ao-128 and Drug-Related-Side-Effects-and-Adverse-Reactions

Unfortunately, clinicians are diagnosing a growing number of patients on hemodialysis (HD) with insulin-resistant, Type 2 diabetes in Japan. While alpha-glucosidase inhibitors (alpha-GI) such as oral antidiabetic agents are indicated for Japanese diabetics on HD, pioglitazone and other PPARgamma agonists are now contraindicated. No prospective study has evaluated the use of thiazolidinediones in diabetics with end-stage renal disease (ESRD) in combination with alpha-GI. In this study we evaluated the efficacy and safety of pioglitazone in Japanese diabetics on HD.. An open-label randomized study was performed on 31 Type 2 diabetics on HD with unstable glycemic control receiving constant doses of voglibose. The patients were randomly assigned to two groups: a combination therapy group (pioglitazone group) administered pioglitazone (fixed dose 30 mg) plus voglibose, and a monotherapy group (control group) administered voglibose alone. The efficacy of the treatments was determined by monitoring glycemic control (plasma glucose and HbA1c) and insulin resistance. Insulin resistance was assessed using the homeostasis model assessment for insulin resistance (HOMA-R). Safety and tolerance were determined by monitoring clinical and laboratory parameters.. The pioglitazone was effective in reducing plasma glucose and HbA1c from the baseline levels from Week 4 onward. It was also effective in reducing triglycerides. HOMA-R decreased significantly at 4 weeks in the pioglitazone group, and the decrease continued up to the last measurement at Week 12. Systolic and diastolic blood pressures at 4 weeks were statistically lower in the pioglitazone group than in the control group. No serious adverse effects such as hypoglycemia, liver impairment or rhabdomyolysis were observed in any of the patients.. Pioglitazone was safe and effective as a treatment for diabetics on dialysis therapy. The 30 mg daily dose of pioglitazone was sufficient for Japanese HD patients, obese and nonobese alike. The combination therapy of pioglitazone with voglibose will add to the list of first-line drug treatments for glycemic control in uremic Type 2 diabetes.

Topics: Aged; Asian People; Blood Glucose; Case-Control Studies; Demography; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inositol; Insulin Resistance; Japan; Lipids; Male; Pioglitazone; Renal Dialysis; Thiazolidinediones

An open-label prospective cross-over trial was performed to compare the efficacy and adverse effects of nateglinide with those of voglibose on Japanese early type 2 diabetes (who were oral hypoglycemic agent naïve and whose HbA(1C) levels were between 7.0 and 7.9% before treatment). Fourteen patients received 270 mg/day of nateglinide and 15 patients received 0.6 mg/day of voglibose. After 12 weeks of either therapy, the drugs were switched and treatment was continued for another 12 weeks. After 3-month treatment with each drug, HbA(1C) value decreased significantly (baseline HbA(1C) 7.24 +/- 0.42%, 6.70 +/- 0.47% with nateglinide: p<0.01, 6.93 +/- 0.62% with voglibose: p<0.05) but the difference in the effect between nateglinide and voglibose was not significant (p = 0.121). Symptoms related to hypoglycemia (e.g., increased appetite, palpitation, sweating, tremor) were scarcely observed with either voglibose or nateglinide treatments. Abdominal fullness/borborygmi was frequently reported, with variable severity, by patients on voglibose but this was absent or mild in those on nateglinide. After completion of both arms of the study, more patients favored nateglinide than voglibose. Our results suggest that nateglinide is an effective and safe drug in the treatment of early type 2 diabetes, similar to voglibose.

Topics: Aged; alpha-Glucosidases; Appetite; Body Weight; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Gastrointestinal Tract; Glycated Hemoglobin; Humans; Hypoglycemia; Inositol; Lipids; Liver Function Tests; Male; Middle Aged; Nateglinide; Phenylalanine; Treatment Outcome

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests