Eritoran: Difference between revisions
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'''Eritoran''' is a synthetic [[lipid]] that [[Antagonist (pharmacology)|inhibits]] the [[Receptor (biochemistry)|receptor]] [[Toll-like receptor 4|TLR4]]. It was [[drug development|developed]] as a potential treatment for severe [[sepsis]], an excessive [[inflammatory response]] to an [[infection]]. It failed a five year [[Phases_of_clinical_research#Phase_III|Phase III]] clinical trial, the results of which were published in 2013 |
'''Eritoran''' is a synthetic [[lipid]] that [[Antagonist (pharmacology)|inhibits]] the [[Receptor (biochemistry)|receptor]] [[Toll-like receptor 4|TLR4]]. It was [[drug development|developed]] as a potential treatment for severe [[sepsis]], an excessive [[inflammatory response]] to an [[infection]]. It failed a five year [[Phases_of_clinical_research#Phase_III|Phase III]] clinical trial, the results of which were published in 2013,<ref name=Chen>{{cite journal |last1=Chen |first1=F |last2=Zou |first2=L |last3=Williams |first3=B |last4=Chao |first4=W |title=Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials. |journal=Antioxidants & redox signaling |date=20 November 2021 |volume=35 |issue=15 |pages=1324-1339 |doi=10.1089/ars.2021.0005 |pmid=33588628|pmc=8817700}}</ref><ref>{{cite journal | vauthors = Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, Wittebole X, Dugernier T, Perrotin D, Tidswell M, Jauregui L, Krell K, Pachl J, Takahashi T, Peckelsen C, Cordasco E, Chang CS, Oeyen S, Aikawa N, Maruyama T, Schein R, Kalil AC, Van Nuffelen M, Lynn M, Rossignol DP, Gogate J, Roberts MB, Wheeler JL, Vincent JL | display-authors = 6 | title = Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial | journal = JAMA | volume = 309 | issue = 11 | pages = 1154–62 | date = March 2013 | pmid = 23512062 | doi = 10.1001/jama.2013.2194 | hdl-access = free | hdl = 1854/LU-4222072 }}</ref> and as of 2014 was no longer being developed.<ref name=Fink>{{cite journal | vauthors = Fink MP, Warren HS | title = Strategies to improve drug development for sepsis | journal = Nature Reviews. Drug Discovery | volume = 13 | issue = 10 | pages = 741–58 | date = October 2014 | pmid = 25190187 | doi = 10.1038/nrd4368 | s2cid = 20904332 }}</ref> |
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It was being developed by the Japanese pharmaceutical company [[Eisai Co.]] and administered intravenously as the [[sodium]] [[salt (chemistry)|salt]] '''eritoran tetrasodium'''.<ref>{{cite news|url=http://www.medinewsdirect.com/?p=303 |title=Eritoran: A Potential Therapeutic Agent In Severe Sepsis |date=17 October 2007 |publisher=MediNEWS.Direct |access-date=26 December 2009 |url-status=dead |archive-url=https://web.archive.org/web/20110714065152/http://www.medinewsdirect.com/?p=303 |archive-date=14 July 2011 }}</ref><ref name="PZonline">{{cite web|last=Kiemer|first=Alexandra K. | name-list-style = vanc |year=2008|title=TLR eröffnen neue Möglichkeiten |work=Pharmazeutische Zeitung online |publisher=Govi-Verlag |language=German |url= http://www.pharmazeutische-zeitung.de/index.php?id=4546 |access-date=26 December 2009}}</ref> |
It was being developed by the Japanese pharmaceutical company [[Eisai Co.]] and administered intravenously as the [[sodium]] [[salt (chemistry)|salt]] '''eritoran tetrasodium'''.<ref>{{cite news|url=http://www.medinewsdirect.com/?p=303 |title=Eritoran: A Potential Therapeutic Agent In Severe Sepsis |date=17 October 2007 |publisher=MediNEWS.Direct |access-date=26 December 2009 |url-status=dead |archive-url=https://web.archive.org/web/20110714065152/http://www.medinewsdirect.com/?p=303 |archive-date=14 July 2011 }}</ref><ref name="PZonline">{{cite web|last=Kiemer|first=Alexandra K. | name-list-style = vanc |year=2008|title=TLR eröffnen neue Möglichkeiten |work=Pharmazeutische Zeitung online |publisher=Govi-Verlag |language=German |url= http://www.pharmazeutische-zeitung.de/index.php?id=4546 |access-date=26 December 2009}}</ref> |
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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<ref>{{cite journal | vauthors = Shirey KA, Lai W, Scott AJ, Lipsky M, Mistry P, Pletneva LM, Karp CL, McAlees J, Gioannini TL, Weiss J, Chen WH, Ernst RK, Rossignol DP, Gusovsky F, Blanco JC, Vogel SN | display-authors = 6 | title = The TLR4 antagonist Eritoran protects mice from lethal influenza infection | journal = Nature | volume = 497 | issue = 7450 | pages = 498–502 | date = May 2013 | pmid = 23636320 | pmc = 3725830 | doi = 10.1038/nature12118 | bibcode = 2013Natur.497..498S }}</ref> 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.<ref>{{Cite web | url = http://vitals.nbcnews.com/_news/2013/05/01/18002315-new-drug-offers-novel-approach-to-taming-flu-virus | title = New drug offers novel approach to taming flu virus | work = NBC News | date= 1 May 2013}}</ref> New flu strains, such as the [[H7N9]] strain, are always emerging. |
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<ref>{{cite journal | vauthors = Shirey KA, Lai W, Scott AJ, Lipsky M, Mistry P, Pletneva LM, Karp CL, McAlees J, Gioannini TL, Weiss J, Chen WH, Ernst RK, Rossignol DP, Gusovsky F, Blanco JC, Vogel SN | display-authors = 6 | title = The TLR4 antagonist Eritoran protects mice from lethal influenza infection | journal = Nature | volume = 497 | issue = 7450 | pages = 498–502 | date = May 2013 | pmid = 23636320 | pmc = 3725830 | doi = 10.1038/nature12118 | bibcode = 2013Natur.497..498S }}</ref> 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.<ref>{{Cite web | url = http://vitals.nbcnews.com/_news/2013/05/01/18002315-new-drug-offers-novel-approach-to-taming-flu-virus | title = New drug offers novel approach to taming flu virus | work = NBC News | date= 1 May 2013}}</ref> New flu strains, such as the [[H7N9]] strain, are always emerging. |
