G 619, a dual thromboxane synthase inhibitor and thromboxane A 2 receptor antagonist, inhibits tumor necrosis factor-α biosynthesis

Abstract

G 619 is 3-carbamyl-(3′-picolyl)-4-methoxy-1-benzamide. The compound is structurally related to picotamide, a previously reported dual thromboxane synthase inhibitor/thromboxane A 2 receptor antagonist, which displays inhibitory activity on tumor necrosis factor-α. The aim of the present work was to study the effect of G 619 on tumor necrosis factor-α synthesis both in vivo and in vitro. Salmonella enteritidis lipopolysaccharide was used to induce tumor necrosis factor-α production. Septic shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg/kg (LD 90) of Salmonella enteritidis lipopolysaccharide. Rats were pretreated with G 619 (50 mg/kg, i.v.) or vehicle (1 ml/kg, i.v.) 1 h before endotoxin challenge. Salmonella enteritidis lipopolysaccharide administration dramatically reduced survival rate (0%, 72 h after endotoxin administration), reduced mean arterial blood pressure, increased plasma levels of thromboxane B 2 and 6-keto-prostaglandin F 1α and enhanced serum levels of tumor necrosis factor. Furthermore, endotoxic shock produced characteristic gastric damage, consisting of haemorrhagic infiltrates. Pretreatment with G 619 in vivo significantly protected against Salmonella enteritidis lipopolysaccharide-induced lethality (80% survival rate and 60% survival rate 24 h and 72 h after Salmonella enteritidis lipopolysaccharide injection, respectively), reduced hypotension, decreased plasma thromboxane B 2 and serum tumor necrosis factor-α levels and enhanced blood levels of 6-keto-prostaglandin F 1α. In rat peritoneal macrophages, G 619 in vitro (25, 50 and 100 μM) significantly blunted ( P < 0.001) Salmonella enteritidis lipopolysaccharide-stimulated production of tumor necrosis factor-α, whereas it increased 6-keto-prostaglandin F 1α and cyclic AMP levels. The present data indicate that G 619 may be useful during disease states characterized by elevated tumor necrosis factor-α levels.