Effects of UR-12633, a new antagonist of platelet-activating factor, in rodent models of endotoxic shock

被引:15
作者
Giral, M [1 ]
Balsa, D [1 ]
Ferrando, R [1 ]
Merlos, M [1 ]
GarciaRafanell, J [1 ]
Forn, J [1 ]
机构
[1] J URIACH & CIA, RES CTR, E-08026 BARCELONA, SPAIN
关键词
UR-12633; WEB-2086; endotoxic shock; platelet-activating factor; disseminated intravascular coagulation; haemoconcentration; hyperglycaemia; hyperlactacidaemia;
D O I
10.1111/j.1476-5381.1996.tb15527.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 The effects of the selective and potent novel platelet-activating factor (PAF) antagonist, UR-12633 (1-(3,3-diphenylpropionyl)-4-(3-pyridylcyanomethyl)piperidine) on several markers of endotoxic shock syndrome were evaluated in rats and mice. 2 UR-12633, administered 60 min after E. coli lipopolysaccharide (LPS), reversed the LPS-induced sustained hypotension in rats at doses of 0.01 to 1 mg kg(-1), i.v. The reference compound WEB-2086 (1 mg kg(-1)) also reversed the LPS-induced hypotension. UR-12633 (1 mg kg(-1)), administered 10 min before LPS, almost fully inhibited sustained hypotension. The immediate hypotension (within 1 min) caused by LPS was not prevented by either UR-12633 or WEB-2086. 3 Pretreatment with 10 mg kg(-1), i.v. of either UR-12633 or WEB-2086 inhibited the increase in disseminated intravascular coagulation markers, such as activated partial thromboplastin time (55 and 74% inhibition, respectively), and prothrombin time (22 and 72% inhibition) and prevented the decrease in plasma fibrinogen content (100 and 29% inhibition). 4 Increases in acid phosphatase (ACP) plasma activity, a marker of lysosomal activation, and in lactate dehydrogenase (LDH), a marker of tissue damage, were inhibited by pretreatment with 10 mg kg(-1), i.v. of either UR-12633 or WEB-2086 (100% and 69% inhibition, ACP; 62 and 48% inhibition, LDH). Hyperglycaemia (71 and 46%) and hyperlactacidaemia (92 and 56%) were also inhibited. 5 UR-12633, but not WEB-2086, inhibited the LPS-induced increase in vascular permeability in rats, as shown by prevention of haemoconcentration and, to a lesser degree, the increase in Evans blue dye extravasation. 6 In a series of nine reference compounds and UR-12633, we found a high correlation (P < 0.001) between PAF antagonist activity, measured as the inhibition of PAF-induced rabbit platelet aggregation or PAF-induced mortality in mice and the inhibition of LPS-induced mortality. 7 In spite of the multifactorial nature of endotoxic shock, in which many mediators may be involved, the new potent PAF antagonist, UR-12633, proved effective in protecting against changes in most shock markers. These data strongly suggest a key role for PAF in the pathogenesis of endotoxic shock in rodents.
引用
收藏
页码:1223 / 1231
页数:9
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