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Eritoran, because of its structural similarity to the gram-negative bacterial lipopolysaccharide (lipid A) acts as TLR4 antagonist. Eritoran did not perform well in phase III clinical trials, however it successfully treated cytokine storm in influenza animal models.<sup>[8]</sup> There were multiple factors that could be attributed to the failure of Eritoran against sepsis, which include poorly designed lipid A scaffold, antagonist designed using mice model where as it is known that there exists species differences (human vs mice) in lipid A recognition, role of MD2/TLR4 PTMs on receptor function is not fully understood, recruitment of heterogeneous patient population, and lack of a well-defined structure activity relationship (SAR) of LPS interaction with MD2/TLR4.<ref |
Eritoran, because of its structural similarity to the gram-negative bacterial lipopolysaccharide (lipid A) acts as TLR4 antagonist. Eritoran did not perform well in phase III clinical trials, however it successfully treated cytokine storm in influenza animal models.<sup>[8]</sup> There were multiple factors that could be attributed to the failure of Eritoran against sepsis, which include poorly designed lipid A scaffold, antagonist designed using mice model where as it is known that there exists species differences (human vs mice) in lipid A recognition, role of MD2/TLR4 PTMs on receptor function is not fully understood, recruitment of heterogeneous patient population, and lack of a well-defined structure activity relationship (SAR) of LPS interaction with MD2/TLR4.<ref name=Fink/> |
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== References == |
== References == |
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Revision as of 15:50, 11 July 2023
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| Other names | E 5564 |
| Routes of administration | Intravenous injection |
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| Formula | C66H126N2O19P2 |
| Molar mass | 1313.677 g·mol−1 |
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Eritoran is a synthetic lipid that inhibits the receptor TLR4. It was developed as a potential treatment for severe sepsis, an excessive inflammatory response to an infection. It failed a five year Phase III clinical trial, the results of which were published in 2013,[1][2] and as of 2014 was no longer being developed.[3]
It was being developed by the Japanese pharmaceutical company Eisai Co. and administered intravenously as the sodium salt eritoran tetrasodium.[4][5]
Mechanism of action
Because of its similarity to the lipopolysaccharide lipid A, eritoran acts as TLR4 antagonist. TLR4 is part of the innate immune system and [lays an important role in triggering defense against pathogens. Scientists think that too much signalling by TLR4 may be part of what causes cytokine storm and sepsis, but as of 2021 no drug that inhibits TLR4 has been shown to prevent or treat sepsis or cytokine storms in humans.[1]
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Cytokine storm
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[6] 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.[7] New flu strains, such as the H7N9 strain, are always emerging.
Eritoran, because of its structural similarity to the gram-negative bacterial lipopolysaccharide (lipid A) acts as TLR4 antagonist. Eritoran did not perform well in phase III clinical trials, however it successfully treated cytokine storm in influenza animal models.[8] There were multiple factors that could be attributed to the failure of Eritoran against sepsis, which include poorly designed lipid A scaffold, antagonist designed using mice model where as it is known that there exists species differences (human vs mice) in lipid A recognition, role of MD2/TLR4 PTMs on receptor function is not fully understood, recruitment of heterogeneous patient population, and lack of a well-defined structure activity relationship (SAR) of LPS interaction with MD2/TLR4.[3]
References
- ^ a b Chen, F; Zou, L; Williams, B; Chao, W (20 November 2021). "Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials". Antioxidants & redox signaling. 35 (15): 1324–1339. doi:10.1089/ars.2021.0005. PMC 8817700. PMID 33588628.
- ^ Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, et al. (March 2013). "Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial". JAMA. 309 (11): 1154–62. doi:10.1001/jama.2013.2194. hdl:1854/LU-4222072. PMID 23512062.
- ^ a b Fink MP, Warren HS (October 2014). "Strategies to improve drug development for sepsis". Nature Reviews. Drug Discovery. 13 (10): 741–58. doi:10.1038/nrd4368. PMID 25190187. S2CID 20904332.
- ^ "Eritoran: A Potential Therapeutic Agent In Severe Sepsis". MediNEWS.Direct. 17 October 2007. Archived from the original on 14 July 2011. Retrieved 26 December 2009.
- ^ Kiemer AK (2008). "TLR eröffnen neue Möglichkeiten". Pharmazeutische Zeitung online (in German). Govi-Verlag. Retrieved 26 December 2009.
- ^ Shirey KA, Lai W, Scott AJ, Lipsky M, Mistry P, Pletneva LM, et al. (May 2013). "The TLR4 antagonist Eritoran protects mice from lethal influenza infection". Nature. 497 (7450): 498–502. Bibcode:2013Natur.497..498S. doi:10.1038/nature12118. PMC 3725830. PMID 23636320.
- ^ "New drug offers novel approach to taming flu virus". NBC News. 1 May 2013.
Further reading
+ Tidswell M, Tillis W, Larosa SP, Lynn M, Wittek AE, Kao R, et al. (January 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. S2CID 19160973.