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Seiyo Ikeda - One of the best experts on this subject based on the ideXlab platform.
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amelioration of hyperglycemia in streptozotocin induced diabetic rats receiving a marginal mass of islet grafts by troglitazone an Oral Antidiabetic Agent
Pancreas, 1996Co-Authors: T Nagai, Yohichi Yasunami, Naoki Nagata, Shinichiroh Ryu, Junko Ono, Seiyo IkedaAbstract:Troglitazone, a novel Oral Antidiabetic Agent, was evaluated to determine whether it could have hypoglycemic effects in streptozotocin (STZ)-induced diabetic rats when a marginal mass of islets was transplanted and hyperglycemia persisted after transplantation. Lewis rats (RTI') were used as both donors and recipients. Five hundred fresh islets were transplanted beneath the kidney capsule of STZ-induced diabetic recipients. Troglitazone was administered Orally (0.34 mmol/kg/day) for 7 days before and for 60 days after islet transplantation. Neither troglitazone treatment without islet transplantation (n = 8) nor islet transplantation alone (n = 7) could produce normoglycemia (<11 mmol/L) in diabetic recipients by 60 days after transplantation. In marked contrast, seven of 10 rats receiving islet grafts and treated with troglitazone became normoglycemic at 26.9 ± 16.4 days (mean ± SD; n = 7) after transplantation. Removal of the kidney bearing the grafts promptly resulted in the normoglycemic recipients (n = 4) becoming diabetic again. Light and electron microscopically, the intact islets with well-granulated β cells could be observed in the transplant site of the normoglycemic recipients. These findings clearly demonstrate that the hyperglycemia in STZ-induced diabetic rats receiving an insufficient number of islet grafts to reverse diabetes was ameliorated by troglitazone treatment.
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Amelioration of hyperglycemia in streptozotocin-induced diabetic rats receiving a marginal mass of islet grafts by troglitazone, an Oral Antidiabetic Agent.
Pancreas, 1996Co-Authors: Nagai T, Yohichi Yasunami, Naoki Nagata, Shinichiroh Ryu, Junko Ono, Seiyo IkedaAbstract:Troglitazone, a novel Oral Antidiabetic Agent, was evaluated to determine whether it could have hypoglycemic effects in streptozotocin (STZ)-induced diabetic rats when a marginal mass of islets was transplanted and hyperglycemia persisted after transplantation. Lewis rats (RTI') were used as both donors and recipients. Five hundred fresh islets were transplanted beneath the kidney capsule of STZ-induced diabetic recipients. Troglitazone was administered Orally (0.34 mmol/kg/day) for 7 days before and for 60 days after islet transplantation. Neither troglitazone treatment without islet transplantation (n = 8) nor islet transplantation alone (n = 7) could produce normoglycemia (
Jeffrey A Johnson - One of the best experts on this subject based on the ideXlab platform.
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insulin versus an Oral Antidiabetic Agent as add on therapy in type 2 diabetes after failure of an Oral Antidiabetic regimen a meta analysis
Open Medicine, 2008Co-Authors: Johnmichael Gamble, Scot H Simpson, Lauren C Brown, Jeffrey A JohnsonAbstract:Background: Although evidence-based guidelines for the treatment of type 2 diabetes mellitus provide clear recommendations for initial therapy, evidence on an optimal treatment strategy after secondary failure is unclear. Purpose: To compare the efficacy of add-on therapy using basal insulin versus an additional Oral Antidiabetic Agent in patients with type 2 diabetes and secondary failure.
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dose response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus a population based cohort study
Canadian Medical Association Journal, 2006Co-Authors: Scot H Simpson, Sumit R Majumdar, Ross T Tsuyuki, Dean T Eurich, Jeffrey A JohnsonAbstract:Background: Over the past 30 years, the relation between use of sulfonylureas to treat type 2 diabetes and the risk of cardiovascular events has been vigorously debated. The purpose of this study was to determine if the risk of death changes with level of exposure to sulfonylurea drugs. Methods: This was a retrospective, inception cohort study using administrative data from Saskatchewan Health (1991– 1999). The 5795 subjects, identified by their first-ever dispensation for an Oral Antidiabetic Agent, were grouped according to their use of such Agents during follow-up. Potential subjects using insulin or combination therapy were excluded. Exposure level was defined by daily dose and degree of adherence. Separate multivariate Cox proportional-hazard models were constructed for each monotherapy group and used to calculate the risk of death associated with higher versus lower exposure category. Disease severity indicators were identified among the administrative data and entered as covariates in each model. The main outcomes were all-cause mortality and death from an acute ischemic event. Results: The mean age of the cohort members was 66.3 (standard deviation [SD] 13.4) years; 43.4% were female; and their mean duration of follow-up was 4.6 (SD 2.1) years. First-generation sulfonylureas were used exclusively by 120 subjects; glyburide, by 4138; and metformin, by 1537. A greater risk of death was associated with higher daily doses of the first-generation sulfonylureas (adjusted hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.0–4.7) and glyburide (HR 1.3, 95% CI 1.2–1.4), but not metformin (HR 0.8, 95% CI 0.7–1.1). Similar associations were observed for death caused by an acute ischemic event. Interpretation: Higher exposure to sulfonylureas was associated with increased mortality among patients newly treated for type 2 diabetes. The same relation was not observed with metformin. This implies that the manner in which blood glucose concentration is lowered may be as important as achieving recommended glucose targets.
