el-Bizri H, Guest I, Varma D R
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Pediatr Res. 1991 Feb;29(2):187-90. doi: 10.1203/00006450-199102000-00017.
Intraperitoneal injections of 6.25, 12.5, 25, 50, and 100 mumols/kg cocaine into pregnant Sprague-Dawley rats once a day from d 0 to 19 of gestation caused a dose-dependent increase in fetal soft tissue malformations, primarily of the genitourinary tract. At 100 mumols/kg, all implants were lost and three of the five animals died after six to seven injections. At 50 and 100 mumols/kg but not at lower doses, cocaine caused a small but significant decrease in body weight and food intake. Cocaine did not affect mean fetal and placental weights, although it increased the number of runts and edematous fetuses, and did not cause skeletal malformations. After intraperitoneal injection of 50 mumols/kg, the plasma t1/2 of cocaine was 21 +/- 5 min and peak plasma concentration (1682 +/- 260 pmol/mL, measured by HPLC) was achieved in 5-10 min; a lower peak plasma concentration (486 +/- 103 pmol/mL) was achieved in 20-60 min after s.c. injection. Concentrations of dopamine, epinephrine, and norepinephrine in brains of fetuses or newborn pups (less than 12 h old) of cocaine (50 mumols/kg)-treated rats were not significantly elevated. Cocaine injections did not affect gestational duration nor the growth pattern and the locomotor activity of offspring. However, three pups born to one cocaine-treated animal died 20 d after birth. Cocaine inhibited the growth of 10.5-d-old embryos in culture in a concentration-dependent manner and was more toxic than procaine. Approximately 80% of cocaine was metabolized during a 48-h period in embryo culture medium. It is concluded that cocaine possesses teratogenic potential that may be partly independent of maternal toxicity.
从妊娠第0天至第19天，每天对怀孕的斯普拉格 - 道利大鼠进行腹腔注射6.25、12.5、25、50和100微摩尔/千克可卡因，导致胎儿软组织畸形呈剂量依赖性增加，主要是泌尿生殖道畸形。在100微摩尔/千克剂量时，所有植入物均丢失，五只动物中有三只在注射六至七次后死亡。在50和100微摩尔/千克剂量下而非较低剂量时，可卡因导致体重和食物摄入量有小幅但显著的下降。可卡因不影响胎儿和胎盘的平均重量，尽管它增加了发育不全胎儿和水肿胎儿的数量，且未导致骨骼畸形。腹腔注射50微摩尔/千克可卡因后，可卡因的血浆半衰期为21±5分钟，血浆峰值浓度（通过高效液相色谱法测定为1682±260皮摩尔/毫升）在5 - 10分钟内达到；皮下注射后20 - 60分钟达到较低的血浆峰值浓度（486±103皮摩尔/毫升）。可卡因（50微摩尔/千克）处理的大鼠的胎儿或新生幼崽（小于12小时龄）大脑中的多巴胺、肾上腺素和去甲肾上腺素浓度没有显著升高。注射可卡因不影响妊娠期，也不影响后代的生长模式和运动活动。然而，一只经可卡因处理的动物所生的三只幼崽在出生后20天死亡。可卡因以浓度依赖性方式抑制培养的10.5日龄胚胎的生长，且比普鲁卡因毒性更大。在胚胎培养基中，约80%的可卡因在48小时内被代谢。结论是可卡因具有致畸潜力，这可能部分独立于母体毒性。
