Coadministration of acetaminophen and troglitazone: pharmacokinetics and safety.

Troglitazone, a PPAR-gamma agonist, enhances the actions of insulin on muscle and liver. It is metabolized predominantly in the liver to a sulfate conjugate and a quinone metabolite. Acetaminophen also undergoes metabolism by conjugation. This three-way crossover study in 12 healthy male volunteers was conducted to investigate the effects of acetaminophen on the metabolism of troglitazone and vice versa. No statistically or clinically relevant differences in area under the concentration-time curve extrapolated to infinity (AUCinfinity) were observed for troglitazone, its quinone metabolite, or acetaminophen. A statistically significant decrease in troglitazone sulfate conjugate during administration with acetaminophen was not clinically relevant. No statistically or clinically relevant differences were observed in maximum concentration (Cmax), time to Cmax (tmax), or elimination half-life of troglitazone, its two main metabolites, and acetaminophen or in acetaminophen urinary sulfate excretion, although there was a slight decrease in acetaminophen glucuronide excretion during administration with troglitazone. Adverse events were minor and similar between treatments. These findings suggest that troglitazone and acetaminophen can be coadministered without adverse clinical consequences.

Troglitazone, an insulin action enhancer, improves glycaemic control and insulin sensitivity in elderly type 2 diabetic patients.

The management of Type 2 diabetes mellitus with currently available oral agents may be complicated in the elderly by an increased frequency of side-effects. The effects of troglitazone, an insulin action enhancer, were studied in elderly patients with Type 2 diabetes in a double-blind, parallel-group, placebo-controlled trial. A total of 229 patients (41% male), mean age 75 (range 69-85) years, with two fasting capillary blood glucose values > or =7 and < or =15 mmol l(-1) (and within 4.0 mmol l(-1) of each other) and previously treated with either diet alone (30%) or oral hypoglycaemic agents, were randomized to placebo or troglitazone 400 mg once daily or 200 mg twice daily, or 800 mg once daily or 400 mg twice daily, for 12 weeks. After 12 weeks' treatment, fasting serum glucose was significantly lower in troglitazone-treated patients (troglitazone, adjusted geometric mean 9.4-10.4 mmol l(-1) vs placebo 12.7 mmol l(-1), p < 0.001). Adjusted geometric mean fructosamine was also lower in troglitazone-treated patients by 5 to 15% compared to placebo (P < 0.05 at all doses except 400 mg od). There was no significant difference between troglitazone doses for improvement in glycaemic control. Troglitazone lowered adjusted geometric mean fasting plasma insulin by 27-34% compared to placebo (P < 0.001) and insulin sensitivity (HOMA-S) improved by 9-15% in all troglitazone dose groups (p < 0.001). Troglitazone also lowered serum non-esterified fatty acids and triglyceride. Adverse event incidence in troglitazone-treated patients was similar to that in patients treated with placebo. No weight gain or symptomatic hypoglycaemia was recorded at any of the doses studied. Troglitazone is effective and well tolerated in elderly patients with Type 2 diabetes mellitus, providing improved glycaemic control in the absence of weight gain.

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.

Improvement in the gastrointestinal absorption of troglitazone when taken with, or shortly after, food.

AIMS: Troglitazone, an insulin action enhancing agent, is currently in clinical development for the treatment of non insulin dependent diabetes mellitus. The objective of this study was to establish the effect of food on the systemic absorption and metabolism of troglitazone. METHODS: After an overnight fast, 12 healthy male volunteers each received, in random order, troglitazone (400 mg orally) alone, concomitantly with (at the start of), and 30 min after, a standardized diabetic breakfast as part of a three-period crossover study. RESULTS: When troglitazone was administered with or after food, geometric mean values of area under the plasma concentration-time curves (AUC[last]) relative to fasting state were increased significantly by 59% in both cases (95% CI 1-150%, P=0.046 and 2-148%, P=0.040) with values of 11.4, 11.5 and 7.2 microg ml(-1) h respectively. Maximum observed plasma concentration (Cmax) increased by 96% and 72% (95% CI 29-197%, P=0.003 and 15-158%, P=0.011) with values of 2.2, 2.0 and 1.1 microg ml(-1) respectively. Changes in t(lag) were not clinically significant. Increases in AUC(0, infinity) for the main circulating sulphate metabolite relative to fasting were also significant (41%, 95% CI 5-89%, P=0.025 and 34%, 95% CI 1-79%, P= 0.044 respectively) with values of 82.6, 78.6 and 58.5 microg h ml(-1). Cmax increased by 68% (95%, CI 10-156%, P=0.019) and 65% (95% CI 9-149%, P=0.020) with values of 3.2, 3.1 and 1.9 microg ml(-1) respectively. Reductions in t1/2 (16 and 21%, 95% CI 0-30, 6-33) although statistically significant (P=0.050 and P=0.009) were not clinically significant with values of 22.3, 20.4 and 24.5 h for with food, after food and fasting respectively. Troglitazone was well tolerated in all cases throughout the study with a trend for improved tolerability of gastrointestinal symptoms when taken 30 min after a meal. CONCLUSIONS: The absorption of troglitazone is enhanced significantly by food with little effect on the main metabolic pathway. Increased absorption of troglitazone in the presence of food is likely to be a consequence of enhanced solubility in bile combined with an increase in dissolution time. On the basis of these findings, troglitazone should be taken either with, or up to 30 min after, food.

