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【Z】GPT5-1指导原则编号：中药、天然药物免疫毒性（过敏性、光过敏反应）研究的技术指导原则二○○五年三月目录一、概述·····················································································································································1二、基本内容·········································································································································2（一）基本原则····························································································································2（二）过敏反应试验··················································································································31、试验中应考虑的问题······································································································32、I型过敏反应试验·············································································································43、II、Ⅲ型过敏反应试验··································································································64、Ⅳ型过敏反应试验···········································································································6（三）光过敏反应试验············································································································6（四）结果分析及评价············································································································7（五）常见问题及处理············································································································8（六）不同剂型的中药、天然药物试验项目的选择············································10三、参考文献·······································································································································10四、附录··················································································································································11（一）主动皮肤过敏试验···································································································11（二）主动全身过敏试验···································································································13（三）被动全身过敏试验···································································································15（四）豚鼠最大化试验和Buehler试验······································································16（五）皮肤光过敏反应试验······························································································18五、著者··················································································································································20中药、天然药物免疫毒性（过敏性、光过敏反应）研究的技术指导原则一、概述免疫毒理学是毒理学中一门重要的分支学科，其目的是探讨外源性化合物对机体（人和实验动物）免疫系统产生的不良影响及机理。免疫毒性是指外源性化合物对机体免疫系统的损伤作用，包括两类，一是免疫抑制，即免疫系统的广泛抑制，可致机体对感染的易感性增加及肿瘤发生率增高；另一是免疫增强，即免疫系统反应性过度增强，可能包括免疫性产生，过敏反应（超敏反应或变态反应）、自身免疫反应以及不良免疫刺激等。过敏反应指变态反应，又称超敏反应，是指机体受同一抗原再次刺激后产生的一种异常或病理性免疫反应。按抗原与抗体或细胞反应的方式和补体是否参加等，将过敏反应分为Ⅰ、Ⅱ、Ⅲ、Ⅳ四型。其中Ⅰ型过敏反应是了解得最多的一种过敏反应，目前采用的过敏试验方法多数是根据Ⅰ型过敏反应发病机制的不同环节而设计建立的。光过敏反应为IV型过敏反应的特殊类型，是局部给药和全身给药后，分布在皮肤的药物中所含的感光物质与光线产生复合作用使得用药后皮肤对光线产生的不良反应。中药、天然药物为一种外源性物质，也可能作为过敏原引发机体产生过敏反应。由于免疫系统是增生活跃的系统，因此对外源性物质非常敏感，但每一种化学物质都有其特定的靶器官，因此不必盲目地对所有受试物进行免疫毒性监测，而是选择性地对某些受试物特别是以免疫系统为靶器官的毒1物进行研究。用于某些适应症的药物，因其作用机制的特殊性，对人体免疫系统可能产生影响；另外，当受试物是已知的免疫调节剂的情况，或在安全性评价过程中初步发现对免疫系统有明显影响的药物也应进行免疫毒性的评价。若需要进行其他免疫毒性评价的药物，建议可在其长期毒性试验中，增加免疫系统损伤的评价指标。因人群免疫毒理学研究存在下述困难：在人群中观察到免疫功能损伤需要的时间较长，且人群接触的剂量较低，也难以观察到剂量-反应关系。人群免疫毒理学研究中缺乏特异性指标，缺乏非损伤性方法。对免疫功能检测结果评定时缺乏正常值或参考值。因此，认为动物免疫毒理学评价对估测人群的免疫毒性具有一定的意义。该技术指导原则适用于拟用于人和/或已上市的中药、天然药物的免疫毒性研究。主要内容包括免疫毒性评价中的过敏反应试验和光过敏试验。二、基本内容（一）基本原则根据《中华人民共和国药品管理法》，药物的免疫毒性试验必须执行“药物非临床研究质量管理规范”。实验设计应符合随机、对照、重复的原则。应在遵循安全性评价普遍规律的基础上，运用具体问题具体分析的方法，结合受试物的自身特点，充分考虑和结合药学、药效学、其他毒理学（长毒、急毒）及拟临床应用情况等信息，体现整体性、综合性的原则，在阐明其研究方法或手段科学、合理的前提下进行规范性试验，对试验结果应进行全面分析和综合评价，以达到免疫毒性研究的目的。2（二）过敏反应试验1．试验中应考虑的问题1.1方法中药、天然药物应进行何种过敏反应研究，可根据药物自身特点、临床适应症和给药方式确定。通常局部给药发挥全身作用的药物（如注射剂和透皮吸收剂等）需考察Ⅰ型过敏反应，如注射剂需进行主动全身过敏试验和被动皮肤过敏试验，透皮吸收剂需进行主动皮肤过敏试验等。Ⅱ和Ⅲ型过敏反应可在进行长期毒性试验中选择相关指标进行观察，如观察动物的体征、一般表现及免疫系统损伤的评价指标等。经皮给药制剂（包括经皮给药发挥全身作用或局部作用的药物）应进行IV型过敏反应试验。具体试验方法的选择应根据给药途径、过敏反应发生机制、影响因素和临床意义等为基础进行选择，如主动皮肤过敏试验、主动全身过敏试验、被动皮肤过敏试验、Buehler分析法（BT）、豚鼠最大值法（Guinea-PigMaximizationTest,GPMT）等，也可采用其它的检测方法，但需阐明其合理性并说明具体方法及操作流程。1.2受试物过敏试验中的受试物应同临床应用制剂相一致，即采用中试或中试以上规模的、制备工艺稳定、符合临床试用质量标准规定的样品。否则，应有充分的理由。同时，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。试验中所用辅料、溶剂或赋形剂等应标明批号、3规格和生产厂家，并符合试验要求。1.3对照过敏试验均应设立阳性对照和阴性对照。1.4剂量可选择多个剂量进行试验，尽可能找出无过敏反应的剂量，以提示临床进行脱敏处理的起始剂量；也可避免因剂量过低而出现假阴性结果；另外，可帮助判断阳性结果是否因强刺激反应而引起。1.5给药途径（1）皮肤给药：经皮给药的受试物应保证在局部的有效暴露时间。（2）静脉给药：应注意给药剂量和给药速度对动物过敏反应发生的影响，排除类过敏反应。静脉注射进行激发试验中应保证足量、一次性快速地将受试物注射入动物体内。2、Ⅰ型过敏反应试验Ⅰ型过敏反应又称速发型过敏反应或超敏反应，药物分子本身为过敏原，进入机体刺激免疫系统产生相应的IgE抗体，IgE抗体附着在肥大细胞及嗜碱性细胞上使之致敏，当同一抗原再次进入机体后，即与肥大细胞及嗜碱性细胞表面的IgE抗体发生抗原抗体反应，导致肥大细胞及嗜碱性细胞脱颗粒并释放生物活性介质，作用于不同的组织和器官，产生不同的病理生理反应。临床表现为过敏性休克、支气管哮喘、变应原鼻炎、胃肠道与皮肤过敏反应等。Ⅰ型过敏反应通常用主动皮肤过敏试验（ACA）、主动全身过敏试验（ASA）和被动皮肤过敏试验（PCA）等考察，对于吸入途径药物常采用呼4吸道敏感性检测。2.1主动皮肤过敏试验（ActiveCutaneousAnaphylaxis,ACA）皮肤过敏是一种受试物产生免疫学传递的皮肤反应。当动物初始接触受试物后至少1周，再进行受试物的激发接触，有可能导致过敏状态。本试验的目的是观察受试物经皮肤重复接触受试物后，机体免疫系统反应在皮肤上的表现，即有无过敏反应及过敏强度如何。2.2主动全身过敏试验（ActiveSystemicAnaphylaxis,ASA）当药物作为抗原或半抗原初次进入体内，刺激机体产生相应的抗体（IgE）。当同样药物再次进入机体，抗原与抗体结合形成的抗原抗体复合物，刺激肥大细胞及嗜碱性细胞释放活性介质，从