Thomas A Baillie - One of the best experts on this subject based on the ideXlab platform.
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studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission
Chemical Research in Toxicology, 2001Co-Authors: Kelem Kassahun, Paul G Pearson, Wei Tang, Ian Mcintosh, Kwan Leung, Charles S Elmore, Dennis C Dean, Regina W Wang, George A Doss, Thomas A BaillieAbstract:Therapy with the Oral Antidiabetic Agent troglitazone (Rezulin) has been associated with cases of severe hepatotoxicity and drug-induced liver failure, which led to the recent withdrawal of the product from the U.S. market. While the mechanism of this toxicity remains unknown, it is possible that chemically reactive metabolites of the drug play a causative role. In an effort to address this possibility, this study was undertaken to determine whether troglitazone undergoes metabolism in human liver microsomal preparations to electrophilic intermediates. Following incubation of troglitazone with human liver microsomes and with cDNA-expressed cytochrome P450 isoforms in the presence of glutathione (GSH), a total of five GSH conjugates (M1−M5) were detected and identified tentatively by LC−MS/MS analysis. In two cases (M1 and M5), the structures of the adducts were confirmed by NMR spectroscopy and/or by comparison with an authentic standard prepared by synthesis. The formation of GSH conjugates M1−M5 reveale...
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studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission
Chemical Research in Toxicology, 2001Co-Authors: Kelem Kassahun, Paul G Pearson, Wei Tang, Ian Mcintosh, Kwan Leung, Charles S Elmore, Dennis C Dean, Regina W Wang, George A Doss, Thomas A BaillieAbstract:Therapy with the Oral Antidiabetic Agent troglitazone (Rezulin) has been associated with cases of severe hepatotoxicity and drug-induced liver failure, which led to the recent withdrawal of the product from the U.S. market. While the mechanism of this toxicity remains unknown, it is possible that chemically reactive metabolites of the drug play a causative role. In an effort to address this possibility, this study was undertaken to determine whether troglitazone undergoes metabolism in human liver microsomal preparations to electrophilic intermediates. Following incubation of troglitazone with human liver microsomes and with cDNA-expressed cytochrome P450 isoforms in the presence of glutathione (GSH), a total of five GSH conjugates (M1-M5) were detected and identified tentatively by LC-MS/MS analysis. In two cases (M1 and M5), the structures of the adducts were confirmed by NMR spectroscopy and/or by comparison with an authentic standard prepared by synthesis. The formation of GSH conjugates M1-M5 revealed the operation of two distinct metabolic activation pathways for troglitazone, one of which involves oxidation of the substituted chromane ring system to a reactive o-quinone methide derivative, while the second involves a novel oxidative cleavage of the thiazolidinedione (TZD) ring, potentially generating highly electrophilic alpha-ketoisocyanate and sulfenic acid intermediates. When troglitazone was administered Orally to a rat, samples of bile were found to contain GSH conjugates which reflected the operation of these same metabolic pathways in vivo. The finding that metabolism of the TZD ring of troglitazone was catalyzed selectively by P450 3A enzymes is significant in light of the recent report that troglitazone is an inducer of this isoform in human hepatocytes. The implications of these results are discussed in the context of the potential for troglitazone to covalently modify hepatic proteins and to cause oxidative stress through redox cycling processes, either of which may play a role in drug-induced liver injury.
Nobuyuki Takasu - One of the best experts on this subject based on the ideXlab platform.
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Cardioprotective effects of troglitazone in streptozotocin-induced diabetic rats.
