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PubMed1998

Establishing the dose response curve for metabolic control with troglitazone, an insulin action enhancer, in type 2 diabetes patients.

Troglitazone is a novel once-daily oral antidiabetic agent for the treatment of type 2 diabetes patients. Here, we report the overall dose response characteristics of troglitazone, with respect to effects on metabolic control, using a pharmacodynamic model. Data from week 12 from two previously reported double-blind, randomized, parallel-group, placebo-controlled, dose-ranging multicentre studies examining once-daily doses of 10, 30, 100, 200, 400, 600 and 800 mg of troglitazone were combined for the analyses. The pharmacodynamic relationships for relevant parameters of metabolic control were modelled using a nonlinear regression modelling programme. The troglitazone dose-concentration relationship was linear over 10-800 mg. Using an inhibitory sigmoid Emax model, ED50 values of approximately 100 mg and 200 mg were found for fasting serum glucose and triglycerides, respectively. The 200 mg dose for HbA1c showed an inconsistent reduction compared with placebo between the two studies; this illustrates the difficulties associated with comparing results from different assay techniques. Insulin and nonesterified fatty acid reductions compared with placebo were not consistent between studies, and no pharmacodynamic modelling was possible. No changes in body weight were observed at any dose. Troglitazone was as well tolerated as placebo across the dose range investigated. This pharmacodynamic analysis has established that 200-600 mg once daily can be considered the therapeutic dose range of troglitazone that significantly improves metabolic control in type 2 diabetes patients.

Adult↗
PubMed1999

Growth inhibition of myeloid leukemia cells by troglitazone, a ligand for peroxisome proliferator activated receptor gamma, and retinoids.

Peroxisome proliferator activated receptor gamma (PPARgamma) plays a central role in the process of adipocyte differentiation. This receptor and its heterodimeric partner, retinoid X receptor alpha (RXRalpha), form a DNA-binding complex that regulates transcription of adipocyte-specific genes. Troglitazone, an antidiabetic drug, has recently been identified as a synthetic ligand for PPARgamma. We studied the effects of troglitazone on proliferation and differentiation of normal and malignant hematopoietic cells. Expression of PPARgamma was easily detectable by Western blot analyses in all five myeloid leukemia cell lines. Troglitazone alone (10-5 M) did not induce differentiation in any of the cell lines; however, this compound suppressed the clonal growth (10-75% of inhibition) of all five myeloid leukemia cell lines. Myelomonocytic U937 cells, which were the most responsive to the growth suppressing effects of troglitazone, were arrested in the G1 phase of the cell cycle when cultured with this compound. Simultaneous treatment of myeloid leukemia cell lines with both troglitazone and a ligand that specifically binds either RXR (LG100268), or retinoic acid receptors (RAR, ATRA, ALART1550), or both (9-cis RA) resulted in additive suppression of clonal growth. In summary, our studies showed that troglitazone when combined with a retinoid was a moderately potent inhibitor of clonogenic growth of acute myeloid leukemia cells.

Alitretinoin↗
PubMedDate not supplied

Primary, secondary, tertiary, and quaternary treatment with troglitazone in type 2 diabetes mellitus in an outpatient clinical practice.

OBJECTIVE: To assess the value of troglitazone in various combinations of therapy with sulfonylureas, biguanides, and insulin, including triple oral agent therapy with and without insulin, in an outpatient clinical practice. METHODS: We compiled results in our first 207 patients with type 2 diabetes treated for 1 year with troglitazone. In eight study groups, troglitazone was added to the following prior regimens: (1) diet alone, (2) sulfonylurea, (3) metformin, (4) sulfonylurea and metformin, (5) insulin, (6) insulin and sulfonylurea, (7) insulin and metformin, and (8) insulin, sulfonylurea, and metformin. Glycosylated hemoglobin, fasting plasma glucose, hemoglobin, weight, and insulin dose were recorded every 3 months for 1 year and are reported. RESULTS: The glycosylated hemoglobin decreased in all study groups during the 1-year period. With the addition of troglitazone, it declined from 8.0% to 6.0% in the diet-only treatment group, from 8.9% to 7.3% in the sulfonylurea group, from 8.4% to 7.2% in the metformin group, and from 8.6% to 7.5% in the group treated with sulfonylurea and metformin. For the groups receiving insulin, glycosylated hemoglobin decreased in conjunction with a significant decline in insulin dose. The dose of insulin was reduced from a baseline of 62 to 41 U per patient in the insulin-only treatment group, from 36 to 12 U per patient in the group treated with insulin and sulfonylurea, and from 28 to 11 U per patient in the group treated with insulin and metformin. In the group treated with insulin, sulfonylurea, and metformin, the dose of insulin was decreased from 36 to 13 U. CONCLUSION: From our data in more than 200 patients with type 2 diabetes, who participated in a 1-year follow-up in an outpatient clinical practice, we found that troglitazone improved glycemic control in each study group and also decreased the insulin dose in the insulin-requiring patients. Troglitazone improves glycemic control as a primary, secondary, tertiary, or even quaternary therapy in patients with type 2 diabetes.

