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Umifenovir

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Umifenovir
Clinical data
Trade namesArbidol
Other namesAR-1I9514, Russian: Арбидол, Chinese: 阿比朵尔.[citation needed]
Pregnancy
category
  • C
Routes of
administration		By mouth (hard capsules, tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability40%
MetabolismHepatic, CYP3A4[3][4]
Elimination half-life17–21 hours[3][4]
Excretion40% excrete as unchanged umifenovir in feces (38.9%) and urine (0.12%)[5]
Identifiers
  • ethyl 6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylsulfanyl)methyl]-1H-indole-3-carboxylate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.247.800 Edit this at Wikidata
Chemical and physical data
FormulaC22H25BrN2O3S
Molar mass477.42 g·mol−1
3D model (JSmol)
  • CCOC(=O)c1c(n(c2c1c(c(c(c2)Br)O)CN(C)C)C)CSc3ccccc3
  • InChI=1S/C22H25BrN2O3S/c1-5-28-22(27)20-18(13-29-14-9-7-6-8-10-14)25(4)17-11-16(23)21(26)15(19(17)20)12-24(2)3/h6-11,26H,5,12-13H2,1-4H3 ☒N
  • Key:KCFYEAOKVJSACF-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Umifenovir, sold under the brand name Arbidol, is sold and used as an antiviral medication for influenza in Russia and China. The drug is manufactured by Pharmstandard (Russian: Фармстандарт). It is not approved by the U.S. Food and Drug Administration (FDA) for the treatment or prevention of influenza.[6]

Medical use

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Testing of umifenovir's efficacy has mainly occurred in China and Russia,[7][8] and it is well known in these two countries.[9] Some of the Russian tests showed the drug to be effective against influenza A and a direct comparison with oseltamivir showed similar efficiency in vitro and in a clinical setting.[7][10] In 2010 Arbidol was the drug brand with the highest sales volume in Russia.[11] In the first quarter of 2020 it had a 16 percent share in the Russian antiviral market.[12]

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.[13]

Some preliminary research suggests it could be useful for flavivirus infection like West Nile virus.[14]

Some studies also indicate that umifenovir also has in vitro effectiveness at preventing entry of Zaire ebolavirus (Kikwit strain), Tacaribe arenavirus and Kaposi's sarcoma-associated herpesvirus in mammalian cell cultures, while confirming umifenovir's suppressive effect in vitro on Hepatitis B and poliovirus infection of mammalian cells when introduced either in advance of viral infection or during infection.[15][16]

Side effects

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Side effects in children include sensitization to the drug. No known overdose cases have been reported and allergic reactions are limited to people with hypersensitivity. The LD50 is more than 4 g/kg.[17]

Pharmacology

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Pharmacodynamics

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Umifenovir inhibits membrane fusion of influenza virus in vitro.[18] Fusion between the viral envelope (surrounding the viral capsid) and the cell membrane of the target cell is inhibited.[19][20] This prevents viral entry to the target cell, and therefore protects it from infection.[21]

Some evidence suggests that the drug's actions are more effective at preventing infections from RNA viruses than infections from DNA viruses.[22]

As well as specific antiviral action against both influenza A and influenza B viruses, umifenovir exhibits modulatory effects on the immune system. The drug stimulates a humoral immune response, induces interferon-production, and stimulates the phagocytic function of macrophages.[23]

Pharmacokinetics

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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.[3] The bioavailability of the drug is about 40% and does not depend on food intake.[3]

The half-life is about 17-21 hours.[3][4] It is metabolized in the liver primarily by CYP3A4 but also by several other enzymes.[4] 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.[4]

Chemistry

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Chemically, umifenovir features an 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.[citation needed] 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.[24][25]

History and criticism

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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 bird flu epidemic, but their application was rejected on the grounds that the lab data provided was not strong enough to justify use.[26][27]

In 2007, the Russian Academy of Medical Sciences stated that the effects of Arbidol (umifenovir) are not scientifically proven.[28]

