Umifenovir, sold under the brand name Arbidol, is sold and used as an

antiviral medication Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are a class of antimicrobial ...

for

influenza Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These sympto ...

Russia Russia, or the Russian Federation, is a country spanning Eastern Europe and North Asia. It is the list of countries and dependencies by area, largest country in the world, and extends across Time in Russia, eleven time zones, sharing Borders ...

and

China China, officially the People's Republic of China (PRC), is a country in East Asia. With population of China, a population exceeding 1.4 billion, it is the list of countries by population (United Nations), second-most populous country after ...

. The drug is manufactured by Pharmstandard (). It is not approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) for the treatment or prevention of influenza.

Medical use

Testing of umifenovir's efficacy has mainly occurred in China and Russia, and it is well known in these two countries. Some of the Russian tests showed the drug to be effective against

influenza A ''Influenza A virus'' (''Alphainfluenzavirus influenzae'') or IAV is the only species of the genus ''Alphainfluenzavirus'' of the virus family '' Orthomyxoviridae''. It is a pathogen with strains that infect birds and some mammals, as well as c ...

and a direct comparison with

oseltamivir Oseltamivir, sold under the brand name Tamiflu among others, 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 complicati ...

showed similar efficiency ''in vitro'' and in a clinical setting. In 2010 Arbidol was the drug brand with the highest sales volume in Russia. In the first quarter of 2020 it had a 16 percent share in the Russian antiviral market. Umifenovir is used primarily as an antiviral treatment for influenza. The drug has also been investigated as a candidate drug for treatment of

hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include ...

. Some preliminary research suggests it could be useful for flavivirus infection like West Nile virus. Some studies also indicate that umifenovir also has ''in vitro'' effectiveness at preventing entry of

Zaire ebolavirus ''Orthoebolavirus zairense'' or Zaire ebolavirus, more commonly known as Ebola virus (; EBOV), is one of six known species within the genus ''Ebolavirus''. Four of the six known ebolaviruses, including EBOV, cause a severe and often fatal hem ...

(Kikwit strain), Tacaribe

arenavirus An arenavirus is a bi- or trisegmented ambisense RNA virus that is a member of the family ''Arenaviridae''. These viruses infect rodents and occasionally humans. A class of novel, highly divergent arenaviruses, properly known as reptarenavirus ...

and

Kaposi's sarcoma-associated herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus. It is also called Human herpesvirus 8, or HHV-8 in short. This virus causes Kaposi's sarcoma, a cancer commonly occurring in AIDS patients, as well as primary ...

in mammalian cell cultures, while confirming umifenovir's suppressive effect ''in vitro'' on

Hepatitis B Hepatitis B is an infectious disease caused by the '' hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. ...

and

poliovirus Poliovirus, the causative agent of polio (also known as poliomyelitis), is a serotype of the species '' Enterovirus C'', in the family of '' Picornaviridae''. There are three poliovirus serotypes, numbered 1, 2, and 3. Poliovirus is composed ...

infection of mammalian cells when introduced either in advance of viral infection or during infection.

Side effects

Side effects In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...

in children include sensitization to the drug. No known overdose cases have been reported and

allergic reactions Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...

are limited to people with

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...

. The is more than 4 g/kg.

Pharmacology

Pharmacodynamics

Umifenovir inhibits membrane fusion of influenza virus in vitro. Fusion between the viral envelope (surrounding the viral capsid) and the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

of the target cell is inhibited. This prevents viral entry to the target cell, and therefore protects it from infection. Some evidence suggests that the drug's actions are more effective at preventing infections from

RNA virus An RNA virus is a virus characterized by a ribonucleic acid (RNA) based genome. The genome can be single-stranded RNA (ssRNA) or double-stranded (Double-stranded RNA, dsRNA). Notable human diseases caused by RNA viruses include influenza, SARS, ...

es than infections from

DNA virus A DNA virus is a virus that has a genome made of deoxyribonucleic acid (DNA) that is replicated by a DNA polymerase. They can be divided between those that have two strands of DNA in their genome, called double-stranded DNA (dsDNA) viruses, and t ...

es. As well as specific antiviral action against both

and influenza B viruses, umifenovir exhibits modulatory effects on the immune system. The drug stimulates a

humoral immune response Humoral immunity is the aspect of immunity that is mediated by macromolecules – including secreted antibodies, complement proteins, and certain antimicrobial peptides – located in extracellular fluids. Humoral immunity is named so because ...

