左乙拉西坦添加治疗难治性部分性癫的疗效及其与多药耐药基因的相关性研究:随机双盲安慰剂对照临床试验

Study on the therapeutic effect of levetiracetam as an additive therapy for refractory partial epilepsy and the relativity between levetiracetam and multidrug resistance gene:a randomised double-blind placebo-controlled trial

目的探讨左乙拉西坦添加治疗难治性部分性癫的临床疗效及其与多药耐药基因1（MDR1）的相关性。方法30例诊断明确的难治性部分性癫患者按照随机双盲安慰剂对照研究方法,分别予抗癫药物左乙拉西坦添加治疗和安慰剂治疗,初始剂量1g（2次/d）,2周后增至2g（2次/d）,再2周后增至3g（2次/d）,维持治疗12周后逐渐减量,进入减量/开放期。评价患者治疗期（16周）每周癫发作频率与回顾性基线期比较降低的百分比及发作频率减少50%的有效率。聚合酶链反应-限制性片段长度多态性检测患者基因型。结果30例患者中27例完成临床试验。基因型检测共检出CC基因型16例,左乙拉西坦添加治疗组（治疗组）9例（完全控制1例、显效3例、有效2例,发作频率减少50%的有效率为66.67%）,安慰剂组7例（仅1例有效,发作频率减少50%的有效率为14.29%）,组间比较差异具有统计学意义（Z=蛳2.013,P=0.042）;CT＋TT基因型11例,治疗组9例（完全控制1例、显效2例、有效4例,发作频率减少50%的有效率为77.78%）,安慰剂组2例。治疗组CC基因型与CT＋TT基因型患者疗效比较,差异无统计学意义（Z=-0.193,P=0.888）。结论左乙拉西坦作为难治性部分性癫患者的添加治疗药物临床效果良好,其主要药理学机制可能与左乙拉西坦是非多药耐药基因1编码的P-糖蛋白底物有关。

Objective To investigate the therapeutic effect of levetiracetam as an additive therapy for refractory partial epilepsy and the relativity between levetiracetam and multidrug resistance gene 1 （MDR1）. Methods Thirty patients with confirmed refractory partial epilepsy enrolled in a randomised, doubled-blind, placebo-controlled trial. The patients were given antiepileptic drug levetiracetam and placebo, respectively. The initiall dose was 1 g （2 / d）, 2 weeks later the dose was increased to 2 g （2 / d）, and another 2 weeks later increased to 3 g （2 / d）. When achieving the above mentioned dose, the dosage was maintained for 12 weeks, then gradually decremented and turn to dose decrement / open period. Assessed the rate of seizure frequency in every week during the 16-week treatment period. Compared with the baseline period, evaluated the percentage of seizure frequency decrement and the effective rate of 50% seizure frequency decrement. Polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） was performed to detect genetype. Results Among 30 patients, 27 accomplished the trial. In genetype test, there were 16 patients with CC genetype including 9 in levetiracetam group （one case with completely controlled, 3 obviously effective and 2 effective; the effective rate of 50% seizure frequency decrement was 66.67%） and 7 in control group （only one effective; the effective rate of 50% seizure frequency decrement was 14.29%）, and 11 patients with CT ＋ TT genetype including 9 in levetiracetam group （one case with completely controlled, 2 obviously effective and 4 effective; the effective rate of 50% seizure frequency decrement was 77.78%） and 2 in controlgroup. The difference of therapeutic efficiency between the patients with CC genetype in levetiracetam group and thosein control group was significant （Z = -2.013, P = 0.042）. There was no significant therapeutic efficiency difference between the patients with CC genetype and those with CT ＋ TT genetype （Z = -0.193, P = 0.888）. Conclusion Levetiracetam as an additive therapy has better therapeutic effect in the treatment for refractory partial epilepsy. The pharmacological mechanism of levetiracetam treatment for refractory epilepsy may be mainly related to levetiracetam which was not the P-glycoprotein （P-gp） substrate encoded by MDR1.