Aged↗
PubMedDate not supplied

Troglitazone add-on therapy to a combination of sulfonylureas plus metformin achieved and sustained effective diabetes control.

OBJECTIVE: To elucidate the effect of triple combination oral agent therapy on type 2 diabetes. METHODS: We performed a prospective longitudinal study on 40 patients with type 2 diabetes who had failed to achieve a glycosylated hemoglobin (HbA1c) of < or = 8.0% despite optimal therapy with a combination of sulfonylureas plus metformin. Troglitazone was added and then titrated, with the intent to achieve at least a 1% reduction in HbA1c within 3 months. Responders were reassessed at 6 and 12 months. Nonresponders were reassessed at 6 months; in the absence of a significant HbA1c response, participation in the study was discontinued. RESULTS: Of the 40 study subjects, 25 were responders, 10 were nonresponders, and 5 were withdrawn from the study before completion of 3 months of therapy because of side effects. The 25 responders had a mean baseline HbA1c of 9.9%, which decreased significantly to 7.8% after 3 months of troglitazone therapy and to 7.4% at 6 months and at 12 months. In addition, the fasting blood glucose (FBG) in the responders decreased significantly from 168 mg/dL at baseline to 118 mg/dL at 6 months, which was sustained at 121 mg/dL at 12 months. In the responder group, a mean HbA1c < or = 8% was achieved in 68% at 6 months and sustained in 65% after 1 year. Furthermore, 40% of responders achieved a mean HbA1c < or = 7.0% at 6 months, and 39% sustained this degree of control at 12 months. The 10 nonresponders showed no significant change in HbA1c or FBG during the 6 months of troglitazone therapy. No difference existed in the mean baseline FBG, HbA1c, or C peptide level between the two groups. Responders, however, had a significantly lower mean body mass index (BMI) (31 kg/m2) than did nonresponders (37 kg/m2). Although responders were older than nonresponders (mean age, 65 years versus 55 years), no significant difference was noted in duration of diabetes (11.6 years versus 8.7 years). Multivariate analysis showed that male gender and BMI were the strongest predictors of a response to troglitazone add-on therapy to the prior combination of sulfonylureas plus metformin. CONCLUSION: This study showed that oral therapy with troglitazone added to sulfonylureas plus metformin achieved and sustained a significant improvement in control of diabetes in 71% of patients who had failed to achieve HbA1c < or = 8% with dual oral agent therapy. The positive response was evident within 3 months, reached maximum by 6 months, and was sustained to 12 months of therapy. Therefore, patients who fail to achieve HbA1c < or = 8% with sulfonylureas plus metformin should have at least 3 months of troglitazone add-on therapy before advancing to traditional insulin treatment.

Administration, Oral↗
PubMed1998

Troglitazone-induced hepatic failure leading to liver transplantation. A case report.

BACKGROUND: Troglitazone is a new drug for the treatment of type 2 diabetes. Although mild liver injury occurred in 1.9% of participants in controlled trials, the U.S. Food and Drug Administration has received reports of five postmarketing cases of severe liver disease that resulted in death or liver transplantation. OBJECTIVE: To report the clinical and histopathologic characteristics of a patient with troglitazone-associated severe liver injury leading to transplantation. DESIGN: Case report. SETTING: Two university hospitals. PATIENT: A 55-year-old woman taking troglitazone, 400 mg/d, and insulin, 120 U/d. INTERVENTION: Discontinuation of troglitazone therapy, pretransplantation liver biopsy, and liver transplantation. RESULTS: Early nonspecific symptoms were attributed to other causes and were not evaluated. After the patient had used troglitazone for 3.5 months, massive loss of liver parenchyma and symptoms of liver failure developed, necessitating liver transplantation. CONCLUSION: Troglitazone may cause subfulminant liver failure.

