Peroxisome proliferator-activated receptor-gamma (PPARgamma) has been implicated in the growth inhibition of a number of cancer cells. In the present study, we investigated the antitumor effect of the PPARgamma agonist rosiglitazone in U87MG human glioma cells. Rosiglitazone treatment in vitro reduced cell proliferation without induction of cell death in a dose- and time-dependent manner. Rosiglitazone decreased cell migration and mRNA level of MMP-9. Rosiglitazone treatment also induced marked changes in glioma cell morphology. Oral administration of rosiglitazone in animals with subcutaneous U87MG glioma cells reduced tumor volume. Subsequent tumor tissue analysis showed that rosiglitazone decreased the number of PCNA-positive staining cells and MMP-9 expression and induced apoptosis of tumor cells. These data suggest that rosiglitazone exerts antineoplastic effect in U87MG cells and may serve as potential therapeutic agent for malignant human gliomas.
Administration, Oral ; Animals ; Apoptosis ; Cell Death ; Cell Movement ; Cell Proliferation ; Glioma ; Humans ; Peroxisomes ; PPAR gamma ; RNA, Messenger ; Thiazolidinediones ; Tumor Burden

OBJECTIVEWe designed a multi-center, double-blind, randomized, parallel, with metformin controlled clinical trial to evaluate the efficacy and safety of low dose rosiglitazone combined with sulphonylurea therapy in type 2 diabetic patients who were inadequately controlled with sulphonylurea alone.

METHODSPatients were treated with 4 mg rosiglitazone once daily plus sulphonylurea (test group) or 0.5 g metformin twice daily plus sulphonylurea (control group) for 12 weeks. The mean levels of HbA(1c), fasting and postprandial plasma glucose were recorded and compared between the two groups.

RESULTSThe mean levels of HbA(1c) decreased by 1.09% and 0.95% in the test group (n = 102) and control group (n = 96) respectively. Fasting and postprandial plasma glucose levels in the test group decreased by 25.0% and 35.6%, and in the control group, decreased by 17.7% and 23.8% as compared with the baseline (both P < 0.01). No liver damage was found.

CONCLUSIONCombination treatment of rosiglitazone and sulphonylurea can effectively improve glycemic control in type 2 diabetic patients inadequately controlled with sulphonylurea alone.

Adult ; Aged ; Blood Glucose ; analysis ; Diabetes Mellitus, Type 2 ; drug therapy ; Double-Blind Method ; Drug Therapy, Combination ; Humans ; Hypoglycemic Agents ; administration & dosage ; Metformin ; administration & dosage ; Middle Aged ; Sulfonylurea Compounds ; administration & dosage ; Thiazoles ; administration & dosage ; Thiazolidinediones

The prevalence of type 2 diabetes mellitus in the Korea has increased dramatically over the past decade. Clinicians can prescribe the following six currently available classes of oral hypoglycemic agents: sulfonylureas, meglitinides, biguanides, thiazolidinediones, alpha-glucosidase inhibitors and dipeptidyl peptidase inhibitors. The availability of various oral hypoglycemic agents has given rise to several adverse effects and may result in worse outcomes in patients with comorbid conditions such as liver dysfunction, renal impairment and heart failure. When taking a cross-sectional view of hepatic dysfunction, we find that hepatitis B and alcoholic liver disease are most prevalent in Korea. The use of oral hypoglycemic agents in type 2 diabetic patients with hepatic dysfunction requires many considerations.
Administration, Oral ; alpha-Glucosidases ; Biguanides ; Diabetes Mellitus, Type 2 ; Heart Failure ; Hepatitis B ; Humans ; Hypoglycemic Agents ; Korea ; Liver Diseases ; Liver Diseases, Alcoholic ; Prevalence ; Protease Inhibitors ; Thiazolidinediones

AIMTo develop limited sampling strategy (LSS) for estimation of C(max) and AUC(0-t) and assessing the bioequivalence of two pioglitazone hydrochloride (PGT) preparations.

METHODSHealthy subjects (n = 20), enrolled in a bioequivalence study, were received 30 mg PGT po of reference or test formulation. The plasma concentration of PGT was determined by the validated HPLC method. A multiple linear regression analysis of the Cmax and AUC(0-t) against the PGT concentration for the reference formulation was carried out to develop LSS models to estimate these parameters. The models were internally validated by the Jackknife method and externally validated using simulated sets generated by Monte Carlo method. The best model was employed to assess bioequivalence of the two PGT formulations.

