Nonpeptide glycoprotein IIb/IIIa inhibitors. 8. Antiplatelet activity and oral antithrombotic efficacy of L-734,217.

The antiplatelet activity of L-734,217, a nonpeptide platelet GPIIb/IIIa antagonist, was evaluated in the rat, guinea pig and dog. IC50 for inhibition of in vitro platelet aggregation for these species (agonists: adenosine diphosphate, collagen) were rat, 838,000 and > 1,100,000 nM; guinea pig, 124 and 156 nM; dog, 42 and 50 nM. In an in vivo rat/in vitro dog platelet aggregation assay, effective antiaggregatory plasma concentrations of L-734,217 were achieved after 8.0 to 16.0 mg/kg p.o. vs. 0.3 to 1.0 mg/kg i.v. to rats. Delays in platelet-dependent hemostatic plug formation in severed mesenteric arteries were observed after 2.0 to 5.0 mg/kg p.o. vs. 0.1 to 0.2 mg/kg i.v. to guinea pigs. Dose-dependent inhibitions of ex vivo platelet aggregation after 0.3 to 3.0 mg/kg p.o. and 0.03 to 0.3 mg/kg i.v. L-734,217 to conscious dogs yielded estimates of 8 to 16% oral bioavailability. The antiplatelet activity of 3.0 mg/kg p.o. L-734,217 in dogs was unaffected by dosage form or food. In a conscious dog model of left circumflex coronary artery electrolytic lesion, 3.0 mg/kg p.o. L-734,217 q4 to 8 hr reduced thrombus mass, prevented occlusive coronary artery thrombosis and reduced or prevented myocardial infarction and ventricular ectopy. In anesthetized dogs, a dissociation between inhibition of ex vivo platelet aggregation and template bleeding time prolongation was observed with i.v. L-734,217. The results of the coadministration of heparin, aspirin and L-734,217 to anesthetized dogs suggested a synergistic effect on template bleeding time with no effect on plasma L-734,217 concentrations. These findings indicate L-734,217 to be an important lead structure for the development of therapeutically useful oral antiplatelet agents.

A recessive mutation causing imperforate vagina in mice.

A recessive mutation (ipv) causing imperforate vagina was discovered in a line of mice selected for low lean tissue mass as a proportion of body weight. Two full sisters were found to have marked swelling of the perineum and complete closure of the vagina. Crosses of heterozygotes identified by progeny testing produced a female progeny ratio not different from the 3 normal: 1 affected (chi 2 = 0.695; p less than .3) expected on the basis of a recessive allele at a single autosomal locus. As a consequence of the imperforate vagina, the uterus and vagina were greatly distended by fluid. The uterus of affected females displayed a swollen uterine lumen and thin endometrial stroma and muscularis. Ovarian tissue of affected females was similar to that of normal mice, and affected females produced ova that were normal in appearance. The mutation causing an imperforate vagina may present a useful model for studying the basis of abnormal vaginal development in other species and increasing the understanding of normal vaginal development in the mouse.

Effects of diazepam on arterial blood gas concentrations and pH of adult rats acutely and chronically exposed to methadone.

The effects of diazepam alone, and in combination with acute and chronic exposure to methadone, on arterial pH, pCO2 and pO2 in the rat were evaluated. Measurements were made before drug administration and at 15, 30, 60, 120, 180 and 240 min postadministration. Diazepam (20 mg/kg s.c.) did not cause any significant changes in arterial pCO2 or pH. However, it did cause a significant increase in arterial pO2 tension (P less than or equal to .05). The magnitude of this effect was essentially the same after acute and chronic diazepam treatment. The increase in arterial pO2 tension was attributed to a decrease in tissue uptake of oxygen associated with the decrease in body temperature that occurred after diazepam treatment. Acute and, to a far lesser extent, chronic administration of methadone (5 mg/kg/day i.p.) caused significant decreases in arterial pH and pO2 and increases in pCO2 (P less than or equal to .05). When given in combination with methadone, diazepam potentiated markedly the respiratory depressant effects of methadone. The most severe respiratory depression occurred when both drugs were used together acutely. The effects of the acute diazepam-chronic methadone treatment were 100 to 200% greater than those that occurred with the chronic diazepam-chronic methadone treatment, indicating the development of a tolerance to the potentiating ability of diazepam. These results show that there is a real potential for severe respiratory depression when these drugs, methadone and diazepam, are used concurrently, especially for the first time.