Characterization of a potential animal model of an idiosyncratic drug reaction: Nevirapine-induced skin rash in the rat
Characterization of a potential animal model of an idiosyncratic drug reaction: Nevirapine-induced skin rash in the rat
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DOI：
10.1021/tx034064
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发表时间：
2003-09-01
影响因子：
4.1
通讯作者：
Uetrecht, JP
中科院分区：
文献类型：
--
作者：
Shenton, JM;Teranishi, M;Uetrecht, JP
由于其不可预测性，很难在人体中研究特异质药物反应。不幸的是，这一特点也阻碍了机制研究所需的动物模型的发展。奈韦拉平，用于治疗人类免疫缺陷病毒（HIV）感染，导致严重的特异质皮疹在一些患者。我们发现奈韦拉平也能在某些品系的大鼠中引起明显的皮疹。在150 mg/kg/天剂量下，雌性Sprague-Dawley大鼠的发生率为6/28（21%），雌性Brown Norway大鼠为32/32（100%），雌性刘易斯大鼠为0/6（0%），而雄性Sprague-Dawley或Brown Norway大鼠均未出现皮疹。雌性SJL小鼠0/7也未出现奈韦拉平诱导的皮肤病变。Brown Norway大鼠中的第一个反应体征是第7-10天的耳红，随后是皮疹，主要在背部结痂;这比Sprague-Dawley大鼠的发作时间短。皮肤的光学显微镜检查显示主要是单核细胞炎性浸润和典型的自我创伤损伤。免疫组化结果表明，浸润由CD 4和CD 8 T细胞以及巨噬细胞组成。40或75 mg/kg/天的较低剂量未导致皮疹，事实上，2周的较低剂量诱导了雌性Brown Norway大鼠对150 mg/kg/天剂量的耐受性。100 mg/kg/天剂量导致2/4（50%）雌性Brown Norway大鼠出现皮疹。在奈韦拉平诱导的皮疹后恢复的Brown Norway大鼠的再激发导致在不到24小时内耳朵发红，随后出现脱毛和偶尔的皮肤病变。尽管再激发时皮疹不太明显，但显微镜下，细胞浸润更明显，尤其是毛囊周围。此外，有界面皮炎与细胞凋亡和卫星病变，表明表皮细胞介导的免疫攻击。虽然初次暴露时未出现全身疾病体征伴发皮疹，但在再激发时，动物表现出普遍不适，并在给药2周或更短时间后被迫处死。重要的是，从再激发动物中分离的脾细胞能够将对奈韦拉平诱导的皮疹的易感性转移至未经处理的Brown Norway雌性受体，这通过受体中皮疹发作的更快时间来说明。该不良反应的特征与在人体中观察到的相似;即，其具有特异质，因为其仅发生在某些动物品系中，延迟发作，在雌性中更常见，具有剂量依赖性，并且似乎是免疫介导的。因此，它可能是研究特异质药物反应的良好动物模型。
Idiosyncratic drug reactions are difficult to study in humans due to their unpredictability. Unfortunately, this characteristic also hinders the development of animal models needed for mechanistic studies. Nevirapine, used to treat human immunodeficiency virus (HIV) infections, results in a severe idiosyncratic skin rash in some patients. We found that nevirapine can also cause a significant rash in some strains of rats. At a dose of 150 mg/kg/day, the incidence in female Sprague-Dawley rats was 6/28 (21%), in female Brown Norway rats 32/32 (100%), and in female Lewis rats 0/6 (0%) while no male Sprague-Dawley or Brown Norway rats developed a rash. Female SJL mice 0/7 also did not develop nevirapine-induced skin lesions. The first sign of a reaction in Brown Norway rats was red ears at days 7-10 followed by a rash with scabbing mainly on the back; this was a shorter time to onset than in Sprague-Dawley rats. Light microscopy of the skin revealed a primarily mononuclear inflammatory infiltrate and lesions typical of self-trauma. Immunohistochemistry results suggest that the infiltrate was composed of CD4 and CD8 T cells as well as macrophages. A lower dose of either 40 or 75 mg/kg/day did not lead to a rash and, in fact, 2 weeks of the lower doses induced tolerance to the 150 mg/kg/day dose in female Brown Norway rats. A dose of 100 mg/kg/day resulted in rash in 2/4 (50%) of female Brown Norway rats. Rechallenge of Brown Norway rats that had been allowed to recuperate after a nevirapine-induced rash led to red ears in less than 24 h followed by hair loss and occasional skin lesions. Although the skin rash was less evident on rechallenge, microscopically, the cellular infiltrate was more prominent, especially surrounding the hair follicles. Moreover, there were lesions of interface dermatitis with apoptosis and satellitosis, indicative of a cell-mediated immune attack on the epidermis. While systemic signs of illness did not accompany the rash on primary exposure, on rechallenge, the animals appeared generally unwell and this forced sacrifice after 2 weeks or less of treatment. Importantly, splenocytes isolated from rechallenged animals were able to transfer susceptibility to nevirapine-induced skin rash to naive female Brown Norway recipients, which was illustrated by a faster time to onset of rash in the recipients. The characteristics of this adverse reaction are similar to that seen in humans; that is, it is idiosyncratic in that it only occurs in some strains of animals, is delayed in onset, is more common in females, is dose-dependent, and appears to be immune-mediated. Therefore, it may represent a good animal model for the study of idiosyncratic drug reactions.