Robinson M K, Cruze C A
Human Safety Department, Procter & Gamble Company and Procter & Gamble Pharmaceuticals, Miami Valley Laboratories, Cincinnati, OH 45253, USA.
Food Chem Toxicol. 1996 May;34(5):495-506. doi: 10.1016/0278-6915(96)87361-3.
Preclinical test methods for allergic contact sensitivity have been widely used for sensitization hazard identification and, with consideration of human exposure conditions, have also been valuable tools for sensitization risk assessment. For many years, the guinea pig has been the test species of choice with a variety of test methods developed to assess the sensitization response. More recently the local lymph node assay (LLNA) in mice has been developed to provide a more objective index of sensitization potential. The standardized methods have proven to be very well suited to most situations in which potential skin sensitization of a chemical needs to be assessed before human exposure. A potential difficulty with all these relatively limited exposure preclinical test methods, however, is in the ability to detect weak contact allergens that prove to be significant clinical allergens due to chronic topical exposure, exposure to compromised skin, and/or highly exaggerated exposure through transdermal delivery. This has been shown with the transdermal drug clonidine and might also be the case for topical antihistamines. The latter are considered significant clinical contact allergens, although predictive preclinical test data are minimal or lacking. A series of guinea pig (modified Buehler) tests with two common antihistamine compounds (triprolidine and diphenhydramine) and LLNA on these and two other compounds (chlorpheniramine and promethazine) was conducted. Positive Buehler test results required use of penetrating vehicle systems and a modified nine-induction patch regimen. Positive LLNA responses were obtained with all four materials (to varying degrees) only if the application site was pre-abraded or a penetrating vehicle (dimethylformamide) was used. These data support the notion that preclinical sensitization test methods can be modified to increase sensitivity. This may be critical for preclinical assessment of topical/transdermal drugs or other materials with chronic or high-concentration exposures in man.
过敏性接触性皮炎的临床前测试方法已被广泛用于识别致敏危害，并且考虑到人类暴露条件，这些方法也是评估致敏风险的重要工具。多年来，豚鼠一直是首选的测试物种，已开发出多种测试方法来评估致敏反应。最近，已开发出小鼠局部淋巴结试验（LLNA），以提供更客观的致敏潜力指标。已证明标准化方法非常适合大多数需要在人体暴露前评估化学物质潜在皮肤致敏性的情况。然而，所有这些相对有限暴露的临床前测试方法的一个潜在困难在于，它们难以检测出由于长期局部暴露、暴露于受损皮肤和/或通过透皮给药导致的高度夸张暴露而被证明是重要临床过敏原的弱接触性过敏原。这已在透皮药物可乐定中得到证实，局部抗组胺药可能也是如此。尽管预测性临床前测试数据很少或缺乏，但后者被认为是重要的临床接触性过敏原。我们对两种常见的抗组胺化合物（曲普利啶和苯海拉明）进行了一系列豚鼠（改良Buehler）试验，并对这两种化合物以及另外两种化合物（氯苯那敏和异丙嗪）进行了LLNA试验。阳性Buehler试验结果需要使用渗透载体系统和改良的九次诱导贴剂方案。只有在应用部位预先擦伤或使用渗透载体（二甲基甲酰胺）的情况下，才能（不同程度地）获得所有四种材料的阳性LLNA反应。这些数据支持了临床前致敏测试方法可以进行修改以提高敏感性的观点。这对于局部/透皮药物或其他在人体中具有慢性或高浓度暴露的材料的临床前评估可能至关重要。