Chromans↗
PubMed2001

The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin. A multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: The thiazolidinediones are a new class of antidiabetes medication that enhances the actions of insulin in muscle, liver, and adipose tissue. Data have been lacking on their use in combination with both sulfonylurea and metformin among patients for whom insulin is the usual therapeutic alternative for improved glycemic control. OBJECTIVE: To determine the effects of troglitazone on hemoglobin A(1c) level in patients treated with maximum tolerated doses of sulfonylurea and metformin who have hemoglobin A(1c) levels of at least 0.085 (8.5%). This trial was completed before troglitazone was taken off the U.S. market. DESIGN: Randomized, double-blind, placebo-controlled trial, followed by an open-label extension during which all patients received troglitazone. SETTING: 16 outpatient clinics in Canada. PATIENTS: 200 patients (mean age, 59 years) with type 2 diabetes mellitus and hemoglobin A(1c) levels at least 0.085 (8.5%) (mean hemoglobin A(1c) level, 0.097 [9.7%] and mean fasting plasma glucose level, 12.9 mmol/L [233 mg/dL]) while receiving maximum doses of sulfonylurea and metformin. MEASUREMENTS: Levels of hemoglobin A(1c), fasting plasma glucose, total insulin, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. RESULTS: Troglitazone, 400 mg/d, when added to sulfonylurea and metformin, significantly decreased hemoglobin A(1c) level by 0.014 +/- 0.002 (95% CI, 0.0167 to 0.0109; P < 0.001) (1.4% +/- 0.2% [CI, 1.67% to 1.09%]) and insulin by 19 +/- 4 pmol/L (CI, 30 to 10 pmol/L; P < 0.001). At 6 months, 43% of troglitazone-treated patients achieved hemoglobin A(1c) levels of 0.08 (8%) or lower compared with 6% of placebo recipients. Efficacy was maintained at 12 months. CONCLUSIONS: The thiazolidinedione troglitazone, at a dosage of 400 mg/d, is effective when used in combination with sulfonylurea and metformin. Thiazolidinediones may therefore offer an effective alternative to insulin for patients treated with sulfonylurea and metformin who do not achieve adequate glycemic control.

Blood Glucose↗
PubMed1999

Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes.

Troglitazone, a new oral antidiabetic drug, is reported to be mostly metabolized to its conjugates and not to be oxidized by cytochrome P-450 (P-450) enzymes. Of fourteen cDNA-expressed human P-450 enzymes examined, CYP1A1, CYP2C8, CYP2C19, and CYP3A4 were active in catalyzing formation of a quinone-type metabolite at a concentration of 10 microM troglitazone, whereas CYP3A4 had the highest catalytic activity at 100 microM substrate. In human liver microsomes, rates of the quinone-type metabolite formation (at 100 microM) were correlated well with rates of testosterone 6beta-hydroxylation (r = 0.98), but those at 10 microM troglitazone were not correlated with any of several marker activities of P-450 enzymes. Quercetin efficiently inhibited quinone-type metabolite formation (at 10 microM troglitazone) in human samples that contained relatively high levels of CYP2C, whereas ketoconazole affected these activities in liver microsomes in which CYP3A4 levels were relatively high. Anti-CYP2C antibodies strongly inhibited quinone-type metabolite formation (at 10 microM troglitazone) in CYP2C-rich human liver microsomes (by approximately 85%); the intensity of this effect depended on the human samples and their P-450 status. The results suggest that in human liver both CYP2C8 and CYP3A4 have major roles in quinone-type metabolite formation and that the hepatic contents of these two P-450 forms determine which P-450 enzymes play major roles in individual humans. CYP3A4 may be expected to play a role in formation of quinone-type metabolite from troglitazone even at a low concentration in humans.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Troglitazone improves whole-body insulin resistance and skeletal muscle glucose use in type II diabetic patients.

