The principal objectives of this research project are to provide an understanding of pregnancy- and gender-related differences in cocaine intoxication, to which little scientific attention has been paid, and to test the antidotal and tocolytic efficacy of the calcium channel blocker nifedipine on cocaine-induced intoxication and premature labor. Since cocaine is hydrolyzed by plasma cholinesterase, and because ovarian steroids appear to modulate the synthesis of cholinesterases, dosages of cocaine that produce intoxication should be different in the fetus, pregnant and nonpregnant female, as well as in the adult male. Chronically instrumented rat and guinea pig models will be used, with arterial and venous catheters, ECG electrodes and in some animals, intrauterine catheters implanted for continuous monitoring of physiological parameters and administration of drugs. Plasma and tissue samples will be obtained for determination of cocaine concentrations, which will be correlated with physiological parameters and behavioral changes. The comparative threshold of acute cocaine toxicity and plasma cholinesterase activity in males and pregnant and hormonally manipulated nonpregnant females will be examined to clarify the role of hormonal mechanisms in cocaine toxicity. Nifedipine's antidotal efficacy in cocaine overdose will be assessed, as will its tocolytic effect on cocaine-induced uterine contractions in the pregnant rat, which may serve to prevent premature labor. Finally, the beneficial effect of intrauterine clearance of cocaine upon the fetus of the cocaine- overdosed mother will be evaluated. The data obtained from these studies will not only contribute to a greater understanding of the risks of the cocaine abuse during pregnancy, but will also lead to methods of preventing both cocaine-induced premature labor and neonatal cocaine intoxication.
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