Aibara S, Mori M, Iwamoto T, Tsubokawa M, Takamori H, Tsukada W
Exploratory Research Laboratories III, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Jpn J Pharmacol. 1993 Apr;61(4):267-76. doi: 10.1254/jjp.61.267.
The anti-allergic and anti-inflammatory activities of DS-4574, which possesses leukotriene antagonism and inhibits the release of immunologically stimulated mediators such as histamine and leukotrienes, were evaluated in several animal models. DS-4574 had dose-dependent inhibitory effects on IgE-mediated passive cutaneous anaphylaxis and the passive Arthus reaction in rats and the phase I response of Forssman antibody-induced bronchoconstriction. In contrast, this compound had no effect on the phase II response of Forssman antibody-induced bronchoconstriction in guinea pigs, the reverse cutaneous anaphylaxis in rats, complement-dependent hemolysis of sheep erythrocytes and the delayed-type hypersensitivity induced by methylated bovine serum albumin in mice. The results obtained in a double sensitization with two IgE antibodies suggested that DS-4574, as well as disodium cromoglycate, did not impair antigen-antibody combination but prevents the release of chemical mediators such as histamine. DS-4574 also had a weak inhibitory activity on carrageenin paw edema in rats, arachidonic acid ear edema in mice and adjuvant arthritis in rats. In addition, this compound inhibited increased vascular permeability in rat skin induced by leukotriene D4 and platelet activating factor-induced pleurisy in rats in a dose-dependent manner. These results indicate that DS-4574 inhibited type III allergic reactions and some inflammatory reactions. Therefore, DS-4574 could be useful in the treatment of allergic diseases such as asthma.
DS - 4574具有白三烯拮抗作用，并能抑制免疫刺激介质如组胺和白三烯的释放，其抗过敏和抗炎活性在多种动物模型中进行了评估。DS - 4574对大鼠IgE介导的被动皮肤过敏反应、被动Arthus反应以及福斯曼抗体诱导的支气管收缩的I期反应具有剂量依赖性抑制作用。相比之下，该化合物对豚鼠福斯曼抗体诱导的支气管收缩的II期反应、大鼠反向皮肤过敏反应、绵羊红细胞的补体依赖性溶血以及小鼠甲基化牛血清白蛋白诱导的迟发型超敏反应均无影响。用两种IgE抗体进行双重致敏实验所得结果表明，DS - 4574与色甘酸二钠一样，不会损害抗原 - 抗体结合，但可阻止组胺等化学介质的释放。DS - 4574对大鼠角叉菜胶性足肿胀、小鼠花生四烯酸耳肿胀以及大鼠佐剂性关节炎也具有微弱的抑制活性。此外，该化合物以剂量依赖性方式抑制白三烯D4诱导的大鼠皮肤血管通透性增加和血小板活化因子诱导的大鼠胸膜炎。这些结果表明，DS - 4574可抑制III型过敏反应和一些炎症反应。因此，DS - 4574可能对治疗哮喘等过敏性疾病有用。