Metabolism: clinical and experimental, 1996Co-Authors: Michio Shimabukuro, Satoshi Higa, Tatsushi Shinzato, Fumio Nagamine, Ichiro Komiya, Nobuyuki TakasuAbstract:Troglitazone, a new Oral Antidiabetic Agent, shows hypoglycemic effects in insulin-resistant animal models and humans. This study was conducted to evaluate the effects of troglitazone on the heart of diabetic animals. Streptozotocin (STZ)-induced diabetic rats and age-matched controls were treated with troglitazone as a 0.2% food admixture for 6 weeks. Basal and postischemic cardiac functions at 14 weeks of age were then examined in isolated working heart. Troglitazone treatment did not attenuate the insulinopenia and hyperglycemia of diabetic rats, but it partially improved the hypertriglyceridemia. Troglitazone treatment partially restored the basal heart rate and cardiac work of diabetic rats to nearly control values. Troglitazone also improved the postischemic functional deficits of diabetic rats: heart rate (untreated 61% of baseline at 30-minute reperfusion v treated 92%, P < .001), left ventricular (LV) developed pressure (54% v 94%, P < .001), peak positive ([LV + dPdt] 54% v 93%, P < .001) and negative ([LV -dPdt] 53% v 94%, P < .001) first derivative of LV, and cardiac work (44% v 98%, P < .001). Diabetic animals showed ultrastructural damage including disarray of sarcomere, disorganization of mitochondrial matrix, cytoplasmic vacuolization, and invagination of nuclear membrane; these were partially normalized by troglitazone treatment. Our results suggest that troglitazone treatment has a cardioprotective effect on the basal and postischemic cardiac function of STZ-induced diabetic rats.
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Effect of troglitazone, a new Oral Antidiabetic Agent, on fructose-induced insulin resistance.
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 1995Co-Authors: N. Yagi, Nobuyuki Takasu, S. Higa, K. Ishikawa, K. Murakami, G. MimuraAbstract:Troglitazone, a newly developed Oral Antidiabetic Agent, improves hyperglycemia, and has been reported to improve insulin resistance and to decrease hepatic glucose production in diabetic animals. However, the exact mechanism of Troglitazone on the improvement of insulin resistance is not known. Chronic administration of fructose to normal rats leads to hyperglycemia, and hyperinsulinemia; it induces insulin resistance. To reveal the mechanism of Troglitazone, we studied the effect of Troglitazone on serum glucose and insulin in the fructose-induced, insulin-resistant rats. Male Sprague-Dawley (SD) rats were fed either on standard chow or one containing fructose. Troglitazone was administrated as a food admixture (150 mg/kg/day) for 8 weeks. The rats were fed on (1) standard chow, (2) standard chow and Troglitazone, (3) fructose-enriched chow, or (4) fructose-enriched chow and Troglitazone. Blood samples were obtained every two weeks, and the levels of serum glucose and insulin were measured. Fructose-enriched chow increased serum glucose and insulin levels and insulin-to-glucose ratios. Troglitazone improved the fructose-induced increases in serum glucose, insulin levels, and insulin/glucose ratios. In conclusion, Troglitazone improved the fructose-induced insulin resistance.
Evy Degrande - One of the best experts on this subject based on the ideXlab platform.
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Vildagliptin: a new Oral treatment for type 2 diabetes mellitus
Vascular Health and Risk Management, 2008Co-Authors: Chantal Mathieu, Evy DegrandeAbstract:Vildagliptin is a new Oral Antidiabetic Agent that enhances pancreatic islet cell responsiveness to glucose. An extensive clinical program involving approximately 22,000 patients and 7000 patient-years of exposure to vildagliptin has shown that the Agent is well tolerated and efficacious in improving glycemic control in patients with type 2 diabetes mellitus (T2DM). Monotherapy trials have shown that significant HbA1c lowering is accompanied by body weight-neutral and lipid-neutral effects, low risk of edema, and low risk of hypoglycemia. These characteristics make vildagliptin a favorable partner for combination therapy. Studies of vildagliptin as an add-on to metformin have shown significant improvements in glycemic control (comparable to that of thiazolidinedione add-on), with the combination being well tolerated and associated with low risks for hypoglycemia and adverse effects on weight or lipid levels. Good tolerability and clinically relevant improvements in glycemic control have also been observed with vildagliptin as an add-on treatment to sulfonylurea, thiazolidinedione, or insulin treatment or in initial combination treatment with pioglitazone. Improved β-cell function and glycemic control have been shown with vildagliptin in subjects with impaired glucose tolerance and in T2DM patients with mild hyperglycemia, with some evidence in the latter suggesting the potential for modifying disease course.