Influence of Plasma Cholesterol and Triglyceride Concentrations and Eritoran (E5564) Micelle Size on its Plasma Pharmacokinetics and Ex Vivo Activity Following Single Intravenous Bolus Dose Into Healthy Female Rabbits

Abdominal Aortic Aneurysm (AAA) is a major cause of mortality and morbidity in men over 65 years of age. Male apolipoprotein E knockout (ApoE -/-) mice infused with angiotensin II (AngII) develop AAA. Although AngII stimulates both JAK/STAT and Tolllike receptor 4 (TLR4) signaling pathways, their involvement in AngII mediated AAA formation is unclear. Here we used the small molecule STAT3 inhibitor, S3I-201, the TLR4 inhibitor Eritoran and ApoE -/- TLR4-/-mice to evaluate the interaction between STAT3 and TLR4 signaling in AngII-induced AAA formation. ApoE -/-mice infused for 28 days with AngII developed AAAs and increased STAT3 activation and TLR4 expression. Moreover, AngII increased macrophage infiltration and the ratio of M1 (proinflammatory)/M2 (healing) macrophages in aneurysmal tissue as early as 7-10 days after AngII infusion. STAT3 inhibition with S3I-201 decreased the incidence and severity of AngII-induced AAA formation and decreased MMP activity and the ratio of M1/M2 macrophages. Furthermore, AngII-mediated AAA formation, MMP secretion, STAT3 phosphorylation and the ratio of M1/M2 macrophages were markedly decreased in ApoE -/-TLR4 -/-mice, and in Eritoran-treated ApoE -/-mice. TLR4 and pSTAT3 levels were also increased in human aneurysmal tissue. These data support a role of pSTAT3 in TLR4 dependent AAA formation and possible therapeutic roles for TLR4 and/or STAT3 inhibition in AAA.

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“…bolus required to maintain blood levels at 50-100 ng/mL over 2 days and to inhibit the increase in TNFα levels in mice treated with LPS. [19] …”

Section: Tlr4mentioning

confidence: 99%

Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3

Qin

Bagley

Sukhova

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…These metabolites are eliminated slowly from the body mainly through feces32. Eritoran formulated in small micelles (8 nm) resulted in increased AUC 0–72h and drug concentration at 5 min, and decreased clearance than large micelles (27 nm) in rabbits33.…”

Section: Eritoran Tetrasodiummentioning

confidence: 99%

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

Barochia

Solomon²,

Cui³

et al. 2011

Expert Opinion on Drug Metabolism & Toxicology

143

105

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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 (TLR4).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. Pre-clinical 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 is 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 will be necessary to define its clinical usage.

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“…In such case, scientists have also tried to find a single protein that could achieve a dramatic therapeutic outcome for these various diseases and TLR4 has been considered one of the best candidates [12,38]. New drugs developed to inhibit TLR4 activity are already in various phases of preclinical and clinical trials for treating acute and chronic inflammation, colitis, sepsis, chronic pain, and addiction withdrawal [12,[17][18][19][20][21]. In animal studies, TLR4 activity inhibition has also been demonstrated to reduce the levels of atherosclerosis and myocardial inflammation [39,40].…”

Section: Discussionmentioning

confidence: 99%

“…TLR4/MD2 signaling further contributes to the secretion of proinflammatory cytokines and chemokines and hence leads to the development of immune and inflammatory diseases. Therefore, TLR4 has become a target for drug design and development, and some such drugs for the treatment of lung inflammation, sepsis, and rheumatoid arthritis have already entered preclinical and clinical trials [12,[17][18][19][20][21]. Recently, TLR4 has been associated with other chronic inflammatory diseases, such as diabetes and atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Truncated Pneumolysin from Streptococcus pneumoniae as a TLR4-Antagonizing New Drug for Chronic Inflammatory Conditions

Chang

Chen

Lin

et al. 2020

Cells

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Microbial proteins have recently been found to have more benefits in clinical disease treatment because of their better-developed strategy and properties than traditional medicine. In this study, we investigated the effectiveness of a truncated peptide synthesized from the C-terminal sequence of pneumolysin, i.e., C70PLY4, in Streptococcus pneumoniae, in treating chronic inflammatory conditions. It has been shown that C70PLY4 significantly blocks the transendothelial migration of neutrophils and attenuates the formation of atherosclerotic plaque and the secretion of soluble forms of the intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule 1 (VCAM-1), and E-selectin in high-fat-diet/streptozotocin-induced inflammatory rats. The mechanism and the docking simulation analysis further indicated that C70PLY4 might serve as a Toll-like receptor 4 (TLR4) antagonist by competing for the binding site of MD2, an indispensable protein for lipopolysaccharide (LPS)–TLR4 interaction signaling, on the TLR4 structure. Moreover, compared to the full-length PLY, C70PLY4 seems to have no cytotoxicity in human vascular endothelial cells. Our study elucidated a possible therapeutic efficacy of C70PLY4 in reducing chronic inflammatory conditions and clarified the underlying mechanism. Thus, our findings identify a new drug candidate that, by blocking TLR4 activity, could be an effective treatment for patients with chronic inflammatory diseases.

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Influence of Plasma Cholesterol and Triglyceride Concentrations and Eritoran (E5564) Micelle Size on its Plasma Pharmacokinetics and Ex Vivo Activity Following Single Intravenous Bolus Dose Into Healthy Female Rabbits

Abstract: These findings suggest that plasma pharmacokinetics and activity of eritoran maybe influenced by eritoran micelle size and plasma TC and TG concentrations.

Cited by 7 publications

References 20 publications

Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3

Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3

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

Truncated Pneumolysin from Streptococcus pneumoniae as a TLR4-Antagonizing New Drug for Chronic Inflammatory Conditions

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