, induces

interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...

-production, and stimulates the

phagocytic Phagocytosis () is the process by which a cell (biology), cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs ph ...

function of

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

Pharmacokinetics

The maximum concentration of umifenovir in blood plasma when taking a dose of 50 mg is achieved after 1.2 hours, with 100 mg the maximum dose is obtained after 1.5 hours. The bioavailability of the drug is about 40% and does not depend on food intake. The half-life is about 17-21 hours. It is metabolized in the liver primarily by

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

but also by several other enzymes. About 40% is excreted unchanged, mainly in bile (38.9%) and in small amounts by the kidneys (0.12%). During the first 24 hours, 90% of the administered dose is eliminated.

Chemistry

Chemically, umifenovir features an

indole Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...

core, functionalized at all but one positions with different substituents. The molecular groups of umifenovir - hydroxy, amino and carboxy - can form different hydrogen-bonded synthons. Umifenovir is characterized by only one polymorphic form but can exist in the form of a large number of crystal solvates, the production of which depends on the medium and conditions of synthesis. Umifenovir is poorly soluble in water. Crystalline solvates and other solid forms may be determined by the spatial structure and conformational equilibria in the saturated solution.

History and criticism

A Russian packet of Arbidol capsules In 2006 the American company Good Earth Medicine applied to the FDA for an Emergency Use Authorization of Arbidol during the

H5N1 Influenza A virus subtype H5N1 (A/H5N1) is a subtype of the influenza A virus, which causes the disease avian influenza (often referred to as "bird flu"). It is enzootic (maintained in the population) in many bird populations, and also panzoo ...

bird flu epidemic, but their application was rejected on the grounds that the lab data provided was not strong enough to justify use. In 2007, the Russian Academy of Medical Sciences stated that the effects of Arbidol (umifenovir) are not scientifically proven. In the early 2010s Russian media criticized lobbying attempts by Tatyana Golikova (then-Minister of Healthcare) to promote umifenovir, and the unsubstantiated claim that Arbidol can speed up recovery from flu or cold by 1.3-2.3 days. They also made claims that comparative clinical studies have proven umifenovir to be inefficient. In January 2020, the Russian drug company OTCPharm (Отисифарм) published advertisements stating that the drug is effective against

SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. The virus previously had the Novel coronavirus, provisional nam ...

. Shortly afterwards the Russian Federal Antimonopoly Service fined the company for violation of its advertising rules. In March 2020 a video promoting the drug for

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic. The symptoms of COVID‑19 can vary but often include fever ...

went viral on Facebook and circulated heavily on WhatsApp, and around the same time a shortage of the drug ensued in Russia.

Research for COVID-19

In early 2020 umifenovir was touted as a potential treatment for

in China, where it was sometimes given to patients in combination with other drugs such as the anti-HIV drug

Darunavir Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir ...

. A three-arm RCT study published in May 2020 in the

Cell Press Cell Press is an all-science publisher of over 50 scientific journals across the life, physical, earth, and health sciences, both independently and in partnership with scientific societies. Cell Press was founded and is currently based in Cambri ...

journal ''Clinical Advances'' found that neither Umifenovir or Lopinavir/

Ritonavir Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhi ...

helped patients with mild to moderate COVID-19. A similar study comparing Umifenovir directly with Lopinavir/Ritonavir found no difference in fever duration between the two groups but found a lower viral load on day 14 in the Umifenovir group. A systemic review and meta-analysis of 16 studies on Umifenovir published in March 2021 concluded that there is "no significant benefit of using Arbidol compared with non‐antiviral treatment or other therapeutic agents against COVID‐19 disease."

References

External links

* {{Portal bar , Medicine Anti-influenza agents Anti–RNA virus drugs Indoles Bromoarenes Hydroxyarenes Dimethylamino compounds Thioethers Ethyl esters Russian drugs Drugs in the Soviet Union