药物类过敏反应的临床前评价方法研究(Ⅰ)——小鼠类过敏反应评价方法的建立和验证

Methodology for preclinical assay of pseudoallergy of injectable drugs(Ⅰ)——mouse model for assay of pseudoallergy induced by injections

目的:建立适用于注射剂类过敏评价的动物模型。方法:小鼠一次性静脉注射含0.4%伊文思蓝(EB)的受试物,以耳廓蓝染发生率和伊文思蓝渗出量作为类过敏评价指标。结果:小鼠静脉注射生理盐水注射液(NS)、5%葡萄糖注射液(Glu)后,未出现耳廓蓝染,说明无类过敏反应发生。阳性对照物质组胺和Compound 48/80均具有明显的致类过敏反应,可造成耳廓明显蓝染和EB大量渗出。采用临床上可发生类过敏反应的多种中、西药注射剂验证了本模型和评价方法的可靠性和敏感性,检测结果与临床一致。结论:小鼠类过敏反应评价方法敏感、可靠,与临床一致性好,适宜于注射剂临床前类过敏反应评价、注射剂生产过程中的安全性检测、上市产品抽验、致敏原筛选、类过敏反应发生机制研究以及类过敏防治方法研究等。

Objective： To develop animal models and methodologies for assay of pseudoallergy induced by injectable drugs. Method ： Mouse anaphylactoid reaction model was developed by intravenous injection of test substance solutions containing Evans blue （EB）. Scores of ear blue staining and quantitation of ear EB exudation were the parameters for the pseudoallergy reaction. Result ： Mouse anaphylactoid reaction was characterized as vascular hyperpermeability which was detectable in ears by quantitation of blue stai- ning score and EB exudation. Compound 48/80 and histamine caused severe ear bluing and EB exudation by inducing obvious vascular hyperpermeability which indicated that they can induce mouse pseudoallergy. Intravenous injection of either normal saline or 5% glu- cose injection showed no ear bluing. The mouse pseudoallergy model was validated by intravenous injections of western drugs and Chi- nese medicine. Conclusion： Mice could be developed into pseudoallergy model for preclinical safety evaluation of injectable drugs. The pseudoallergy reaction in this model is of high clinic consistency, sensitivity, reproducibility, and maneuverability. The model is suitable for the evaluation for pseudoallergy induced by injectable products prepared from Chinese materia medica. This model can also be used for safety assay and quality control in manufacturing process, spot checking of marketed products, screening of allergen as well as studying of pseudoallergy mechanism.