Seeds E A, Kilfeather S, Okiji S, Schoupe T S, Donigi-Gale D, Page C P
Department of Pharmacology, King's College, University of London, UK.
Eur J Pharmacol. 1995 Dec 7;293(4):369-76. doi: 10.1016/0926-6917(95)90057-8.
The effect of a novel leuktriene B4 receptor antagonist N-[5[[8-(1-hydroxy-2- phenyl)ethyl]dibenzofuran-2yl]5-hydroxypentanoyl]pyrrolidine (PF 10042) has been evaluated in comparison with 2-[3(1-hydroxyhexyl)phenoxymethyl]quinoline hydrochloride (PF 5901), a specific inhibitor of the 5-lipoxygenase pathway of arachidonic acid metabolism, against platelet activating factor (PAF) and allergen induced bronchial hyperresponsiveness and pulmonary eosinophil infiltration in the guinea pig. PF 10042 significantly displaced radiolabelled [3H]leukotriene B4 from binding sites on human neutrophils with an EC50 of 3 muM. PF 10042 (100 mg/kg, i.p.) significantly inhibited PAF and allergen induced bronchial hyperresponsiveness without reducing the concomitant eosinophil infiltration, whereas PF 5901 (100 mg/kg, p.o.) significantly inhibited both PAF and allergen induced bronchial hyperresponsiveness and eosinophil infiltration. We suggest from these results that PAF and allergen induced bronchial hyperresponsiveness may be secondary to the release of leukotriene B4, but this lipoxygenase metabolite does not contribute significantly to the observed eosinophil infiltration.
已将新型白三烯B4受体拮抗剂N-[5[[8-(1-羟基-2-苯基)乙基]二苯并呋喃-2-基]5-羟基戊酰基]吡咯烷(PF 10042)与2-[3-(1-羟基己基)苯氧基甲基]喹啉盐酸盐(PF 5901，花生四烯酸代谢5-脂氧合酶途径的特异性抑制剂)进行比较，评估其对豚鼠血小板活化因子(PAF)和变应原诱导的支气管高反应性及肺嗜酸性粒细胞浸润的作用。PF 10042能以3μM的半数有效浓度(EC50)从人中性粒细胞的结合位点上显著置换放射性标记的[3H]白三烯B4。PF 10042(100mg/kg，腹腔注射)能显著抑制PAF和变应原诱导的支气管高反应性，而不减少伴随的嗜酸性粒细胞浸润，而PF 5901(100mg/kg，口服)能显著抑制PAF和变应原诱导的支气管高反应性及嗜酸性粒细胞浸润。从这些结果我们推测，PAF和变应原诱导的支气管高反应性可能继发于白三烯B4的释放，但这种脂氧合酶代谢产物对观察到的嗜酸性粒细胞浸润没有显著作用。
