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

Expert Review of Anti-Infective Therapy

Volumn 9, Issue 5, 2011, Pages 507-520

  Tidswell, Mark ^a   LaRosa, Steven P ^b  

^a BAYSTATE MEDICAL CENTER   (United States)

^b BROWN UNIVERSITY   (United States)

Author keywords

E5564; endotoxin; eritoran tetrasodium; sepsis; severe sepsis; TLR 4

Indexed keywords

ANTIINFECTIVE AGENT; CENTOXIN; ENDOTOXIN; ENDOTOXIN ANTIBODY; ERITORAN; HYDROCORTISONE; LIPOPROTEIN; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY E5; PLACEBO; POLYMYXIN B; PROTEIN MD 2; RECOMBINANT PROTEIN; RESATORVID; TOLL LIKE RECEPTOR 4; UNCLASSIFIED DRUG;

ACUTE KIDNEY FAILURE; ADAPTIVE IMMUNITY; ANEMIA; ARTHRITIS; ASTHMA; AUTOIMMUNE DISEASE; AUTOIMMUNITY; BACTEREMIA; CARCINOGENESIS; CARDIOPULMONARY BYPASS; CONTINUOUS INFUSION; DIARRHEA; DISEASE COURSE; DISEASE SEVERITY; DRUG EFFICACY; DRUG ELIMINATION; DRUG ERUPTION; DRUG HALF LIFE; DRUG INTERMITTENT THERAPY; DRUG MECHANISM; DRUG MEGADOSE; DRUG METABOLISM; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; ENDOTOXEMIA; GRAM NEGATIVE BACTERIUM; GRAM POSITIVE BACTERIUM; HEART ATRIUM FIBRILLATION; HEART MUSCLE ISCHEMIA; HUMAN; IN VITRO STUDY; INFLAMMATION; INJECTION SITE INFLAMMATION; INJECTION SITE PAIN; INNATE IMMUNITY; INSOMNIA; LIPOPROTEIN BLOOD LEVEL; LUNG INJURY; MAXIMUM PLASMA CONCENTRATION; METHEMOGLOBINEMIA; MONOCYTE; MORTALITY; NEPHROTOXICITY; NEUROTOXICITY; NONHUMAN; PATHOGENESIS; PATHOPHYSIOLOGY; PHLEBITIS; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN LOCALIZATION; REPERFUSION INJURY; REVIEW; SEPSIS; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; SYSTEMIC INFLAMMATORY RESPONSE SYNDROME;

ANTIBODIES, NEUTRALIZING; CLINICAL TRIALS AS TOPIC; DISACCHARIDES; FEMALE; GRAM-NEGATIVE BACTERIA; GRAM-POSITIVE BACTERIA; HUMANS; LIPOPOLYSACCHARIDES; MALE; PHOSPHOLIPIDS; RENAL DIALYSIS; SEPSIS; SIGNAL TRANSDUCTION; SUGAR PHOSPHATES; TOLL-LIKE RECEPTOR 4; UNITED STATES;

EID: 79957588414     PISSN: 14787210     EISSN: 17448336     Source Type: Journal    
DOI: 10.1586/eri.11.27     Document Type: Review

References (131)

