Best Brookie M, Burns Jane C, DeVincenzo John, Phelps Stephanie J, Blumer Jeffrey L, Wilson John T, Capparelli Edmund V, Connor James D
Department of Pediatrics, University of California at San Diego, Children's Hospital and Health Center, San Diego, California, CA.
Departments of Pediatrics and.
Curr Ther Res Clin Exp. 2003 Feb;64(2):96-115. doi: 10.1016/S0011-393X(03)00018-3.
In infants and children, treatment of Kawasaki disease (KD) with high-dose intravenous immunoglobulin (IVIG) and acetylsalicylic acid ([ASA] aspirin) diminishes inflammatory response and reduces the risk for coronary artery abnormalities. However, patients with high serum concentrations of tumor necrosis factor (TNF)-alpha, which is associated with vascular damage, may develop coronary artery lesions even with treatment. The hemorheologic agent pentoxifylline blocks the production of TNF-alpha and may be an appropriate adjunctive therapy to IVIG and ASA.
The objective of this study was to assess the pharmacokinetic characteristics and tolerability of a new oral syrup formulation of pentoxifylline as an adjunct to IVIG and ASA in the treatment of KD in children.
Hospitalized boys and girls aged 6 months to 5 years and who were diagnosed with KD within the first 10 days of illness were eligible. Patients were assigned to 1 of 4 pentoxifylline treatment groups, by dose level (dose levels 1, 2, 3, and 4: 10, 15, 20, and 25 mg/kg daily, respectively, divided into 3 doses). Six plasma samples collected at the time the first dose was administered, and 4 samples collected after administration of the last dose on study day 6, were assessed by high-performance liquid chromatography using noncompartmental and 1-compartment pharmacokinetic analyses for pentoxifylline and its active metabolite (M-1). TNF-alpha levels on days 1 and 6 were assessed using electroimmunoassay.
Fourteen boys and 10 girls were enrolled. The mean age, body weight, and illness day at study entry were 34.5 months, 13.8 kg, and 6, respectively. Pentoxifylline exhibited nonlinear kinetic characteristics, with median area under the plasma concentration-time curve from time 0 to infinity(AUC0-∞) values of 622, 3428, 8416, and 10,347 ng/mL · h for dose levels 1 to 4, respectively, on study day 1. Pentoxifylline noncompartmental oral clearance and volume of distribution were significantly lower, and dose-normalized AUC0-∞ was significantly higher, for dose level 3 than dose level 1. M-1 parameters were not significantly different between dose levels. No accumulation of pentoxifylline or M-1 was noted. Fifteen of 24 patients (63%) reported mild to moderate adverse events that may or may not have been treatment related. Frequency and severity did not differ significantly between dose levels.
In the children in this study, pentoxifylline was well tolerated at the doses studied. No notable differences in clinical outcomes were observed between dose levels, and dose levels 3 and 4 (20 and 25 mg/kg daily, respectively) resulted in similar exposure to both pentoxifylline and M-1. Future efficacy and tolerability studies should use a daily dose of 20 mg/kg of pentoxifylline in acute KD.
在婴幼儿和儿童中，用大剂量静脉注射免疫球蛋白（IVIG）和乙酰水杨酸（[ASA]阿司匹林）治疗川崎病（KD）可减轻炎症反应并降低冠状动脉异常的风险。然而，血清肿瘤坏死因子（TNF）-α浓度高的患者与血管损伤有关，即使经过治疗也可能发生冠状动脉病变。血液流变学药物己酮可可碱可阻断TNF-α的产生，可能是IVIG和ASA的合适辅助治疗药物。
本研究的目的是评估一种新的己酮可可碱口服糖浆制剂作为IVIG和ASA辅助药物治疗儿童KD的药代动力学特征和耐受性。
年龄在6个月至5岁之间、在疾病的前10天内被诊断为KD的住院男孩和女孩符合条件。患者按剂量水平分为4个己酮可可碱治疗组之一（剂量水平1、2、3和4：分别为每日10、15、20和25 mg/kg，分为3剂）。在首次给药时采集6份血浆样本，并在研究第6天最后一剂给药后采集4份样本，采用高效液相色谱法，对己酮可可碱及其活性代谢物（M-1）进行非房室和一室药代动力学分析。使用电免疫测定法评估第1天和第6天的TNF-α水平。
共纳入14名男孩和10名女孩。研究开始时的平均年龄、体重和患病天数分别为34.5个月、13.8 kg和6天。己酮可可碱表现出非线性动力学特征，在研究第1天，剂量水平1至4的血浆浓度-时间曲线下从时间0到无穷大（AUC0-∞）的中位数分别为622、3428、8416和10347 ng/mL·h。与剂量水平1相比，剂量水平3的己酮可可碱非房室口服清除率和分布容积显著降低，剂量标准化AUC0-∞显著升高。各剂量水平之间的M-1参数无显著差异。未观察到己酮可可碱或M-1的蓄积。24名患者中有15名（63%）报告了轻度至中度不良事件，这些事件可能与治疗有关，也可能无关。各剂量水平之间的频率和严重程度无显著差异。
在本研究的儿童中，在所研究的剂量下，己酮可可碱耐受性良好。各剂量水平之间未观察到临床结果的显著差异，剂量水平3和4（分别为每日20和25 mg/kg）导致己酮可可碱和M-1的暴露量相似。未来的疗效和耐受性研究应在急性KD中使用每日20 mg/kg的己酮可可碱剂量。
