers were identified by molecular biologic techniques. RESULTS Treatment of rats with diabetes by VVSEE attenuates decreased body weight, liver weight and liver glycogen content. Additionally, increases in fasting blood glucose levels and liver enzyme levels and decreases in serum insulin levels were ameliorated. Lesser histopathologic changes were also observed: decreased inflammation and apoptosis, as indicated by decreased levels of inflammatory markers (TNF-α, NF-Kβ, IKK-β, IL-6, IL-1β) and apoptosis markers (caspase-3, caspase-9 and Bax). VVSEE treatment induces increase in hepatocyte regeneration, as indicated by increased PCNA and Ki-67 distribution in the livers of rats with diabetes. Several molecules identified in VVSEE via gas chromatography mass spectrometry might contribute to these effects. CONCLUSIONS The anti-inflammatory, anti-apoptotic and pro-proliferative effects of VVSEE could account for its hepatoprotective actions in diabetes.

Delayed progression of diabetic cataractogenesis and retinopathy by Litchi chinensis in STZ-induced diabetic rats

Abstract Context: The study was carried out to evaluate the effect of the aqueous fruit pericarp extract of Litchi chinensis (APLC) on parameters which leads to diabetic cataractogenesis and retinopathy in the streptozotocin-induced diabetic rats. Objective: The objective of the study is to evaluate the APLC for in vivo antioxidant activity and its role in inhibiting the polyol pathway and formation of advanced glycation end products (AGEs). Materials and methods: The diabetic animals were treated with L. chinensis for a period of 12 weeks. At the end of 12 weeks, the animals were killed and the biochemical pathways involved in the pathogenesis of cataract such as oxidative stress by protein content, superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and polyolpathway by aldose reductase (AR) in lens homogenates, alterations in protein carbonyl content (PCO) and AGEs in both serum and lens the APLC-treated diabetic rats were compared against diabetic control rats. Cataract progression due to hyperglycemia was monitored by slit lamp bio microscope and classified into four stages. Fundoscope test and retinal histopathology were done for assessing retinopathy. Results: Statistically significant reduction in glucose, and elevation of protein content, SOD, CAT, and GSH levels and decreased levels of AR and PCO in lens homogenate and significant reduction in AGEs serum and lens homogenate were observed. Slit lamp examination, fundoscope, and histopathology showed improvement in retinal changes in APLC-treated rats compared to diabetic control animals. Conclusion: The treatment with APLC found to delay the progression of diabetic cataractogenesis and retinopathy, which might be due to its antioxidant activity, because of the presence of active phytochemicals in APLC.

Influence of curcumin on the pharmacodynamics and pharmacokinetics of gliclazide in animal models

Purpose Patients suffering from obesity-related diseases use multiple prescription drugs to control their condition, and it is therefore essential to determine the safety and efficacy of any combination. Gliclazide is one of the most commonly used drug of choice for treatment of type 2 diabetes, and curcumin is a widely used herbal supplement to counter obesity condition. The objective of this study was to investigate the effect of oral administration of curcumin on pharmacodynamics and pharmacokinetics of gliclazide in rats and rabbits to further evaluate the safety and effectiveness of this combination. Methods Influence of curcumin on the activity of gliclazide was determined by conducting single- and multiple-dose interaction studies in rats (normal and diabetic) and rabbits. Blood samples collected at predetermined time intervals from experimental animals were used for the estimation of glucose and insulin levels by using automated clinical chemistry analyzer and radioimmunoassay method, respectively. The insulin resistance and β-cell function were determined by homeostasis model assessment. Additionally, serum gliclazide levels in rabbits were analyzed by high-performance liquid chromatography. Results Gliclazide showed peak reduction in blood glucose levels at 2 and 8 hours in rats and at 3 hours in rabbits. This activity of gliclazide was not altered by single-dose treatment with curcumin. However, in multiple-dose interaction studies, samples analyzed from all time points showed subtle but significantly greater reduction in percent blood glucose ranging from 23.38% to 42.36% in normal rats, 27.63% to 42.27% in diabetic rats, and 16.50% to 37.88% in rabbits. The pharmacokinetics of gliclazide was not altered by single- or multiple-dose curcumin treatments in rabbits. Conclusion The interaction of curcumin with gliclazide up on multiple-dose treatment was pharmacodynamic in nature, indicating the need for periodic monitoring of glucose levels and dose adjustment as necessary when this combination is prescribed to obese patients.

Therapeutic Potentials of Triterpenes in Diabetes and its Associated Complications.

Diabetes is a major chronic metabolic disorder globally and around of 285 million people are affected by the disease and the number is expected to double in the next two decades. The major focus of anti-diabetic therapies is to enhance insulin production, sensitivity and/or reduce the blood glucose level. Although several synthetic drugs have been developed as antidiabetic agents but their utility has been hampered due to their side effects and poor efficacy. In this scenario, research on natural products has been gained importance due their safety profile in toxicity studies. Terpenoids belong to an important class of natural products and several terpenoids have been reported as antidiabetic agents. Some of them are under various stages of pre-clinical and clinical evaluation to develop them as antidiabetic agents. These agents can inhibit enzymes responsible for the development of insulin resistance, normalization of plasma glucose and insulin levels and glucose metabolism. Triterpenes can act as promising agents in the treatment of diabetic retinopathy, neuropathy and nephropathy or in impaired wound healing by inhibiting several pathways involved in the diabetes and associated complications. However, efforts in understanding the biological actions and clinical studies involving the applications of triterpenes in treating diabetes are very limited. Hence, special attention is imperative to explore the therapeutic potential of these compounds and provide new information to the scientific community. This review aims to provide the recent advances in triterpenes chemistry, its derivatives, biological interventions and its therapeutic applications with special emphasis on diabetes and its associated disorders.