Tamargo Rafael J, Rossell Lisa Ann, Kossoff Eric H, Tyler Betty M, Ewend Matthew G, Aryanpur John J
Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Epilepsy Res. 2002 Feb;48(3):145-55. doi: 10.1016/s0920-1211(01)00330-8.
An alternative strategy for the treatment of intractable seizures may be to administer anticonvulsants directly into the brain near the site of a seizure focus using controlled-release polymers. We describe the pharmacokinetics of a phenytoin-ethylene-vinyl acetate (EVAc) controlled-release polymer and report the reduction of seizures in a cobalt-induced rat model of epilepsy with the intracerebral delivery of phenytoin using surgically implanted polymers.
In the pharmacokinetics study, the drug release rate of 50%-loaded phenytoin-EVAc polymers (n=3) was determined in vitro over 15 weeks initially and then several months later (over a 2-week period after 1 year of in vivo release). In the efficacy study, 85 rats underwent implantation of skull-mounted cortical electrodes for electrocorticography (ECoG) and then underwent application of cobalt chloride to the cerebral cortex for the induction of seizures. Rats in the treatment group (n=9) underwent surgical implantation of phenytoin-EVAc polymers and rats in the control group (n=10) underwent implantation of empty EVAc polymers. In the morbidity study, the potential histologic pathology of the intracerebral delivery of increasing doses of phenytoin from the polymer (10, 20, 30, and 50% loading) was assessed.
Phenytoin was released in vitro from EVAc polymers in a controlled fashion with an initial release of 0.20% of the total loaded dose per week and a continued release of 0.70% of the total loaded dose per week after 365 days of implantation in the brain. The intracerebral controlled-release of phenytoin resulted in a statistically significant reduction in seizure activity in the treatment group as evidenced by lower Racine scores. The four groups of rats (n=5 per group) that underwent intracerebral implantation of 10, 20, 30, or 50%-loaded phenytoin-EVAc polymers displayed expected average weight gain and normal behavior over 365 days. One rat in the 50% group, however, died 354 days after polymer implantation for undetermined reasons.
The intracerebral delivery of phenytoin using an EVAc polymer, which will release this drug for a calculated period of 3.5 years, resulted in a significant reduction in seizures in a rat model of cobalt-induced epilepsy by both behavioral and ECoG criteria. In rats, the long-term interstitial delivery of phenytoin in the brain was not associated with any deleterious effects.
治疗顽固性癫痫的一种替代策略可能是使用控释聚合物将抗惊厥药物直接注入癫痫病灶附近的大脑。我们描述了苯妥英 - 乙烯 - 醋酸乙烯酯（EVAc）控释聚合物的药代动力学，并报告了在钴诱导的大鼠癫痫模型中，通过手术植入聚合物进行脑内递送苯妥英后癫痫发作次数的减少情况。
在药代动力学研究中，最初在体外测定了50%负载量的苯妥英 - EVAc聚合物（n = 3）在15周内的药物释放速率，然后在数月后（体内释放1年后的2周期间）再次测定。在疗效研究中，85只大鼠接受了颅骨安装皮质电极用于脑电图（ECoG）监测，然后在大脑皮质应用氯化钴诱导癫痫发作。治疗组（n = 9）的大鼠接受了苯妥英 - EVAc聚合物的手术植入，对照组（n = 10）的大鼠接受了空EVAc聚合物的植入。在发病率研究中，评估了从聚合物中增加剂量的苯妥英（10%、20%、30%和50%负载量）进行脑内递送的潜在组织病理学情况。
苯妥英从EVAc聚合物中以可控方式在体外释放，植入大脑365天后，初始释放速率为每周总负载剂量的0.20% /，之后持续释放速率为每周总负载剂量的0.70%。苯妥英的脑内控释导致治疗组癫痫活动在统计学上显著减少，拉辛评分降低证明了这一点。四组大鼠（每组n = 5）接受了10%、20%、30%或50%负载量的苯妥英 - EVAc聚合物的脑内植入，在365天内显示出预期的平均体重增加和正常行为。然而，50%组中的一只大鼠在聚合物植入354天后因不明原因死亡。
使用EVAc聚合物进行脑内递送苯妥英，该聚合物将在预计3.5年的时间内释放这种药物，通过行为和ECoG标准在钴诱导的大鼠癫痫模型中导致癫痫发作显著减少。在大鼠中，苯妥英在脑内的长期间质递送未产生任何有害影响。