1. Takayama K, Qureshi N, Beutler B, Kirkland TN. Diphosphoryl lipid A from Rhodopseudomonas sphaeroides ATCC 17023 blocks induction of cachectin in macrophages by lipopolysaccharide. Infect. Immun. 57, 1336-1338 (1989).
2. Loppnow H, Libby P, Freudenberg M et al. Cytokine induction by lipopolysaccharide (LPS) corresponds to lethal toxicity and is inhibited by nontoxic Rhodobacter capsulatus LPS. Infect. Immun. 58(11), 3743-3750 (1990).
3. Tanamoto K. Predominant role of the substitutuents on the hydrowyl groups of 3-hydroxy fatty acids of non-reducing glucosamine in lipid A for the endotoxic and antagonistic activity. FEBS Lett. 351, 325-329 (1994).
4. Matsuura M, Kiso M, Hasegawa A. Activity of monosaccharide lipid A analogues in human monocytic cells as agonists or antagonists of bacterial lipopolysaccharide. Infect. Immun. 67(12), 6286 (1999).
5. Opal SM, Scannon PJ, Vincent JL et al. Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. J. Infect. Dis. 180, 1584-1589 (1999).
6. Marshall JC, Foster D, Vincent J-L et al. Diagnostic and prognostic implications of endotoxemia in critical illness: results of the MEDIC Study. J. Infect. Dis. 190, 527-534 (2004).
7. Nakamura T, Ushiyama C, Suzuki Y et al. Combination therapy with polymyxin B-immobilized fibre haemoperfusion and teicoplanin for sepsis due to methicillinresistant Staphylococcus aureus. J. Hosp. Inf. 53, 58-63 (2003).
8. Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit. Care Med. 37, 291-304 (2009). Outstanding review article on the pathogenesis of sepsis.
9. Ferrandon D, Imler J-L, Hetru C, Hoffman JA. The Drosophila systemic immune response: sensing and signalling during bacterial and fungal infections. Nature 7, 862-874 (2007).
10. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 124, 783-801 (2006).
11. Shimazu R, Akashi S, Ogata H et al. MD-2, a molecule that confers lipoolysaccharide responsiveness on toll-like receptor 4. J. Exp. Med. 189, 1777-1782 (1999).
12. Visintin A, Halmen KA, Latz E, Monks BG, Golenbock DT. Pharmacological inhibition of endotoxin responses is achieved by targeting the TLR4 coreceptor, MD-2. J. Immunol. 175, 6465-6472 (2005).
13. Muroi M, Tanamoto K. Structural regions of MD-2 that determine the agonist-antagonist activity of lipid IVa. J. Biol. Chem. 281, 5484-5491 (2006).
14. Kim HM, Park BS, Kim J-I et al. Crystal structure of the TLR4 - MD-2 complex with bound endotoxin antagonist eritoran. Cell 130, 906-917 (2007).
15. Park BS, Song DH, Kim HM et al. The structural basis of lipoplysaccharide recognition by the TLR4-MD2 complex. Nature 458, 1191-1196 (2009).
16. Resman N, Vasl J, Oblak A et al. Essential roles of hydrophobic residues in both MD-2 and Toll-like receptor 4 in activation by endotoxin. J. Biol. Chem. 284, 15052-15060 (2009). Outlines the importance of the MD2 adaptor protein to endotoxin signaling via the TLR-4 receptor.
17. Beutler B, Rietschel ET: Innate immune sensing and its roots: the story of endotoxin. Nat. Rev. Immunol. 3, 169-176 (2003).
18. Kawai T, Akira S, The role of pattern recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11(5), 373-384 (2010).
19. Akira S, Takeda K. Toll-like receptor signaling. Nat. Rev. Immunol. 4, 499 (2004).
20. O'Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signaling. Nat. Rev. Immunol. 7, 353-364 (2007).
21. Fink MP. Bench-to-bedside review: cytopathic hypoxia. Crit. Care 6, 491-499 (2002).
22. Mantell LL, Parrish WR, Ulloa L. HMGB1 as a therapeutic target for infectious and inflammatory disorders. Shock 25, 4-11 (2006).
23. Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin. Thromb. Hemost.24, 33-44 (1998).
24. Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101, 3765-3777 (2003).
