Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Apr;7(4):479-94.
doi: 10.1517/17425255.2011.558190. Epub 2011 Feb 17.

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

Amisha Barochia  1 , Steven Solomon, Xizhong Cui, Charles Natanson, Peter Q Eichacker
Affiliations
Review

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

Amisha Barochia et al. Expert Opin Drug Metab Toxicol. 2011 Apr.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interest

The authors declare intramural funding from the National Institutes of Health

Figures

Figure 1
Figure 1
A. LPS signaling through TLR4-MD2 interaction. Molecules are not drawn to scale. Reproduced from [5] with permission from the Nature Publishing Group. B. Comparison of chemical structures of E. coli lipid A, R. sphaeroides lipid A and eritoran. Reproduced, with permission from Thomson Reuters and Rossignol DP, Lynn M: TLR4 antagonists for endotoxemia and beyond Current Opinion in Investigational Drugs (2005) 6(5):496–502. Copyright 2005, Thomson Reuters (Professional) UK Limited (TRPUL).” [66]
Figure 1
Figure 1
A. LPS signaling through TLR4-MD2 interaction. Molecules are not drawn to scale. Reproduced from [5] with permission from the Nature Publishing Group. B. Comparison of chemical structures of E. coli lipid A, R. sphaeroides lipid A and eritoran. Reproduced, with permission from Thomson Reuters and Rossignol DP, Lynn M: TLR4 antagonists for endotoxemia and beyond Current Opinion in Investigational Drugs (2005) 6(5):496–502. Copyright 2005, Thomson Reuters (Professional) UK Limited (TRPUL).” [66]
Figure 2
Figure 2
Macrophage mediated activation of innate immunity by LPS. Extracellular LPS is transferred to membrane bound CD14 (mCD14) by the action of LPS binding protein (LBP), and then interacts with TLR4-MD2 complex to initiate an intracellular response. In physiological situations, LPS signaling via TLR4-MD2 results in comparably small amounts of cytokine and chemokine mediator release, leading to activation of host defences against invading micro-organisms. If this response is deregulated, unbalanced levels of inflammatory mediators lead to a pathological state with life-threatening results as seen in severe sepsis or septic shock. (Adapted from [14] with permission from Sage Publications.
Figure 3
Figure 3
Effect of eritoran (E5564) on the hazard ratio for death (mean ± SE) in E. coli challenged rats with varying drug doses, times of treatment and routes of infection. Sprague-Dawley rats (n = 1550) were challenged with intravascular (IV), intrabronchial (IB) or intraperitoneal (IP) E. coli (designed to produce 60–70% mortality in controls), and treated with eritoran (0.03 to 3mg/kg IV bolus, followed by a 24h infusion of 10% of this dose/h) or placebo at 1h prior to, or 1 or 3h after infection. A. Effect of increasing doses of E5564 administered 1 h before IV challenge (p = 0.0001, for all doses combined). B. Effect of delaying treatment in IV challenged rats, for different doses of eritoran. Across all treatment doses, eritoran was less beneficial when delayed (p = 0.004, for loss of beneficial effect for delayed [1 or 3 h] vs. early [−1 h] treatment). C. Effect of increasing doses of eritoran administered 1 h after IV or extravascular (IP or IB) challenge. An inverse pattern was found: increasing doses of eritoran were more beneficial for intravascular challenge, but less beneficial for extravascular challenge. (Reproduced from [35] with permission of Oxford University Press).
Figure 4
Figure 4
A. All-cause mortality at day 28 by treatment groups in the modified intention-to-treat population (total n = 293) from the Tidswell et al. study. Although mortality was lower in the eritoran 105mg group, it was not statistically different from placebo. B. All cause 28-day mortality in pre-specified subgroups defined by APACHE II quartiles treated with eritoran 105mg. Quartile I corresponds to an APACHE II score < 21, (n = 25, eritoran and n = 23, placebo); quartile 2, score 21–24 (n = 22, for both eritoran and placebo); quartile 3, score 25–28 (n = 26, eritoran and n = 19, placebo); and quartile 4, score > 28 (n = 21, eritoran and n = 32, placebo). Mortality in the treated group was lower than placebo for the 4th quartile with the highest APACHE II scores, but higher than placebo in the lowest quartile, with APACHE II < 21. Reproduced from [39]; with permission of Wolters Kluwer Health
Figure 5
Figure 5
Relationship between severity of illness and efficacy of eritoran in septic patients randomized to eritoran vs. placebo (Tidswell et al). Patients were divided into quartiles based on their APACHE II score. Odds ratios of survival for each quartile of patients receiving eritoran were plotted against control odds of death calculated from observed mortality in the corresponding quartile of the placebo arm. The odds ratios of survival are shown as circles with 95% confidence intervals shown by the vertical lines. The regression lines in this figure show that the effect of both low (45mg) and high (105mg) dose eritoran, either separately (panels A and B, respectively), or combined (Panel C) were similar, and appear directly related to control odds of death. Both doses were most beneficial in the APACHE II quartile with the highest control mortality rate, but this benefit declined as control mortality rate decreased, and was no longer evident in the quartile with the lowest mortality rate. The correlation between effect and control odds was high (r ≥ 0.97 for each), and the slope of each regression line was significant (p ≤ 0.025). (Reproduced from [57] with permission of Wolters Kluwer Health).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2000 Aug 17;406(6797):782–7. - PubMed
    1. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001 Aug;2(8):675–80. - PubMed
    1. Akira S, Hemmi H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett. 2003 Jan 22;85(2):85–95. - PubMed
    1. Janeway CA, Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216. - PubMed
    1. Park BS, Song DH, Kim HM, et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature. 2009 Apr 30;458(7242):1191–5. - PubMed

Publication types

MeSH terms

LinkOut - more resources