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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.
AuthorsD Altavilla, F Squadrito, P Canale, M Ioculano, G Squadrito, G M Campo, M Serranò, A Sardella, G Urna, G Spignoli
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 286 Issue 1 Pg. 31-9 (Nov 3 1995) ISSN: 0014-2999 [Print] NETHERLANDS
PMID8566149 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzamides
  • Lipopolysaccharides
  • Picolines
  • Receptors, Thromboxane
  • Tumor Necrosis Factor-alpha
  • 3-carbamyl-(3'-picolyl)-4-methoxy-1-benzamide
  • Thromboxane B2
  • 6-Ketoprostaglandin F1 alpha
  • Cyclic AMP
  • Thromboxane-A Synthase
Topics
  • 6-Ketoprostaglandin F1 alpha (blood)
  • Animals
  • Benzamides (pharmacology)
  • Cyclic AMP (analysis)
  • Gastric Mucosa (drug effects, pathology)
  • Lipopolysaccharides
  • Macrophages, Peritoneal (drug effects)
  • Male
  • Picolines (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Thromboxane (antagonists & inhibitors)
  • Salmonella enteritidis
  • Shock, Septic (chemically induced, prevention & control)
  • Thromboxane B2 (blood)
  • Thromboxane-A Synthase (antagonists & inhibitors)
  • Tumor Necrosis Factor-alpha (analysis, antagonists & inhibitors)

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