Combined effects of troglitazone and muscle contraction on insulin sensitization in Balb-c mouse muscle.

Thiazolidinediones, represented by troglitazone, are insulin-sensitizing agents with proven efficacy for the treatment of type 2 diabetes. Exercise is also recommended for patients with type 2 diabetes because it both stimulates glucose uptake directly and it increases insulin sensitivity following exercise. The purpose of this study was to investigate the effects of troglitazone combined with exercise on 2-deoxyglucose (2DG) uptake in both the epitrochlearis and soleus muscle of Balb-c mice. Acute, 1-h treatment with troglitazone (10 or 20 microM), in the presence or absence of insulin, had no effect on 2DG uptake in either muscle. Chronic treatment with troglitazone by feeding enhanced the insulin sensitivity and responsiveness of 2DG uptake primarily in the epitrochlearis. Direct electrical stimulation of in situ muscle was used to model exercise while the contralateral muscle was used as the unexercised control. This model mimicked exercise in that glycogen was depleted, immediate 2DG uptake was enhanced, and there was a post-exercise increase in insulin sensitivity. Troglitazone feeding had no effect on 2DG uptake in the soleus when measured immediately after electrical stimultion. However, 2DG uptake in the unstimulated epitrochlearis from troglitazone-fed mice was elevated when measured immediately after removal such that no additional effects of the electrical stimulation were measured. We found that the insulin-sensitizing effect of troglitazone was not additive to the insulin-sensitizing effect of exercise, which suggests that troglitazone and exercise share similar pathways. A unique finding in this study was the differential response to troglitazone between the epitrochlearis (fast twitch) and the soleus (slow twitch) muscle types. Possible mechanisms are discussed.

Thromboxane synthase activity and platelet function after furegrelate administration in man.

Furegrelate sodium (U-63,557A), a pyridine-derivative thromboxane synthase inhibitor, was administered orally in single doses of 200 to 1600 mg to normal male subjects. Furegrelate produced a dose-related inhibition of thromboxane synthesis for 8-12 hours when measured either ex vivo from platelet-rich plasma (PRP) or in vivo from urine. In general, the extent of thromboxane synthesis inhibition was greater in PRP than in urine. Furegrelate significantly inhibited platelet aggregation, but the effect was variable and measurements of thromboxane synthase did not predict the impact on platelet aggregation. Bleeding times and coagulation parameters were not altered significantly. Furegrelate was well absorbed orally with Tmax = 1 hr and t1/2 = 3.5 to 5 hrs. There was no marked metabolism; elimination was primarily by renal excretion of parent compound. Thus, furegrelate is an effective inhibitor of thromboxane synthase in man with a relatively long biologic and circulating half-life.

Multiple dose trial of the thromboxane synthase inhibitor furegrelate in normal subjects.

Furegrelate sodium, a pyridinyl derivative thromboxane synthase inhibitor, was evaluated for its effects on thromboxane synthesis in normal volunteers after multiple dose administration. Twenty-four subjects were randomized to 200, 400, 800 or 1600 mg furegrelate or placebo treatment BID for 4 1/2 days. Furegrelate (800 or 1600 mg) significantly inhibited thromboxane synthesis throughout the dosing interval as assessed by thromboxane B2 generation from platelet-rich plasma challenged with arachidonic acid or from serum. Platelet aggregation was inhibited, but the effect was variable and a clear dose response relationship was not apparent. Bleeding times were also variable but tended to increase at the higher doses. There was no clinically significant change in any coagulation parameters or in any safety laboratory evaluations. Peak serum concentrations occurred approximately 1 h after dosing; t1/2ke was approximately 2 h. There was no significant change in furegrelate's effects or pharmacokinetics over time (ie. Day 1 vs Day 5).