RESULTSThe linear relationship between pharmacokinetics parameters and single concentration point was poor. Several models for these parameters estimation met the predefined criteria (r2 > 0.9). The Jackknife validation procedure revealed that LSS models based on two sampling times (C1, C2.5 and C1.5, C2.5 for C(max); C1.5, C9 and C2.5, C9 for AUC(0-t) predict accurately. Mean prediction errors (MPE) were less than 3%, and mean absolute prediction error (MAE) were less than 9%. The prediction error (PE) beyond 20% was less than 5% of total samples. Model external validation by Monte Carlo simulated data indicated that the most informative sampling combinations were C1.5, C2.5 for C(max), and C1.5, C9 for AUC(0-t), respectively. MPE and MAE of the proposed models were less than 5% , and 9% respectively. The PE beyond 20% was less than 5% of the total. Bioequivalence assessment of the two PGT formulations, based on the best LSS models, provided results similar to those obtained using all the observed concentration-time data points, and indicated that the two PGT formulations were bioequivalent.

CONCLUSIONThe LSS method for bioequivalence assessment of PGT formulations was established and proved to be applicable and accurate. Thus, it could be considered appropriate for PGT bioequivalence study with inexpensive cost of sampling acquisition and analysis. Key words: pioglitazone hydrochloride; limited sampling strategy; Monte Carlo simulation; bioequivalence

Administration, Oral ; Adult ; Area Under Curve ; Chromatography, High Pressure Liquid ; Humans ; Hypoglycemic Agents ; administration & dosage ; blood ; pharmacokinetics ; Male ; Models, Biological ; Monte Carlo Method ; Sample Size ; Therapeutic Equivalency ; Thiazolidinediones ; administration & dosage ; blood ; pharmacokinetics

The object of this study is to investigate the pharmacokinetic interaction of pioglitazone hydrochloride and atorvastatin calcium in healthy adult Beagle dogs following single and multiple oral dose administration. A randomized, cross-over study was conducted with nine healthy adult Beagle dogs assigned to three groups. Each group was arranged to take atorvastatin calcium (A), pioglitazone hydrochloride (B), atorvastatin calcium and pioglitazone hydrochloride (C) orally in the first period, to take B, C, A in the second period, and to take C, A, B in the third period for 6 days respectively. The blood samples were collected at the first and the sixth day after the administration, plasma drug concentrations were determined by LC-MS/MS, a one-week wash-out period was needed between each period. The pharmacokinetic parameters of drug combination group and the drug alone group were calculated by statistical moment method, calculation of C(max) and AUC(0-t) was done by using 90% confidence interval method of the bioequivalence and bioavailability degree module DAS 3.2.1 software statistics. Compared with the separate administration, the main pharmacokinetic parameters (C(max) and AUC(0-t)) of joint use of pioglitazone hydrochloride and atorvastatin calcium within 90% confidence intervals for bioequivalence statistics were unqualified, the mean t(max) with standard deviation used paired Wilcoxon test resulted P > 0.05. There was no significant difference within t1/2, CL(int), MRT, V/F. Pioglitazone hydrochloride and atorvastatin calcium had pharmacokinetic interaction in healthy adult Beagle dogs.
Administration, Oral ; Animals ; Anticholesteremic Agents ; administration & dosage ; blood ; pharmacokinetics ; Area Under Curve ; Atorvastatin Calcium ; administration & dosage ; blood ; pharmacokinetics ; Biological Availability ; Cross-Over Studies ; Dogs ; Drug Interactions ; Female ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; administration & dosage ; blood ; pharmacokinetics ; Hypoglycemic Agents ; administration & dosage ; blood ; pharmacokinetics ; Male ; Random Allocation ; Thiazolidinediones ; administration & dosage ; blood ; pharmacokinetics

BACKGROUNDFew studies have given suggestions on appropriate initiation insulin dosage when combined with oral antidiabetic drugs (OADs). This research was to investigate appropriate initiation insulin doses for insulin-naive type 2 diabetes patients with different combinations and the relationship between insulin dosage and relevant factors.

METHODSThis was a randomized, open-label, treat to target study. The target was 20% decrease of both fasting plasma glucose (FPG) and 2 hours post-breakfast blood glucose (P2hBG). One hundred and forty-seven insulin-naive Chinese patients recruited were randomly assigned to 3 groups: group A, patients received insulin monotherapy; group B, received insulin plus metformin (0.5 g, tid) and group C, received insulin plus metformin (0.5 g, tid) and pioglitazone (15 mg, qd). Insulin doses were initiated with a dose of 0.3 U×kg(-1)×d(-1) and titrated according to FPG and P2hBG till reached the targets.

