Paulson R B, Sucheston M E, Hayes T G, Weiss H S, Sachs L A, Oca M, Kernan B, Weiss S
Department of Oral Biology, College of Dentistry, Ohio State University, Columbus 43210.
J Craniofac Genet Dev Biol. 1988;8(1):35-45.
This study reports the effects of valproic acid (VA) on the CD-1 mouse fetus when the drug is administered continuously via osmotic minipumps at human therapeutic drug plasma levels. Two VA-filled Alzet osmotic minipumps were implanted subcutaneously on gestation day 5 for continuous exposure of a total daily dosage of 850 mg/kg on gestation days 5-12. Dams were then exposed continuously to either normoxic (21% oxygen), hyperoxic (50% oxygen), or hypoxic (12% oxygen) controlled environments during gestation days 5-12, in order to determine if hyperoxic maternal conditions offered a protective environment for the fetus, and conversely, if hypoxia exacerbated teratogenicity. Dams were sacrificed on gestation day 18, and litter and fetal data were collected. It was determined in separate groups under normoxic conditions that the osmotic minipump system maintained VA plasma levels corresponding to human therapeutic levels. Sodium valproate was found to induce developmental toxicity in the CD-1 mouse fetus at human therapeutic drug plasma levels. Fetal weights were reduced, and the number of resorptions, deaths, and hematomas was increased. While hypoxia exacerbated the toxic effect on the fetus, hyperoxia failed to ameliorate the outcome.
本研究报告了在以人体治疗药物血浆水平通过渗透微型泵持续给药丙戊酸（VA）时，其对CD - 1小鼠胎儿的影响。在妊娠第5天皮下植入两个充满VA的Alzet渗透微型泵，以便在妊娠第5 - 12天持续暴露于每日总剂量850 mg/kg的药物中。然后在妊娠第5 - 12天期间，将母鼠持续暴露于常氧（21%氧气）、高氧（50%氧气）或低氧（12%氧气）的受控环境中，以确定高氧母体环境是否为胎儿提供了保护性环境，反之，低氧是否会加剧致畸性。在妊娠第18天处死母鼠，并收集窝仔和胎儿数据。在常氧条件下的单独分组中确定，渗透微型泵系统维持的VA血浆水平与人体治疗水平相当。发现丙戊酸钠在人体治疗药物血浆水平时会诱导CD - 1小鼠胎儿发育毒性。胎儿体重减轻，吸收、死亡和血肿数量增加。虽然低氧加剧了对胎儿的毒性作用，但高氧未能改善结果。