25. Hotchkiss RS, Swanson PE, Freeman BD et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit. Care Med. 27, 1230-1251(1999).
26. + T lymphocytes in humans. J. Immunol. 166, 6952-6963 (2001).
27. Tidswell M, Tillis W, LaRosa S et al. Phase II trial of eritoran (E5564) an antagonist of endotoxin, in patients with severe sepsis. Crit. Care Med. 38, 72-83 (2010). Results of Phase II trial of dose and tolerability of eritoran in 300 subjects with severe sepsis.
28. Hong-Geller E, Gupta G. Therapeutic approaches to superantigen-based diseases: a review. J. Mol. Recognit. 16, 91-101 (2003).
29. Rice TW, Wheeler AP, Morris PE et al. Safety and efficacy of affinity-purified, anti-tumor necrosis factor-α, ovine Fab for injection (CytoFab) in severe sepsis. Crit. Care Med. 34, 2271-2281 (2006).
30. Sevransky JE, Shaked G, Novogrodsky A, et al. Tyrphostin AG556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis. J. Clin. Invest. 99(8), 1966-1973 (1997).
31. Lutterloh E, Opal SM, Pittman D et al. Inhibition of receptor for advanced glycation end products as a novel treatment strategy in severe sepsis. Crit. Care 11, 122-130 (2007).
32. Chung CS, Chen Y, Grutkoski PS, Doughty L, Ayala A. SOCS-1 is a central mediator of steroid-increased thymocyte apoptosis and decreased survival following sepsis. Apoptosis 12, 1143-1153 (2007).
33. Weisman LE, Thackray HM, Garcia-Prats JA et al. Phase I/II double-blind, placebocontrolled, dose escalation, safety, and pharmacokinetic study of pagibaximab (BSYX-A110), and antistaphylococcal monoclonal antibody for the prevention of staphylococcal bloodstream infections, in very-low-birth-weight neonates. Antimicrob. Agents Chemother. 53, 2879-2886 (2009).
34. Saravolatz LD, Markowitz N, Collins MS, Bogdanoff D, Pennington JE. Safety, pharmacokinetics, and functional activity of human anti-Pseudomonas aeruginosa monoclonal antibodies in septic and nonseptic patients. J. Infect. Dis. 164, 803-806 (1991).
35. Murakami K, Enkhbaatar P, Shimoda K et al. Inhibition of poly (ADP-ribose) polymerase attenuates acute lung injury in an ovine model of sepsis. Shock 21, 126-133 (2004).
36. Finfer S, Ranieri MV, Thompson BT et al. Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock. Intensive Care Med. 34, 2319-2331 (2008).
37. Saito H, Maruyama I, Shimazaki S et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a Phase III, randomized, double-blind clinical trial. J. Thromb. Haemost. 5, 31-41 (2007).
38. Kerschen EJ, Fernandez JA, Cooley BC et al. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J. Exp. Med. 204, 2439-2448 (2007).
39. Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J. Leukoc. Biol. 88, 233-240 (2010).
40. Meisel C, Schefold JC, Pschowski R et al. Granulocyte-macrophage colonystimulating factor to reverse sepsisassociated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am. J. Respir. Crit. Care Med. 180, 640-648 (2009).
41. Michalek SM, Moore RN, McGhee JR, Rosenstreitch DL, Mergenhagen SE. The primary role of lymphoreticular cells in the mediation of host responses to bacterial endotoxin. J. Infect. Dis. 141, 55-63 (1980).
42. Poltorak A, Smirnova I, He XI et al. Genetic and physical mapping of the Lps locus- identification of the Toll 4 receptor as a candidate gene in the critical region. Blood Cells Mol. Dis. 24, 340-355 (1998). This study established the TLR-4 receptor as the site for endotoxin signaling.
43. Krauss JH, Seydel U, Weckesser J, Mayer H. Structural analysis of the nontoxic lipid A of Rhodobacter capsulatus 37b4. Eur. J. Biochem. 180, 519-526 (1989).
44. Christ WJ, Asano O, Robidoux AL et al. E5531, a pure endotoxin antagonist of high potency. Science 268 (5207), 80-83 (1995).
