Effect of thromboxane synthetase inhibition on vulnerability to ventricular arrhythmia following coronary occlusion.

Release of thromboxane (TXA2) during acute myocardial infarction may be an important contributing factor in the genesis of ventricular fibrillation (VF). We assessed the effect of selective TXA2 inhibition on vulnerability to VF after total occlusion of the anterior descending coronary artery in chloralose-anesthetized cats. Animals were pretreated with vehicle or with CGS-13080, a TXA2 synthetase inhibitor, 3.0 or 9.0 mg/kg intravenously. There was an apparent dose-dependent protective effect following CGS-13080 administration, in which the decrease in VF threshold following coronary occlusion was attenuated. Also, the incidence of spontaneous ventricular arrhythmia in the first 30 minutes after occlusion was reduced by two thirds in the 9.0 mg/kg CGS-13080 group compared to the vehicle-treated animals. This protective effect does not appear to be due to a change in hemodynamics, effective refractory periods, or extent of ischemia. TXA2 released during coronary occlusion appears to be arrhythmogenic, and inhibiting its synthesis may be protective.

High-dose intravenous IgG in the management of pregnancy in women with idiopathic thrombocytopenic purpura.

Idiopathic thrombocytopenic purpura (ITP) may develop during pregnancy or affect later pregnancies, causing serious risks of bleeding to the mother and fetus. High-dose intravenous immunoglobulin (IGIV) has caused an immediate and predictable rise in platelet count during the infusion in both adults and children with chronic or acute ITP. The rapid rise in platelet counts may be important in preparing pregnant women with ITP for surgery or delivery. We report our experience in managing two women at weeks 29 and 37 week of gestation who required splenectomy and/or cesarean section. Both patients demonstrated an increase in platelet counts, underwent surgery without excess bleeding, and had normal infants with normal platelets, and with mild thrombocytopenia at delivery.

Evaluation of signal detection theory on the effects of psychotropic drugs on critical flicker-fusion frequency in normal subjects.

Critical flicker-fusion frequency (CFF) has often been applied to psychotropic drug evaluation as a measure of cortical arousal. There are several variables that must be considered for proper conclusions to be obtained from CFF experimental data. Psychological variables such as subject response bias are especially difficult to control. We studied the effects of single oral doses of 10 mg diazepam and 10 mg amphetamine sulfate on CFF values obtained by a block up-down spatial forced-choice method on 13 healthy volunteers (seven males and six females). Signal detection theory was also used to obtain the non-parametric value P(A) as a measure of sensory function and B as a measure of the psychological function of response bias. As a group, amphetamine increased CFF (Hz) and P(A) and diazepam decreased CFF (Hz) and P(A), with the most significant effects observed at 2 and 3 h after drug administration. B scores showed more individual variation with a trend towards a low score, or a tendency to report more flicker responses after diazepam. Separated by sex, the males had a higher percentage of subjects that demonstrated a reduction of CFF after diazepam, while the females had a higher percentage that demonstrated an increase in CFF after amphetamine. The results suggest that CFF changes following diazepam and amphetamine are mostly changes in sensory function and not changes in response bias. It is possible to apply signal detection theory to flicker-fusion studies and the accounting of bias by controlling, measuring or eliminating it is essential in interpretation of CFF data.

An evaluation of tamoxifen as a partial agonist by classical receptor theory--an explanation of the dual action of tamoxifen.

Tamoxifen is known to have both agonist and antagonist properties. Classical receptor theory predicts that given the relative concentrations of a partial agonist and full agonist acting on the same receptor, the partial agonist may reduce the effect of the full agonist. The immature rat uterine model is an excellent system to evaluate the interactions of estradiol and tamoxifen by application of receptor theory. Using this model, tamoxifen demonstrates both additive and antagonistic effects to estradiol in the fashion predicted by theory. The effects of tamoxifen are additive at low doses of estradiol and antagonistic over higher estradiol doses. It is possible that the dualism of agonism and antagonism seen in other target organs and species is a function of these basic characteristics of a partial agonist.

The effects of a new thromboxane synthetase inhibitor, CGS-13080, in man.

CGS-13080 is a new potent selective inhibitor of thromboxane synthetase. This study reports the results of a safety and efficacy study of single oral doses in normal healthy volunteers. The compound was well tolerated by all subjects without evidence of any adverse reactions. Serum thromboxane B2 levels (the stable metabolic product of thromboxane A2) were significantly reduced after administration of the compound, with the maximal effect of a 99 per cent reduction occurring at 0.5 and 1 hour after administration. There was a concomitant increase in PGE2 and 6-keto-PGF1 alpha (the stable metabolic product of PGI2), suggesting a shunting of cyclic endoperoxide metabolism. The apparent half-life of the compound is about 1 hour, but return to 50 per cent of the original thromboxane B2 levels was achieved between 4 and 6 hours. Platelet aggregation to collagen and bleeding times failed to demonstrate significant changes after drug administration. Bleeding times showed a slight increase 2 hours after administration of the compound.