Teelmann K, Bollag W
Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd, Basle, Switzerland.
Dermatologica. 1990;180(1):30-5. doi: 10.1159/000247981.
The combination of the results of mouse antipapilloma tests with those from hypervitaminosis A tests in mice as the basis for calculating a therapeutic index has been used for more than 20 years in the search for retinoids as useful drugs in human dermatology. A number of retinoids identified as active or inactive when administered systemically in these mouse systems have gone into clinical trials; clinical results on 11 retinoids were available for a retrospective analysis on the predictive relevance of the mouse models for retinoid activity in human psoriasis. This analysis revealed that the therapeutic index in mice correctly identified eleven compounds and differentiated them into markedly active, moderately active or inactive retinoids when subsequently used clinically in the treatment of various forms of psoriasis. Acidic retinoids were more difficult to assess than nonacidic ones and the therapeutic index appeared to underestimate their potency in humans. One retinoid, motretinide, showed a favorable therapeutic index but failed to demonstrate antipsoriatic activity in the clinic. The reason for this discrepancy is that humans and mice metabolize this compound differently. Thus, although chemically induced skin papillomas in mice reflect only certain analogies to human psoriasis and other keratinizing dermatoses, they may be considered a useful tool in the search for retinoids for the treatment of keratinization disorders.
将小鼠抗乳头瘤试验结果与小鼠维生素A过多症试验结果相结合，以此为基础计算治疗指数，在寻找可用于人类皮肤病治疗的类维生素A药物的过程中，这种方法已经使用了20多年。在这些小鼠系统中全身给药时被鉴定为有活性或无活性的一些类维生素A已进入临床试验；有11种类维生素A的临床结果可用于回顾性分析小鼠模型对人类银屑病中类维生素A活性的预测相关性。该分析表明，小鼠中的治疗指数正确地识别了11种化合物，并在随后用于治疗各种形式的银屑病时，将它们区分为明显有活性、中度有活性或无活性的类维生素A。酸性类维生素A比非酸性类维生素A更难评估，治疗指数似乎低估了它们在人类中的效力。一种类维生素A，即莫维A酯，显示出良好的治疗指数，但在临床上未能表现出抗银屑病活性。这种差异的原因是人类和小鼠对这种化合物的代谢方式不同。因此，尽管化学诱导的小鼠皮肤乳头瘤仅反映出与人类银屑病和其他角化性皮肤病的某些相似之处，但它们可能被认为是寻找用于治疗角化异常的类维生素A的有用工具。
