A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-α antibody afelimomab in patients with sepsis syndrome

Abstract

Multidose therapy with afelimomab was safe, well tolerated, and had predictable linear kinetics. A large randomized trial comparing afelimomab to placebo in patients with well defined sepsis has recently been completed.

Suppression of Inflammatory Cytokine Production by Carbon Monoxide Involves the JNK Pathway and AP-1

“…There is a well described correlation between serum IL-6 levels and poor outcome in sepsis (8,(23)(24)(25)(26), and increased IL-6 is an independent predictor of survival in human sepsis (27). In our mouse model, serum IL-6 and IL-1␤ were markedly attenuated by exogenous CO administration.…”

Anti-tumor necrosis factor α F(ab')2 antibody fragments protect in murine polymicrobial sepsis: Concentration and early intervention are fundamental to the outcome

“…With the inhibition of this cytokine the induction of these events is avoided. In contrast, the elimination of TNFa in a polymicrobial sepsis model [33,34] and in clinical trails [35,36] has frequently yielded negative results regarding protection. We believe that in this model, the excessive decrease in TNFa can modify the immune response, affect the antimicrobial protection mechanisms and, as a consequence, make the animals more susceptible.…”

“…Due to the key role of TNFa in the development of SIRS, experimental immunotherapies in sepsis have sought to eliminate this and other pro-infl ammatory cytokines. In this context, it has been reported that while treatment with anti-TNFa has provided protection in endotoxic shock induced by the administration of purifi ed lipopolysaccharides, in other murine models such as polymicrobial sepsis [33,34] and even in controlled clinical trials, negative results have frequently been obtained [35,36]. This is probably because the approach aimed at eliminating TNFa and other cytokines underestimates their homeostatic and microbicide role.…”

Défaillance rénale

“…Ainsi, des récepteurs solubles de TNF_ (TNFsRp55) apportent une protection rénale chez des souris en choc septique [38]. Une étude prospective randomisée portant sur l'administration d'anticorps monoclonaux anti-TNF_ (MONARCS [Anti-TNF monoclonal]) n'a pas mis en évidence d'amélioration de la survie des patients en choc septique [41,42]. L'endotoxémie est associée à la production de radicaux oxygénés qui peuvent contribuer à la vasoconstriction précoce de la défaillance rénale.…”