中药、天然药物一般药理学研究技术指导原则

【Z】GPT1-1指导原则编号：中药、天然药物一般药理学研究技术指导原则二OO五年三月目录一、概述···················································································································································1二、基本原则········································································································································1（一）实验管理···································································································································1（二）具体问题具体分析·············································································································1（三）试验设计···································································································································2三、基本内容········································································································································2（一）受试物········································································································································2（二）生物材料···································································································································2（三）样本数和对照························································································································3（四）给药途径···································································································································3（五）剂量或浓度······························································································································3（六）给药次数和检测时间········································································································3（七）观察指标···································································································································4（八）结果及分析·····························································································································6四、不同情况的一般药理学研究的要求·············································································6五、名词解释········································································································································7六、参考文献········································································································································7七、著者··················································································································································8中药、天然药物一般药理学研究技术指导原则一、概述广义的一般药理学研究是指主要药效学作用以外广泛的药理学研究，包括安全药理学和次要药效学研究。本指导原则所指的一般药理学研究，仅限于安全药理学研究的内容。一般药理学研究的目的包括：确定受试物可能关系到人的安全性的非期望出现的药物效应；评价受试物在毒理学和/或临床研究中观察到的药物不良反应和/或病理生理作用；研究所观察到的和/或推测的药物不良反应机制。通过一般药理学研究，可为临床研究和安全用药提供信息，也可为长期毒性试验设计和开发新的适应症提供参考。本指导原则是根据中药、天然药物的特点，结合国际上药物安全性评价的要求和我国药物安全性研究现状而制订的。本指导原则适用于中药、天然药物的一般药理学研究。二、基本原则（一）实验管理一般药理学研究中，重要生命功能系统的安全药理学研究一般应执行“药物非临床研究质量管理规范”，追加的和/或补充的安全药理学研究应尽可能的最大限度遵守“药物非临床研究质量管理规范”。（二）具体问题具体分析中药、天然药物的情况复杂，本指导原则不可能涵盖中药、天然药物1一般药理学研究的全部实际情况，当进行中药、天然药物一般药理学研究时，应遵循“具体问题具体分析”的原则。（三）试验设计试验设计应符合随机、对照、重复的基本原则。三、基本内容（一）受试物受试物应能充分代表临床试验样品和上市药品，因此应采用制备工艺稳定、符合临床试验用质量标准规定的样品。一般用中试或中试以上规模的样品，并注明其名称、来源、批号、含量（或规格）、保存条件及配制方法等。如不采用中试样品，应有充分的理由。如果由于给药容量或给药方法限制，可采用提取物（如浸膏、有效部位等）进行试验。试验中所用溶媒和/或辅料等应标明批号、规格、生产厂家。（二）生物材料为了获得科学有效的一般药理学信息，应选择最适合的动物或其他生物材料。选择生物材料需考虑的因素包括生物材料的敏感性、可重复性，实验动物的种属、品系、性别和年龄，受试物的背景资料等。应说明选择特殊动物/模型等生物材料的理由。1．常用的实验动物实验动物常用小鼠、大鼠、犬等。常用清醒动物进行试验。如果使用麻醉动物，应注意麻醉药物的选择和麻醉深度的控制。所用动物应符合国家有关药物非临床安全性研究的要求。2．常用的体外生物材料2体外生物材料可用于支持性研究（如研究受试物的活性特点，研究体内试验观察到的药理作用的发生机制等）。常用体外生物材料主要包括：离体器官和组织、细胞、亚细胞器、受体、离子通道和酶等。（三）样本数和对照为了对试验数据进行科学和有意义的解释，一般药理学研究动物数和体外试验样本数应十分充分。每组小鼠和大鼠数一般不少于10只，犬一般不少于6只。原则上动物应雌雄各半，当临床拟用于单性别时，可采用相应性别的动物。试验设计应考虑采用合理的空白、阴性对照，必要时还应设阳性对照。（四）给药途径原则上应与临床拟用药途径一致。如采用不同的给药途径，应说明理由。（五）剂量或浓度体内研究：应尽量确定不良反应的量效关系和时效关系（如不良反应的发生和持续时间），至少应设三个剂量组。低剂量应相当于主要药效学的有效剂量，高剂量以不产生严重毒性反应为限。体外研究：应尽量确定受试物的剂量-反应关系。受试物的上限浓度应尽可能不影响生物材料的理化性质和其他影响评价的特殊因素。（六）给药次数和检测时间一般应采用单次给药。如果受试物的药效作用在给药一段时间后才出现，或者重复给药的非临床研究结果或人用结果出现安全性问题时，应根据这些作用或问题合理设计给药次数。应根据受试物的药效学和药代动力3学特性，选择检测一般药理学参数的时间点。（七）观察指标根据器官系统与生命功能的重要性，可选用相关器官系统进行一般药理学研究。心血管系统、呼吸系统和中枢神经系统是维持生命的重要系统，临床前一般药理学试验必须完成对这些系统的一般观察。当其他非临床试验及临床试验中观察到或推测对人和动物可能产生某些不良反应时，应进一步追加对前面重要系统的深入研究或补充对其他器官系统的研究，并在申请生产许可之前完成。1、对重要生命功能系统的安全药理学研究根据对生命功能的重要性，观察受试物对中枢神经系统、心血管系统和呼吸系统的影响。1．1中枢神经系统直接观察给药后动物的一般行为表现、姿势、步态，有无流涎、肌颤及瞳孔变化等；定性和定量评价给药后动物的自发活动、机体协调能力及与镇静药物的协同/拮抗作用。如出现明显的中枢兴奋、抑制或其他中枢系统反应时，应进行相应的体内或体外试验的进一步研究。1．2心血管系统测定并记录给药前后血压（包括收缩压、舒张压和平均动脉压）、心电图（包括QT间期、PR间期、ST段和QRS波等）和心率等的变化。治疗剂量出现明显血压或心电图改变时，应进行相应的体内或体外试验的进一步研究。1．3呼吸系统4测定并记录给药前后的呼吸频率、节律和呼吸深度等。治疗剂量出现明显的呼吸兴奋或抑制时，应进行相应的体内或体外试验的进一步研究。2、追加或补充的安全药理学研究根据对中枢神经系统、心血管系统和呼吸系统的一般观察及临床研究、体内和体外试验或文献等，预测受试物可能产生某些不良反应时，应适当选择追加和/或补充安全药理学研究内容，以进一步阐明产生这些不良反应的可能原因。下述项目无需全部进行研究，可在综合分析非临床和临床资料基础上，根据实际情况选择相应的研究项目。2．1追加的安全药理学研究中枢神经系统：观察药物对行为药理、学习记忆、神经生化、视觉、听觉和/或电生理等的影响。心血管系统：观察药物对心输出量、心肌收缩作用、血管阻力等的影响。呼吸系统：观察药物对气道阻力、肺动脉压力、血气分析等的影响。2．2补充的安全药理学研究泌尿系统：观察药物对肾功能的影响，如对尿量、比重、渗透压、pH、电解质平衡、蛋白质，细胞和血生化（如尿素氮、肌酐、蛋白质）等指标的检测。自主神经系统：观察药物对自主神经系统的影响，如与自主神经系统有关受体的结合，体内或体外对激动剂或拮抗剂的功能反应，对自主神经的直接刺激作用和对心血管反应、压力反射和心率等的检测。5胃肠系统：观察药物对