Effect of SR 27417 on oedema formation induced in rabbit skin by platelet-activating factor or antigen.

SR 27417, the first member of a newly developed series of platelet activating factor (PAF) antagonists inhibited in a dose-dependent manner PAF-induced oedema formation in rabbit skin when administered i.d. premixed with PAF (ED50 = 3.3 +/- 0.15 pmol/site i.d. (intradermally) (n = 5). The effect of SR 27417 was over 660 times more potent than that of the triazolothienodiazepine, WEB-2086 (ED50 = 5.4 +/- 0.71 nmol/site i.d.) (n = 5). SR 27417 protected rabbits from PAF-induced plasma extravasation with an ED50 value of 16 +/- 3 micrograms/kg when given i.v. 1 h before PAF challenge. It was also effective when given p.o. 3 h before PAF i.d. administration (ED50 = 0.18 +/- 0.07 mg/kg p.o.) (n = 5). This effect of SR 27417 was selective for PAF since inflammatory responses induced by other mediators (bradykinin, histamine, N-formyl-L-methionyl-L-leucyl-L-phenyl-alanine, leukotriene B4) were not affected. After i.v. or oral administration (1 and 5 mg/kg respectively) SR 27417 had an extended duration of activity (between 72 and 96 h). In presensitized rabbits, SR 27417 premixed with the allergen inhibited dose-dependently allergen-induced plasma exudation (ED50 = 12 +/- 0.08 nmol/site i.d.) (n = 5) (vs. 850 +/- 98 nmol/site (n = 5) for WEB-2086). Similarly, i.v. injection of SR 27417 (1 mg/kg i.v.) inhibited allergen-induced vascular permeability. These results confirm that PAF plays a major role in the development of cutaneous anaphylaxis and that SR 27417 may be an effective prophylactic drug.