R.M. McClain

Reproduction studies in rats treated with ornidazole

Reproduction studies were performed with ornidazole, a compound with trichomonacidal activity. Male rats were treated for 61 days prior to mating and female rats were treated for 2 weeks prior to mating and throughout gestation and lactation at doses of 0 (control), 25, 100, and 400 mg of ornidazole/kg/day. A decrease in the pregnancy rate was observed in high-dose rats without altered mating performance. Crossover matings between high-dose treated and control male and female rats showed that male but not female fertility was affected and that the effect on fertility was reversible within several days after the cessation of treatment. Testicular and epididymal weights were not altered in treated male rats. Histopathological examination revealed that spermatogenesis and the testes were normal and that the epididymides of treated male rats contained normal appearing sperm. It is concluded that ornidazole, at high dosages, produces infertility in the male rat; however, unlike many other 5-nitroimidazole compounds which are reported to inhibit spermatogenesis, no effect on spermatogenesis was observed under the conditions of these studies. This in conjunction with the rapid reversibility of infertility suggests that the mode of action of ornidazole involves a rapidly reversible effect on epididymal sperm function.

The placental transfer of lead-chelate complexes in the rat☆

Abstract The placental permeability and transfer of lead nitrate alone and lead chelated with ethylenediaminetetraacetic acid (PbEDTA), nitrilotriacetic acid (PbNTA), iminodiacetic acid (PbIDA), and penicillamine (PbPEN) were determined. 210 Pb(NO 3 ) 2 was infused into pregnant rats on day 18 of gestation at a rate of 0.5 mg/kg/min alone and with an equimolar amount of chelating agent. The results showed that the placental transfer of lead is increased with the infusion of PbNTA, PbPEN, and PbEDTA despite the fact that maternal whole blood and plasma lead concentrations were about one-third that with lead alone. Little or no differences in maternal blood lead content or fetal lead content were observed with the PbIDA complex. The administration of a single iv dose of lead alone (50 mg/kg) or with equimolar amounts of chelating agents resulted in approximately a 400% increase in fetal lead content with PbPEN and PbNTA and a 50% increase with PbEDTA by 4 hr after administration as compared to lead alone. During this time PbNTA, PbPEN, and PbEDTA had been mostly eliminated by the maternal animal so that no further increase in placental transfer occurred. The net result of increased permeability and maternal elimination was a fetal lead content similar to lead alone with PbPEN and PbNTA and a greatly reduced fetal lead content with PbEDTA at 24 and 48 hr after administration. It is concluded that the membrane permeability and the placental transfer of lead can be increased with lead-chelate complexes. Under the conditions of our experiments this factor is balanced by more rapid maternal elimination and faster termination of the fetal exposure to lead when present in its chelated form.

The effects of various chelating agents on the teratogenicity of lead nitrate in rats

Abstract Lead nitrate alone or lead chelated with ethylene-diaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), iminodiacetic acid (IDA), and penicillamine (PEN) was administered iv to pregnant rats on days 9, 11, or 16 of gestation (day 1 = vaginal plug) at a 1:1 molar ratio of chelating agent to lead at a dosage of 35 or 50 mg/kg with respect to lead nitrate. Lead nitrate alone caused resorptions and fetal malformations on day 9, resorptions on day 11, and resorptions and hydrocephalus following treatment on day 16. The lead-chelate complex either reduced or equaled but did not enhance the overall embryo or fetal toxicity. There were no qualitatively different effects produced with chelated lead versus lead alone. The chelating agents were more effective after treatment on gestation day 9 that after days 11 or 16. Ethylenediaminetetraacetic acid produced the greatest reduction in overall effect, with PEN and NTA intermediate, while IDA provided the least overall protective effects.

Reproduction studies with carprofen, a nonsteroidal anti-inflammatory agent in rats.