RESULTSBoth the time of getting 20% reduction of FPG and P2hBG showed significant differences among the three groups. The time was shortest in Group C. The insulin doses needed to achieve glucose reduction of 20% in three treatment groups were (0.40 ± 0.04) U×kg(-1)×d(-1) for Group A, (0.37 ± 0.04) U×kg(-1)×d(-1) for Group B, and (0.35 ± 0.03) U×kg(-1)×d(-1) for Group C, respectively. Multiple linear stepwise regression analysis showed that insulin doses correlated with body weight, FPG, diabetes duration, age and history of sulfonylurea treatment. The standardized regression coefficients were 0.871, 0.322, 0.089, 0.067 and 0.063 (with all P < 0.05).

CONCLUSIONSTo achieve blood glucose's reduction of 20% within safety context, initial insulin doses were recommended as the following: 0.40 U×kg(-1)×d(-1) for insulin mono-therapy, 0.37 U×kg(-1)×d(-1) for insulin plus metformin treatment, and 0.35 U×kg(-1)×d(-1) for insulin plus metformin and pioglitazone treatment in Chinese type 2 diabetes outpatients. Body weight is found the most closely related factor to the insulin dosage.

Adult ; Aged ; Blood Glucose ; analysis ; Body Weight ; drug effects ; Diabetes Mellitus, Type 2 ; blood ; drug therapy ; Drug Therapy, Combination ; Female ; Humans ; Hypoglycemic Agents ; administration & dosage ; Insulin ; administration & dosage ; adverse effects ; therapeutic use ; Linear Models ; Male ; Metformin ; administration & dosage ; adverse effects ; Middle Aged ; Outpatients ; Regression Analysis ; Thiazolidinediones ; administration & dosage ; adverse effects

BACKGROUNDAs an agonist of peroxisome proliferator-activated receptor-gamma (PPARγ), rosiglitazone can prevent acute fatty acid-induced insulin resistance in rats, however, the precise mechanisms by which rosiglitazone alleviates insulin resistance induced by high-fat diet need to be further investigated.

METHODSWistar rats aged 23-24 weeks were divided into three groups: (1) aged control group (OC), (2) high-fat diet (HF) group and (3) high-fat diet plus rosiglitazone maleate tablets (HF + Rosi) treatment group (n = 20 in each group). Insulin sensitivity was evaluated by conscious hyperinsulinemic-euglycemic clamp technique. mRNA levels of fatty acid translocase (FAT/CD36), AMP-activated protein kinase α1 (AMPKα1), AMPKα2 and acetyl CoA carboxylase (ACC) of rat skeletal muscle were determined using real-time PCR, while muscle carnitine palmitoyltransferase-1 (CPT-1β) was determined using semi-quantitative PCR. Protein expression levels of FAT/CD36, AMPK phosphorylation (reflecting AMPK activity), P-ACC (inversely related with ACC activity) and muscle CPT-1M in rat skeletal muscles were measured using Western blotting.

RESULTSAged rats fed by diet rich in fat for more than 8 weeks led to significant increases of plasma lipids, skeletal muscle intramuscular triglyceride and long-chain fatty acyl-CoA (LCACoA) compared to aged rats fed by normal chow diet (OC) (P < 0.05), which might correlate with the lower (reduced by 42.4%) whole body insulin sensitivity in HF rats. FAT/CD36 protein concentrations and mRNA levels increased in untreated HF aged rats (P < 0.01) and high-fat diet induced a significant decrease in P-AMPK, P-ACC, CPT-1M protein concentrations and AMPKα2 and CPT-1β mRNA levels in rat skeletal muscles (P < 0.05). No change in AMPKα1 mRNA levels was observed in the HF group.

CONCLUSIONHigh-fat diet in aged rats results in a lipid accumulation and subsequent insulin resistance, while rosiglitazone can alleviate the insulin resistance by reducing fatty acid uptake as well as enhancing lipometabolism.

AMP-Activated Protein Kinases ; genetics ; Acetyl-CoA Carboxylase ; genetics ; Animals ; CD36 Antigens ; genetics ; Dietary Fats ; administration & dosage ; Hypoglycemic Agents ; pharmacology ; Insulin Resistance ; Male ; Muscle, Skeletal ; enzymology ; RNA, Messenger ; analysis ; Rats ; Rats, Wistar ; Thiazolidinediones ; pharmacology

