Löscher W, Hönack D
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Epilepsia. 1995 Sep;36(9):929-37. doi: 10.1111/j.1528-1157.1995.tb01637.x.
Recently, sustained-release (SR) preparations of valproate (VPA) have been developed to minimize or prevent problems associated with plasma level fluctuations during therapy with conventional preparations. In the present experiments, the anticonvulsant activity of VPA was assessed during prolonged treatment with different administration protocols using the intravenous (i.v.) pentylenetetrazol (PTZ)-infusion seizure threshold model in rats. To simulate a controlled-release (CR) preparation, VPA was infused in a constant rate through chronically implanted intrajugular catheters in some of the experiments. In all experiments, the PTZ seizure threshold was repeatedly determined in individual rats with chronically implanted catheters at daily intervals. Injection of saline three times daily in a control group showed that the PTZ seizure threshold was stable throughout the experiment. Acute administration of VPA 200 mg/kg intraperitoneally (i.p.) significantly increased the seizure threshold. During prolonged treatment with three daily doses of 200 mg/kg i.p., anticonvulsant activity markedly increased on the second day of treatment and thereafter compared to the acute effect of VPA, although plasma levels measured at each seizure threshold determination did not differ significantly. This increase in anticonvulsant activity of VPA during prolonged treatment was much less pronounced with one instead of three daily doses. One daily intraperitoneal injection of VPA (200 mg/kg) plus continuous, constant-rate intravenous infusion of 400 mg/kg/day led to a marked increase in anticonvulsant activity similar to that in the experiment with three daily doses, indicating that not the peak levels but the duration of maintenance of active drug concentrations was important for development of enhanced anticonvulsant activity.(ABSTRACT TRUNCATED AT 250 WORDS)
最近，丙戊酸盐（VPA）缓释（SR）制剂已被开发出来，以尽量减少或预防传统制剂治疗期间与血浆水平波动相关的问题。在本实验中，使用大鼠静脉注射（i.v.）戊四氮（PTZ）输注惊厥阈值模型，通过不同给药方案的长期治疗来评估VPA的抗惊厥活性。为了模拟控释（CR）制剂，在一些实验中，通过长期植入的颈静脉导管以恒定速率输注VPA。在所有实验中，每天定期在有长期植入导管的个体大鼠中重复测定PTZ惊厥阈值。对照组每日三次注射生理盐水表明，整个实验过程中PTZ惊厥阈值稳定。腹腔注射（i.p.）200mg/kg的VPA急性给药显著提高了惊厥阈值。在用每天三次200mg/kg i.p.的长期治疗期间，与VPA的急性作用相比，治疗第二天及之后抗惊厥活性显著增加，尽管每次惊厥阈值测定时测得的血浆水平无显著差异。VPA在长期治疗期间抗惊厥活性的增加，单剂量给药时比三剂量给药时要小得多。每天一次腹腔注射VPA（200mg/kg）加持续恒定速率静脉输注400mg/kg/天导致抗惊厥活性显著增加，类似于三剂量给药的实验，表明对于增强抗惊厥活性的发展而言，重要的不是峰值水平而是活性药物浓度的维持持续时间。（摘要截断于250字）
