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J R Rowland

Publications and source records attributed to J R Rowland.

11 recordsLinked to original sources
PubMed1990

Developmental toxicity and pharmacokinetics of phenytoin in the rhesus macaque: an interspecies comparison.

The developmental toxicity and pharmacokinetic fate of phenytoin in the pregnant rhesus macaque (Macaca mulatta) were examined. Oral administration of 60 to 600 mg/kg phenytoin once daily from gestational day 21 to 50 resulted in dose-dependent maternal toxicity of the central nervous system and gastrointestinal tract and an increase in embryonic loss, but no teratogenic insult. Sustained plasma levels as high as 40 micrograms/mL of total phenytoin occurred at the beginning of the treatment period. However, significant increases in the rate of elimination resulted in the reduction of total phenytoin exposure as treatment progressed. This was evidenced by large increases in phenytoin clearance, and decreases in elimination half-life and area under the time versus plasma concentration curve. Maternal toxicity, but not embryolethality, correlated with plasma phenytoin levels. Interspecies comparisons of these parameters from published data were evaluated in the mouse, rat, rabbit, rhesus macaque, and human.

Abnormalities, Drug-Induced↗
PubMed1990

Developmental toxicity and pharmacokinetics of oral and intravenous phenytoin in the rat.

Correlations between oral and intravenous (i.v.) doses of phenytoin, maternal plasma levels, and subsequent developmental toxicity were examined in the Sprague-Dawley rat. Oral administration of 150 to 1500 mg/kg and i.v. administration of 25 to 100 mg/kg phenytoin from gestational days (GD) 8 to 17 resulted in a dose-dependent increase in maternal death and toxicity [impaired motor function, decreased maternal weight gain (oral dose only)], embryolethality, and intrauterine growth retardation, in addition to significant increases in craniofacial (1125 mg/kg oral; 75 mg/kg i.v.) and urogenital (1125 mg/kg oral) malformations. Pharmacokinetic sampling in oral and i.v. groups on GD 8-9 and 16-17 revealed significant increases in maternal drug exposure over the treatment period, as evidenced by 2- to 3-fold increases in total plasma phenytoin (bound + free) half-life, area under the concentration curve, peak concentration (oral dose only), and decreases in clearance. These findings emphasize the importance of pharmacokinetics in the evaluation of phenytoin-induced developmental toxicity.

Abnormalities, Drug-Induced↗
PubMed1988

Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: an interspecies comparison.

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.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

The Health Reform Consensus Act: proceed with caution.

Congress must seize the opportunity President Clinton has created to make some long-needed changes to the nation's health system. But we can't afford the expensive and experimental measures contained in the Clinton bill or in the other measures now being debated in Congress. What we can do this year is pass measures that revamp the insurance market, expand access to the uninsured through community health centers, eliminate administrative burdens, and reform our medical malpractice and antitrust systems.

Community Health Centers↗