Thromboxane A2 inhibition: therapeutic potential in bronchial asthma.
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.
Dogné
Jean-Michel
JM
Department of Medicinal Chemistry, University of Liège, Avenue de l'Hôpital 1, B36, B-4000 Liège, Belgium.
de Leval
Xavier
X
Benoit
Patricia
P
Delarge
Jacques
J
Masereel
Bernard
B
D018927:Anti-Asthmatic Agents / Q000737:chemistry / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D006538:Heptanoic Acids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008689:Methacrylates / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D013928:Thromboxane A2 / Q000502:physiology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D018927:Anti-Asthmatic Agents; D016227:Benzoquinones; D002227:Carbazoles; D006538:Heptanoic Acids; D008689:Methacrylates; D017482:Receptors, Thromboxane; D013449:Sulfonamides; C060230:seratrodast; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase; C034364:ozagrel; C063119:ramatroban