UNLABELLED: Recently, troglitazone has emerged as an insulin sensitizer for the treatment of type II diabetes. However, its effect on skeletal muscle glucose use (SMGU) has not been studied. METHODS: To investigate the effect of troglitazone on SMGU in patients with type II diabetes, we undertook skeletal muscle (18)F-FDG PET dynamic imaging under insulin clamping before and after administration of SMGU to 20 patients with type II diabetes. Data were compared with those for 12 age-matched healthy volunteers. RESULTS: The whole-body glucose disposal rate (GDR) was significantly lower in patients (29.9 +/- 9.83 micromol/min/kg) than in control subjects (55.6 +/- 16.5 micromol/min/kg, P < 0.01), as was the SMGU (patients, 3.27 +/- 2.17 micromol/min/kg; control subjects, 10.9 +/- 6.4 micromol/min/kg; P < 0.01). After the therapy, GDR significantly improved in patients (29.3 +/- 14.6 micromol/min/kg, P < 0.05), as did SMGU (5.06 +/- 2.11 micromol/min/kg, P < 0.05). When results for patients with and without hypertension were separately analyzed, a significant improvement in SMGU after troglitazone was seen in both normotensive and hypertensive patients (normotensive [n = 10]: baseline, 3.67 +/- 2.89 micromol/min/kg; after therapy, 5.28 +/- 2.61 micromol/min/kg; P < 0.05; hypertensive [n = 10]: baseline, 2.89 +/- 1.22 micromol/min/kg; after therapy, 4.72 +/- 1.39 micromol/min/kg; P < 0.05). GDR in patients with and without hypertension was significantly improved by troglitazone (normotensive: baseline, 17.9 +/- 10.2 micromol/min/kg; after therapy, 31.9 +/- 15.9 micromol/min/kg; P < 0.01; hypertensive: baseline, 39.6 +/- 15.1 micromol/min/kg; after therapy, 47.7 +/- 23.8 micromol/min/kg; P < 0.05). The plasma free fatty acid concentration during insulin clamping was not changed by troglitazone (baseline, 1.1 +/- 0.86 mEq/L; after therapy, 0.93 +/- 0.65 mEq/L; P = not significant). CONCLUSION: Troglitazone can improve whole-body insulin resistance through the improvement of SMGU but not through a decline in plasma free fatty acid concentration in patients with type II diabetes with or without hypertension.

Blood Glucose↗
PubMed1997

Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice and dogs.

The pharmacokinetics of troglitazone (CAS 97322-87-7, CS-045), a new oral antidiabetic drug for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), were investigated in rats, mice and dogs following oral and intravenous administration of 14C-labeled troglitazone at doses of 5 mg/kg. The absorption rates, calculated from the AUC ratios of total radioactivity after oral and intravenous administration, or from the biliary excretion rate after intraduodenal administration in rats were both as high as 75%. High uptake by the liver, one of the pharmacological target organs, was demonstrated in both rats and mice. Furthermore, in the KK mouse, an obese NIDDM model animal, the radioactivity was incorporated selectively as troglitazone itself to muscle, the peripheral target organ. Troglitazone reversibly bound to serum albumin with a high ratio (> 99%). Troglitazone was mostly metabolized to the conjugates: sulfate (M 1) and glucuronide (M 2). The oxidized metabolite, a quinone-type metabolite (M 3), was found to be further metabolized to the sulfate (U 2). The biliary excretion rates of these conjugates were high in each animal, and the occurrence of enterohepatic circulation of the conjugates was also suggested. Sex differences in pharmacokinetics were observed in rats; i.e. females showed a higher plasma concentration of troglitazone, and a lower concentration of M 1, than males, and they excreted the sex-related metabolite, a hydroxylated M 1 (U 1), in the bile.

Administration, Oral↗
PubMed1998

Effect of troglitazone on urinary excretion of 6beta-hydroxycortisol.

