Suda H, Okamoto M, Fukumoto M
Central Research Laboratories, Santen Pharmaceutical Co., Ltd., Osaka, Japan.
Immunopharmacol Immunotoxicol. 1993 Aug;15(4):387-96. doi: 10.3109/08923979309035235.
Delayed-type skin allergic (DTA) reactions induced by various sulfhydryl compounds were investigated. Sulfhydryl compounds investigated were bucillamine and D-penicillamine: antirheumatic agents, SA981: an intramolecular cyclic disulfide of bucillamine, tiopronin: a hepatoprotective and potent antirheumatic agent and captopril: antihypertensive and potent antirheumatic agent. Guinea pigs were sensitized on day 1 by subcutaneous injection and day 7 by subcutaneous and intramuscular injection of emulsions of these compounds (3 mg/animal) with Freund's complete adjuvant. Two weeks after the second sensitization, 0.3 mg/animal of each compound was intradermally challenged and the 24 hr DTA reaction was evaluated. A large number of sulfhydril compounds showed positive in the DTA reactions and the intensity of these reactions had a good correlation with the frequency of the skin rashes referred to by the adverse effects in clinical reports of anti-rheumatic drugs. It is suggested that guinea pig DTA reaction may provide a good screening way to find new sulfhydryl or disulfide compounds with low incidence of skin rash. A novel sulfhydryl compound N-(2,2-dimethyl-3-mercaptopropionyl)-L-cysteine (SA3441) and its intramolecular cyclic disulfide (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid (SA3443), which show no DTA activity in guinea pigs, were found using the above-mentioned DTA reaction.
研究了由各种巯基化合物引起的迟发型皮肤过敏（DTA）反应。所研究的巯基化合物有布西拉明和D - 青霉胺：抗风湿药；SA981：布西拉明的分子内环二硫化物；硫普罗宁：一种保肝且有效的抗风湿药；以及卡托普利：抗高血压且有效的抗风湿药。豚鼠在第1天通过皮下注射进行致敏，在第7天通过皮下和肌肉注射这些化合物（3毫克/只动物）与弗氏完全佐剂的乳剂进行致敏。第二次致敏两周后，将每种化合物0.3毫克/只动物皮内注射进行激发，并评估24小时的DTA反应。大量的巯基化合物在DTA反应中呈阳性，并且这些反应的强度与抗风湿药物临床报告中提到的副作用所涉及的皮疹发生率有良好的相关性。提示豚鼠DTA反应可能为寻找皮疹发生率低的新型巯基或二硫化物化合物提供一种良好的筛选方法。使用上述DTA反应发现了一种新型巯基化合物N -（2,2 - 二甲基 - 3 - 巯基丙酰基）-L - 半胱氨酸（SA3441）及其分子内环二硫化物（4R）-六氢 - 7,7 - 二甲基 - 6 - 氧代 - 1,2,5 - 二硫氮杂环庚烷 - 4 - 羧酸（SA3443），它们在豚鼠中无DTA活性。
