BENZYDAMINE PROTECTION IN A MOUSE MODEL OF ENDOTOXEMIA

Objective: Previous studies have shown that benzydamine (40 mg/kg s.c. ) is able to inhibit tumor necrosis factor (TNF) production and to red uce mouse lethality when administered before or concomitantly with LPS . The present study was designed to further investigate benzydamine ac tivity against LPS-induced toxicity in terms of potency and therapeuti c effects. Methods: Female Balb/c mice were used. A dose-response curv e of animal lethality versus endotoxin dose was performed (LD50 = 45 m u g/mouse). Therapeutic effects were studied selecting the dose of LPS to achieve an LD100, (160 mu g/mouse). Mortality was assessed daily a nd mice were followed for 8 days. The potential mode of action of ther apeutically administered benzydamine was also investigated. TNF alpha and IL-1 beta levels were measured, at 5 h after LPS injection, both i n sera and in lungs. Moreover, the drug was assayed in a TNF-dependent cytoxicity test. Results: Benzydamine, administered at 20 mg/kg s.c. simultaneously with the endotoxin, significantly increased LPS LD50 UP to 230 mu g/mouse (p < 0.05). Moreover, the drug significantly protec ted mice against LPS-induced lethality when administered either 30 min or 4 h after endotoxin injection (p < 0.001). Benzydamine, therapeuti cally administered at 20 mg/kg s.c., significantly reduced TNF alpha a nd IL-1 beta production induced by LPS both in serum and lungs and it was shown to inhibit TNF-dependent cytoxicity on L929 cells. Conclusio ns: These results clearly demonstrate the therapeutic activity of benz ydamine in a simple model of endotoxic shock, Available data confirm t he potential role of benzydamine as an anti-cytokine agent and provide suggestions for novel therapeutic applications of this anti-inflammat ory drug.