In the early 2010s Russian media criticized lobbying attempts by Tatyana Golikova (then-Minister of Healthcare) to promote umifenovir,[29] and the unsubstantiated claim that Arbidol can speed up recovery from flu or cold by 1.3-2.3 days.[30] They also made claims that comparative clinical studies have proven umifenovir to be inefficient.[31][32]

In January 2020, the Russian drug company OTCPharm (Отисифарм) published advertisements stating that the drug is effective against SARS-CoV-2. Shortly afterwards the Russian Federal Antimonopoly Service fined the company for violation of its advertising rules.[33] In March 2020 a video promoting the drug for COVID-19 went viral on Facebook and circulated heavily on WhatsApp, and around the same time a shortage of the drug ensued in Russia.[34]

Research for COVID-19

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See also: COVID-19 drug repurposing research

In early 2020 umifenovir was touted as a potential treatment for COVID-19 in China, where it was sometimes given to patients in combination with other drugs such as the anti-HIV drug Darunavir.[35][36][37][38][39] A three-arm RCT study published in May 2020 in the Cell Press journal Clinical Advances found that neither Umifenovir or Lopinavir/Ritonavir helped patients with mild to moderate COVID-19.[40] 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.[41] 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."[42]

See also

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References

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  1. ^ a b "阿比朵尔抑制新冠，先声药业生产的吗？". 全民健康网 (in Chinese). Archived from the original on 17 June 2020. Retrieved 17 June 2020.
  2. ^ "ИНСТРУКЦИЯ ПО ПРИМЕНЕНИЮ АРПЕТОЛ (ARPETOL)". Vidal (in Belarusian). Archived from the original on 26 January 2018. Retrieved 17 June 2020.
  3. ^ a b c d e Liu MY, Wang S, Yao WF, Wu HZ, Meng SN, Wei MJ (April 2009). "Pharmacokinetic properties and bioequivalence of two formulations of arbidol: an open-label, single-dose, randomized-sequence, two-period crossover study in healthy Chinese male volunteers". Clinical Therapeutics. 31 (4): 784–792. doi:10.1016/j.clinthera.2009.04.016. PMC 7133634. PMID 19446151.
  4. ^ a b c d e Deng P, Zhong D, Yu K, Zhang Y, Wang T, Chen X (April 2013). "Pharmacokinetics, metabolism, and excretion of the antiviral drug arbidol in humans". Antimicrobial Agents and Chemotherapy. 57 (4): 1743–1755. doi:10.1128/aac.02282-12. PMC 3623363. PMID 23357765.
  5. ^ "Full Prescribing Information: Arbidol (umifenovir) film-coated tablets 50 and 100 mg: Corrections and Additions". State Register of Medicines (in Russian). Open joint-stock company "Pharmstandard-Tomskchempharm". Retrieved 3 June 2015.[permanent dead link‍]
  6. ^ "FDA Approved Drugs for Influenza". U.S. Food and Drug Administration. 8 December 2022.
  7. ^ a b Leneva IA, Fediakina IT, Gus'kova TA, Glushkov RG (2005). "[Sensitivity of various influenza virus strains to arbidol. Influence of arbidol combination with different antiviral drugs on reproduction of influenza virus A]". Terapevticheskii Arkhiv (Russian translation). 77 (8). ИЗДАТЕЛЬСТВО "МЕДИЦИНА" (Publishing House "Medicine"): 84–88. PMID 16206613.
  8. ^ Wang MZ, Cai BQ, Li LY, Lin JT, Su N, Yu HX, et al. (June 2004). "[Efficacy and safety of arbidol in treatment of naturally acquired influenza]". Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae. 26 (3): 289–293. PMID 15266832.
