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

INTRODUCTION: Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs that inhibit the pro-inflammatory effects of lipopolysaccharide (LPS) and improve outcome when added to conventional sepsis treatments are lacking. Eritoran tetrasodium (E5564) is a promising candidate therapy for sepsis belonging to a new class of such drugs which inhibit LPS-induced inflammation by blocking toll-like receptor 4. AREAS COVERED: This review focuses on the rationale for the use of eritoran tetrasodium in sepsis as well as on its pharmacokinetics, pharmacodynamics, efficacy and safety. Preclinical and clinical studies from a MEDLINE/PubMed literature search in August 2010 with the search terms 'eritoran' and 'E5564' are discussed. EXPERT OPINION: 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. While early clinical results are promising, its efficacy and safety for treating patients with sepsis are currently under investigation. Even if the ongoing Phase III clinical trial enrolling patients with severe sepsis and increased risk of death shows benefit from eritoran, questions remain and confirmatory studies would be necessary to define its clinical usage.

Can we predict the effects of NF-kappaB inhibition in sepsis? Studies with parthenolide and ethyl pyruvate.

BACKGROUND: Based partially on encouraging findings from preclinical models, interest has grown in therapeutic inhibition of NF-kappaB to limit inflammatory injury during sepsis. However, NF-kappaB also regulates protective responses, and predicting the net survival effects of such inhibition may be difficult. OBJECTIVES: To highlight the caution necessary with this therapeutic approach, we review our investigations in a mouse sepsis model with parthenolide and ethyl pyruvate, two NF-kappaB inhibitors proposed for clinical study. RESULTS: Consistent with published studies, parthenolide decreased NF-kappaB binding activity and inflammatory cytokine release from lipopolysaccharide (LPS) stimulated RAW 264.7 cells in vitro. In LPS-challenged mice (C57BL/6J), however, while both agents decreased lung and kidney NF-kappaB binding activity and plasma cytokines early (1-3 h), these measures were increased later (6-12 h) in patterns differing significantly over time. Furthermore, despite studying several doses of parthenolide (0.25-4.0 mg/kg) and ethyl pyruvate (0.1-100 mg/kg), each produced small but consistent decreases in survival which overall were significant (p < or = 0.04 for each agent). CONCLUSION: While NF-kappaB inhibitors hold promise for inflammatory conditions such as sepsis, caution is necessary. Clear understanding of the net effects of NF-kappaB inhibitors on outcome will be necessary before such agents are used clinically.