Protective effect of T-686, an inhibitor of plasminogen activator inhibitor-1 production, against the lethal effect of lipopolysaccharide in mice.
We have examined the effects of an inhibitor of plasminogen activator inhibitor-1 (PAI-1) production, (3E,4E)-3-benzylidene-4-(3,4,5-trimethoxy-benzylidene)pyrrol idine-2,5-dione (T-686), on lipopolysaccharide (LPS)-induced death in mice. Oral administration of T-686 (10 and 100 mg/kg/day) for 8 days prior to the LPS injection (35 mg/kg, i.v.) protected mice from the lethal effect of LPS in a dose-dependent fashion. Moreover, treatment with 100 mg/kg T-686 attenuated the increase in plasma PAI-1 activity and the decrease in AT-III activity induced by LPS. We conclude that T-686 can reduce the mortality of mice induced by LPS, which seems to be partially correlated with both hypercoagulation and hypofibrinolysis.
Murakami
J
J
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
Ohtani
A
A
Murata
S
S
D000805:Angiotensin III / Q000378:metabolism; D000818:Animals; D000925:Anticoagulants / Q000037:antagonists & inhibitors / Q000633:toxicity; D001597:Benzylidene Compounds / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005342:Fibrinolysis / Q000187:drug effects; D006493:Heparin / Q000633:toxicity; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D012772:Shock, Septic / Q000401:mortality / Q000517:prevention & control; D013388:Succinimides / Q000494:pharmacology*; D015996:Survival Rate
D000925:Anticoagulants; D001597:Benzylidene Compounds; D004731:Endotoxins; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D013388:Succinimides; D000805:Angiotensin III; C104988:T 686; C044101:endotoxin, Escherichia coli; D006493:Heparin