  9. ^ Boriskin YS, Leneva IA, Pécheur EI, Polyak SJ (2008). "Arbidol: a broad-spectrum antiviral compound that blocks viral fusion". Current Medicinal Chemistry. 15 (10): 997–1005. doi:10.2174/092986708784049658. PMID 18393857.
  10. ^ Leneva IA, Burtseva EI, Yatsyshina SB, Fedyakina IT, Kirillova ES, Selkova EP, et al. (February 2016). "Virus susceptibility and clinical effectiveness of anti-influenza drugs during the 2010-2011 influenza season in Russia". International Journal of Infectious Diseases. 43: 77–84. doi:10.1016/j.ijid.2016.01.001. PMID 26775570.
  11. ^ "Russian Pharmaceutical Market 2010" (PDF). DSM Group. Archived from the original (PDF) on 20 December 2018. Retrieved 17 June 2020.
  12. ^ "Most popular antiviral medication brands in the Russian pharmaceutical market in 1st quarter 2020 by sales value share". Statista. Retrieved 17 June 2020.
  13. ^ Pécheur EI, Lavillette D, Alcaras F, Molle J, Boriskin YS, Roberts M, et al. (May 2007). "Biochemical mechanism of hepatitis C virus inhibition by the broad-spectrum antiviral arbidol". Biochemistry. 46 (20): 6050–6059. doi:10.1021/bi700181j. PMC 2532706. PMID 17455911.
  14. ^ Qian X, Qi Z (June 2022). "Mosquito-Borne Flaviviruses and Current Therapeutic Advances". Viruses. 14 (6): 1226. doi:10.3390/v14061226. PMC 9229039. PMID 35746697.
  15. ^ Pécheur EI, Borisevich V, Halfmann P, Morrey JD, Smee DF, Prichard M, et al. (January 2016). "The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses". Journal of Virology. 90 (6): 3086–3092. doi:10.1128/JVI.02077-15. PMC 4810626. PMID 26739045.
  16. ^ Hulseberg CE, Fénéant L, Szymańska-de Wijs KM, Kessler NP, Nelson EA, Shoemaker CJ, et al. (April 2019). "Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses". Journal of Virology. 93 (8). doi:10.1128/JVI.02185-18. PMC 6450122. PMID 30700611.
  17. ^ "АРБИДОЛ (ARBIDOL)". Vidal. Archived from the original on 4 February 2009.
  18. ^ Leneva IA, Russell RJ, Boriskin YS, Hay AJ (February 2009). "Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol". Antiviral Research. 81 (2): 132–140. doi:10.1016/j.antiviral.2008.10.009. PMID 19028526.
  19. ^ Kadam RU, Wilson IA (January 2017). "Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol". Proceedings of the National Academy of Sciences of the United States of America. 114 (2): 206–214. Bibcode:2017PNAS..114..206K. doi:10.1073/pnas.1617020114. PMC 5240704. PMID 28003465.
  20. ^ Haviernik J, Štefánik M, Fojtíková M, Kali S, Tordo N, Rudolf I, et al. (April 2018). "Arbidol (Umifenovir): A Broad-Spectrum Antiviral Drug That Inhibits Medically Important Arthropod-Borne Flaviviruses". Viruses. 10 (4): 184. doi:10.3390/v10040184. PMC 5923478. PMID 29642580.
  21. ^ Boriskin YS, Pécheur EI, Polyak SJ (July 2006). "Arbidol: a broad-spectrum antiviral that inhibits acute and chronic HCV infection". Virology Journal. 3: 56. doi:10.1186/1743-422X-3-56. PMC 1559594. PMID 16854226.
  22. ^ Shi L, Xiong H, He J, Deng H, Li Q, Zhong Q, et al. (2007). "Antiviral activity of arbidol against influenza A virus, respiratory syncytial virus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo". Archives of Virology. 152 (8): 1447–1455. doi:10.1007/s00705-007-0974-5. PMID 17497238. S2CID 13595688.
  23. ^ Glushkov RG, Gus'kova TA, Krylova LI, Nikolaeva IS (1999). "[Mechanisms of arbidole's immunomodulating action]". Vestnik Rossiiskoi Akademii Meditsinskikh Nauk (in Russian) (3): 36–40. PMID 10222830.
