Inosine pranobex

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Isoprinosine
INN: Inosine acedoben dimepranol
Chemical structures of the three components of inosine pranobex (from top to bottom: inosine, acedoben and dimethylamino isopropanol)
Combination of
InosineImmunostimulant
DimethylaminoisopropanolImmunostimulant
AcedobenImmunostimulant
Clinical data
Trade namesImunovir, Delimmun, Isoprinosine
Other namesMethisoprinol
AHFS/Drugs.comhttps://www.drugs.com/international/isoprinosine-500mg.html
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
PubChem CID
ChemSpider
UNII
KEGG
ECHA InfoCard100.048.313 Edit this at Wikidata

Inosine pranobex (BAN; also known as inosine acedoben dimepranol (INN), methisoprinol, inosiplex or Isoprinosine) is an antiviral drug that is a combination of inosine and dimepranol acedoben (a salt of acetamidobenzoic acid and dimethylaminoisopropanol) in a ratio of 1 to 3. It is used primarily in European countries, especially as a treatment for acute viral infections, such as the common cold.

Stimulation of the immune system[edit]

Inosine pranobex acts as an immunostimulant, an analog of thymus hormones[1]. It is indicated for an entire spectrum of patients with clinical manifestations of immune deficiency. It modulates the immune system by immunostimulation or immunooptimisation of defensive inflammation[2] at the cellular level, e.g. by interfering with energy metabolism, cell signalling and proliferation. It also modulates components of innate immunity, NK cells and dendritic cells[3]. Inhibits the production of pro-inflammatory cytokines TNF-α and IL-6[4]. It also optimizes the functional polarization of Th1, Th2, Th17 and Treg T-cell subsets. In clinical studies, the drug normalized impaired cellular immunity by inducing a Th1-type response that initiates T-cell maturation and differentiation.

Antiviral properties[edit]

It also has direct antiviral properties[2] via inhibition of the viral RNA synthesis. There is direct evidence of inosine pranobex inhibiting replication of RNA and DNA-viruses by lowering the concentration of viral mRNA. In simple terms, the inhibition happens as a result of inosine replacing adenine in the viral mRNA, through the wobble base pair mechanism, which in the end impedes the transcription of mRNA into viral particles. As this mechanism is common among all viruses, there is no specific selectivity of viruses, as is with most antivirals, and there is no way for viruses to gain resistance.

Antiviral activity has been documented in vivo on several animal models, and experimentally tested on the cytomegalovirus and Influenza disease strains. In vitro, there is antiviral activity documented for many RNA and DNA viruses including, but not limited to: herpes simplex virus, cytomegalovirus, adenovirus, poliovirus, and Influenza A and B viruses.[5]

Indications[edit]

Preventative use[edit]

For patients with suboptimally functioning immune systems, inosine pranobex can also be helpful in managing and decreasing the incidence[6] of common viral infections, such as the common cold or influenza.[7] As such, it is commonly prescribed preventatively, albeit at a lower dose.

Herpesvirus infections[edit]

Typically, inosine pranobex is indicated as a safe antiviral for herpesviruses, such as herpes simplex virus types 1 and 2, cytomegalovirus (CMV), and Epstein-Barr virus (EBV).[8] The drug also proved helpful in managing complicated cases of lengthy reactivations of herpesviruses such as EBV, and subsequent post-viral fatigue.

Human Papilloma Virus (HPV) infections[edit]

Inosine pranobex may be prescribed for the treatment of HPV infections, as a very safe and effective alternative therapy. Usually it is administred in combination with other treatment methods, such as CO2 laser and podophyllotoxin.

