Fenspiride: an anti-inflammatory drug with potential benefits in the treatment of endotoxemia.
Using a model of endotoxemia triggered by the intravenous injection of bacterial lipopolysaccharide (0.1 and 1 mg/kg) to guinea-pigs, we investigated the interference of fenspiride, an anti-inflammatory drug recommended for the treatment of inflammatory diseases of the upper respiratory tract. Administered orally at 60 mg/kg, fenspiride reduced the lipopolysaccharide-induced early rise of tumor necrosis factor concentrations in serum (4.2 +/- 0.9 vs. 2.3 +/- 0.5 ng/ml, P < 0.05) and in the bronchoalveolar lavage fluid (55.7 +/- 20 vs. 19.7 +/- 7.5 ng/ml, P < 0.05). The lipopolysaccharide-induced primed stimulation of alveolar macrophages, defined as their enhanced release of arachidonic acid metabolites as compared to cells from untreated controls upon stimulation with N-formyl-methionyl-phenylalanine was also reduced by fenspiride (1551.5 +/- 183.7 vs. 771.5 +/- 237.5 pg/mu g protein, P < 0.05 for thromboxane B2 and 12.6 +/- 4.9 vs. 3.6 +/- 0.9 pg/ mu g protein, P < 0.05 for leukotriene C4). Finally, fenspiride reduced the increased serum concentrations of extracellular type II phospholipase A2 (3.9 +/- 1.2 vs. 1.2 +/- 0.1 nmol/ml per min, P < 0.01), the intensity of the neutrophilic alveolar invasion and the lethality due to the lipopolysaccharide. The protective effect of fenspiride may result from the inhibition of the formation of tumor necrosis factor, a major mediator of the effects of lipopolysaccharide.
De Castro
C M
CM
Unite de Pharmacologie Cellulaire, Unite Associee Institut Pasteur-INSERM 285, Paris, France.
Nahori
M A
MA
Dumarey
C H
CH
Vargaftig
B B
BB
Bachelet
M
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D000242:Cyclic AMP / Q000032:analysis; D004731:Endotoxins / Q000097:blood*; D006168:Guinea Pigs; D008070:Lipopolysaccharides; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D010741:Phospholipases A / Q000097:blood; D054467:Phospholipases A2; D013141:Spiro Compounds / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000893:Anti-Inflammatory Agents; D004731:Endotoxins; D008070:Lipopolysaccharides; D013141:Spiro Compounds; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D010741:Phospholipases A; D054467:Phospholipases A2; C084775:fenspiride