  24. ^ Eventova VA, Belov KV, Efimov SV, Khodov IA (January 2023). "Conformational Screening of Arbidol Solvates: Investigation via 2D NOESY". Pharmaceutics. 15 (1): 226. doi:10.3390/pharmaceutics15010226. PMC 9865235. PMID 36678855.
  25. ^ Belov KV, Dyshin AA, Khodov IA (March 2024). "Conformational analysis of arbidol in supercritical carbon Dioxide: Insights into 'opened' and 'closed' conformer groups". Journal of Molecular Liquids. 397: 124074. doi:10.1016/j.molliq.2024.124074. S2CID 267232952.
  26. ^ Rohrabaugh G. "PIND number 73,739 - arbidol" (PDF). Archived from the original (PDF) on 2021-11-04. Retrieved 1 July 2024.
  27. ^ "FDA and Arbidol". good-earth-medicine.com. Retrieved 1 July 2024.
  28. ^ "Resolution". Meetings of the Presidium of the Formulary Committee. Russian Academy of Medical Sciences. 16 March 2007.
  29. ^ "How do we plant federal ministers". MKRU (in Russian). 21 April 2011.
  30. ^ Golunov I (23 December 2013). "13 most popular flu cures: do they work?". Professional Journalism Platform (in Russian).
  31. ^ Svetlana R. "Палка в колеса" [Stick in the wheel]. Esquire (in Russian).
  32. ^ "Повторение — мать учения" [Repetition - the mother of learning]. Esquire (in Russian).
  33. ^ "Antimonopoly Service of Russia found violation in advertisement of drug, which stated its effectiveness against COVID-2019 - Crane IP". Retrieved 1 July 2024.
  34. ^ Cockerell I (2 April 2020). "The campaign to promote a mysterious Soviet-era drug as a coronavirus miracle cure". Coda Story. Retrieved 1 July 2024.
  35. ^ Ng E (4 February 2020). "Coronavirus: are cocktail therapies for flu and HIV the magic cure?". South China Morning Post. Bangkok and Hangzhou hospitals put combination remedies to the test.
  36. ^ Zheng W, Lau M (4 February 2020). "China's health officials say priority is to stop mild coronavirus cases from getting worse". South China Morning Post.
  37. ^ Leneva I, Kartashova N, Poromov A, Gracheva A, Korchevaya E, Glubokova E, et al. (August 2021). "Antiviral Activity of Umifenovir In Vitro against a Broad Spectrum of Coronaviruses, Including the Novel SARS-CoV-2 Virus". Viruses. 13 (8): 1665. doi:10.3390/v13081665. PMC 8402645. PMID 34452529.
  38. ^ Lu H (March 2020). "Drug treatment options for the 2019-new coronavirus (2019-nCoV)". BioScience Trends. 14 (1): 69–71. doi:10.5582/bst.2020.01020. PMID 31996494.
  39. ^ Chen J, Ling Y, Xi X, Liu P, Li F, Li T, et al. (2020-02-21). "Efficacies of lopinavir/ritonavir and arbidol in the treatment of novel coronavirus pneumonia". Chinese Journal of Infectious Diseases (in Chinese). 38: E008. doi:10.3760/cma.j.cn311365-20200210-00050. ISSN 1000-6680.
  40. ^ Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, et al. (December 2020). "Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients with Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial". Med. 1 (1): 105–113.e4. doi:10.1016/j.medj.2020.04.001. PMC 7235585. PMID 32838353.
  41. ^ Zhu Z, Lu Z, Xu T, Chen C, Yang G, Zha T, et al. (July 2020). "Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19". The Journal of Infection. 81 (1): e21–e23. doi:10.1016/j.jinf.2020.03.060. PMC 7195393. PMID 32283143.
  42. ^ Amani B, Amani B, Zareei S, Zareei M (December 2021). "Efficacy and safety of arbidol (umifenovir) in patients with COVID-19: A systematic review and meta-analysis". Immunity, Inflammation and Disease. 9 (4): 1197–1208. doi:10.1002/iid3.502. PMC 8426686. PMID 34347937.
[edit]
  • "Umifenovir". Drug Information Portal. U.S. National Library of Medicine.
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