The limb plates and craniofacial regions in rabbit fetuses were examined shortly after the last dose of phenytoin on day 16 after daily administration by gavage with either 150 mg/kg on days 14-16 or 300 mg/kg on days 15-16. Both treatment regimens resulted in similar changes. Histologically, the digital areas of the limb plates showed extensive edema and dilated blood vessels within 2 h. After 8 h, vascular disruption occurred with hemorrhages. At 24-48 h after dosing, mesenchymal necrosis and, on some occasions, amputation of digits was observed. In the craniofacial region, well-defined superficial hemorrhage was seen in the frontal and nasal region at 8 h. Histologically, subectodermal hemorrhage caused by vascular disruption and microfocal mesenchymal necrosis was observed. At 48 h, some fetuses showed severe diffuse intracranial and superficial hemorrhage, resulting in massive tissue damage, also in the central nervous system (CNS). Maternal heart rate, blood pressure, PO2, and PCO2 were also measured in awake pregnant rabbits 6 h after the last dose on day 16 after daily administration with 150 mg/kg during gestational days 14-16. An attempt was also made to measure fetal heart rate in anesthetized rabbits. The maternal heart rate and blood pressure decreased with about 15% in phenytoin-treated animals, resulting in a decrease in PO2 (approximately 15%) and an increase in PCO2 (approximately 15%). A decrease in fetal heart rate was also registered. The results thus indicate that phenytoin exerts its teratogenic effects by inducing fetal hypoxia, leading to vascular disrupture and necrosis of existing and developing structures.

In a recent study, the vasodilating drugs nifedipine, nitrendipine, felodipine, and hydralazine induced phalangeal defects in rabbits, when given on day 16 of pregnancy. Histologically, the changes were characterized by disturbed chondrogenesis. In order to elucidate mechanisms behind the defects, the fetal concentration of felodipine was measured, and the fetal limb plates were examined histologically, at 0, 2, 4, 8, 12, and 24 hours after single oral administration of felodipine (12 mumol/kg) on day 16 in pregnant rabbits. The effects of nifedipine, nitrendipine, and felodipine were also investigated in an in vitro system, in which chick embryonic mesenchymal limb bud cells differentiated into chondrocytes. In this system, no inhibition of chondrogenesis was observed below concentrations 3 x 10(5) M. At this concentration, unspecific cytotoxicity was found. The highest fetal concentrations of felodipine were more than 500 times lower than what was required for in vitro toxicity. Histologically, the digital areas of the limb plates showed extensive edema and dilatation of marginal sinus within 2 hours. After 8 hours, rupture of the thin-walled vessels occurred with hemorrhages. Finally, small necroses and blisters were observed. Similar early changes have been reported in experiments where digital defects were induced by clamping uterine vessels. This study thus indicates that the phalangeal defects after administration of high doses of vasodilators are secondary to pharmacological action (associated with a significant reduction in the uteroplacental blood flow), and not a direct effect on fetal chondrogenesis.

Abstract:The relationship between free drug concentration and toxicity of bupivacaine and ropivacaine, a new local anaesthetic agent, was studied in a pregnant rat model. The compounds were given subcutaneously to rats in late pregnancy. Dose levels (bupivacaine 5.5 to 24 mgikg and ropivacaine 5.3 to 26 mg/kg) were selected based upon the proposed human dosage and the known pharmacological activity of the compounds. Chewing, spasm, dyspnoea, drowsiness, salivation and convulsions were observed in a dose-dependent manner in the animals given 14 to 24 mg/kg of bupivacaine, while only a few animals receiving 26 mg/kg of ropivacaine showed less severe symptoms. Deaths from clonic convulsions were occasionally seen in animals receiving 14 mg/kg or more of bupivacaine. No animals receiving ropivacaine died. No effects on litter size, offspring loss or weight of the offspring at birth were observed with one exception. After 24 mgikg of bupivacaine an increased postnatal loss of the offsprings were noticed, most likely due to impaired maternal care. Protein binding, at expected C, , , , were significantly lower for ropivacaine (around 49%) compared with bupivacaine (around 69%) at dose levels. The results suggest an increased safety margin before onset of toxic side effects after treatment with ropivacaine, compared to bupivacaine, in pregnant rase.Clinical data confirm that bupivacaine is a useful drug in obstetric anaesthesia if proper precautions are taken (Editorial 1986;Moore et al. 1971). However, reversible maternal as well as fatal reactions secondary to convulsions and cardiac arrest have been reported for bupivacaine in human labour due to excessive doses, low individual toxic thresholds or unrecognized intravascular injections (Editorial 1986;Moore et al. 1971;Ryan 1973;Hodgkinson 1978;Albright 1979;Thornburn & Moir 1984). Animal studies suggest an increase in systemic toxicity (both cardioand neurotoxicity) following administration of bupivacaine in a late state of pregnancy (Morishima et al. 1985; Crandell & Kotelko 1985;Ravindran et al. 1982;Datta et al. 1983). Serious foetalheonatal reactions seem to be very rare, but have been reported after paracervical block, most likely as a result of the direct entry of bupivacaine into the placental circulation (Beazley 1972).Ropivacaine is a new long-acting local anaesthetic agent with pharmacodynamic properties similar to those of bupivacaine (Akerman et al. 1988). Unlike bupivacaine, which is a racemic mixture, ropivacaine is exclusively the S(-)-enantiomer. Ropivacaine is less cardio-and neurotoxic in non-pregnant animals than bupivacaine (Rutten et al. 1989; Arthur et al. 1986) and has been less prone to produce central nervous and cardiovascular symptoms after intravenous injection in human volunteers (Scott et al. 1989). Comparative data regarding its toxicity in humans are for obvious reasons very difficult to obtain. The main objective of this investigation was to compare the threshold for the induction of toxic effects in pregnant rats in relation to the p...