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指导原则编号:【Z】GPT2-1中药、天然药物急性毒性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）实验动物··································································································································2（三）试验分组··································································································································2（四）给药途径·································································································2（五）给药容量·································································································································2（六）观察期限·································································································································3（七）观察指标·································································································································3（八）结果处理及分析·················································································································3四、不同情况的中药、天然药物急毒试验的要求······················································4五、参考文献·································································································································5六、附录·············································································································································5附录Ⅰ···················································································································································5急性毒性试验一般可测定的几个反应剂量附录Ⅱ···················································································································································7急性毒性试验的一般观察结果与可能涉及的组织、器官、系统七、著者············································································································································8中药、天然药物急性毒性研究技术指导原则一、概述急性毒性是指动物一次或24小时内多次接受一定剂量的受试物，在一定时间内出现的毒性反应。其目的是为新药的研发提供参考信息。中华人民共和国卫生部于1994年颁发的《中药新药研究指南》和国家药品监督管理局1999年颁发的《中药新药药理毒理研究的技术要求》，对于统一、规范中药急性毒性试验，推动我国中药的研究和开发起到了积极的作用。但随着新药研究手段的不断改进，对中药、天然药物认识的进一步深入，这些要求越来越表现出它的局限性。多数中药、天然药物作用相对温和，中药复方制剂通过合理的配伍，也可能使毒性减轻。多数中药、天然药物新药，其处方来源有些是古方，有些是医院制剂或临床经验方，有一定的临床应用基础。但由于现代中药、天然药物制剂运用了大量的新技术甚至新的理论，与传统中药相比，物质基础和给药方式可能有明显改变，而有些改变带来的结果又是未知的，特别是当某些成分的含量明显提高后，其药理作用可能会明显增强，毒性反应也可能明显增大。因此，中药、天然药物进行急性毒性试验研究十分必要。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、天然药物的急性毒性试验。二、基本原则（一）实验管理根据《中华人民共和国药品管理法》，急性毒性试验必须执行“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急性毒性试验的全部内容，在进行中药、天然药物急性毒性试验时，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、重复的原则。三、基本内容（一）受试物受试物应能充分代表临床试验受试物和上市药品，因此建议受试物采用制备工艺稳定、符合临床试用质量标准规定的中试样品，并注明受试物的名称、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，可采用原料药进行试验。溶媒和/或辅料：应提供所用溶媒和/或辅料的批号、规格、生产厂家。（二）实验动物一般应采用哺乳动物，雌雄各半，如临床为单性别用药，则可采用相对应的单一性别的动物。根据具体情况，可选择啮齿类和/或非啮齿类动物。所用动物应符合国家有关药物非临床安全性研究的要求。通常采用健康成年动物进行试验。如果受试物拟用于儿童，建议考虑采用幼年动物。动物初始体重不应超过或低于平均体重的20％。（三）试验分组除设受试物的不同剂量组外，还应设空白和／或阴性对照组。（四）给药途径给药途径不同，受试物的吸收率、吸收速度和暴露量会有所不同，为了尽可能观察到动物的急性毒性反应，可采用不同给药途径进行急性毒性试验，其中一种应与拟临床给药途径一致，如不采用拟临床途径给药，必须充分说明理由。经口给药时应禁食不禁水。（五）给药容量2经口给药，大鼠给药容量一般每次不超过20ml/kg，小鼠一般每次不超过40ml/kg；其他动物及给药途径的给药容量可参考相关文献及根据实际情况确定。（六）观察期限一般为14天，如果毒性反应出现较慢，应适当延长观察时间，如观察时间不足14天，应充分说明理由。（七）观察指标包括动物体重变化、饮食、外观、行为、分泌物、排泄物、死亡情况及中毒反应（中毒反应的症状、严重程度、起始时间、持续时间、是否可逆）等。对濒死及死亡动物应及时进行大体解剖，其他动物在观察期结束后进行大体解剖，当发现器官出现体积、颜色、质地等改变时，则对改变的器官进行组织病理学检查。（八）结果处理和分析1、根据所观察到的各种反应出现的时间、严重程度、持续时间等，分析各种反应在不同剂量时的发生率、严重程度。根据观察结果归纳分析，考察每种反应的剂量-反应及时间-反应关系。2、急性毒性试验一般测定最大给药量、最大无毒性反应剂量、最大耐受量、致死量等反应剂量（参考附录一）。3、判断出现的各种反应可能涉及的组织、器官或系统等（参考附录二）。4、根据大体解剖中肉眼可见的病变和组织病理学检查的结果，初步判断可能的毒性靶器官。如组织病理学检查发现有异常变化，应附有相应的组织病理学照片。组织病理学检查报告应经检查者签名和病理检查单位盖章。5、说明所使用的计算方法和统计学方法，必要时提供所选用方法合理性的依据。6、应根据急性毒性试验结果，提示在其他安全性试验、临床试验、质量控制方面应注意的问题，同时，结合其他安全性试验、有效性试验及质3量可控性试验结果，权衡利弊，分析受试物的开发前景。四、不同情况的中药、天然药物急性毒性试验的要求由于中药、天然药物的特殊性，在具体进行试验时可参照以下要求进行，如不按以下要求进行，应充分说明理由。1．未在国内上市销售的从中药、天然药物中提取的有效成分及其制剂，未在国内上市销售的来源于植物、动物、矿物等药用物质制成的制剂，未在国内上市销售的中药材新的药用部位制成的制剂，未在国内上市销售的从中药、天然药物中提取的有效部位制成的制剂，未在国内上市销售的由中药、天然药物制成的注射剂。以上情况，由于其物质基础较传统中药发生了明显改变，或应用经验较少，一般采用两种给药途径、啮齿类和非啮齿类两种动物，全面考察受试物的急性毒性反应情况，并对结果进行分析，如不按以上要求进行，应说明理由。如临床为非血管内给药，则建议另一给药途径采用静脉给药方式，