Abstract Reproduction and teratology studies were performed in rats given carprofen, a nonsteroidal anti-inflammatory agent. Dosages of 2, 6, and 20 mg/kg/day were administered orally as a carboxymethylcellulose suspension. In a teratology study no adverse effects on embryonic and fetal development were noted at dosages of carprofen up to 20 mg/kg/day in spite of toxicity in some of the dams. In reproduction studies, characteristic effects of prostaglandin synthetase inhibitors were observed including a slightly prolonged gestation period and an increased incidence of dead pups at birth. Otherwise, no adverse effects upon fertility or reproduction were seen. During the course of these reproduction studies it was observed that the toxic response to carprofen was much greater in lactating dams as compared to nonlactating controls. The physiological state of the animal rather than the length of treatment appeared to be responsible for this increased toxicological response.

Reproduction studies with 1α,25-dihydroxyvitamin D3 (calcitriol) in rats and rabbits☆☆☆

Reproduction and teratology studies were performed in rats and rabbits with 1α,25-dihydroxyvitamin D3 (calcitriol). Dosages of 0.02, 0.08, and 0.3 μg/kg/day were administered orally as a solution in Neobee oil. In rat teratology studies, no substantial differences were noted between control animals and animals treated with calcitriol from Days 7 through 15 of gestation with respect to litter sizes, resorption rates, pup weights, or external, visceral, and skeletal abnormalities. No adverse effects on either fertility or neonatal development were noted in rat reproduction studies in which male and female rats were pretreated prior to mating through sacrifice on Day 13 of gestation or through lactation Day 21. No adverse effect on perinatal development was noted in litters from females treated from Day 15 of gestation through Day 21 of lactation. However, hypercalcemia and hypophosphatemia were observed in treated pregnant female rats at dosages of 0.08 and 0.3 μg/kg/day and increased serum urea nitrogen was observed at 0.3 μg/kg/day. Hypercalcemia calcemia was noted in pups from dams receiving 0.08 and 0.3 μg/kg/day calcitriol. There was no decrease in the percentage bone ash as determined on lactation Day 21 in either treated females or their pups as compared to controls. In rabbits treated from Days 7 through 18 of gestation with 0.3 μg/kg/day, 316 rabbits died. Other signs of toxicity included maternal weight loss, an increased resorption rate and neonatal mortality. Two litters at 0.3 μg/kg/day and 1 litter at 0.08 μg/kg/day contained fetuses with multiple abnormalities. These studies demonstrated that in pregnant animals the observed effects of calcitriol are characteristic of those reported for vitamin D3. In rabbits, dosages of 0.3 μg/kg/day calcitriol produced maternal and fetotoxic effects.

The effect of flunitrazepam on reproduction in the rat. The use of cross-fostering in the evaluation of postnatal parameters in rat reproduction studies☆

Abstract During the course of reproduction studies in rats with flunitrazepam, a benzodiazepine derivative, a high incidence of neonatal loss at delivery and during the first 2 days of the lactation period was observed. At delivery the female rats treated with 25 mg/kg/day flunitrazepam exhibited signs of central nervous system depression and were indifferent during parturition resulting in an increased incidence of dead pups at delivery. In addition, flunitrazepam induced a peculiar voracious behavior causing some animals to cannibalize their litter shortly after dosing. A crossfostering experiment was conducted in order to determine whether the observed neonatal loss was the result of a direct toxic effect of flunitrazepam on the neonates or was secondary to aberrant maternal behavior. Cross-fostering in itself did not produce adverse neonatal effects since the survival of control neonates in litters that had been fostered was equivalent to control animals whose litters were not fostered. Treated dams nursing neonates from control litters cannibalized these apparently normal pups indicating that the observed cannibalism after delivery was due to abnormal maternal behavior. Treated neonates placed with control dams exhibited a survival rate which although much better than control pups with treated dams, was still somewhat lower than controls, suggesting that decreased viability of pups delivered from treated dams was an additional factor in the neonatal loss. The survival rate of Cesarean-delivered pups, however, from treated dams and fostered by untreated dams was not significantly different from control neonates similarly handled. This latter result demonstrated that the decreased viability of pups from treated dams appears to be the result of trauma during delivery rather than a direct toxic effect of flunitrazepam on the neonate or on the fetus in utero .