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Effect of FR128998, a novel PAF receptor antagonist, on endotoxin-induced disseminated intravascular coagulation.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 1994 Jun 13; Vol. 258 (3), pp. 239-46. - Publication Year :
- 1994
-
Abstract
- This study aimed to evaluate the effect of FR128998, (1s,6s)-1-benzyl-10-(3-pyridyl-methyl)-7-thia-10-azaspiro [5,6]-dodecan-11-one 7,7-dioxide hydrochloride, a novel platelet activating factor (PAF) receptor antagonist, on endotoxin lipopolysaccharide-induced disseminated intravascular coagulation in rats. Experimental disseminated intravascular coagulation was induced by an infusion of lipopolysaccharide at 0.25 mg/kg/h for 4 h. Simultaneous infusion of FR128998 (0.25 and 1.0 mg/kg/h) with lipopolysaccharide dose dependently inhibited thrombocytopenia, but not leukopenia. The changes in coagulation parameters of disseminated intravascular coagulation, i.e., prolongation of activated partial thromboplastin time and elevated levels of fibrinogen/fibrin degradation products, were also prevented by the treatment with FR128998. In addition, FR128998 attenuated the increase in serum tumor necrosis factor (TNF) which appeared during the initial stage of disseminated intravascular coagulation. FR128998 (10 microM) also inhibited the TNF production by peripheral blood leukocytes or alveolar macrophages stimulated by lipopolysaccharide in vitro. Furthermore, TNF production induced by PAF itself in vitro was also inhibited in the presence of FR128998. These data indicate that PAF plays a pivotal role in the development of disseminated intravascular coagulation via TNF production.
- Subjects :
- Animals
Cells, Cultured
Disseminated Intravascular Coagulation etiology
Endotoxins toxicity
Humans
Leukocyte Count drug effects
Leukocytes drug effects
Leukocytes metabolism
Lipopolysaccharides
Macrophages, Alveolar drug effects
Macrophages, Alveolar metabolism
Male
Platelet Activating Factor pharmacology
Platelet Count drug effects
Rabbits
Rats
Rats, Wistar
Spiro Compounds administration & dosage
Spiro Compounds therapeutic use
Tumor Necrosis Factor-alpha biosynthesis
Tumor Necrosis Factor-alpha metabolism
Blood Coagulation drug effects
Disseminated Intravascular Coagulation blood
Platelet Membrane Glycoproteins antagonists & inhibitors
Receptors, Cell Surface
Receptors, G-Protein-Coupled
Spiro Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0014-2999
- Volume :
- 258
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 8088357
- Full Text :
- https://doi.org/10.1016/0014-2999(94)90485-5