PARALYSIS - ITS ANTAGONISM DURING SURGERY AND ANESTHESIA

这是对药理学特征的继续努力， 尤其是药物动力学和药效学， 重要的神经肌肉阻滞药物及其拮抗剂。 有 三个具体目标。 第一，一个概念模型， 本授权期将用于关联药代动力学， 拮抗剂新斯的明、吡啶斯的明和 依地芬 这些药物的药代动力学先前已被 已确定，但尚未与药效学相关，因为 缺乏一个合适的模型--这个实验室现在已经设计出来了， 测试. 使用该模型在正常患者中获得的数据将是 与病理改变（例如肾衰竭）患者相比 或生理学（例如体温过低）。 第二，前面提到的 分析开发方面的专业知识（例如化学电离选择离子质量 泮库溴铵的光谱测定）将扩展到开发一种气体 色谱和气相色谱质谱分析， 泮库溴铵、维库溴铵及其衍生物鉴别和定量 代谢物。 这一新增的分析能力将有助于快速 泮库溴铵的药代动力学和代谢特征的测定 和维库溴铵。 阿曲库铵的基础和临床药理 将重点研究定量和定性分析， 其自发和酶介导的分解产物和代谢产物。 在 此外，主要药物的药代动力学和临床药理学 代谢物劳丹诺新，一种已知的中枢神经系统（CNS）兴奋剂， 将被确定。 这些研究将有助于安全管理 神经肌肉阻滞药物及其拮抗剂，并将有助于 避免副作用，如延长神经肌肉阻滞， 术后呼吸衰竭

This is a continuation of efforts to characterize the pharmacology, especially the pharmacokinetics and pharmacodynamics, of clinically important neuromuscular blocking drugs and their antagonists. There are three specific aims. First, a conceptual model developed during the present granting period will be used to correlate the pharmacokinetics and pharmacodynamics of the antagonists neostigmine, pyridostigmine and edrophonium. The pharmacokinetics of these drugs have been previously determined but have not been correlated with the pharmacodynamics due to the lack of a suitable model -- which this laboratory has now designed and tested. The data obtained in normal patients using this model will be compared with those in patients with altered pathology (e.g. renal failure) or physiology (e.g. hypothermia). Second, the previously described expertise in assay development (e.g. chemical ionization selected ion mass spectrometric assay for pancuronium) will be extended to develop a gas chromatographic and a gas chromatographic mass spectrometric assay for the identification and quantitation of pancuronium, vecuronium and their metabolites. This added analytical capability will facilitate the rapid determination of the pharmacokinetics and metabolic profiles of pancuronium and vecuronium. Third, the basic and clinical pharmacology of atracurium will be studied focusing on the quantitative and qualitative analysis of its spontaneous and enzyme-mediated breakdown products and metabolites. In addition, the pharmacokinetics and clinical pharmacology of the predominant metabolite, laudanosine, a known central nervous system (CNS) stimulant, will be determined. These studies will facilitate the safe administration of neuromuscular blocking drugs and their antagonists, and will help to avoid adverse effects such as prolonged neuromuscular blockade and postoperative respiratory failure.