Pentoxifylline and the two analogues HWA138 and HWA448, at concentrations exceeding 60 μg/ml, inhibited malaria antigen or lipopolysaccharide (LPS) induced TNF‐α and IL‐1α secretion, but not IL‐6 secretion, from human peripheral blood mononuclear cells in vitro. HWA448 had lower inhibitory activity in vitro than pentoxyfylline and HWA138. A small enhancement of cytokine secretion was induced by pentoxifylline and the two analogues at low concentrations. The drugs did not affect cell viability. Pentoxifylline, HWA138 and HWA448 also inhibited LPS induced TNF production in vivo in female CF1xBalb/c mice. The drugs were inhibitory at 0.5–1 mg per mouse when mixed with LPS, and 1 mg per mouse of the drugs was inhibitory when injected 1 h before LPS challenge. HWA448 had similar inhibitory activities in vivo compared to pentoxifylline and HWA138, possibly because of the longer serum half‐life of HWA448. The pentoxifylline analogues may have lower toxicity than pentoxifylline itself and may therefore be useful in future treatment of diseases induced by endotoxic substances.

01 Jun 1996·ShockQ2 · MEDICINE

COMPARISON OF THE EFFICACY OF PENTOXIFYLLINE AND ALBIFYLLIN (HWA 138) ON ENDOTOXIN-INDUCED CYTOKINE PRODUCTION, COAGULATION DISTURBANCES, AND MORTALITY

Q2 · MEDICINE

Article

Author: Shiga, H ; Bahrami, S ; Yao, Y M ; Leichtfried, G ; Schlag, G ; Redl, H

We have evaluated two different xanthine derivatives, pentoxifylline (POF) and albifyllin (HWA), in rat endotoxemia for their ability to reduce 1) cytokine formation, 2) coagulation disturbances, and 3) mortality. The animals were injected with lipopolysaccharide (LPS) (15 mg/kg i.p.) and received HWA or POF (25, 50, or 100 mg/kg) or saline 30 min before LPS administration. The plasma tumor necrosis factor levels were significantly reduced and in a similar manner by pretreatment with HWA or POF in vivo as well as in vitro. Neither the coagulation disturbance nor the characteristic leukopenia that follow an LPS challenge were significantly influenced by the xanthine derivatives. At a dose of 100 mg/kg, the 6 day mortality was significantly reduced by HWA to 36% but only attenuated by POF to 55% as compared to 80% in the control group. The similar effect of both agents on cytokine formation and coagulation disturbances indicate that, at least to a substantial degree, other mechanisms may account for the significant protection of rats against endotoxin-induced mortality by HWA only. HWA 138 may, therefore, be a new powerful agent against endotoxin-related disorders and mortality.

01 Feb 1996·Acta Anaesthesiologica ScandinavicaQ4 · MEDICINE

Effects on complement activation and cytokine (TNF‐α and IL‐8) release of infusion of anti‐TNF‐antibodies or a xanthine derivative (HWA 138) in septic baboons

Q4 · MEDICINE

Article

Author: H. Redl ; A. Bengtsson ; T. E. Mollnes ; G. Schlag ; K. Högåsen

Background. Sepsis and septic shock lead to activation of the complement cascade and to the release of pro‐inflammatory cytokines.Methods. The effects of E coli infusion and of infusion of anti‐TNF antibodies and a xanthine derivative (HWA 138) on complement activation and cytokine release was evaluated in 17 baboons. All animals received 5×108 live bacteria per kg body weight. Five animals received only bacteria, five received in addition 0.5 mg per kg body weight of anti‐TNF‐antibody, and seven received an infusion of 6 mg per kg body weight of HWA 138 in addition to the bacteria.Results. In baboons receiving 5×108 live E coli per kg body weight increased plasma levels of TCC, TNF‐α and IL‐8 were found. The release of TNF‐α was lower in the group receiving HWA 138 at 2 h after the infusion. In baboons receiving an infusion of anti‐TNF antibody the concentration of IL‐8 was lower at 2 and 4 h than in animals receiving just E coli or HWA 138.Conclusion. Infusion of anti‐TNF‐antibody before E coli infusion will decrease the formation of IL‐8. Infusion of HWA 138 before the E coli infusion will also inhibit the formation of TNF‐α.

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