UK-38,485, a novel imidazole derivative, was used in two clinical trials with healthy male subjects to study the influence of thromboxane synthetase inhibition on prostanoid formation. In an open pharmacokinetic study, UK-38,485 administered orally in doses of 10,20, 40, 60, and 100 mg significantly reduced serum thromboxane (TXB2) concentrations. With lower doses (10 and 20 mg) peak inhibition of serum thromboxane occurred 2 hr after dosing, with a mean percentage inhibition of 78% and 91%, respectively. For the higher doses (40, 60, and 100 mg) peak inhibition exceeded 99% 1 hr after dosing. After 8 hr the inhibition was dose related, ranging between 59% and 75%, and after 24 hr between 0 and 35%. In a second multiple-dose, double-blind, placebo-controlled, cross-over study, 50 mg UK-38,485 given twice daily for 1 week selectively inhibited thromboxane synthetase. The excretion of 2,3-dinor-TXB2, the major urinary metabolite of endogenously formed thromboxane, was significantly reduced, whereas the urinary excretion of 2,3-dinor-6-keto-PGF,a, the main metabolite of endogenous prostacyclin, and the plasma concentrations of 6-keto-PGF,a showed no significant increases compared with levels in the placebo period. In platelet suspensions stimulated ex vivo with arachidonic acid and in serum of incubated whole blood, TXB2 concentrations were reduced and a significant redirection of endoperoxide metabolism to antiaggregatory and vasodilatory prostaglandins '2, E2, and D2 was demonstrated after the influence of UK-38,485. Platelet lipoxygenase metabolites were not measurably altered. The drug was well tolerated. In both studies, no clinically relevant changes in laboratory safety and hemodynamic parameters, bleeding, or clotting time were observed. From the time course of the plasma drug concentrations, the inhibition of thromboxane synthesis, and the redirection of endoperoxide metabolism it can be concluded that UK-38,485 is rapidly absorbed and has a long-lasting effect on prostanoid formation. Circulation 68, No. 4, 821-826, 1983. THROMBOXANE A2 (TXA2) and prostaglandin (PG) 12 exert opposite effects on platelet aggregation and vascular resistance, and the balance between these compounds has been proposed to be one of the factors that determine platelet reactivity, endothelial thromboresistance, and vascular tone. 485,'5 in healthy male subjects.The potency and specificity of action of this drug were examined by

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1. All patients are basically suitable for early extubation, with the presence of preoperative risk factors used in this study being poor predictors of prolonged ventilation. 2. The necessity of prolonged ventilation is primarily determined by intra- or perioperative complications.

Nonthoracotomy lead systems for implantable cardioverter defibrillators (ICDs) have reduced operative mortality and morbidity as compared to epicardial lead systems but are usually associated with higher defibrillation thresholds (DFTs). The purpose of this prospective randomized trial was to investigate if the second defibrillation electrode in the left subclavian vein can increase defibrillation efficacy and decrease DFT as compared to the superior vena cava (SVC) position in nonthoracotomy lead systems for ICDs. Seventeen patients (mean age: 49.9 +/- 11.3 years, mean ejection fraction: 46.1% +/- 15.8%) were implanted with an investigational unipolar electrode (Medtronic 13001) used as the defibrillation anode. DFT testing was started in the SVC (n = 10, group A) or the left subclavian vein (n = 7, group B), and repeated in the alternative position starting at the DFT of the initial position. Fifteen patients were eligible for analysis (group A: n = 9, group B: n = 6). With the electrode in the SVC, ventricular fibrillation could be successfully terminated in 9 out of 15 patients (60%). In the left subclavian vein the success rate was 100% (P < 0.01). Mean DFT in the SVC was 13.0 +/- 5.2 J and in the left subclavian vein 10.2 +/- 4.9 J. DFTs in the left subclavian vein were either lower (group A: n = 5/9, group B: n = 5/6) or equal to the results in the SVC position (P < 0.001). Thus, the left subclavian vein appears to be a superior alternative for positioning of the defibrillation anode as compared to the SVC for nonthoracotomy lead systems using two separate leads.

Isolation of the corticosteroid-binding globulin CBG was achieved by 5 chromatographical steps on cortisol Sepharose, QAE-Sephadex A-50, Con A-Sepharose and hydroxylapatite. The purity of the isolated CBG was demonstrated in polyacrylamide gel electrophoresis, SDS electrophoresis, immunodiffusion and ultracentrifugation. Microheterogeneity was shown in isoelectric focusing by 5 bands in the pH range of 3.7–4.2, which could be reduced to one major band after neuraminidase treatment. The equimolar binding of cortisol to CBG was demonstrated by binding studies. The association constant for cortisol was 2.8 × 108 m−1, for progesterone 1.7 × 106 m−1. From analytical ultracentrifugation, the molecular weight was calculated on 50 700; the sedimentation coefficient was 3.6 S, the partial specific volume 0.690 ml/g, the Stokes radius 38 Å and the frictional coefficient ratio 1.5. A specific radioimmunoassay for CBG was established using the purified CBG for immunization, radioiodination and for calibration standards. The normal range of CBG levels in human serum was 2.4–4.4 mg/100 ml (mean ± 2 sd). Studies were performed to compare the levels of CBG and thyroxine-binding globulin (TBG). No sex differences but a significant biphasic age dependence were observed for both proteins. In pregnancy and under oestrogen treatment of women and men, CBG was demonstrated to be the more distinct indicator of oestrogenic activity as compared with TBG, whereas the sensitivity of TBG was more pronounced to supposedly antioestrogenic substances like Danazol, and in severe disease. No coincidence of genetic CBG and TBG deficiencies have been found so far.