Influence of CYP2C9 gene polymorphisms on response to glibenclamide in type 2 diabetes mellitus patients.

PURPOSE: The antidiabetic drug glibenclamide is metabolized by the enzyme cytochrome P450 2C9 (CYP2C9) encoded by the polymorphic gene CYP2C9. Previous studies involving healthy volunteers have shown a significant influence of variant CYP2C9 genotypes on glibenclamide metabolism. The aim of this study was to investigate the influence of genetic polymorphisms of CYP2C9 on the response to glibenclamide and on glibenclamide plasma levels in type 2 diabetes mellitus patients. METHODS: The study cohort consisted of type 2 diabetes mellitus patients (n = 80) on regular therapy with glibenclamide either alone or with concomitant metformin. Plasma levels of glibenclamide were estimated by reverse phase high pressure liquid chromatography. The variant alleles of CYP2C9, namely CYP2C9 *2 and *3, were identified by PCR-restricted fragment length polymorphism. The plasma levels of glibenclamide and occurrences of hypoglycemic adverse effects with their severity were compared between the genotype groups. RESULTS: Of the 80 patients (61 males, 19 females), 78 were on concomitant treatment with two drugs, namely, glibenclamide and metformin, and two were on monotherapy with glibenclamide. There was a significant association (p < 0.001) between genotype status of CYP2C9 and the control of diabetes in patients receiving treatment with glibenclamide. There were no statistically significant differences in hypoglycemic adverse effects between the genotype groups. CONCLUSION: The type 2 diabetes mellitus patients participating in this study with variant genotypes of CYP2C9 were found to respond better to treatment with glibenclamide than those with the normal genotype. The variant genotype CYP2C9 *1/*3 did not significantly influence the hypoglycemic adverse effects among those patients on long-term glibenclamide treatment.

Novel applications of nanotechnology in medicine.

Current modalities of diagnosis and treatment of various diseases, especially cancer have major limitations such as poor sensitivity or specificity and drug toxicities respectively. Newer and improved methods of cancer detection based on nanoparticles are being developed. They are used as contrast agents, fluorescent materials, molecular research tools and drugs with targeting antibodies. Paramagnetic nanoparticles, quantum dots, nanoshells and nanosomes are few of the nanoparticles used for diagnostic purposes. Drugs with high toxic potential like cancer chemotherapeutic drugs can be given with a better safety profile with the utility of nanotechnology. These can be made to act specifically at the target tissue by active as well as passive means. Other modalities of therapy such as heat induced ablation of cancer cells by nanoshells and gene therapy are also being developed. This review discusses the various platforms of nanotechnology being used in different aspects of medicine like diagnostics and therapeutics. The potential toxicities of the nanoparticles are also described in addition to hypothetical designs such as respirocytes and microbivores. The safety of nanomedicine is not yet fully defined. However, it is possible that nanomedicine in future would play a crucial role in the treatment of human diseases and also in enhancement of normal human physiology.

Hepatoprotective activity of six polyherbal formulations in paracetamol induced liver toxicity in mice.

BACKGROUND & OBJECTIVE: Polyherbal formulations available with a wide range of indications like protective to liver, appetite and growth promoters, gastrointestinal and hepatic regulator, as treatment for hepatic dysfunction, for hepatic regeneration as well as liver stimulant and tonic. Despite the widespread use, there is a lack of scientific evidence on their efficacy and safety. This study was undertaken to evaluate the hepatoprotective activity of six commercially available formulations, namely Liv 52, Livergen, Livokin, Octogen, Stimuliv and Tefroliv in acute liver toxicity in mice model induced by paracetamol (PCM). METHODS: Swiss albino mice of either sex were used, divided in 28 groups with six in each group. The dose of the polyherbal formulations was calculated from human dose (20 ml/day) using a standard conversion table. They were given as pretreatment (2.60 ml/kg/day) for 7 days by oral route twice a day prior to PCM administration. Hepatotoxicity was induced by administering a single oral dose of PCM (500 mg/kg bw) on day 8. The study parameters were conducted on day 9. The biochemical parameters included liver enzyme levels alanine tranaminases (ALT), aspartate transaminases (AST) and alkaline phosphatase (ALP). The pharmacological and pathological parameters were phenobarbitone sleeping time and macroscopic and microscopic changes of liver tissues respectively. RESULTS: PCM toxicity significantly increased ALT, AST and ALP (321.00 +/- 87.93, 273.17 +/- 45.68, 257.50 +/- 17.64 IU/l vs normal control, 33.33 +/- 0.61, 89.33 +/- 9.50, 152.17 +/- 11.40 IU/l respectively, P<0.05), prolonged phenobarbitone induced sleeping time (from 277.50 +/- 8.04 min to 335.83 +/- 7.00 min, P<0.05). When PCM higher dose (1g/kg p.o. single dose) was used, the liver tissue, in macroscopic appearance, showed extensive necrosis associated with haemorrhages. Low dose (500 mg/kg p.o. single dose) showed punctate haemorrhagic necrosis of liver tissue. In the microscopic studies, PCM induced toxicity showed haemorrhages, fatty changes and necrosis. The pretreatment in low doses (2.6 ml/kg/day) with liquid formulations of Liv 52 and Livergen reversed the PCM induced liver toxicity. At higher doses (5.2 ml/ kg/day), all the six herbal formulations conclusively showed marked beneficial effects in the studied pharmacological, biochemical and histological parameters. INTERPRETATION & CONCLUSION: The present findings demonstrated the efficacy of polyherbal liquid formulations at two dose levels in PCM induced hepatotoxicity in mice. However, it suggests that a dose adjustment may be necessary to optimize the effects in clinical settings.

Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine.

Silymarin, a flavonolignan from 'milk thistle' (Silybum marianum) plant is used almost exclusively for hepatoprotection and amounts to 180 million US dollars business in Germany alone. In this review we discuss about its safety, efficacy and future uses in liver diseases. The use of silymarin may replace the polyherbal formulations and will avoid the major problems of standardization, quality control and contamination with heavy metals or bacterial toxins. Silymarin consists of four flavonolignan isomers namely--silybin, isosilybin, silydianin and silychristin. Among them, silybin being the most active and commonly used. Silymarin is orally absorbed and is excreted mainly through bile as sulphates and conjugates. Silymarin offers good protection in various toxic models of experimental liver diseases in laboratory animals. It acts by antioxidative, anti-lipid peroxidative, antifibrotic, anti-inflammatory, membrane stabilizing, immunomodulatory and liver regenerating mechanisms. Silymarin has clinical applications in alcoholic liver diseases, liver cirrhosis, Amanita mushroom poisoning, viral hepatitis, toxic and drug induced liver diseases and in diabetic patients. Though silymarin does not have antiviral properties against hepatitis virus, it promotes protein synthesis, helps in regenerating liver tissue, controls inflammation, enhances glucuronidation and protects against glutathione depletion. Silymarin may prove to be a useful drug for hepatoprotection in hepatobiliary diseases and in hepatotoxicity due to drugs. The non traditional use of silymarin may make a breakthrough as a new approach to protect other organs in addition to liver. As it is having a good safety profile, better patient tolerability and an effective drug at an affordable price, in near future new derivatives or new combinations of this drug may prove to be useful.

Do mast cell degranulators release prostaglandins from frog atria?

Isolated atria of frogs responded to compound 48/80 and d-tubocurarine with a delayed stimulation that showed tachyphylaxis and cross-tachyphylaxis indicating a common indirect mechanism. The blockers of H2-histamine, serotonin and beta-adrenergic receptors did not significantly antagonise these responses. However, in experiments with ex vivo and in vitro indomethacin-treated atria, the stimulant effects of mast cell degranulators were not observed, indicating a possible involvement of the prostaglandins.

Seasonal variation in amylase, invertase, cellulase activity and carbon dioxide evolution in a tropical protected grassland of Orissa, India, sprayed with carbaryl insecticide.

A distinct seasonal variation in the enzyme activities and carbon dioxide evolution in soil, with a maximum in summer, was observed in soil treated with carbaryl and in control soil. There was no significant difference in the rate of enzyme activity between 0 and 10 cm and 10 and 20 cm depth of soil. Carbaryl insecticide applied at a normal agricultural dose did not have any inhibitory effect on soil enzyme activity, or on the rate of CO(2) evolution. However, the cellulase activity was greater in the surface soil of the control plot than in the treated plot.

Psycho-social dysfunctions in patients after recovery from mania and depression.

Contrary to popular opinion, complete functional recovery does not occur in approximately 25% of patients with a diagnosis of mood disorders. The current study aimed at finding the recovery status in major mood disorders. A sample group of 122 patients (77 bipolar and 45 major depression) was selected from the outpatient department, fulfilling the DSM-IV diagnostic criteria. All patients had their index episodes at least one year prior to their date of inclusion and were either asymptomatic or mildly symptomatic during that time. Manics and depressives were rated with the Bech Raefelson Mania Scale (BRMS) and Hamilton Depression Rating Scale (HDRS) respectively. All the patients were also rated on the Brief Psychiatric Rating Scale (BPRS), Dysfunction Analysis Questionnaire (DAQ) and Global Evaluation Scale of Disability Assessment Schedule by WHO (GES/DAS). They were compared with 40 age and sex matched normal controls. It was found that the symptomatic recovery was better than the functional recovery in both manics and depressives and patients with major depression were marginally more dysfunctional compared to those with mania. It is concluded that a majority of patients of both mania and depression do not achieve complete functional recovery and are in need of on-going psychosocial rehabilitation.