Coadministration of troglitazone reduces the plasma concentrations of terfenadine and ethinyl estradiol. Because these drugs are metabolized at least in part by cytochrome P450 3A (CYP3A), it is possible that troglitazone induces CYP3A activity, thereby reducing plasma concentrations of these agents. Known inducers of CYP3A, such as rifampin, phenytoin, carbamazepine, and phenobarbital, increase the urinary excretion of 6beta-hydroxycortisol and the ratio of 6beta-hydroxycortisol to cortisol. This evaluation examined the effect of troglitazone on urinary excretion of 6beta-hydroxycortisol and the ratio of 6beta-hydroxycortisol to cortisol as a marker for CYP3A induction. Urine samples were collected from 11 subjects who completed a study evaluating the effect of multiple-dose administration of troglitazone 400 mg once daily (days 11-20) on the steady-state pharmacokinetics of digoxin (0.25 mg daily on days 1-20). A single urine sample was collected at baseline on day 1, and 24-hour urine samples were collected on days 10 and 20. Mean +/- standard deviation 24-hour excretion rate of cortisol was unchanged, whereas that of 6beta-hydroxycortisol increased during troglitazone administration. The ratio of 24-hour urinary 6beta-hydroxycortisol to cortisol excretion increased from 7.4 +/- 2.7 on day 10 to 16.1 +/- 6.2 on day 20. The ratio observed on day 10 was similar to that obtained at baseline. These results are consistent with the hypothesis that troglitazone induces CYP3A activity.

Aryl Hydrocarbon Hydroxylases↗
PubMed2002

Selective suppressions of human CYP3A forms, CYP3A5 and CYP3A7, by troglitazone in HepG2 cells.

Troglitazone is an insulin sensitizer and also known as an agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma). In the present study, we have studied the influence of troglitazone on CYP3A form expressions in HepG2 cells for a model of human tissue. Interestingly, constitutively expressed forms of cytochrome P450, CYP3A5 and CYP3A7, were suppressed by the pretreatment of troglitazone but not of the related thiazolidinediones, pioglitazone and rosiglitazone in this cell line. A major liver CYP3A form, CYP3A4, was not detected in this cell line with and without troglitazone treatment. The troglitazone-mediated suppressions of CYP3A5 and CYP3A7 were found to be independent of expression levels of nuclear transcriptional factors, PXR, RXRalpha and PPARgamma. These results suggest that the selectively suppressive effects of troglitazone on CYP3A5 and CYP3A7 expressions may be caused by a novel pathway.

Journal Article↗
PubMed1997

Determination of protein binding of troglitazone stereoisomers by fluorometric titration.

Determination of the protein binding of troglitazone is difficult because of its high adsorption to filters and membranes and the instability of the stereoisomers. We attempted to assess the protein binding of four stereoisomers of troglitazone in the plasma and albumin from several species by the method using fluorescent probes. The inhibition constants (Ki) for the stereoisomers of troglitazone were obtained from the decreases in fluorescence intensity of dansylsarcosine caused by competitive inhibition. Each stereoisomer of troglitazone displaced dansylsarcosine, a typical specific fluorescent probe for the diazepam binding site on human serum albumin (HSA). The highest binding affinity for dansylsarcosine was observed with HSA (dissociation constant, Kd,1 = 0.5 microM), while it was lowest in the mouse (Kd,1 = 18 microM). The Ki values for KK and ddY mouse plasma and mouse and rat albumin were in the range 2-15 microM, and there were no large variations among stereoisomers, the maximum differences being twofold. For human plasma and albumin, the displacement could not be accounted for by a simple competitive inhibition. Comparison between unbound fraction (fu) values calculated from thus obtained Ki values and those of a mixture of the four stereoisomers determined by high-performance frontal analysis showed that the fu values obtained by fluorometric titration were higher, while the relative differences among the stereoisomers in terms of animal species and strain were comparable for the two methods. Small differences in protein binding among stereoisomers of troglitazone may not be the major reason for their stereoselective pharmacokinetics.

Animals↗
PubMed1997

Troglitazone has a scavenging effect on reactive oxygen species.

Troglitazone (CS-045), a newly developed antidiabetic thiazolidinedione that enhances insulin sensitivity, is similar in structure to several antioxidants, including alpha-tocopherol and probucol. The in vitro antioxidant activity of troglitazone has been demonstrated in alloxan-induced hyperlipoperoxidemic and hyperlipidemic mice. In this study, we found that troglitazone had a scavenging effect on reactive oxygen produced by xanthine-xanthine oxidase and generated by stimulated neutrophils and tends to be the radical form. Our results suggest that troglitazone is an antioxidant similar to alpha-tocopherol. However, under the same conditions, pioglitazone, another thiazolidinedione drug, did not have a scavenging effect. The antioxidant action of troglitazone, which is attributable to the similarity of its molecular structure to that of alpha-tocopherol, may be of benefit in preventing diabetic vascular complications, in addition to having hypoglycemic and hypolipidemic effects.

