Developmental and Therapeutic Pharmacology of Antiepileptic Drugs

1. 在未接受其他抗惊厥药物治疗的患者中，研究丙戊酸钠（VPA）对卡马西平（CBZ）、卡马西平- 10,11 -环氧化物（CBZ- e）及其二醇代谢物10,11 -二羟基卡马西平（CBZ- h）稳态血浆浓度的影响。CBZ被广泛代谢为活性代谢物CBZ- e，最终转化为无活性代谢物CBZ- h。我们的研究表明，合并CBZ和VPA治疗的患者血浆CBZ- e水平和CBZ- e /CBZ比值明显高于单用CBZ治疗的患者，而合并CBZ和VPA治疗组血浆CBZ- h /CBZ- e比值明显低于单用CBZ治疗组。同时服用VPA可提高CBZ和CBZ- e的游离分数。因此，与CBZ剂量相比，同时给药VPA增加了血浆总CBZ- e水平，与CBZ和CBZ- e的游离分数升高有关。在一些患者中，高浓度的CBZ-E可能是引起副作用的原因。研究了唑尼沙胺（ZNS）在每日1次单药治疗的隐源性定位相关癫痫患儿中的临床疗效和血浆水平。ZNS从胃肠道吸收缓慢，与其他流行的抗癫痫药物相比，其生物半衰期较长。在早晨给药前和4小时后分别取血样测定血浆水平，每一血样代表一天中的波谷和峰值水平。峰谷血浆水平比小至约1.25。血浆水平（杯/米）与剂量（mg/kg/天）之比由血浆水平波谷和峰值估算，两者都随着年龄的增长而增加。患者的临床效果符合公认的ZNS治疗血浆水平范围，即15 ~ 40mug/ml。同时给药CBZ降低了大多数患者的ZNS血浆浓度，尽管ZNS保持高血浆水平，但每日一次剂量的ZNS单药治疗不能控制癫痫发作。少

1. The influence of concurrently administered sodium valproate (VPA) on the steady-state plasma concentrations of carbamazepine (CBZ), carbamazepine-10, 11-epoxide (CBZ-E) and its diol metabolite 10, 11-dihydroxycarbamazepine (CBZ-H) was investigated in patients receiving CBZ together with VPA, who received no other anticonvulsants. CBZ is extensively metabolized to the active metabolite CBZ-E and finally to the inactive CBZ-H.Our study showed that the plasma levels of CBZ-E and CBZ-E/CBZ ratio were significantly higher in the patients treated concurrently with CBZ and VPA than in those treated with CBZ alone, whereas the plasma CBZ-H/CBZ-E ratio was significantly lower in the former group.It was shown also that the concurrent administration of VPA raises the free fraction of both CBZ and CBZ-E. Consequently, a simultaneous administration of VPA increases the total plasma CBZ-E level relative to the CBZ dose, associated with the raised free fraction of CBZ and CBZ-E. The high plasma co … More ncentration of CBZ-E may be responsible for the side effects in some patients.2. The clinical effects and plasma levels of zonisamide (ZNS) were investigated in children with cryptogenic localization-related epilepsies, who were administered ZNS once a day as a single drug. ZNS is absorbed slowly from the gastrointestinal tract, and its biological half-life is long compared with the other prevalent antiepileptic drugs. Blood samples for determination of plasma levels were taken before and 4 hours after the morning dose, each of which represents the trough and peak levels in a day.The peak to trough plasma level ratios were as small as approximately 1.25. The plasma level (mug/m) to dose (mg/kg/day) ratios estimated by the trough and peak plasma levels increased both with advance in age. The clinical effects in the patients were in agreement with the range of generally accepted therapeutic plasma levels of ZNS, that is 15-40mug/ml.The concurrent administration of CBZ decreased the plasma concentrations of ZNS in most of the patients, whose seizures were not controlled by once-daily dose of ZNS monotherapy, in spite of maintaining the high plasma levels. Less