PURPOSE: Thiazolidinediones are insulin-sensitizing agents that reduce neointimal proliferation and the adverse clinical outcomes associated with percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM). There is little data on whether or not low dose pioglitazone reduces adverse clinical outcomes. MATERIALS AND METHODS: The study population included 121 DM patients with coronary artery disease and they were randomly assigned to 60 patients taking 15 mg of pioglitazone daily in addition to their diabetic medications and 61 patients with placebo after the index procedure with drug-eluting stents (DESs). The primary end points were rate of in-stent restenosis (ISR) and change in atheroma volume and in-stent neointimal volume. The secondary end points were all-cause death, myocardial infarction (MI), stent thrombosis and re-PCI. RESULTS: There were no statistical differences in the clinical outcomes and the rate of ISR between the two groups [all-cause death; n=0 (0%) in the pioglitazone group vs. n=1 (1.6%) in the control group, p=0.504, MI; n=2 (3.3%) vs. n=1 (1.6%), p=0.465, re-PCI; n=6 (10.0%) vs. n=6 (9.8%), p=0.652, ISR; n=4 (9.3%) vs. n=4 (7.5%), p=1.000, respectively]. There were no differences in changes in neointimal volume, percent neointimal volume, total plaque volume and percent plaque volume between the two groups on intravascular ultrasonography (IVUS) study. CONCLUSION: Our study demonstrated that low dose pioglitazone does not reduce rate of ISR, neointimal volume nor atheroma volume in DM patients who have undergone PCI with DESs, despite the limitations of the study.
Aged ; Coronary Artery Disease/drug therapy/radiography/*therapy ; Coronary Restenosis/*prevention & control ; *Drug-Eluting Stents ; Female ; Humans ; Hypoglycemic Agents/therapeutic use ; Male ; Middle Aged ; Thiazolidinediones/administration & dosage/*therapeutic use

Renal tubulointerstitial fibrosis is the common ending of progressive renal disease. It is worth developing new ways to stop the progress of renal fibrosis. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have been studied to treat diabetic nephropathy, cisplatin-induced acute renal injury, ischemia reperfusion injury and adriamycin nephropathy. In this study, unilateral ureteral obstruction (UUO) was used to establish a different renal fibrosis model. PPAR? agonist pioglitazone was administrated by oral gavage and saline was used as control. At 7th and 14th day after the operation, mice were sacrificed for fibrosis test and T lymphocytes subsets test. Unexpectedly, through MASSON staining, immunohistochemistry for α-SMA, and Western blotting for a-SMA and PDGFR-β, we found that pioglitazone failed to attenuate renal fibrosis in UUO mice. However, flow cytometry showed that pioglitazone down-regulated Th1 cells, and up-regulated Th2 cells, Th17 cells and Treg cells. But the Th17/Treg ratio had no significant change by pioglitazone. Real-time PCR results showed that TGF-β and MCP-1 had no significant changes, at the same time, CD4(+) T cells associated cytokines were partially regulated by pioglitazone pretreatment. Taken together, pioglitazone failed to suppress renal fibrosis progression caused by UUO.
Animals ; Chemokine CCL2 ; metabolism ; Fibrosis ; Kidney ; pathology ; Kidney Diseases ; drug therapy ; etiology ; Male ; Mice ; Mice, Inbred C57BL ; PPAR gamma ; agonists ; T-Lymphocyte Subsets ; drug effects ; Thiazolidinediones ; administration & dosage ; pharmacology ; therapeutic use ; Transforming Growth Factor beta ; metabolism ; Urethral Obstruction ; complications

Patients with hyperglycemia are at a high risk of cardio- and cerebrovascular diseases. Diabetes patients also have poor outcomes after cerebrovascular disease development. Several classes of drugs are used for diabetes management in clinical practice. Thiazolidinedione (TZD) was introduced in the late 1990s, and new antidiabetic agents have been introduced since 2000. After issues with rosiglitazone in 2007, the U.S. Food and Drug Administration strongly recommended that trials investigating cardiovascular risk associated with new antidiabetic medications should be conducted before drug approval in the United States, to prove the safety of these new drugs and to determine their superiority to previous medications. Currently, results are available from two studies with TZD focusing on cardiovascular diseases, including stroke, and from 12 cardiovascular outcome trials focusing on major adverse cardiovascular events associated with new antidiabetic agents (four with dipeptidyl peptidase-4 inhibitors, three with sodium-glucose cotransporter-2 inhibitors, and five with glucagon-like peptide-1 analogues). These studies showed different results for primary cardiovascular outcomes and stroke prevention. It is important to determine whether prescription of TZD or new antidiabetic medications compared to conventional treatment, such as sulfonylurea or insulin, is better for stroke management. Furthermore, it is unclear whether drugs in the same class show greater safety and efficacy than other drugs for stroke management.
Cardiovascular Diseases ; Cerebrovascular Disorders ; Diabetes Mellitus ; Dipeptidyl-Peptidase IV Inhibitors ; Drug Approval ; Glucagon-Like Peptide 1 ; Humans ; Hyperglycemia ; Hypoglycemic Agents ; Insulin ; Prescriptions ; Stroke ; Thiazolidinediones ; United States ; United States Food and Drug Administration