Dogné Jean-Michel, de Leval Xavier, Benoit Patricia, Delarge Jacques, Masereel Bernard
Department of Medicinal Chemistry, University of Liège, Avenue de l'Hôpital 1, B36, B-4000 Liège, Belgium.
Am J Respir Med. 2002;1(1):11-7. doi: 10.1007/BF03257158.
Bronchial asthma is a disease defined by reversible airway obstruction, bronchial hyperresponsiveness and inflammation. In addition to histamine and acetylcholine, recent studies have emphasized the role of arachidonic acid metabolites (leukotrienes, prostaglandins and thromboxane A(2)) in the pathogenesis of asthma. Among these mediators, thromboxane A(2) (TXA(2)) has attracted attention as an important mediator in the pathophysiology of asthma because of its potent bronchoconstrictive activity. Thromboxane A(2) is believed to be involved not only in late asthmatic responses but also in bronchial hyperresponsiveness, a typical feature of asthma. Strategies for inhibition of TXA(2) include TXA(2) receptor antagonism and thromboxane synthase inhibition. Results of double-blind, placebo-controlled clinical trials have proven the efficacies of the thromboxane receptor antagonist seratrodast and the thromboxane synthase inhibitor ozagrel in the treatment of patients with asthma. Seratrodast and ozagrel are available in Japan for the treatment of asthma. Ramatroban, another thromboxane receptor antagonist, is currently under phase III clinical evaluation in Europe and Japan for the treatment of asthma. The pharmacological profiles of the thromboxane modulators may be improved by combination with leukotriene D(4) receptor antagonists. A multi-pathway inhibitory agent such as YM 158, which is a novel orally active dual antagonist for leukotriene D(4) and thromboxane A(2 )receptors, may have potent therapeutic effects in the treatment of bronchial asthma. Large scale clinical trials are necessary to further define the role of thromboxane modulators in the treatment of patients with asthma.
支气管哮喘是一种由可逆性气道阻塞、支气管高反应性和炎症所定义的疾病。除组胺和乙酰胆碱外，最近的研究强调了花生四烯酸代谢产物（白三烯、前列腺素和血栓素A2）在哮喘发病机制中的作用。在这些介质中，血栓素A2（TXA2）因其强大的支气管收缩活性，作为哮喘病理生理学中的一种重要介质而受到关注。血栓素A2不仅被认为参与哮喘迟发反应，还参与哮喘的典型特征——支气管高反应性。抑制TXA2的策略包括TXA2受体拮抗和血栓素合酶抑制。双盲、安慰剂对照临床试验的结果已证实血栓素受体拮抗剂塞曲司特和血栓素合酶抑制剂奥扎格雷在治疗哮喘患者方面的疗效。塞曲司特和奥扎格雷在日本可用于治疗哮喘。另一种血栓素受体拮抗剂雷马曲班目前正在欧洲和日本进行治疗哮喘的III期临床评估。血栓素调节剂的药理学特性可通过与白三烯D4受体拮抗剂联合使用而得到改善。一种多途径抑制剂，如YM 158，它是一种新型的对白三烯D4和血栓素A2受体具有口服活性的双重拮抗剂，可能在治疗支气管哮喘方面具有强大的治疗效果。需要进行大规模临床试验以进一步明确血栓素调节剂在治疗哮喘患者中的作用。
