POLYTHERAPY MECHANISMS IN PREGNANCY

妊娠期的综合治疗机制

• 批准号: 3328041
• 负责人: JOAN S LOCKARD
• 金额: $ 40.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3328041
• 关键词: Macaca fascicularis; animal developmental psychology; carbamazepine; cognition disorders; combination chemotherapy; covalent bond; cytochrome P450; drug metabolism; embryo /fetus drug adverse effect; enzyme inhibitors; enzyme mechanism; epilepsy; epoxide hydrolase; female; glutathione; glutathione transferase; longitudinal animal study; magnetic resonance imaging; neuromuscular function; nonhuman therapy evaluation; phenytoin; postnatal growth disorder; pregnancy; prenatal growth disorder; teratogens; urinalysis

Teratogenicity is a considerable problem for women with epilepsy. Under most circumstances it would be detrimental to their health to have the antiepileptic medication withdrawn during pregnancy. At the same time, there is risk to the fetus exposed to certain anticonvulsants. The problem is compounded if the epileptic woman has multiple seizure types or seizures refractory to monotherapy. Under these circumstances, polytherapy is required to control seizures and the rate of teratogenicity is two to threefold higher with multiple drugs. In rodent systems, growth and other physical anomalies apparent in the embryo or at birth, resulting from phenytoin (PHT) exposure during gestation, have been linked to reactive metabolite exposure. However, no studies have sought to identify the cause of learning and behavioral deficits which become apparent after birth. Carbamazepine (CBZ) apparently forms at least one reactive arene oxide metabolite, but no studies have been conducted to link any form of carbamazepine-induced teratogenicity to reactive metabolite exposure, although the likelihood of this mechanism has been recognized. The proposed research will test the hypothesis that teratogenicity in the form of growth problems at birth and (more importantly) developmental delays after birth, first in PHT therapy, and second in CBZ therapy, is due to reactive metabolite exposure. We propose to conduct in vivo inhibition, pharmacokinetic, and teratogenicity studies using a pregnancy monkey model. These studies will be accomplished by utilizing a nonteratogenic second drug stiripentol (STP), which in polytherapy with PHT (or CBZ) inhibits cytochrome P-450 and thus decreases reactive metabolite exposure while maintaining the plasma concentration of the parent compound.

对于患有癫痫女性的女性，致畸性是一个相当大的问题。 在大多数情况下 怀孕期间撤离抗癫痫药。 同样 时间，暴露于某些抗惊厥药的胎儿有风险。 这 如果癫痫女性有多种癫痫发作类型，问题会更加复杂 或对单一疗法的癫痫发作。 在这种情况下， 需要多疗法来控制癫痫发作和速率 多种药物使用多种药物，致畸性高两到三倍。 在啮齿动物系统中，生长和其他物理异常明显 胚胎或出生时，由苯苯苯苯苯克号（PHT）导致 妊娠与反应性代谢物暴露有关。 但是，不 研究试图确定学习和行为的原因 出生后显而易见的缺陷。 卡马西平（CBZ） 显然形成至少一种反应性氧化物代谢物，但没有 已经进行了研究以连接任何形式的卡马西平诱导的 致力于反应性代谢物暴露，尽管可能性 这种机制已被认可。 拟议的研究将检验致死性的假设 以出生时的增长问题的形式（更重要的是） 出生后的发育延迟，首先是PHT疗法，在CBZ中第二 治疗是由于反应性代谢产物的暴露。 我们建议进行 使用A的体内抑制作用，药代动力学和致畸性研究 怀孕猴子模型。 这些研究将通过利用 非伴生毒剂搅拌酚（STP），该药物在多疗法中与 PHT（或CBZ）抑制细胞色素P-450，从而降低反应性 代谢物暴露，同时保持血浆浓度 父级化合物。