45. Wasan KM, Stobel FW, Parrott SC, Lipoprotein distribution of a novel endotoxin antagonist, E5531, in plasma from human subjects with various lipid levels. Antimicrob. Agents Chemother. 43(10), 2562-2564 (1999).
46. Qureshi N, Takayama K, Kurtz R. Diphosporyl lipid A obtained from the nontoxic lipoolysaccharide of Rhodopseudomonas sphaeroides is an endotoxin antagonist in mice. Infect. Immun. 59(1), 441-444 (1991).
47. Rose JR, Mullarkey MA, Christ WJ et al. Consequences of interaction of a lipophilic endotoxin antagonist with plasma lipoproteins. Antimicrob. Agents Chemother. 44(3), 504-510 (2000).
48. Rossignol DP, Wasan KM, Choo E et al. Safety, pharmacokinetics, pharmacodynamics, and plasma lipoprotein distribution of eritoran (E5564) during continuous intravenous infusion into healthy volunteers. Antimicrob. Agents Chemother. 48(9), 3233-3240 (2004).
49. Hawkins LD, Christ WJ, Rossignol DP. Inhibition of endotoxin response by synthetic TLR4 antagonists. Curr. Top. Med. Chem. 4, 1147-1171 (2004).
50. Russell JA. Management of sepsis. N. Engl. J. Med. 355(16), 1699-1713 (2006); erratum in: N. Engl. J. Med. 355, 2267 (2006).
51. Angus DC, Linde-Zwirble WT, Lidicker J et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29, 1303-1310 (2001).
52. Dellinger RP, Levy MM, Carlet JM et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock. Crit. Care Med. 36, 296-327 (2008). Erratum in: Crit. Care Med. 36, 1394-1396 (2008). This guideline document reviews the resuscitation and management bundles for patients with sepsis.
53. Kumar A, Roberts D, Wood KE et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit. Care Med. 34, 1589-1596 (2006).
54. Rivers E, Nguyen B, Havstad S et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N. Engl. J. Med. 345, 1368-1377 (2001).
55. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N. Engl. J. Med. 342, 1301-1308 (2000).
56. Annane D, Sebille V, Charpentier C et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288, 862-871 (2002).
57. Sprung CL, Annane D, Keh D et al. Hydrocortisone therapy for patients with septic shock. N. Engl. J. Med. 358, 111-124 (2008).
58. Bernard GR, Vincent JL, Laterre PF et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344, 699-709 (2001).
59. Ely EW, Laterre PF, Angus DC et al. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit. Care Med. 31, 12-19 (2003).
60. Abraham E, Laterre PF, Garg R et al. Drotrecogin Alfa (activated) for adults with severe sepsis and a low risk of death. N. Engl. J. Med. 353, 1332-1341 (2005).
61. Van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in critically ill patients. N. Engl. J. Med. 345, 1359-1367 (2001).
62. NICE-SUGAR Study Investigators, Finfer S, Chittock DR et al. Intensive versus conventional glucose control in critically ill patients. N. Engl. J. Med. 360, 1283-1297 (2009).
63. Ferrer R, Artigas A, Levy MM et al. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA 299, 2294-2303 (2008).
64. Levy MM, Dellinger RP, Townsend SR et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit. Care Med. 38, 367-374 (2010).
65. Ziegler EJ, McCutchan JA, Fierer J et al. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N. Engl. J. Med. 307, 1225-1230 (1982).
66. Calandra T, Glauser MP, Schellekens J, Verhoef J. Treatment of gram-negative septic shock with human IgG antibody to Escherichia coli J5: a prospective, doubleblind, randomized trial. J. Infect. Dis. 158, 312-319 (1988).
67. Ziegler EJ, Fisher CJ Jr, Sprung CL et al. Treatment of Gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebocontrolled trial. The HA-1A Sepsis Study Group. N. Engl. J. Med. 324, 429-436 (1991).
68. McCloskey RV, Straube RC, Sanders C, Smith SM, Smith CR. Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann. Intern. Med. 121, 1-5 (1994).
