Kokwaro Gilbert O, Ogutu Bernhards R, Muchohi Simon N, Otieno Godfrey O, Newton Charles R J C
Kenya Medical Research Institute Centre for Geographic Medicine Research (Coast)/Wellcome Trust Collaborative Research Programme, Kilifi, Kenya.
Br J Clin Pharmacol. 2003 Oct;56(4):453-7. doi: 10.1046/j.1365-2125.2003.01951.x.
Phenobarbital is commonly used to treat status epilepticus in resource-poor countries. Although a dose of 20 mg kg(-1) is recommended, this dose, administered intramuscularly (i.m.) for prophylaxis, is associated with an increase in mortality in children with cerebral malaria. We evaluated a 15-mg kg(-1) intravenous (i.v.) dose of phenobarbital to determine its pharmacokinetics and clinical effects in children with severe falciparum malaria and status epilepticus.
Twelve children (M/F: 11/1), aged 7-62 months, received a loading dose of phenobarbital (15 mg kg(-1)) as an i.v. infusion over 20 min and maintenance dose of 5 mg kg(-1) at 24 and 48 h later. The duration of convulsions and their recurrence were recorded. Vital signs were monitored. Plasma and cerebrospinal fluid (CSF) phenobarbital concentrations were measured with an Abbott TDx FLx fluorescence polarisation immunoassay analyser (Abbott Laboratories, Diagnostic Division, Abbott Park, IL, USA). Simulations were performed to predict the optimum dosage regimen that would maintain plasma phenobarbital concentrations between 15 and 20 mg l(-1) for 72 h.
All the children achieved plasma concentrations above 15 mg l(-1) by the end of the infusion. Mean (95% confidence interval or median and range for Cmax) pharmacokinetic parameters were: area under curve [AUC (0, infinity)]: 4259 (3169, 5448) mg l(-1).h, t(1/2): 82.9 (62, 103) h, CL: 5.8 (4.4, 7.3) ml kg(-1) h(-1), Vss: 0.8 (0.7, 0.9) l kg (-1), CSF: plasma phenobarbital concentration ratio: 0.7 (0.5, 0.8; n= 6) and Cmax: 19.9 (17.9-27.9) mg l(-1). Eight of the children had their convulsions controlled and none of them had recurrence of convulsions. Simulations suggested that a loading dose of 15 mg kg(-1) followed by two maintenance doses of 2.5 mg kg(-1) at 24 h and 48 h would maintain plasma phenobarbital concentrations between 16.4 and 20 mg l(-1) for 72 h.
Phenobarbital, given as an i.v. loading dose, 15 mg kg(-1), achieves maximum plasma concentrations of greater than 15 mg l(-1) with good clinical effect and no significant adverse events in children with severe falciparum malaria. A maintenance dose of 2.5 mg kg(-1) at 24 h and 48 h was predicted to be sufficient to maintain concentrations of 15-20 mg l(-1) for 72 h, and may be a suitable regimen for treatment of convulsions in these children.
在资源匮乏国家，苯巴比妥常用于治疗癫痫持续状态。尽管推荐剂量为20mg/kg（-1），但该剂量肌内注射用于预防时，会增加脑型疟疾患儿的死亡率。我们评估了15mg/kg（-1）静脉注射苯巴比妥的剂量，以确定其在患有严重恶性疟和癫痫持续状态患儿中的药代动力学及临床效果。
12名年龄在7至62个月的儿童（男/女：11/1），静脉输注20分钟给予苯巴比妥负荷剂量（15mg/kg（-1）），并在24小时和48小时后给予5mg/kg（-1）的维持剂量。记录惊厥持续时间及其复发情况。监测生命体征。使用雅培TDx FLx荧光偏振免疫分析仪（美国伊利诺伊州雅培公园雅培实验室诊断部）测定血浆和脑脊液中苯巴比妥浓度。进行模拟以预测能使血浆苯巴比妥浓度在15至20mg/L（-1）维持72小时的最佳给药方案。
输注结束时，所有儿童血浆浓度均高于15mg/L（-1）。平均（95%置信区间或Cmax的中位数及范围）药代动力学参数为：曲线下面积[AUC（0，无穷大）]：4259（3169，5448）mg/L·h，t（1/2）：82.9（62，103）小时，CL：5.8（4.4，7.3）ml/kg（-1）·h（-1），Vss：0.8（0.7，0.9）L/kg（-1），脑脊液：血浆苯巴比妥浓度比：0.7（0.5，0.8；n = 6），Cmax：19.9（17.9 - 27.9）mg/L（-1）。8名儿童惊厥得到控制，且均无惊厥复发。模拟表明，15mg/kg（-1）的负荷剂量后，在24小时和48小时给予两次2.5mg/kg（-1）的维持剂量，可使血浆苯巴比妥浓度在16.4至20mg/L（-1）维持72小时。
对于患有严重恶性疟的儿童，静脉注射15mg/kg（-1）的苯巴比妥负荷剂量可使血浆浓度达到大于15mg/L（-1）的最大值，临床效果良好且无明显不良事件。预计在24小时和48小时给予2.5mg/kg（-1）的维持剂量足以使浓度在15 - 20mg/L（-1）维持72小时，这可能是治疗这些儿童惊厥的合适方案。
