Selective thromboxane synthetase inhibition by picotamide and effects on endotoxin-induced lethality.
The efficacy of N,N'-bis-(3-picolyl)-methoxyisophthalamide (picotamide) as an in vitro thromboxane synthetase inhibitor and its effect on endotoxin (LPS)-induced lethality in rats were assessed. Picotamide at 0.5 and 1.0 mM concentrations significantly (P less than 0.05) inhibited basal and LPS-stimulated synthesis of TxA2 measured by its stable immunoreactive (i) metabolite TxB2 in rat peritoneal macrophages. This compound did not inhibit synthesis of i6-keto-PGF1 alpha, the stable metabolite of PGI2, and produced significant shunting to i6-keto-PGF1 alpha. For lethality studies rats were pretreated, by gavage with picotamide, at either 75, 150, 300, or 600 mg/kg 2 hr prior to iv S. enteritidis (LPS, 20 mg/kg). Both 150 and 300 mg/kg doses of picotamide significantly (P less than 0.05) improved survival in endotoxin shock at 48 hr. These studies demonstrate that picotamide is a selective thromboxane synthetase inhibitor, and that it may be useful during disease states characterized by increased TxA2 synthesis.
Matera
G
G
Istituto di Microbiologia Medica, Università di Messina, Italy.
Chisari
M
M
Altavilla
D
D
Foca
A
A
Cook
J A
JA
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D008070:Lipopolysaccharides; D008264:Macrophages / Q000378:metabolism; D008297:Male; D010529:Peritoneal Cavity / Q000166:cytology; D010795:Phthalic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012477:Salmonella enteritidis; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D013928:Thromboxane A2 / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D008070:Lipopolysaccharides; D010795:Phthalic Acids; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C011581:picotamide; D013930:Thromboxane-A Synthase