ANTITUMOR NECROSIS FACTOR PROPERTIES OF NONPEPTIDE DRUGS IN ACUTE-PHASE RESPONSES

Dexamethasone (sodium phosphate), pentoxifylline, fusidic acid (sodium salt), pentamidine (isethionate) and R-phenylisopropyladenosine (R-PI A) were tested for their anti-tumor necrosis factor (TNF) activities i n an endotoxin-induced shock rat model. All the drugs reduced serum TN F 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 pentox ifylline. Administration of the drugs to rats before intraplantar inje ction of carrageenan reduced paw edema by 50-70%. Injection of a monoc lonal anti-TNF antibody reproduced the inhibitory effect. Moreover, th e time course of tissue-associated TNF following carrageenan injection was compatible with mediation of edema by TNF. Results obtained for t his acute, non-immunological inflammatory reaction strongly suggest th at the model is TNF-dependent. Our results reinforce the idea that TNF is a crucial target in the therapeutics of inflammatory reactions. Th ese drugs, which are able to cross cell barriers, might have clinical applications in localized and/or chronic diseases in which TNF is invo lved.