Selective thromboxane synthetase inhibition by picotamide and effects on endotoxin-induced lethality.

Abstract

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.

• Authors: G Matera, M Chisari, D Altavilla, A Foca, J A Cook
• Journal: Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) (Proc Soc Exp Biol Med) Vol. 187 Issue 1 Pg. 58-61 (Jan 1988) ISSN: 0037-9727 [Print] United States
• PMID: 3277192 (Publication Type: Journal Article)

Chemical References

• Lipopolysaccharides
• Phthalic Acids
• Thromboxane B2
• Thromboxane A2
• 6-Ketoprostaglandin F1 alpha
• picotamide
• Thromboxane-A Synthase

Topics

• 6-Ketoprostaglandin F1 alpha (biosynthesis)
• Animals
• Cells, Cultured
• Lipopolysaccharides
• Macrophages (metabolism)
• Male
• Peritoneal Cavity (cytology)
• Phthalic Acids (pharmacology, therapeutic use)
• Rats
• Salmonella enteritidis
• Shock, Septic (chemically induced, drug therapy, metabolism)
• Thromboxane A2 (biosynthesis)
• Thromboxane B2 (metabolism)
• Thromboxane-A Synthase (antagonists & inhibitors)