Concomitant administration of cholestyramine influences the absorption of troglitazone.

AIM: Troglitazone is an orally active anti-diabetic agent. Cholestyramine is an orally administered lipid-lowering agent which acts by binding to bile acids and removing them from enterohepatic circulation. Preclinical studies suggesting the potential for an interaction between troglitazone and cholestyramine require confirmation in a clinical setting. METHODS: In vitro and in vivo experiments in the dog were carried out prior to a clinical study. Twelve healthy volunteers (mean age 32 years, range 20-44 years) each received a single oral dose of troglitazone 400 mg alone and with cholestyramine 12 g (taken 1 h after troglitazone) in an open, two-way crossover study. RESULTS: In vitro, about 99% of troglitazone was adsorbed by cholestyramine at an incubate concentration of 3 microg ml(-1) whilst at 500 microg ml(-1) adsorption fell to about 90%. In vivo, AUC of troglitazone was reduced by an average of 42% (22.7 vs 12.2 microg ml(-1) h (95% CI for difference 28-57, P=0.01) in 11 beagle dogs receiving troglitazone 200 mg and cholestyramine 1 g compared with control values. Mean maximum plasma concentration (Cmax) was 49% of control values (7.08 vs 3.42 microg ml(-1) (95% CI for difference 14-85, P=0.05)). In the clinical study median AUC for troglitazone and its two major metabolites were statistically significantly lower when troglitazone was administered with cholestyramine (17.9 vs 5.2 microg ml(-1) h (95% CI for difference -20.5, -8.7), 133.7 vs 27 1 microg ml(-1) h (-166.4, -67.8) and 18.4 vs 2.5 microg ml(-1) h (-21.6, -10.6) for troglitazone, sulphate and quinone metabolite respectively (all P < 0.01) representing percentage decreases of 71, 80 and 86% respectively. A statistically significant reduction was also observed in Cmax for the sulphate metabolite (4.56 vs 1.28 microg ml(-1) (95% CI for difference -4.42, -1.99, P < 0.01)), but not for troglitazone (1.85 vs 1.23 microg ml(-1) (-1.13, 0.49) or the oxidative metabolite (0.84 vs 0.45 microg ml(-1) (-0.77, 0.09)). CONCLUSIONS: The results were indicative of an alteration in the extent of troglitazone's absorption. Concomitant administration of troglitazone and cholestyramine could severely impair troglitazone's clinical utility as an antihyperglycaemic agent.

Constant infusion and bolus injection of stable-label tracer give reproducible and comparable fasting HGO.

We have investigated the reproducibility of fasting hepatic glucose output (HGO) estimates by use of isotope dilution methodology of stable-label tracers. Six normal subjects were studied on two occasions 1 wk apart. After an overnight fast, the subjects received a bolus injection of 7 mg/kg of [U-13C]glucose and, simultaneously, a primed constant infusion of 0.05 mg.kg-1.min-1 of [6,6(-2)H]glucose. The bolus injection provided one estimate of HGO (HGOBOL), and the constant infusion provided two estimates of HGO, namely, HGO at 2 h (HGOINF2) and HGO at 4 h (HGOINF4), both with the assumption of steady-state conditions. All estimates were similar in value; HGOBOL was highest, followed by HGOINF2 and HGOINF4 [2.30 +/- 0.11 (SE), 2.17 +/- 0.12, and 2.01 +/- 0.13 mg.kg-1.min-1]. The constant infusion gave highly reproducible results. In the case of HGOINF2, the within-subject coefficient of variation (CV) was only 3% compared with 5% of HGOINF4. The reproducibility of HGOBOL was comparable with the within-subject CV of 7%. We conclude that a constant infusion and a bolus injection of stable-label tracer give reproducible and comparable estimates of HGO.

Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Troglitazone Study Group.