69. The French National Registry of HA-1A (Centoxin) in septic shock. A cohort study of 600 patients. The National Committee for the Evaluation of Centoxin. Arch. Intern. Med. 154, 2484-2491 (2004).
70. Warren HS, Amato SF, Fitting C et al. Assessment of ability of murine and human anti-lipid A monoclonal antibodies to bind and neutralize lipopolysaccharide. J. Exp. Med. 177, 89-97 (1993).
71. Quezado ZM, Natanson C, Alling DW et al. A controlled trial of HA-1A in a canine model of Gram-negative septic shock. JAMA 269, 2221-2227 (1993).
72. Natanson C, Esposito CJ, Banks SM. The sirens' songs of confirmatory sepsis trials: selection bias and sampling error. Crit. Care Med. 26, 1927-1931 (1998).
73. Sprung CL, Eidelman LA, Pizov R et al. Influence of alterations in forgoing life-sustaining treatment practices on a clinical sepsis trial. Crit. Care Med. 25, 383-387 (1997).
74. Wortel CH, von der Möhlen MA, van Deventer SJ et al. Effectiveness of a human monoclonal anti-endotoxin antibody (HA-1A) in Gram-negative sepsis: relationship to endotoxin and cytokine levels. J. Infect. Dis. 166, 1367-1374 (1992).
75. Greenman RL, Schein RM, Martin MA et al. A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of Gram-negative sepsis. The XOMA Sepsis Study Group. JAMA 266, 1097-1102 (1991).
76. Bone RC, Balk RA, Fein AM et al. A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. The E5 Sepsis Study Group. Crit. Care Med. 23, 994-1006 (1995). Erratum in: Crit. Care Med. 23, 1616 (1995).
77. Angus DC, Birmingham MC, Balk RA et al. E5 murine monoclonal antiendotoxin antibody in Gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. JAMA 283, 1723-1730 (2000).
78. Weiss J, Elsbach P, Shu C et al. Human bactericidal/ permeability increasing protein and a recombinant NH2-terminal fragment cause the killing of serumresistant Gram negative bacteria in whole blood and inhibit tumor necrosis release induced by bacteria. J. Clin. Invest. 90, 1122-1130 (1992).
79. Ammons WS, Mallari C. An N-terminal fragment of bactericidal/permeability - increasing protein protects against hemodynamic and metabolic derangements in rat Gram-negative sepsis. J. Endotoxin Res. 3, 57-66 (1996).
80. von der Möhlen MA, Kimmings AN, Wedel NI et al. Inhibition of endotoxin-induced cytokine release and neutrophil activation in humans by use of recombinant bactericidal/permeability-increasing protein. J. Infect. Dis. 172, 144-151 (1995).
81. 21 Meningococcal Sepsis Study Group. Lancet 356, 961-967 (2000).
82. 21 for adjunctive treatment of children with severe meningococcemia. Crit. Care Med. 29, S130-S135 (2001).
83. Gordon BR, Parker TS, Levine DM et al. Safety and pharmacokinetics of an endotoxin-binding phospholipids emulsion. Ann. Pharmacother. 37, 948-950 (2003).
84. Goldfarb RD, Parker TS, Levine DM et al. Protein-free phospholipids emulsion improved cardiopulmonary function and survival in porcine sepsis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R550-R557 (2003).
85. Gordon BR, Parker TS, Levine DM et al. Neutralization of endotoxin by a phospholipid emulsion in healthy volunteers. J. Infect. Dis. 191, 1515-1522 (2005).
86. Dellinger RP, Tomayko JF, Angus DC et al. Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a Phase II multicenter, randomized, placebocontrolled, dose-finding clinical trial. Crit. Care Med. 37, 2929-2938 (2009).
87. Macias WL, Vallet B, Bernard GR et al. Sources of variability on the estimate of treatment effect in the PROWESS trial: implications for the design and conduct of future studies in severe sepsis. Crit. Care Med. 32(12), 2385-2391 (2004).
88. Kushi H, Miki T, Nakahara J et al. Hemoperfusion with an immobilized Polymyxin B fiber column improves tissue oxygen metabolism. Ther. Apher. Dial. 10(5), 430-435 (2006).
