Study of the pharmacogenetic analysis of an arachidonic acid cascade in asthma and the made-to-order treatment for an asthma patient

我们报告了以下两点：1)支气管哮喘儿童的血液样本在每个成人约20个时间点（n=121）和每个儿童2或3个时间点（n=54）采集。使用NONMEM进行群体药代动力学分析。普鲁司特的浓度-时间过程用一阶吸收的单室模型描述。使用200个bootstrap样本对最终模型的稳健性进行了评估。结果儿童和成人的表观清除率分别为1.81和1.14 L/h/kg。根据儿童亚组，3 ~ 6岁婴幼儿和7 ~ 14岁学龄儿童CL/F无显著差异。CL/F的个体间变异率为48.7%。加性和比例残留变异率分别为7.33 ng/mL和73.8%。所有固定效应参数都落在自举平均值的10%以内。2)分别采用酶免疫法（ETA）和放射免疫法（RIA）测定尿LTE_4和11DTXB_2水平。在稳定状态和急性发作期间测量哮喘儿童的尿样。结果，急性发作时（肌酐中位数476 pg/mg， 191 ~ 1100 pg/mg）和稳定状态时（肌酐中位数332 pg/mg， 128 ~ 965 pg/mg）尿LTE_4水平显著高于对照组（肌酐中位数233 pg/mg， 103 ~ 389 pg/mg） （P<0.05）。急性发作期和稳定期尿11DTXB_2水平（中位数为1666（110 ~ 5105）和1009 (46 ~ 6070)pg/mg肌酐）显著高于对照组（中位数为252 pg/mg肌酐，中位数为41 ~ 716）（P<0.05）。不同哮喘分期比较，急性发作时LTE_4水平显著高于稳定期（P<0.05）；然而，尿TXB_2水平没有差异。结论：高水平的CysLTs和TXA_2与支气管哮喘的发病有关。尿LTE_4和11DTXB_2的测定有助于了解哮喘患儿的个体发病机制。少

We reported two points of the following :1)Blood samples from bronchial asthma children were obtained at approximately 20 time points per adult (n=121) and 2 or 3 time points per child (n=54). Population pharmacokinetic analysis was performed with use of NONMEM. The concentration-time course of pranlukast was described by using a one-compartment model with first-order absorption. The robustness of the final model was evaluated by using 200 bootstrap samples.In results Apparent Clearance (CL/F) was 1.81 and 1.14 L/h/kg in children and adults, respectively. According to subgrouping of the children, no significant difference was observed in CL/F between infants (3 to 6 years old) and schoolchildren (7 to 14 years old). The interindividual variability of CL/F accounted for 48.7%. The additive and proportional residual variability were 7.33 ng/mL and 73.8%, respectively. All the fixed effect parameters fell within 10% of the bootstrapped mean.2)We measured Urinary LTE_4 and 11DTXB_2 levels … More by enzyme immunoassay (ETA) and radioimmunoassay (RIA), respectively. Urine samples from asthmatic children were measured during the stable condition and during an acute attack. In result, Urinary LTE_4 levels during an acute attack (median 476 pg/mg creatinine ; range 191-1100 pg/mg creatinine) and during the stable condition (median 332 pg/mg creatinine ; range 128-965 pg/mg creatinine) were significantly higher (P<0.05) than those of controls (median 233 pg/mg creatinine ; range 103-389 pg/mg creatinine). Urinary 11DTXB_2 levels during an acute attack and during the stable condition (median 1666 (range 110-5105) and 1009 (range 46-6070) pg/mg creatinine, respectively) were significantly higher (P<0.05) than those of controls (median 252 pg/mg creatinine ; range 41-716 pg/mg creatinine). Comparing different stages of asthma, LTE_4 levels during an acute attack were significantly higher (P<0.05) than during the stable condition ; however, there was no difference in urinary TXB_2 levels.In Conclusions : The present findings suggest that high levels of CysLTs and TXA_2 are associated with the pathogenesis of bronchial asthma. The measurement of urinary LTE_4 and 11DTXB_2 would be useful in understanding the individual pathogenesis of asthmatic children. Less