This study was undertaken to assess the developmental toxicity and drug distributional and metabolic characteristics of prenatal valproic acid (VPA) exposure in rhesus monkeys. Oral administration of 20-600 mg/kg/day VPA (approximately 1-15 X human therapeutic dose) to 33 animals on variable gestational days (GD) during organogenesis resulted in dose-dependent developmental toxicity manifested as increased embryo/fetal mortality, intrauterine growth retardation, and craniofacial and skeletal defects. Biphasic plasma elimination curves were observed for total and free VPA on the first (GD 21) and last (GD 50) days of treatment in the 100- and 200-mg/kg/day dose groups. VPA exhibited dose-independent elimination kinetics at the plasma concentrations observed in this study. There was no significant change in pharmacokinetic parameters (maternal plasma elimination rate, area under the curve, peak plasma concentration) between the first and last days of treatment at either dose level. Placental transfer studies indicated that embryos were exposed to half the free VPA concentrations present in maternal plasma on GD 37. Comparisons of interspecies sensitivity to VPA-induced developmental toxicity in the mouse, rat, monkey, and man are made.

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Previous developmental and reproductive toxicity studies conducted in rats with Losartan, a potent AT1 subtype selective angiotensin II receptor antagonist, noted treatment-related effects on the pups of dams treated beyond the second trimester through lactation, as demonstrated by increases in pre- and postweaning pup deaths and decreased pup body weights [Spence et al. (1995) Teratology 51:000-000]. The studies presented here were designed to define the critical period for the induction of neonatal toxicity and to examine the effects of Losartan on kidney development when the drug is administered to the dam beyond the second trimester through lactation. In a developmental toxicity study with postweaning evaluation, pregnant rats were administered 5, 20, and 100 mg Losartan/kg/day on gestation days 6 through 15 (GD 6-15). There were no adverse effects on the F1 generation as assessed by mortality, clinical signs, weight gain, external examinations, developmental signs, behavioral tests, and gross or microscopic examination of the kidney. In a fostering/cross-fostering study, pregnant rats were administered 100 mg Losartan/kg/day on GD 15 through lactation day 20 (LD 20). Following delivery, pups from dams treated with Losartan were fostered to control dams, pups from control dams were fostered to Losartan-treated dams, and pups were also fostered to dams within the same group. Maternal exposure to Losartan during lactation increased the incidence of pup deaths on postnatal days 1-3 (PND 1-3), caused decreased pup weights on PND 7, and decreased performance in the auditory startle test in females and increased performance on the second swim maze test in males, relative to controls. Maternal exposure to Losartan during gestation was associated with decreased pup weight on PND 21 and effects observed on male performance in the swim maze test. Treatment during gestation was also associated with decreased pup cardiac weight as well as drug-induced histopathological changes of the kidneys from F1 pups, including medial hypertrophy of intracortical arterioles and dilatation of the renal pelvis. While the cardiac and renal vascular effects disappeared with time, significant renal lesions were still evident by PND 90. In a late-gestation/lactation study with renal evaluation, pregnant rats were administered 0.5, 1.0, 5.0, 20, and 100 mg Losartan/kg/day on GD 15-LD 20. Maternal toxicity was evident as decreased body weight gain in the 100 mg Losartan/kg/day group.(ABSTRACT TRUNCATED AT 250 WORDS)

L-368,899 [1S-((-7,7-dimethyl-2-endo-(2S-amino-4-(methylsulfonyl)bu~ramido)-bicyclo(2.2.1)-heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl)piper~inel was characterized in vitro and in vivo as a potent and selective, orally bioavailable oxytocin (OT) antagonist. L-368,899 exhibits high affinity for rat (Ki, 3.6 nM) and human (Ki, 13 nM) uterine OT receptors with selectivity versus liver arginine-vasopressin (AVP)-VI and kidney AVP-V2 receptors in both species. In vitro, L-368,899 is a potent and competitive OT antagonist in the rat isolated uterus (pA2, 8.9) and mouse anococcygeus muscle (pA2, 8.3) and is inactive against a number of different contractile agents in these preparations. L-368,899 also inhibits OT-stimulated phosphatidylinositol turnover in rat uterine slices and exhibits no agonist-like activity in any of the in vitro assays. In vivo, L-368,899 selectively antagonizes the uterine contractile effects of OT in the anesthetized rat given both i.v. and intraduodenally (i.d.) (AD50; 350 Fg/kg i.v., 7 mg/kg i.d.) with a moderate duration of action. In near-term pregnant rhesus macaques, L-368,899 is a potent inhibitor of OT-stimulated uterine activity (AD50, 27 pg/kg i.v.) and OT-mediated spontaneous, nocturnal uterine contractions. L-368,899 is orally bioavailable in several species and, combined with adequate aqueous solubility, represents a potential new tocolytic agent for both oral and i.v. use. o 1993 WiIey-Liss, inc.

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