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

Abstract
1. The effects of the selective and potent novel platelet-activating factor (PAF) antagonist, UR-12633 (1-(3,3-diphenylpropionyl)-4-(3-pyridylcyanomethyl)piperidin e) 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.
AuthorsM Giral, D Balsa, R Ferrando, M Merlos, J Garcia-Rafanell, J Forn
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 118 Issue 5 Pg. 1223-31 (Jul 1996) ISSN: 0007-1188 [Print] England
PMID8818347 (Publication Type: Journal Article)
Chemical References
  • Azepines
  • Lipopolysaccharides
  • Piperidines
  • Platelet Aggregation Inhibitors
  • Triazoles
  • WEB 2086
  • UR 12633
Topics
  • Analysis of Variance
  • Animals
  • Azepines (metabolism)
  • Blood Pressure (drug effects)
  • Cell Membrane (metabolism)
  • Disease Models, Animal
  • Escherichia coli
  • Hypotension (chemically induced, drug therapy)
  • Lipopolysaccharides (antagonists & inhibitors)
  • Male
  • Mice
  • Piperidines (pharmacology)
  • Platelet Aggregation Inhibitors (metabolism, pharmacology)
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Shock, Septic (drug therapy)
  • Triazoles (metabolism)

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