Akagi M, Nishioka E, Kanoh R, Tachibana M, Fukuishi N
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Japan.
Arzneimittelforschung. 1997 Dec;47(12):1364-9.
Apafant (4-(2-chlorophenyl)-9-methyl-2-(3-morpholino-3-oxopropyl)-6H-thieno[3,2- f] [1,2,4]triazolo[4,3-a][1,4] diazepine, CAS 105219-56-5, WEB 2086), as a specific platelet activating factor (PAF) antagonist, inhibited PAF-induced increases of bronchial inflation pressure (delta Pi), pulmonary artery perfusion pressure (delta Pp) and microvascular permeability (wet-to-dry lung weight ratios), dose-dependently, in rats. Apafant also inhibited antigen-induced increase of delta pi, delta Pp and microvascular permeability in passively sensitized rats. Ozagrel also inhibited PAF- and antigen-induced increase of delta Pi, delta Pp and microvascular permeability. Apafant almost completely inhibited the increase of intratracheal pressure and microvascular permeability, but incompletely inhibited the increase of pulmonary artery pressure. At 1 microgram/ml, the effects of ozagrel were almost comparable to that of apafant at the same concentration, but the inhibitory effect on intratracheal pressure was less than that of apafant. Apafant inhibited PAF-induced increase in perfusate of thromboxane (TX) B2 and leukotrine C4/D4E4 (LTs), and antigen-induced increase of TXB2, LTs, PAF and histamine. Ozagrel also inhibited the PAF-induced increase of TXB2, but not the increase of LTs. Apafant inhibited antigen-induced increase of TXB2 and LTs more strongly than PAF-induced increase. The order of inhibitory effects of apafant against generation and release of chemical mediators was TXB2, LTs, PAF and histamine. These findings suggest that TXA2, LTs and PAF may contribute to the increase of intratracheal pressure and microvascular permeability, and histamine may contribute to the increase of vascular resistance in rats. Apafant may inhibit bronchopulmonary responses through PAF receptor antagonism. In addition, apafant can be considered to be useful for the treatment of some allergic diseases when the drug is employed in clinical use.
阿帕泛（4-（2-氯苯基）-9-甲基-2-（3-吗啉代-3-氧代丙基）-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂卓，CAS 105219-56-5，WEB 2086）作为一种特异性血小板活化因子（PAF）拮抗剂，在大鼠中剂量依赖性地抑制PAF诱导的支气管充气压力（ΔPi）、肺动脉灌注压力（ΔPp）和微血管通透性（肺湿重与干重比）升高。阿帕泛还抑制被动致敏大鼠中抗原诱导的ΔPi、ΔPp和微血管通透性升高。奥扎格雷也抑制PAF和抗原诱导的ΔPi、ΔPp和微血管通透性升高。阿帕泛几乎完全抑制气管内压力和微血管通透性升高，但不完全抑制肺动脉压力升高。在1微克/毫升时，奥扎格雷的作用与相同浓度的阿帕泛几乎相当，但对气管内压力的抑制作用小于阿帕泛。阿帕泛抑制PAF诱导的血栓素（TX）B2和白三烯C4/D4/E4（LTs）灌流液增加，以及抗原诱导的TXB2、LTs、PAF和组胺增加。奥扎格雷也抑制PAF诱导的TXB2增加，但不抑制LTs增加。阿帕泛抑制抗原诱导的TXB2和LTs增加比抑制PAF诱导的增加更强。阿帕泛对化学介质生成和释放的抑制作用顺序为TXB2、LTs、PAF和组胺。这些发现表明，TXA2、LTs和PAF可能促成气管内压力和微血管通透性升高，而组胺可能促成大鼠血管阻力升高。阿帕泛可能通过PAF受体拮抗作用抑制支气管肺反应。此外，当该药物用于临床时，阿帕泛可被认为对治疗某些过敏性疾病有用。