89. Uriu K, Osajima A, Hiroshige K et al. Endotoxin removal by direct hemoperfusion with an adsorbent column using Polymyxin B-immobilized fiber ameliorates systemic circulatory disturbance in patients with septic shock. Am. J. Kidney Dis. 39(5), 937-947 (2002).
90. Tani T, Shoji H, Guadagni G, Perego A. Extracorporeal removal of endotoxin: the polymyxin B-immobilized fiber cartridge. In: Endotoxemia and Endotoxin Shock. Disease, Diagnosis and Therapy. Contributions to Nephrology Volume 167. Ronco C, Piccinni P, Rosner MH (Eds). Karger, Basel, Switzerland, 35-44 (2010).
91. Cantaluppi V, Assenzio B, Pasero D et al. Polymyxin-B hemoperfusion inactivates circulating proapoptotic factors. Intensive Care Med. 34, 1638-1645 (2008).
92. Sakamoto Y, Mashiko K, Matsumoto H et al. Effect of direct hemoperfusion with a polymyxin B immobilized fiber column on high mobility group box-1 (HMGB1) in severe septic shock: report of a case. ASAIO J. 52, e37-e39 (2006).
93. Cruz DN, Perazella MA, Bellomo R et al. Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review. Crit. Care 11, R47 (2007).
94. Yamada M, Ichikawa T, Li M et al. Discovery of novel and potent smallmolecule inhibitors of NO and cytokine production as antisepsis agents: synthesis and biological activity of alkyl 6-(N-substituted sulfamoyl)cyclohex- 1-ene-1-carboxylate. J. Med. Chem. 48, 7457-7467 (2005).
95. Zanotti-Cavazzoni SL, Goldfarb RD, Dellinger RP et al. A cytokine production inhibitor (TAK-242) improves cardiovascular performance, inhibits cytokine release and increases survival in a porcine model of Gram negative sepsis. Crit. Care Med. 32 (Suppl.), A15 (2004).
96. Rice TW, Wheeler AP, Bernard GR et al. A randomized, double-blind, placebocontrolled trial of TAK-242 treatment for severe sepsis. Crit. Care Med. 38, 1685-1694 (2010).
97. Mullarkey M, Rose JR, Bristol J et al. Inhibition of endotoxin response by E5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J. Pharm. Exp. Ther. 304(3), 1093-1102 (2003).
98. Kaneko K, Ueda R, Kawata T et al. LPS binding protein does not participate in the pharmacokinetic of E5564. J. Endotoxin Res. 10(3) 185-194 (2003).
99. Solomon SB, Cui X, Gerstenberger E et al. Effective dosing of lipid A analogue e5564 in rates depends on the timing of treatment and the route of Escherichia coli infection. J. Infect. Dis. 193, 634-644 (2006).
100. Kaneko K, Ueda R, Nemoto H et al. Disposition of a synthetic analogue of lipid A (E5564) in rats. Xenobiotica 33(3), 323-339 (2003).
101. Wong YN, Rossignol D, Rose JR et al. Safety, pharmacokinetics, and pharmacodynamics of E5564, a lipid A antagonist, during an ascending single-dose clinical study. J. Clin. Pharmacol. 43, 735-742 (2003).
102. Wasan KM, Sivak O, Cote RA et al. Association of the endotoxin antagonist E5564 with high-density lipoproteins in vitro: dependence on low-density and triglyceride-rich lipoprotein concentrations. Antimicrob. Agents Chemother. 47(9), 2796-2803 (2003).
103. Lynn M, Rossignol DP, Wheeler JL et al. Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia. J. Infect. Dis. 187, 631-639 (2003).
104. Rossignol DP, Wong N, Noveck R, Lynn M. Continuous pharmacodynamic activity of eritoran tetrasodium, a TLR4 antagonist, during intermittent intravenoux infusion into normal volunteers. Innate Immun. 14(6) 383-394 (2008).
105. Lynn M, Wong N, Wheeler JL et al. Extended in vivo pharmacodynamic activity of E5564 in normal volunteers with experimental endotoxemia. J. Pharm. Exp. Ther. 308 (1), 175-181 (2003).
106. Knaus WA, Draper EA, Wagner DP et al. APACHE II: a severity of disease classification system. Crit. Care Med. 13, 818-829 (1985).
