title: G 619, a dual thromboxane synthase inhibitor and thromboxane A2 receptor antagonist, inhibits tumor necrosis factor-alpha 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 A2 receptor antagonist, which displays inhibitory activity on tumor necrosis factor-alpha. The aim of the present work was to study the effect of G 619 on tumor necrosis factor-alpha synthesis both in vivo and in vitro. Salmonella enteritidis lipopolysaccharide was used to induce tumor necrosis factor-alpha production. Septic shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg/kg (LD90) 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 B2 and 6-keto-prostaglandin F1 alpha 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 B2 and serum tumor necrosis factor-alpha levels and enhanced blood levels of 6-keto-prostaglandin F1 alpha. In rat peritoneal macrophages, G 619 in vitro (25, 50 and 100 microM) significantly blunted (P < 0.001) Salmonella enteritidis lipopolysaccharide-stimulated production of tumor necrosis factor-alpha, whereas it increased 6-keto-prostaglandin F1 alpha and cyclic AMP levels. The present data indicate that G 619 may be useful during disease states characterized by elevated tumor necrosis factor-alpha levels.
authors.affiliation: Institute of Pharmacology, School of Medicine, University of Messina, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Altavilla
authors.forename: F
authors.initials: F
authors.lastname: Squadrito
authors.forename: P
authors.initials: P
authors.lastname: Canale
authors.forename: M
authors.initials: M
authors.lastname: Ioculano
authors.forename: G
authors.initials: G
authors.lastname: Squadrito
authors.forename: G M
authors.initials: GM
authors.lastname: Campo
authors.forename: M
authors.initials: M
authors.lastname: Serranò
authors.forename: A
authors.initials: A
authors.lastname: Sardella
authors.forename: G
authors.initials: G
authors.lastname: Urna
authors.forename: G
authors.initials: G
authors.lastname: Spignoli
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D000242:Cyclic AMP / Q000032:analysis; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008297:Male; D010847:Picolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D012477:Salmonella enteritidis; D012772:Shock, Septic / Q000139:chemically induced / Q000517:prevention & control; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D008070:Lipopolysaccharides; D010847:Picolines; D017482:Receptors, Thromboxane; D014409:Tumor Necrosis Factor-alpha; C074732:3-carbamyl-(3'-picolyl)-4-methoxy-1-benzamide; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D000242:Cyclic AMP; D013930:Thromboxane-A Synthase