中南药学

目的 研究神香草提取物对哮喘大鼠的药效作用并建立药动学-药效学（PK-PD）结合模型，进行神香草提取物活性成分迷迭香酸体内药动学特征与其药效学变化的相关性分析。方法利用卵清蛋白诱导哮喘大鼠模型，灌胃给予神香草乙醇提取物，并从行为学特征、血清炎症因子含量来考察其治疗效果。以神香草中迷迭香酸血药浓度为药动学考察指标，以血清中炎症因子免疫球蛋白E(IgE)、白细胞介素-5(IL-5)、肿瘤坏死因子-α(TNF-α)作为药效学指标，利用Phoenix WinNonlin软件构建PK-PD模型。结果 给予神香草乙醇提取物后，大鼠血清中IgE、IL-5、TNF-α水平较模型组有所降低，哮喘肺部病理形态改善。建立的PK-PD模型提示神香草提取物抗哮喘药效的发挥与迷迭香酸的血药浓度存在滞后现象，PK-PD模型适用于间接连接模型。结论 神香草提取物具有明显的抗哮喘作用，可能与下调炎症因子水平有关。大鼠体内迷迭香酸的血药浓度与药物效应值存在滞后现象，这可能是因为神香草中迷迭香酸进入体内并不会立即作用于相应的靶点，而是通过间接机制产生药理作用。

Objective To determine the effect of extract from Hyssopus cuspidatus Boriss. on asthmatic rats, to establish a combined pharmacokinetics-pharmacodynamics(PK-PD) model to describe the PK profiles of rosmarinic acid and correlation with its PD effects. Methods A rat model of asthma was established by ovalbumin induction. The rats were subjected to ethanol extract of Hyssopus cuspidatus Boriss. intragastrically. The therapeutic effect was assessed by evaluating the behavioral characteristics and the serum levels of inflammatory cytokines. The PK-PD model was constructed by Phoenix WinNonlin software, with rosmarinic acid concentrations as the PK indicators and immunoglobulin E(Ig E), interleukin-5(IL-5) and tumor necrosis factor-α(TNF-α) levels in the serum as the PD indicators. Results The levels of IgE, IL-5 and TNF-α in the serum of rats were reduced, and pathological morphology of the lung tissue was improved after the administration of extract of Hyssopus cuspidatus Boriss. compared with those of the model group. The established PK-PD model suggested a lag between the anti-asthmatic effect of the extract and the blood concentration of rosmarinic acid. An indirect connection model was fitted for the PK-PD model. Conclusion The extract of Hyssopus cuspidatus Boriss. shows obvious anti-asthmatic effect, which may be related to the down-regulation of inflammatory factor levels. There is a lag between the blood concentrations of rosmarinic acid and the therapeutic effects in rats, which may potentially be attributable to the fact that rosmarinic acid in Hyssopus cuspidatus Boriss. does not act on the target directly, but through an indirect pharmacological action.