b-1287 and Sepsis

Eisai Co Ltd is developing the injectable endotoxin antagonist E-5564, for the potential prevention of the pathophysiological effects of endotoxin-mediated responses caused by bacterial infection, including septic shock.

Topics: Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Endotoxemia; Endotoxins; Humans; Lipid A; Randomized Controlled Trials as Topic; Sepsis; Structure-Activity Relationship

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 sepsis.. Prospective, randomized, double-blind, placebo-controlled, multicenter, ascending-dose phase II trial.. Adult intensive care units in the United States and Canada.. Three hundred adults within 12 hrs of recognition of severe sepsis, with Acute Physiology and Chronic Health Evaluation (APACHE) II-predicted risk of mortality between 20% and 80%.. Intravenous eritoran tetrasodium (total dose of either 45 mg or 105 mg) or placebo administered every 12 hrs for 6 days.. Prevalence of adverse events was similar among subjects treated with 45 mg or 105 mg of eritoran tetrasodium or with placebo. For modified intent-to-treat subjects, 28-day all-cause mortality rates were 26.6% (eritoran tetrasodium 105 mg), 32.0% (eritoran tetrasodium 45 mg), and 33.3% in the placebo group. Mortality rate in the eritoran tetrasodium 105-mg group was not significantly different from placebo (p = .335). In prespecified subgroups, subjects at highest risk of mortality by APACHE II score quartile had a trend toward lower mortality rate in the eritoran tetrasodium 105-mg group (33.3% vs. 56.3% placebo group, p = .105). A trend toward a higher mortality rate was observed in subjects in the lowest APACHE II score quartile for the eritoran 105-mg group (12.0% vs. 0.0% placebo group, p = .083).. Eritoran tetrasodium treatment appears well tolerated. The observed trend toward a lower mortality rate at the 105-mg dose, in subjects with severe sepsis and high predicted risk of mortality, should be further investigated.

Topics: Adult; Aged; APACHE; Bacterial Infections; Cohort Studies; Critical Care; Critical Illness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Hospital Mortality; Humans; Infusions, Intravenous; Intensive Care Units; Lipid A; Male; Maximum Tolerated Dose; Middle Aged; Prospective Studies; Risk Assessment; Sepsis; Survival Analysis; Toll-Like Receptor 4; Treatment Outcome

Topics: Anti-Inflammatory Agents; APACHE; Cause of Death; Critical Care; Critical Illness; Female; Hospital Mortality; Humans; Intensive Care Units; Lipid A; Male; Prognosis; Risk Assessment; Sepsis; Survival Rate

To investigate the therapeutic effect of E5564 (a clinically used TLR4 inhibitor) in murine abdominal sepsis elicited by intraperitoneal infection with a highly virulent Escherichia coli in the context of concurrent antibiotic therapy.. Mice were infected with different doses (~2 × 10(4)-2 × 10(6) CFU) of E. coli O18:K1 and treated after 8 h with ceftriaxone 20 mg/kg i.p. combined with either E5564 10 mg/kg i.v. or vehicle. For survival studies this treatment was repeated every 12 h. Bacterial loads and inflammatory parameters were determined after 20 h in peritoneal lavage fluid, blood, liver and lung tissue. Plasma creatinin, AST, ALT and LDH were determined to assess organ injury.. E5564 impaired bacterial clearance under the antibiotic regime after infection with a low dose E. coli (1.7 × 10(4) CFU) while renal function was slightly preserved. No differences were observed in bacterial load and organ damage after infection with a tenfold higher (1.7 × 10(5) E. coli) bacterial dose. While treatment with E5564 slightly attenuated inflammatory markers provoked by the sublethal doses of 104-105 E. coli under the antibiotic regime, it did not affect lethality evoked by infection with 1.7 × 106 E. coli.. The impact of TLR4 inhibition during abdominal sepsis by virulent E. coli bacteria is only beneficial at low infection grade at cost of bactericidal activity.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Ascitic Fluid; Bacterial Load; Ceftriaxone; Cytokines; Escherichia coli; Escherichia coli Infections; Female; Lipid A; Liver; Lung; Mice, Inbred C57BL; Peritoneal Lavage; Peritonitis; Sepsis; Toll-Like Receptor 4

Glucose analogues 5 and 9 of E5564 were synthesized, and their LPS-antagonistic activities were measured. The inhibitory activities (IC50) on LPS-induced TNFalpha production of these two compounds towards human whole blood cells were 0.06 and 0.83 nM, respectively. Inhibitory doses (ID50) of compounds 5 and 9 on TNFalpha production induced by coinjection of galactosamine and LPS in C3H/HeN mice in vivo were measured and were 0.55 and <0.20 mg/kg, respectively. And also C3H/HeN mice preinjected with compounds 5 and 9 were protected from lethality induced by coinjection of galactosamine and LPS; out of eight mice preinjected with 1 mg/kg of the compounds, one-six and three of eight mice were protected, respectively.

Topics: Animals; Escherichia coli; Glucose; Lipid A; Male; Mice; Molecular Structure; Sepsis; Tumor Necrosis Factor-alpha

E5564, a competitive lipid A antagonist, inhibits endotoxin-stimulated inflammation and is under study in patients with sepsis.. We tested whether clinically relevant variables, including the timing of treatment and the route of infection, influenced the effective dosing of E5564 in Escherichia coli-challenged rats.. All E5564 doses (0.3, 1.0, 2.0, and 3.0 mg/kg intravascular bolus followed by 10% of the bolus dose infused hourly for 24 h) administered 1 h before intravascular E. coli challenge similarly reduced the risk of death. Delaying the start of E5564 to 1 or 3 h after intravascular E. coli challenge significantly reduced the beneficial effect of the doses tested. However, increasing the dose of E5564 reversed some loss of efficacy for delayed treatment (P=.004, for increasing benefit with increasing dose at 1 h). During intrabronchial or intraperitoneal (extravascular) E. coli challenge, the pattern of effective E5564 dosing was the inverse of that for intravascular E. coli challenge (P=.001, for the interaction)--lower doses of E5564 were beneficial and higher doses were not (0.03, 0.3, 1.0, 2.0, and 3.0 mg/kg bolus followed by infusion) (P=.05, for decreasing benefit with increasing dose at 1 h).. These findings suggest that, for maximal clinical benefit, E5564 should be given early and that dosing should be adjusted upward for intravascular infection and downward for extravascular infection.

Topics: Animals; Blood Chemical Analysis; Blood Circulation; Colony Count, Microbial; Disease Models, Animal; Endotoxins; Escherichia coli Infections; Leukocyte Count; Lipid A; Lipopolysaccharides; Lung; Random Allocation; Rats; Rats, Sprague-Dawley; Sepsis; Survival Analysis; Time Factors; Tumor Necrosis Factor-alpha