Kern Steven E, Xie Guoming, White Julia L, Egan Talmage D
Department of Pharmaceutics, University of Utah, Salt Lake City, 84108, USA.
Anesthesiology. 2004 Jun;100(6):1373-81. doi: 10.1097/00000542-200406000-00007.
Characterizing drug interactions using a response surface allows for the determination of the interaction over a complete range of clinically relevant concentrations. Gathering the data necessary to create this surface is difficult to do in a clinical setting and requires the use of volunteer experiments with surrogate noxious stimuli to adequately control the process for data collection. The pharmacodynamic synergy of opioids and hypnotics was investigated using a volunteer study paradigm.
Twenty-four volunteer subjects (12 male, 12 female) were studied using computer-controlled infusions of propofol and remifentanil to create an increasing staircase drug concentration profile in each subject. Three different drug delivery profiles were administered to subjects, one with a single agent and two with combinations of propofol and remifentanil. At each plateau of the staircase profile, drug effect was assessed using four surrogate measures: Observer Assessment of Alertness/Sedation score, tibial pressure algometry, electrical tetany, and response to laryngoscopy. Response surfaces were developed that mapped the interaction of propofol and remifentanil to these surrogate effect measures in all subjects. An interaction parameter was used to assess whether these two drugs behave synergistically to blunt response to noxious stimuli.
The response surfaces showed considerable synergy between remifentanil and propofol for blunting response to the noxious stimuli. The interaction index, a measure of synergy, was 8.2 and 14.7 for response to algometry and tetany, respectively (P < 0.001), and 5.1 and 33.2 for sedation and laryngoscopy, respectively (P < 0.001), using the Greco interaction model. The surrogate stimuli mapped to clinically relevant concentrations for these agents in combination.
The response surface models reveal the tremendous synergy between remifentanil and propofol. The surface morphologic features give some indication of the relative contribution of sedation and analgesia to blunting subject response. Further, the results of this investigation validate the volunteer study paradigm and use of surrogate effect measures for its clinical relevance.
使用响应面来表征药物相互作用能够确定在整个临床相关浓度范围内的相互作用情况。在临床环境中收集创建此表面所需的数据很困难，并且需要使用替代有害刺激的志愿者实验来充分控制数据收集过程。使用志愿者研究范式对阿片类药物和催眠药的药效学协同作用进行了研究。
对24名志愿者受试者（12名男性，12名女性）进行研究，通过计算机控制输注丙泊酚和瑞芬太尼，在每个受试者中创建递增的阶梯式药物浓度曲线。向受试者给予三种不同的药物给药曲线，一种为单一药物，另外两种为丙泊酚和瑞芬太尼的组合。在阶梯曲线的每个平台期，使用四种替代指标评估药物效果：观察者警觉/镇静评分、胫部压力测痛法、电强直以及喉镜检查反应。绘制了响应面，以描绘丙泊酚和瑞芬太尼在所有受试者中与这些替代效应指标的相互作用。使用相互作用参数评估这两种药物是否协同作用以减弱对有害刺激的反应。
响应面显示瑞芬太尼和丙泊酚在减弱对有害刺激的反应方面具有显著的协同作用。使用Greco相互作用模型，作为协同作用度量的相互作用指数，对测痛法和强直反应的分别为8.2和14.7（P < 0.001），对镇静和喉镜检查反应的分别为5.1和33.2（P < 0.001）。替代刺激对应于这些药物联合使用时的临床相关浓度。
响应面模型揭示了瑞芬太尼和丙泊酚之间巨大的协同作用。表面形态特征给出了镇静和镇痛对减弱受试者反应的相对贡献的一些指示。此外，本研究结果验证了志愿者研究范式以及替代效应指标在临床相关性方面的应用。
