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

我们报道了以下两点：1)哮喘儿童的血液样本是在每个成人大约20个时间点(n=121)和每个儿童大约2到3个时间点(n=54)采集的。采用NONMEM软件进行群体药代动力学分析。普鲁司特的血药浓度-时间过程符合一级吸收的一室模型。结果表明，儿童和成人的表观清除系数(CL/F)分别为1.81和1.14 L/h/kg。按儿童分组，婴幼儿(3~6岁)与学龄儿童(7~14岁)CL/F差异无统计学意义。CL/F的个体间变异占48.7%。添加残差为7.33 ng/m L，比例残差为73.8%。所有固定效应参数均在自举均值的10%以内。2)测定尿液LTE_4和11DTXB_2水平…多采用酶免疫分析法(ETA)和放射免疫分析法(RIA)。哮喘儿童的尿样在缓解期和急性发作期被检测。因此，急性发作期(中位数476 pg/mg肌酐；范围191-1100 pg/mg肌酐)和稳定期(中位数332 pg/mg肌酐；范围128-965 pg/mg肌酐)尿LTE_4水平显著高于对照组(中位数233 pg/mg肌酐；范围103-389 pg/mg肌酐)。急性发作期和稳定期尿11DTXB_2水平(中位数分别为1666(110~5105)和1009(46~6070)pg/mg肌酐)显著高于对照组(中位数252 pg/mg肌酐；41~716 pg/mg肌酐)(P<0.05)。哮喘急性发作期与缓解期比较，LTE_4水平显著升高(P<0.05)，而尿TXB_2水平无明显差异。结论：高水平的CysLTS和TXA_2参与了哮喘的发病过程。尿液LTE_4和11DTXB_2的测定有助于了解哮喘儿童的个体发病机制。较少

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