It was proven to be effective at treating genital warts[9], in combination with conventional non-surgical treatments, vulvar HPV infection, and cervical dysplasia[10]. It was also suggested as a possible alternative treatment for young women with chronic vulvodynia.[11] Several long-term studies have shown efficacy even compared to surgical method at treating oral HPV-positive proliferative verrucous leucoplakia (PVL).[12][13]

Influenza and Rhinovirus infections[edit]

The evidence in treating rhinovirus infections is mixed. While no statistically significant effect was observed in rhinovirus 44 or 32 infection[14], its administration in rhinovirus 21 infection led to statistically improved health outcomes in patients, shortened infectivity and decreased viral shedding.[7] In Influenza and Influenza-like (RSV, adenovirus and parainfluenza virus) infections, inosine pranobex did lower the symptom severity and duration.[15][13]

COVID-19[edit]

When the global coronavirus pandemic hit in 2020, inosine pranobex was one of the first medication used experimentally to treat the SARS-CoV-2 induced virosis, mainly due to its remarkably wide area of use and general antiviral properties. Several clinical trials were conducted returning largely positive results.

Its use was pioneered in the Czech Republic, where it was first noted that use greatly decreases mortality among elderly.[16] In 2022, a large Phase 3 trial concluded that administration of inosine pranobex should start as early as possible with greatly improved outcomes in mild to moderate COVID-19 patients.[17]

Type B and C Viral Hepatitis[edit]

In type B hepatitis, inosine pranobex was found ineffective during the acute phase of the infection, though in 28 days lower bilirubin and transaminase levels were detected. Greater number of patients became antigen-negative within a 90 day timeframe indicating a faster recovery rate.[18]

Type C hepatitis was not studied as extensively, hence not so much data is available. It has been shown that inosine pranobex therapy in combination with ribavirin normalises alanine aminotransferase levels in patients unresponsive to interferon treatment.[19]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)[edit]

There is also some evidence of the drug being helpful in treating chronic post-viral fatigue[20]. In 2003, the possibility of using inosine pranobex for treating myalgic encephalomyelitis/chronic fatigue syndrome was investigated experimentally and returned promising results[21], when 6 out of 10 subjects reported noticeable improvement. Promised Phase II and III clinical trials confirming initially observed effects have not been conducted yet as of 2024.

In 2021, the US ME/CFS Clinician Coalition recommended the use of inosine pranobex for "immune dysfunction" symptoms, specifically "frequent viral infections, herpes simplex outbreaks, low natural killer cell activity, sore throat, tender nodes, low grade fevers".[22]

Subacute Sclerosing Panencephalitis (SSPE)[edit]

Although the effect is unclear, several case reports have suggested that inosine pranobex may provide beneficial therapeutic effects in managing the illness. Several long-term studies suggested that the drug both increased survival and decreased neurological deficiencies.[23] It is not a cure for the illness though, as currently no cure exists.

Human Immunodeficiency Virus (HIV) and AIDS[edit]

Inosine pranobex as been proven to delay AIDS progression in HIV positive patients. In a large study of 831 HIV-positive patients, it was found to be very safe with no serious side effects reported.[24]

Dosing[edit]

For acute infection, the typical dose is 50 mg/day/kg of body weight. For prevention of chronic issues lower doses are typically recomended, usually under 2 g/day. The maximum dose permitted is around 4 g/day.

Safety[edit]

The most commonly found effects are nausea and vomiting. Hypotension, drowsiness and skin irritation may also occur. Metabolism of the inosine component of the drug can lead to an increase in uric acid levels in both blood and urine. The occurrence of transient reversible hyperuricaemia occurs in about 10% of patients taking inosine pranobex.[25] Due to the potential risk of hyperuricosuria and the development of urate nephrolithiasis, increased fluid intake and exclusion of acidic foods is recommended during isoprinosine therapy. Its administration is not recommended in combination with immunosuppressing medicine.

