Eritoran

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Eritoran
Eritoran free acid skeletal.svg
Systematic (IUPAC) name
[(2R,3R,4R,5S,6R)-4-Decoxy-5-hydroxy-6-[[(2R,3R,4R,5S,6R)-4-[(3R)-3-methoxydecoxy]-6-(methoxymethyl)-3-[[(Z)-octadec-11-enoyl]amino]-5-phosphonatooxyoxan-2-yl]oxymethyl]-3-(3-oxotetradecanoylamino)oxan-2-yl] phosphoric acid
Clinical data
Legal status
  • Investigational
Routes Intravenous injection
Identifiers
CAS number 185955-34-4 N
185954-98-7 (tetrasodium salt)
ATC code None
PubChem CID 6912404
UNII 551541VI0Y N
ChEMBL CHEMBL501259 N
Synonyms E 5564
Chemical data
Formula C66H126N2O19P2 
Mol. mass 1313.656 g/mol
 N (what is this?)  (verify)

Eritoran is an investigational drug for the treatment of severe sepsis, an excessive inflammatory response to an infection. It is being developed by the Japanese pharmaceutical company Eisai Co. and administered intravenously as the sodium salt eritoran tetrasodium.[1][2]

In a phase III clinical trial,[3] eritoran did not perform better than existing treatments for the treatment of sepsis.[4][5]

Mechanism of action[edit]

Toll-like receptors (TLRs) play an important role in the innate immune system. They recognise microbes and activate inflammatory immune responses. Toll-like receptor 4 (TLR4) detects lipopolysaccharides found in most Gram-negative bacteria.[6]

Because of its similarity to the lipopolysaccharide lipid A, eritoran acts as TLR4 antagonist and so blocks the excessive reaction triggered by this receptor.[2][7]

Lipid A as found in E. coli, a gram-negative bacterium
Eritoran

Cytokine storm[edit]

While eritoran did not perform well in the treatment of sepsis, it was shown to combat another, related phenomenon called cytokine storm in influenza cases involving certain virus strains (involving preliminary experimentation on mice, not in other animals or humans, led by a University of Maryland School of Medicine researcher).A further study in mice and rats by the same group[8] showed it prevented acute lung injury. A cytokine storm can help to cause sepsis and can in concert with it or by itself cause serious illness or death if not soon controlled. Mortality rates for sepsis, cytokine storm, and especially septic shock and organ dysfunction are still quite high despite progress made. This is in no small part due to the prevalence of nosocomial (hospital-acquired) infections, as well as ongoing mutations which confer multi-drug resistance in pathological microorganisms such as bacteria and viruses (most strains of flu are resistant to amantadine and rimantadine, and some are resistant to oseltamivir), and delays and mistakes in the recognition and treatment of disease.[9] New flu strains, such as the H7N9 strain, are always emerging.

References[edit]

  1. ^ "Eritoran: A Potential Therapeutic Agent In Severe Sepsis". MediNEWS.Direct. 17 October 2007. Retrieved 26 December 2009. 
  2. ^ a b Kiemer, Alexandra K. (2008). "TLR eröffnen neue Möglichkeiten". Pharmazeutische Zeitung online (in German). Govi-Verlag. Retrieved 26 December 2009. 
  3. ^ ClinicalTrials.gov NCT00334828 ACCESS: A Controlled Comparison of Eritoran Tetrasodium and Placebo in Patients With Severe Sepsis
  4. ^ Steven M. Opal, et al. (2013). "Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis: The ACCESS Randomized Trial". JAMA 309 (11): 1154–1162. doi:10.1001/jama.2013.2194. 
  5. ^ "Phase III Study for Eritoran Does Not Meet Primary Endpoint". drugs.com. 
  6. ^ "Entrez Gene: TLR4 toll-like receptor 4". 
  7. ^ Tidswell, M; Tillis, W; Larosa, SP; Lynn, M; Wittek, AE; Kao, R; Wheeler, J; Gogate, J et al. (2010). "Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis". Critical Care Medicine 38 (1): 72–83. doi:10.1097/CCM.0b013e3181b07b78. PMID 19661804. 
  8. ^ Shirey,K A;Lai,W;Scott,A J et al(2013)"TLR4 antagonist Eritoran protects mice from lethal influenza infection" Nature 497: 498 - 503
  9. ^ "New drug offers novel approach to taming flu virus". NBC News. 1 May 2013.