Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis*

@article{Tidswell2010Phase2T,
  title={Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis*},
  author={Mark Alan Tidswell and William P Tillis and Steven P. LaRosa and Melvyn Lynn and Alec E. Wittek and Richard Kao and Janice L Wheeler and Jagadish P Gogate and Steven M. Opal},
  journal={Critical Care Medicine},
  year={2010},
  volume={38},
  pages={72-83}
}
Objectives:Endotoxin is a potent stimulus of proinflammatory response and systemic coagulation in patients with severe sepsis. Endotoxin is a component of Gram-negative bacteria that triggers an innate immune response through Toll-like receptor 4 signaling pathways in myeloid cells. We evaluated safety and tolerability of two dose regimens of eritoran tetrasodium (E5564), a synthetic Toll-like receptor 4 antagonist, and explored whether it decreases 28-day mortality rate in subjects with severe… 

Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.

Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality, and no significant differences were observed in any of the prespecified subgroups.

Risk of death and the efficacy of eritoran tetrasodium (E5564): design considerations for clinical trials of anti-inflammatory agents in sepsis.

The results of a randomized, multicenter phase II trial of eritoran tetrasodium (E5564), a synthetic competitive lipopolysaccharide inhibitor, suggest that only patients with a predicted mortality rate of ≥50% might benefit from E5564, and suggest that practitioners must clearly understand whether and in which low-risk patients the diminution of E 5564’s efficacy may cross over to a potential harmful effect.

Toll-like receptor-4 antagonist eritoran tetrasodium for severe sepsis

Eritoran tetrasodium is a nonpathogenic analog of bacterial endotoxin that antagonizes inflammatory signaling by the immune receptor Toll-like receptor-4 that is being evaluated for the treatment of patients with severe sepsis.

Influence of Severity of Illness on the Effects of Eritoran Tetrasodium (E5564) and on Other Therapies for Severe Sepsis

Potential survival benefits of eritoran in severe sepsis patients were associated with high severity of illness and similar treatment by severity-of-illness interaction was found in most recent sepsi trials.

Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies

Preclinical in vitro and in vivo studies of eritoran tetrasodium indicate it can limit excessive inflammatory mediator release associated with LPS and improve survival in sepsis models.

Toll-like Receptor 4 Modulation as a Strategy to Treat Sepsis

Recent data of various drugs targeting TLR4 expression and pathway and their potential role as adjunctive therapy in severe sepsis and septic shock are focused on.

Toll-Like Receptors and Opportunities for New Sepsis Therapeutics

  • J. Boyd
  • Biology, Medicine
    Current Infectious Disease Reports
  • 2012
Toll-like receptors are a family of transmembrane innate immune receptors that play a major role in both phases of sepsis, and their physiology and the therapeutic strategies employed to date are reviewed.

Current insights in sepsis: from pathogenesis to new treatment targets

  • W. Wiersinga
  • Medicine, Biology
    Current opinion in critical care
  • 2011
Sepsis can be seen as a PRR-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital.

Treatment of myocardial dysfunction in sepsis: the Toll-like receptor antagonist approach.

E5564/eritoran tetrasodium, a synthetic lipodisaccharide, has been shown to block LPS-mediated activation of NF-.B and cytokine production by direct antagonism of TLR-4 (9), and eritoran Tetrasodium could represent a novel approach in septic shock treatment.

Renal effects of treatment with a TLR4 inhibitor in conscious septic sheep

Results show that treatment with a TLR4 inhibitor is able to reverse a manifest impairment in renal function caused by sepsis, and provide evidence that the mechanism underlying the effect of TAK-242 on renal function does not involve improved macro-circulation or micro- Circulation, enhanced renal oxygen delivery, or attenuation of tubular necrosis.
...

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