Antioxidants↗
PubMed1999

Troglitazone suppresses cell growth of myeloid leukemia cell lines by induction of p21WAF1/CIP1 cyclin-dependent kinase inhibitor.

In a human eosinophilic leukemia cell line, EoL-1, cell proliferation was suppressed by 2-day treatment with troglitazone. EoL-1 cells treated with troglitazone were arrested and maintained in the G0/G1 phase in the cell cycle. This suppression correlated with the up-regulation of mRNA for p21WAF1/CIP1 cyclin-dependent kinase (Cdk) inhibitor. The inhibitory effects of troglitazone on cell proliferation and expression of p21 mRNA were observed in a human myelomonocytic cell line, U937, and a human myelomonoblastic cell line, KPB-M15. In addition, in EoL-1 cells, p21 protein was induced by troglitazone treatment and the induction was inhibited by protein synthesis inhibitor, cycloheximide. These data suggest that troglitazone inhibits cell proliferation in myeloid leukemia cell lines at least in part by induction of p21 Cdk inhibitor.

Antineoplastic Agents↗
PubMed2001

Dual function of troglitazone in ICAM-1 gene expression in human vascular endothelium.

Our previous work has shown that troglitazone (an antidiabetic, thiazolidione drug and a synthetic ligand for peroxisome proliferator-activated receptor gamma, PPARgamma) stimulated basal level of intercellular adhesion molecule-1 (ICAM-1) protein expression in the absence of cytokine stimulation in human vascular endothelial cells. In this study, we examine the molecular mechanism of troglitazone on the basal and TNFalpha-induced ICAM-1 gene expression. Activation of transcription factors, NF-kappaB and AP-1 proteins, known to regulate ICAM-1 gene expression upon external stimulators, was examined. In human vascular endothelial cells (ECV304 cells), troglitazone inhibited TNFalpha-induced ICAM-1 gene expression by suppressing NF-kappaB/DNA binding activity, NF-kappaB transcriptional responses, c-Fos mRNA and protein levels via a ligand-dependent, PPARgamma-activated manner. In contrast, both troglitazone (at 10 microM) and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2), at 15 microM), a natural ligand for PPARgamma, induce c-Jun phosphorylation by activation of c-Jun N-terminal kinase (JNK) through a posttranslational regulation of c-Jun activity, therefore increasing AP-1/DNA binding activity and transcriptional responses as results of increasing basal ICAM-1 gene expression. These findings suggest dual function of troglitazone in the modulation of both basal and stimulated ICAM-1gene expression in human vascular endothelial cells.

Base Sequence↗
PubMed1998

Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone.

Insulin resistance is associated with a decreased vasodilator response to insulin. Because insulin's vasodilator effect is nitric oxide dependent, this impairment may reflect endothelial dysfunction. Troglitazone, an insulin-sensitiser, might thus improve insulin-dependent and/or endothelium-dependent vascular function in insulin resistant obese subjects. For 8 weeks, fifteen obese subjects were treated with either 400 mg troglitazone once daily or placebo, in a randomised, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses (plethysmography) to intra-arterial administered acetylcholine and sodium nitroprusside; insulin sensitivity and insulin-induced vascular and neurohumoral responses (clamp); vasoconstrictor responses to NC-monomethyl-L-arginine (L-NMMA) during hyperinsulinaemia; and ambulatory 24-h blood pressure (ABPM). Baseline data (placebo) of obese subjects were compared with those obtained in lean control subjects. Obese subjects were insulin resistant compared with leans (whole-body glucose uptake: 26.8+/-3.0 vs. 53.9+/-4.3 [tmol kgl min-, p < 0.001). Troglitazone improved whole-body glucose uptake (to 31.9+/-3.3 micromol x kg(-1) x min(-1) , p=0.028), and forearm glucose uptake (from 1.09+/-0.54 to 2.31+/-0.69 micromol dL(-1) x min(-1), p=0.006). Insulin-induced vasodilatation was blunted in obese subjects (percent increase in forearm blood flow (FBF) in lean 66.5+/-23.0%, vs. 10.1+/-11.3% in obese, p=0.04), but did not improve during troglitazone. Vascular responses to acetylcholine, sodium nitroprusside and L-NMMA did not differ between the obese and lean group, nor between both treatment periods in the obese individuals. In conclusion, in insulin resistant obese subjects, endothelial vascular function is normal despite impaired vasodilator responses to insulin. Troglitazone improved insulin sensitivity but it had no effects on endothelium-dependent and -independent vascular responses. These data do not support an association between insulin resistance and endothelial function.