The effects of troglitazone, a novel thiazolidinedione, in non-insulin-dependent diabetic (NIDDM) patients were studied in a double-blind, parallel-group, placebo-controlled, dose-ranging trial. A total of 330 patients (63% male), mean age 57 years (range 39-72), with two fasting capillary blood glucose values > or = 7 and < or = 15 mmol/l (within 2.5 mmol/l of each other) were randomised to treatment with placebo or troglitazone at doses of 200, 400, 600 or 800 mg once daily, or 200 or 400 mg twice daily, for 12 weeks. Prior to the study, treatment had been with diet alone (38% patients) or with oral hypoglycaemic agents which were stopped 3-4 weeks before study treatment started. During treatment, HbA1c tended to rise in patients taking placebo (7.2-8.0%), but remained unchanged with all doses of troglitazone. After 12 weeks of treatment, HbA1c was significantly lower in the troglitazone-treated (mean 7.0-7.4%) compared to the placebo-treated (8.0%) patients (p = 0.055 to < 0.001), as was fasting serum glucose concentration (troglitazone, 9.3-11.0 mmol/l vs placebo, 12.9 mmol/l, p < 0.001). All doses of troglitazone were equally effective. Troglitazone also lowered fasting plasma insulin concentration, by 12-26% compared to placebo (p = 0.074 to < 0.001). Insulin sensitivity assessed by homeostasis model assessment (HOMA) was greater after 12 weeks of treatment in troglitazone-treated patients (troglitazone, 34.3-42.8% vs placebo, 29.9%, p < 0.05). In addition, serum triglyceride and non-esterified fatty acid concentrations were significantly lower and HDL cholesterol higher at troglitazone doses of 600 and 800 mg/day. LDL cholesterol increased at 400 and 600 mg doses only (from 4.3 and 3.9 mmol/l at baseline to 4.8 and 4.5 mmol/l, respectively at 12 weeks, p < 0.05), but not at doses of 800 mg once daily or 400 mg twice daily. LDL/HDL ratio did not change during treatment. All doses were well tolerated; incidence of adverse events in troglitazone-treated patients was no higher than in those treated with placebo. However, a tendency to reduced neutrophil counts was observed in patients taking the highest doses of troglitazone. We conclude that troglitazone is effective and well-tolerated and shows potential as a new therapeutic agent for the treatment of NIDDM.

The effects of oral sumatriptan, a 5-HT1 receptor agonist, on circulating ACTH and cortisol concentrations in man.

1. The effects of oral sumatriptan (50, 100 and 200 mg), a 5-HT1 receptor agonist, and placebo, on circulating adrenocorticotrophic hormone (ACTH) and cortisol concentrations were determined over 24 h after dosing, in 26 healthy male subjects. ACTH was measured by immunoradiometric assay and cortisol by radioimmunoassay. 2. After sumatriptan all subjects displayed a normal diurnal rhythm for circulating ACTH and cortisol compared with placebo. 3. There was a reduction in the trough circulating ACTH concentration over 0-4 h which was 18% with 100 mg (P = 0.002), and 25% with 200 mg (P < 0.001). The 5 h, post-prandial, peak ACTH concentration was reduced by 21% with 100 mg (P = 0.018) and by 20% with 200 mg (P = 0.024). The weighted mean ACTH over 24 h was reduced by 8% with 100 mg (P = 0.029) and by 8% with 200 mg (P = 0.018). The nadir concentration of ACTH over the 24 h and the ACTH concentration 24 h after sumatriptan were not, however, significantly reduced. All results are compared with placebo. 4. There was a reduction in the trough circulating cortisol concentration over 0-4 h which was 15% with 50 mg (P = 0.015), 14% with 100 mg (P = 0.022) and 24% with 200 mg (P < 0.001). The 5 h, post-prandial, peak cortisol concentration was reduced by 16% with 100 mg (P = 0.012) and by 15% with 200 mg (P = 0.017).(ABSTRACT TRUNCATED AT 250 WORDS)

Ranitidine bismuth citrate and aspirin-induced gastric mucosal injury.

The aim of this study was to investigate the protective action of a new compound, ranitidine bismuth citrate, in the prevention of aspirin-induced acute mucosal injury to the upper gastrointestinal tract of healthy human volunteers. In a double-blind randomized three-way cross-over study 24 male volunteers received placebo, 900 mg aspirin or 900 mg aspirin and 800 mg ranitidine bismuth citrate at 12-h intervals for nine doses with a 2-week wash-out period between each treatment. The median (interquartile range) number of erosions seen at endoscopy when ranitidine bismuth citrate was given with aspirin (1 [0-4]) was significantly lower than aspirin alone (24 [16-32]) (P < 0.001) and not significantly different from either baseline or placebo (0 [0-2]). These findings were similarly reflected in the effects on microbleeding following the ninth dose: 12.1 (7.1-21.0) microL/10 min following aspirin alone compared to levels with placebo of 1.2 (0.4-2.9), and with aspirin and ranitidine bismuth citrate of 1.6 (0.8-2.6) (P < 0.005). Ranitidine bismuth citrate conferred substantial protection from aspirin-induced injury to the gastric and duodenal mucosa as determined by both endoscopic assessment and microbleeding rates, reducing injury to placebo levels.