107. Ren M, Gao L, Wu X. TLR4: the receptor bridging Acanthamoeba challenge and intracellular inflammatory responses in human corneal cell lines. Immunol. Cell Biol. 88, 529-536 (2010).
108. Mockenhaupt FP, Cramer JP, Hamann L et al. Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria. Proc. Natl Acad. Sci. USA 103(1), 177-182 (2006).
109. Smirnova I, Mann N, Dols A et al. Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc. Natl Acad. Sci. USA 100(10) 6075-6080 (2003).
110. Bennett-Guerrero E, Grocott HP, Levy JH et al. A Phase II, double-blind, placebocontrolled, ascending-dose study of eritoran (E5564), a lipid A antagonist, in patients undergoing cardiac surgery with cardiopulmonary bypass. Anesth. Analg. 104, 378-383 (2007).
111. Shimamoto A, Chong AJ, Yada M et al. Inhibition of Toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation 114(1), I270-I274 (2006).
112. Worthen GS, Haslett C, Smedly LA et al. Lung vascular injury induced by chemotactic factors: enhancement by bacterial endotoxins. Fed. Proc. 45(1), 7-12 (1986).
113. Lv T, Shen X, Shi Y, Song Y. TLR4 is essential in acute lung injury induced by unresuscitated hemorrhagic shock. J. Trauma 66(1), 124-131, (2009).
114. Andonegui G, Bonder CS, Green F et al. Endothelium-derived Toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs. J. Clin. Invest. 111, 1011-1020 (2003).
115. Imai Y, Kub K, Neely GG et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133, 235-249 (2008).
116. Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J. Exp. Med 196, 1645-1651 (2002).
117. Hammad H, Chieppa M, Perros F, Willart MA, Germain RN, Lambrecht BN. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nature Med. 15, 410-416 (2009).
118. Bedoret D, Wallemacq H, Marichal T et al. Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice. J. Clin. Invest. 119(12), 3723-3738 (2009).
119. Blander JM, Medzhitov R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440(6), 808-812 (2006).
120. Zanoni I, Ostuni R, Capuano G et al. CD14 regulates the dendritic cell life cycle after LPS exposures through NFAT activation. Nature 460, 264-268 (2009).
121. Murphy TJ, Paterson HM, Mannick JA, Lederer JA. Injury, sepsis, and the regulation of Toll-like receptor responses. J. Leukoc. Biol. 75, 400-407 (2004).
122. Mittal D, Saccheri F, Vénéreau E, Pusterla T, Bianchi ME, Rescigno M. TLR4- mediated skin carcinogenesis is dependent on immune and radioresistant cells. EMBO J. 29, 2242-2252 (2010).
123. Szajnik M, Szczepanski MJ, Czystowska M et al. TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene 28, 4353-4363 (2009).
124. Flohé SB, Flohé S, Schade FU. Deterioration of the immune system after trauma: signals and cellular mechanisms. Innate Immun. 14(6), 333-344 (2008).
125. Maroso M, Salosso S, Ravizza T et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nature Med. 16(4), 413-420 (2010).
126. Choe JY, Crain B, Wu SR, Corr M. Interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by toll-like receptor 4 signaling. J. Exp. Med 197, 537-542 (2003).
127. Stewart CR, Stuart LM, Wilkinson K et al. CD36 ligands promote steril inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat. Immunol. 11, 155-161 (2010).
128. Kiechl S, Lorenz E, Reindl M et al. Toll-Like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med. 347(3), 185-192 (2002).
129. Efficacy and Safety of Drotrecogin Alfa (Activated) in Adult Patients With Septic Shock http://clinicaltrials.gov/ct2/show/NCT00604214
130. Safety and Efficacy of Polymyxin B Hemoperfusion (PMX) for Septic Shock (EUPHRATES) http://clinicaltrials.gov/ct2/show/ NCT01046669
131. ACCESS: A Controlled Comparison of Eritoran Tetrasodium and Placebo in Patients With Severe Sepsis http://clinicaltrials.gov/ct2/show/NCT00334828