Eritoran is an investigational drug for the treatment of severe

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

, an excessive

inflammatory response Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...

to an

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

. In a phase III clinical trial, eritoran did not perform better than placebo for the treatment of sepsis. It was being developed by the Japanese pharmaceutical company

Eisai Co. is a Japanese pharmaceutical company headquartered in Tokyo, Japan. It has some 10,000 employees, among them about 1,500 in research. Eisai is listed on the Tokyo Stock Exchange and is a member of the Topix 100 and Nikkei 225 stock indices. ...

and administered intravenously as the

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...

eritoran tetrasodium.

Mechanism of action

Toll-like receptor Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are Bitopic protein, single-pass membrane-spanning Receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophage ...

s (TLRs) play an important role in the

innate immune system The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...

. They recognise

microbe A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...

s and activate inflammatory immune responses.

Toll-like receptor 4 Toll-like receptor 4 is a protein that in humans is encoded by the ''TLR4'' gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an ...

(TLR4) detects

lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...

s found in most

Gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

bacteria. Because of its similarity to the lipopolysaccharide

lipid A Lipid A is a lipid component of an endotoxin held responsible for the toxicity of gram-negative bacteria. It is the innermost of the three regions of the lipopolysaccharide (LPS), also called endotoxin molecule, and its hydrophobic nature allows it ...

, eritoran acts as TLR4

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

and so blocks the excessive reaction triggered by this receptor.

Cytokine storm

While eritoran did not perform well in the treatment of sepsis, it was shown to combat another, related phenomenon called

cytokine storm A cytokine storm, also called hypercytokinemia, is a physiological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Norma ...

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 The University of Maryland School of Medicine (abbreviated UMSOM), located in Baltimore City, Maryland, U.S., is the medical school of the University of Maryland, Baltimore and is affiliated with the University of Maryland Medical Center and Me ...

researcher).A further study in mice and rats by the same group 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 Septic shock is a potentially fatal medical condition that occurs when sepsis, which is organ injury or damage in response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism. The Third International Con ...

and organ dysfunction are still quite high despite progress made. This is in no small part due to the

prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...

nosocomial A hospital-acquired infection, also known as a nosocomial infection (from the Greek , meaning "hospital"), is an infection that is acquired in a hospital or other health care facility. To emphasize both hospital and nonhospital settings, it is ...

(hospital-acquired) infections, as well as ongoing mutations which confer

multi-drug resistance Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are c ...

in pathological microorganisms such as bacteria and viruses (most strains of flu are resistant to

amantadine Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to wid ...

and

rimantadine Rimantadine ( INN, sold under the trade name 'Flumadine'') is an orally administered antiviral drug used to treat, and in rare cases prevent, influenzavirus A infection. When taken within one to two days of developing symptoms, rimantadine can s ...

, and some are resistant to

oseltamivir Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B, viruses that cause the flu. Many medical organizations recommend it in people who have complications or are at hig ...

), and delays and mistakes in the recognition and treatment of disease. New flu strains, such as the

H7N9 Influenza A virus subtype H7N9 (A/H7N9) is a bird flu strain of the species Influenza virus A (avian influenza virus or bird flu virus). Avian influenza A H7 viruses normally circulate amongst avian populations with some variants known to occ ...

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.^{/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.

References

{{reflist, 2

Immunosuppressants}