Ogutu Bernhards R, Newton Charles R J C, Muchohi Simon N, Otieno Godfrey O, Edwards Geoffrey, Watkins William M, Kokwaro Gilbert O
Kenya Medical Research Institute Centre for Geographic Medicine Research-Coast/Wellcome Trust Collaborative Research Programme, Kilifi, Kenya.
Br J Clin Pharmacol. 2003 Jul;56(1):112-9. doi: 10.1046/j.1365-2125.2003.01829.x.
Status epilepticus is common in children with severe falciparum malaria and is associated with poor outcome. Phenytoin is often used to control status epilepticus, but its water-soluble prodrug, fosphenytoin, may be more useful as it is easier to administer. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus.
Children received intravenous (i.v.) phenytoin as a 18 mg kg-1 loading dose infused over 20 min followed by a 2.5 mg x kg(-1) 12 hourly maintenance dose infused over 5 min (n = 11), or i.v. fosphenytoin, administered at a rate of 50 mg x min(-1) phenytoin sodium equivalents (PE; n = 16), or intramuscular (i.m.) fosphenytoin as a 18 mg x kg(-1) loading dose followed by 2.5 mg x kg(-1) 12 hourly of PE (n = 11). Concentrations of phenytoin in plasma and cerebrospinal fluid (CSF), frequency of seizures, cardiovascular effects (respiratory rate, blood pressure, trancutaneous oxygen tension and level of consciousness) and middle cerebral artery (MCA) blood flow velocity were monitored.
After all routes of administration, a plasma unbound phenytoin concentration of more than 1 microg x ml(-1) was rapidly (within 5-20 min) attained. Mean (95% confidence interval) steady state free phenytoin concentrations were 2.1 (1.7, 2.4; i.v. phenytoin, n = 6), 1.5 (0.96, 2.1; i.v. fosphenytoin, n = 11) and 1.4 (0.5, 2.4; i.m. fosphenytoin, n = 6), and were not statistically different for the three routes of administration. Median times (range) to peak plasma phenytoin concentrations following the loading dose were 0.08 (0.08-0.17), 0.37 (0.33-0.67) and 0.38 (0.17-2.0) h for i.v. fosphenytoin, i.v. phenytoin and i.m. fosphenytoin, respectively. CSF: plasma phenytoin concentration ratio ranged from 0.12 to 0.53 (median = 0.28, n = 16). Status epilepticus was controlled in only 36% (4/11) following i.v. phenytoin, 44% (7/16), following i.v. fosphenytoin and 64% (7/11) following i.m. fosphenytoin administration, respectively. Cardiovascular parameters and MCA blood flow were not affected by phenytoin administration.
Phenytoin and fosphenytoin administration at the currently recommended doses achieve plasma unbound phenytoin concentrations within the therapeutic range with few cardiovascular effects. Administration of fosphenytoin i.v. or i.m. offers a practical and convenient alternative to i.v. phenytoin. However, the inadequate control of status epilepticus despite rapid achievement of therapeutic unbound phenytoin concentrations warrants further investigation.
癫痫持续状态在重度恶性疟患儿中很常见，且与不良预后相关。苯妥英常用于控制癫痫持续状态，但其水溶性前体药物磷苯妥英可能更有用，因为它更易于给药。我们研究了苯妥英和磷苯妥英钠在重度恶性疟和癫痫持续状态患儿中的药代动力学及临床效果。
患儿接受静脉注射苯妥英，负荷剂量为18mg/kg，在20分钟内输注完毕，随后以2.5mg·kg⁻¹每12小时一次的维持剂量在5分钟内输注完毕（n = 11）；或静脉注射磷苯妥英，以50mg·min⁻¹苯妥英钠等效物（PE）的速率给药（n = 16）；或肌肉注射磷苯妥英，负荷剂量为18mg·kg⁻¹，随后以2.5mg·kg⁻¹每12小时一次的PE给药（n = 11）。监测血浆和脑脊液（CSF）中苯妥英的浓度、癫痫发作频率、心血管效应（呼吸频率、血压、经皮氧分压和意识水平）以及大脑中动脉（MCA）血流速度。
所有给药途径后，均在5 - 20分钟内迅速达到血浆游离苯妥英浓度超过1μg·ml⁻¹。平均（95%置信区间）稳态游离苯妥英浓度分别为2.1（1.7，2.4；静脉注射苯妥英，n = 6）、1.5（0.96，2.1；静脉注射磷苯妥英，n = 11）和1.4（0.5，2.4；肌肉注射磷苯妥英，n = 6），三种给药途径之间无统计学差异。负荷剂量后达到血浆苯妥英峰值浓度的中位时间（范围），静脉注射磷苯妥英为0.08（0.08 - 0.17）小时，静脉注射苯妥英为0.37（0.33 - 0.67）小时，肌肉注射磷苯妥英为0.38（0.17 - 2.0）小时。脑脊液：血浆苯妥英浓度比值范围为0.12至0.53（中位数 = 0.28，n = 16）。静脉注射苯妥英后仅36%（4/11）的癫痫持续状态得到控制，静脉注射磷苯妥英后为44%（7/16），肌肉注射磷苯妥英后为64%（7/11）。心血管参数和MCA血流不受苯妥英给药的影响。
按当前推荐剂量给予苯妥英和磷苯妥英可使血浆游离苯妥英浓度达到治疗范围，且心血管效应较少。静脉注射或肌肉注射磷苯妥英为静脉注射苯妥英提供了一种实用且便捷的替代方法。然而，尽管迅速达到了治疗性游离苯妥英浓度，但癫痫持续状态控制不佳，这值得进一步研究。
