Anti-tumor necrosis factor properties of non-peptide drugs in acute-phase responses.
Dexamethasone (sodium phosphate), pentoxifylline, fusidic acid (sodium salt), pentamidine (isethionate) and R-phenylisopropyladenosine (R-PIA) were tested for their anti-tumor necrosis factor (TNF) activities in an endotoxin-induced shock rat model. All the drugs reduced serum TNF concentrations in a dose-dependent manner, whereas their effects on serum interleukin-6 levels differed. Doses that reduced TNF levels by 50% were 0.012 mg/kg for dexamethasone, 0.06 mg/kg for R-PIA, 0.24 mg/kg for pentamidine, 6.5 mg/kg for fusidic acid and 15 mg/kg for pentoxifylline. Administration of the drugs to rats before intraplantar injection of carrageenan reduced paw edema by 50-70%. Injection of a monoclonal anti-TNF antibody reproduced the inhibitory effect. Moreover, the time course of tissue-associated TNF following carrageenan injection was compatible with mediation of edema by TNF. Results obtained for this acute, non-immunological inflammatory reaction strongly suggest that the model is TNF-dependent. Our results reinforce the idea that TNF is a crucial target in the therapeutics of inflammatory reactions. These drugs, which are able to cross cell barriers, might have clinical applications in localized and/or chronic diseases in which TNF is involved.
Chen
Y L
YL
Département de Pharmacologie, CNRS 1534, Pavillon Gustave Roussy, Hôpital Cochin, Paris, France.
Le Vraux
V
V
Giroud
J P
JP
Chauvelot-Moachon
L
L
D000210:Acute-Phase Reaction / Q000188:drug therapy*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy; D005672:Fusidic Acid / Q000494:pharmacology / Q000627:therapeutic use; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D010419:Pentamidine / Q000494:pharmacology / Q000627:therapeutic use; D010431:Pentoxifylline / Q000494:pharmacology / Q000627:therapeutic use; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D010660:Phenylisopropyladenosine; D005672:Fusidic Acid; D010419:Pentamidine; D010431:Pentoxifylline