Cutaneous rhinosporidiosis in a patient of lepromatous leprosy--a case report.

A rare coincidence of cutaneous Rhinosporidiosis and Lepromatous leprosy is reported. The clinical course of the cutaneous nodules simulated the feature of certain histoid nodule with ulceration.

First care givers of mentally ill patients: a multicenter study.

Pathways to psychiatric care were evaluated among three hundred and eighty four first-contact psychiatric patients from five socio-culturally different regions of India by a modified version of World Health Organization encounter form for 'pathways in psychiatric care'. Concerning first caregivers, out of 384 respondents 34.1% had chosen the psychiatrists, 29.4% the general practitioners and 26% had chosen faith healers and exorcists. Choice for the first caregiver was not influenced by gender differences, literacy status and family type. Mostly the subjects hailing from rural areas and those presenting with somatic symptoms chose psychiatrist as their first caregivers.

Hepatoprotective activities of picroliv, curcumin, and ellagic acid compared to silymarin on carbon-tetrachloride-induced liver toxicity in mice.

INTRODUCTION: To evaluate the hepatoprotective activity of active phytochemicals, picroliv, curcumin, and ellagic acid in comparison to silymarin in the mice model of carbon tetrachloride (CCl(4)) induced liver toxicity. In addition, attempts were made to elucidate their possible mechanism(s) of action. MATERIALS AND METHODS: Oxidative stress was induced in Swiss albino mice by a single injection (s.c.) of CCl(4), 1 ml/kg body weight, diluted with arachis oil at a 1:1 ratio. The phytochemicals were administered once a day for 7& days (p.o.) as pretreatment at two dose levels (50 and 100 mg/kg/day). RESULTS: CCl(4)-induced hepatotoxicity was manifested by an increase in the activities of liver enzymes (alanine transaminase, P < 0.001, aspartate transaminase, P < 0.001 and alkaline phosphatase, P < 0.001), malondialdehyde (MDA, P < 0.001)) levels and a decrease in activity of reduced glutathione (P < 0.001) and catalase in liver tissues. The histopathological examination of liver sections revealed centrizonal necrosis, fatty changes, and inflammatory reactions. The pretreatment with picroliv, curcumin, and ellagic acid normalized serum aminotransferase activities (P < 0.001), decreased levels of MDA (P < 0.001), improved the antioxidant status, and normalized the hepatic histo-architecture. The restoration of phenobarbitone-induced sleeping time also suggested the normalization of liver cytochrome P450 enzymes. CONCLUSION: This study supports the use of these active phytochemicals against toxic liver injury, which may act by preventing lipid peroxidation, augmenting the antioxidant defense system or by regenerating the hepatocytes.

Role of pharmacogenomics in drug discovery and development.

Pharmacogenetics and pharmacogenomics are two major emerging trends in medical sciences, which influence the success of drug development and therapeutics. In current times, though pharmacogenetic studies are being done extensively for research, its application for drug development needs to get started on a large scale. The major determinants of success of a new drug compound, viz safety and efficacy, have become more predictable, with the advent of pharmacogenetic studies. There is a need felt for pharmacogenomic studies, where the effects of multiple genes are assessed with the study of entire genome.Pharmacogenetic studies can be used at various stages of drug development. The effect of drug target polymorphisms on drug response can be assessed and identified. In clinical studies, pharmacogenetic tests can be used for stratification of patients based on their genotype, which corresponds to their metabolizing capacity. This prevents the occurrence of severe adverse drug reactions and helps in better outcome of clinical trials. This can also reduce attrition of drug compounds. Further, the variations in drug response can be better studied with the wider application of pharmacogenomic methods like genome wide scans, haplotype analysis and candidate gene approaches. The cost of pharmacogenetic testing has become very low, with the advent of newer high throughput genotyping systems. However, the cost of pharmacogenomic methods continues to be very high. As the treatment with several drugs is being more and more pharmacogeneticaly guided (e.g. warfarin and irinotecan), the FDA has laid down guidelines for pharmaceutical firms regarding submission of pharmacogenetic data for their drug products in labelling.