Ex vivo effects of SR 27417, a novel PAF antagonist, on rabbit platelet aggregation and [3H]-PAF binding.
Pharmacodynamics of SR 27417, a novel, specific platelet-activating factor (PAF) antagonist was monitored with ex vivo PAF-induced platelet aggregation in the rabbit. Single per os administration of SR 27417 (5 mg/kg) resulted in complete inhibition of this aggregation for at least 3 days. The magnitude of this inhibitory effect was dose-dependent with a maximum effect 1-3 h after oral administration. IC50 values for PAF-induced platelet aggregation were 80, 35, 50 and 1250 micrograms/kg, 1, 3, 24 and 72 h after oral intake of SR 27417 respectively. This effect was irreversible in nature since it could not be overcome by prolonged incubation of platelets isolated from treated animals in plasma from controls or in buffer. Examination of [3H]-PAF binding to washed platelets isolated 5 min after i.v. administration of increasing concentrations of SR 27417 revealed a competitive-type of inhibition whereas 24 h after p.o. administration, SR 27417 antagonized [3H]-PAF binding in a non-competitive manner.
Herbert
J M
JM
Haemobiology Research Department Sanofi Recherche, Toulouse, France.
Laplace
M C
MC
Maffrand
J P
JP
D000284:Administration, Oral; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D013223:Statistics as Topic; D013844:Thiazoles / Q000494:pharmacology*
D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles; C039351:platelet activating factor receptor; C071317:Foropafant