Yegnanarayan Radha, Mahesh Suryavanshi D, Sangle Shashi
Department of Pharmacology, B. J. Medical College & Sassoon General Hospitals, Pune 411-001, India.
Chronobiol Int. 2006;23(5):1035-46. doi: 10.1080/07420520600921112.
The objective of this study was to compare the efficacy and safety of a chronotherapeutic dosing schedule of phenytoin and carbamazepine versus a conventional dosing schedule for the treatment of tonic-clonic epileptic patients. Of 148 epileptic subjects found to have subtherapeutic trough drug levels (subtherapeutic group, STG), 103 subjects who completed the study were randomized to either STG I (n=51) for treatment by the conventional dosing schedule (tablet phenytoin 100-400 mg/day OD or BD, tablet carbamazepine 200-800 mg BD, or both, equally divided doses with no fixed time of drug intake), with a dose increment but no change in usual time of drug administration allowed; or to STG II (n=52), with no dose increment permitted but a shift in all or most (two-thirds or three-fourths) of the daily dose of one or both medications to 20:00 h. The 62 patients who experienced drug toxicity reactions (toxicity group, TG) and who had serum drug levels in the toxic range were assigned to TG I for dose reduction or TG II for dose reduction and drug administration at 20:00 h. Those 16 subjects in STG I and 47 subjects in STG II who initially evidenced subtherapeutic trough drug concentrations exhibited therapeutic drug levels by the end of four weeks of treatment (p<0.01). A significantly greater number of TG II, as compared to TG I, subjects who experienced toxic reactions showed improved drug tolerance. There were no poor responders and more good responders (control of epilepsy for one year) in STG II compared to STG I subjects. The findings of this study indicate that a chronotherapeutic dosing schedule of phenytoin and carbamazepine involving the administration of most or all the daily dose of medication(s) at 20:00 h can improve the response of diurnally active epileptic patients not responding to standard doses, achieve therapeutic drug levels, and reduce toxic manifestations in subjects having drug concentrations beyond the therapeutic range.
本研究的目的是比较苯妥英钠和卡马西平的时辰治疗给药方案与传统给药方案治疗强直阵挛性癫痫患者的疗效和安全性。在148名癫痫患者中发现药物谷浓度低于治疗水平（亚治疗组，STG），完成研究的103名患者被随机分为STG I（n = 51），采用传统给药方案治疗（苯妥英钠片100 - 400 mg/天，每日一次或两次；卡马西平片200 - 800 mg，每日两次，或两者并用，剂量均分，服药时间不固定），允许增加剂量但不改变通常的给药时间；或分为STG II（n = 52），不允许增加剂量，但将一种或两种药物的全部或大部分（三分之二或四分之三）日剂量调整至20:00服用。62名经历药物毒性反应的患者（毒性组，TG），其血清药物水平处于毒性范围，被分配至TG I进行剂量减少，或分配至TG II进行剂量减少并于20:00给药。STG I中的16名受试者和STG II中的47名受试者最初表现为药物谷浓度低于治疗水平，在治疗四周结束时呈现出治疗性药物水平（p < 0.01）。与TG I相比，经历毒性反应的TG II受试者中，表现出药物耐受性改善的人数显著更多。与STG I受试者相比，STG II中无反应不佳者，且有更多反应良好者（癫痫得到控制一年）。本研究结果表明，苯妥英钠和卡马西平的时辰治疗给药方案，即将大部分或全部日剂量药物于20:00给药，可改善对标准剂量无反应的日间发作癫痫患者的反应，达到治疗性药物水平，并减少药物浓度超出治疗范围的受试者的毒性表现。