Acetylcholine↗
PubMed2001

Troglitazone selectively inhibits glyoxalase I gene expression.

AIMS/HYPOTHESIS: The hyperglycaemia associated with diabetes causes excessive production of cytotoxic methylglyoxal, an alpha-oxo-aldehyde. The glyoxalase system, composed of glyoxalase I and glyoxalase II, with glutathione (GSH) as the cofactor, plays an important role in the detoxification of alpha-oxo-aldehydes. We tested the hypothesis that troglitazone, an insulin-sensitizing drug previously used in the treatment of Type II (non-insulin-dependent) diabetes mellitus, up-regulates the glyoxalase system either by increasing phase 2 enzyme activities and thereby increasing cellular GSH, or, by inducing glyoxalase enzyme activities. METHODS: Human astroglial cells, rat hepatocytes and cardiac myocytes were cultured and exposed to either troglitazone, or tertiary-butylhydroquinone (tBHQ, a phase 2 enzyme inducer). Glutathione content, advanced glycation end products (AGEs) and enzyme (glyoxalase I, glyoxalase II as well as the phase 2 enzymes, glutathione S-transferase and thioredoxin reductase) activities were determined. Glyoxalase I mRNA was also measured. RESULTS: Troglitazone had no effect on cellular GSH nor phase 2 enzyme activities but significantly reduced the activities of glyoxalase I and II; this inhibitory effect was concentration-dependent and time-dependent and was associated with reduced mRNA contents and increased AGEs formation. Rosiglitazone had no effect on glyoxalase I gene expression. tBHQ, a classic phase 2 enzyme inducer, had no effect on the glyoxalase system but did increase glutathione contents and the activities of glutathione S-transferase and thioredoxin reductase. CONCLUSION/INTERPRETATION: Our study shows that troglitazone is a selective inhibitor of the glyoxalase system. This inhibition of the glyoxalase system could contribute to troglitazone's hepatotoxic action which has previously been reported in a small percentage of individuals.

Animals↗
PubMedDate not supplied

Pilot study of prescription-event monitoring in Japan comparing troglitazone with alternative oral hypoglycemics.

OBJECTIVE: To examine adverse events reported in a pilot study of the prescription-event monitoring in Japan (J-PEM) scheme, comparing troglitazone with other oral hypoglycemics. METHODS: We used a cohort study with a concurrent control in which information was gathered from both doctors and pharmacists. Crude event rates were calculated and compared between troglitazone (T) and alternative oral hypoglycemics (control drugs, C) using the likelihood ratio test. When the difference was statistically significant, possible confounding mechanisms were examined using Poisson regression analysis. RESULTS: Of 3,115 patient codes registered, pharmacists were sent 2,078 questionnaires and returned 1,814 (87%), while doctors were sent 1,858 questionnaires and returned 671 (36%). The difference in crude rates was statistically significant in 11 events (seven where T > C and four where C > T) reported by pharmacists and ten events (three where T > C and seven where C > T) reported by doctors. Among those, in two events, "weight increased" (T > C) and "abnormal hepatic function" (T > C), significant differences were observed in data from both doctors and pharmacists. Regression analysis revealed that the difference in crude rates for "nausea" (T > C) was possibly due to an uneven distribution of genders and that for "weight increased" (T >C) was possibly due to an uneven distribution of compliance. Patients with hepatic function abnormalities associated with troglitazone could be divided into two subtypes: one with a slight increase in serum lactate dehydrogenase concentration only and the other with elevated serum alanine aminotransferase. CONCLUSIONS: Comparison of the event rates between troglitazone and control drugs, followed by regression analysis, revealed several features of adverse events associated with drugs, including possible confounding mechanisms. Troglitazone-induced hepatic function abnormalities may be divided into two subtypes.

Adolescent↗