Protective effect of BN 50739, a new platelet-activating factor antagonist, in endotoxin-treated rabbits.
Platelet-activating factor (PAF) has been demonstrated in the circulation and organs of animals exposed to gram negative endotoxins, whereas PAF antagonists have been shown to exhibit some efficacy in modifying the course of endotoxemia. In this study we evaluated BN 50739, a novel specific PAF antagonist, for its capacity to block PAF or lipopolysaccharide endotoxin (LPS)-mediated effects in rabbits. Pretreatment with BN 50739 (3 and 10 mg/kg i.p.) inhibited PAF (500 pmol/kg i.v.)-induced thrombocytopenia, leukopenia and plasma thromboxane B2 elevation in a dose-dependent manner. The inhibitory effect lasted 3.5 to 4.5 hr. BN 50739 (10 mg/kg) prevented the early phase of LPS (50 micrograms/kg i.v.)-induced thrombocytopenia and thromboxane B2 elevation, and reduced the 24-hr mortality rate from 75 to 22% (P less than .05). Post-treatment with BN 50739 increased the 10-hr survival rate from 33 to 87% (P less than .05); however, it had no effect on the 24-hr mortality. BN 50739 did not affect LPS-induced leukopenia or the elevation in plasma tumor necrosis factor. Our data support possible therapeutic efficacy of PAF antagonists in septic shock despite their inability to prevent the generation of tumor necrosis factor.
Department of Pharmacology, SmithKline Beecham, King of Prussia, Pennsylvania.
T L
TL
Yue
M
M
Farhat
R
R
Rabinovici
P Y
PY
Perera
S N
SN
Vogel
G
G
Feuerstein
D000818:Animals; D001381:Azepines / Q000627:therapeutic use*; D001772:Blood Cell Count; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011817:Rabbits; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood; D014230:Triazoles / Q000627:therapeutic use*
D001381:Azepines; D004731:Endotoxins; D010972:Platelet Activating Factor; D014230:Triazoles; C064509:BN 50739; D013929:Thromboxane B2