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目的:全麻中两种以上的药物合并应用比单一麻醉剂更为有效.本研究是为确定中国成年患者全麻期间合并应用七氟醚与瑞芬太尼时药物相互作用的方式,并以反应曲面模型法对其进行表述.方法:1. 试验设计: 研究采用平行实验设计,65例病人(ASA I级,各项指标正常,无长期服用阿片类药物史)入选本次试验,随机选定并维持一定的呼末七氟醚浓度[≤2MAC(0.3%-3.4%)],逐渐增加靶控输注的瑞芬太尼浓度(≤10 ng/mL),观察不同浓度组合时患者对喉镜置入刺激的反应以确定麻醉是否完全.2. 反应曲面模型法进行药物动力学/药效动力学分析: 两药合用的效果通过对喉镜置入时的反应进行评估,0和1分别代表有或没有体动反应.以下面的药效学模型表述体动反应消失的概率(P)其中Us,Ur分别为标准化的七氟醚与瑞芬太尼水平;U50为达最大效应一半时的药物综合标准化水平;r为形状因子;I(Q)为药物相互作用的强度函数.模型通过作图、目标函数改变以及参数的生理/临床学的合理性等几方面进行评价.P=(Us+Ur)r/[U50/I(Q)]r+(Us+Ur)r 结果与结论:研究表明瑞芬太尼与七氟醚合用时为协同式相互作用,上述反应曲面模型与实际观测值有较好的拟合.应用NONMEM得到喉镜置入刺激时的参数(RSE%)为U50=6.62(10.6),C50,sevo=1.71%(12.9),C50,remi=12.4 ng/mL(19.0),Imax=2.31,Qmax=0.706.所得数值的加权残差均小于3.结果表明与传统方法相比,反应曲面模型法可以得到较好的拟合质量,为药物相互作用的研究提供了一种新颖思路和有效手段.“,”AIM: To determine the interactions with response-surface modeling methodologies when sevoflurane (Sevo) and remifentanil (Remi) were administered simultaneously. METHODS: (1) Patients, Study design and drug delivery: Based on parallel slices design, sixty-five patients were randomly assigned to inhale a specific end-tidal concentration of sevoflurane (0.3% to 3.4%), with different level of remifentanil (0-10 ng/mL). The responses to laryngoscopy were observed for each given concentration pair. (2) Pharmacokinetic/pharmacodynamic analysis with response surface mode: The probability of no response (P) was assessed in the modeling process as below. P=(Us+Ur)r/[U50/I(Q)]r+(Us+Ur)r RESULTS AND DISCUSSION: NONMEM estimated average values (RSE%) of the model parameters for laryngoscopy of C50,Sevo, C50,remi, U50, r, Imax and Qmax are 1.71% (12.9), 12.4 ng/mL (19.0), 6.62 (10.6), 1.53 (8.76), 2.31 (8.23), 0.706 (2.46), respectively. The inter-individual variability (CV%) in parameter Imax and inter-occasion variability (S.D.) in this model are 12.7 and 0.0316, respectively. It is concluded that the response-surface modeling approach provided a novel method to study drug-drug interactions.