Tolerance studies in healthy individuals and patients have consistently shown that inosine pranobex has no serious side effects and is remarkably well tolerated by the organism. Continuous administration of the drug for up to 7 years, at doses ranging from 1 to 8 g per day, has only occasionally caused transient nausea. This nausea was associated with a large number of tablets ingested. In addition, transient increases in serum and urinary uric acid levels have been reported. This increase in serum uric acid concentration is more common in male patients than in females.[26]

References[edit]

  1. ^ "Inosine Pranobex". American Cancer Society. Archived from the original on 23 August 2010. Retrieved 31 July 2013.
  2. ^ a b "Imunologie člověka | WorldCat.org". search.worldcat.org (in Czech). Retrieved 2024-05-01.
  3. ^ McCarthy, Michael T.; Lin, Da; Soga, Tomoyoshi; Adam, Julie; O'Callaghan, Christopher A. (January 2020). "Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression". European Journal of Immunology. 50 (1): 130–137. doi:10.1002/eji.201847948. ISSN 0014-2980.
  4. ^ Petrova, Mihaela; Jelev, Dejan; Ivanova, Aneta; Krastev, Zahariy (April 2010). "Isoprinosine affects serum cytokine levels in healthy adults". Journal of Interferon & Cytokine Research: The Official Journal of the International Society for Interferon and Cytokine Research. 30 (4): 223–228. doi:10.1089/jir.2009.0057. ISSN 1557-7465. PMID 20038210.
  5. ^ Muldoon, R. L.; Mezny, L.; Jackson, G. G. (September 1972). "Effect of isoprinosine against influenza and some other viruses causing respiratory diseases". Antimicrobial Agents and Chemotherapy. 2 (3): 224–228. doi:10.1128/AAC.2.3.224. ISSN 0066-4804. PMID 4790561.
  6. ^ Osidak, L. V.; Викторовна, ОСИДАК Людмила; Obraztsova, E. V.; Викторовна, ОБРАЗЦОВА Елена (2012-04-15). "EFFICACY OF THE INOSINE PRANOBEX MOLECULE IN THERAPEUTIC AND PEDIATRIC PRACTICE". Epidemiology and Infectious Diseases. Current Items (in Russian). 0 (4): 26–32. ISSN 2414-9640.
  7. ^ a b Waldman, R. H.; Ganguly, R. (1977-03-04). "Therapeutic efficacy of inosiplex (Isoprinosine) in rhinovirus infection". Annals of the New York Academy of Sciences. 284: 153–160. doi:10.1111/j.1749-6632.1977.tb21946.x. ISSN 0077-8923. PMID 81636.
  8. ^ Hashimoto K, Hosoya M (January 2021). "Advances in Antiviral Therapy for Subacute Sclerosing Panencephalitis". Molecules. 26 (2): 427. doi:10.3390/molecules26020427. PMC 7830519. PMID 33467470.
  9. ^ Davidson-Parker, J; Dinsmore, W; Khan, M H; Hicks, D A; Morris, C A; Morris, D F (1988-12-01). "Immunotherapy of genital warts with inosine pranobex and conventional treatment: double blind placebo controlled study". Sexually Transmitted Infections. 64 (6): 383–386. doi:10.1136/sti.64.6.383. ISSN 1368-4973.
  10. ^ Gudz, O. V.; Kamilova, I. K.; Miklin, O. P. (2016). "HPV infection of the cervix uteri: Prospects for combination treatment". Rossiiskii vestnik akushera-ginekologa. 16 (2): 99. doi:10.17116/rosakush201616299-103. ISSN 1726-6122.
  11. ^ Sand Petersen, C; Weismann, K. (1996-09-01). "Isoprenosine improves symptoms in young females with chronic vulvodynia". Acta Dermato-Venereologica. 76 (5): 404–404. doi:10.2340/0001555576404404. ISSN 1651-2057.
  12. ^ Femiano, F.; Gombos, F.; Scully, C. (August 2001). "Oral proliferative verrucous leukoplakia (PVL); open trial of surgery compared with combined therapy using surgery and methisoprinol in papillomavirus-related PVL". International Journal of Oral and Maxillofacial Surgery. 30 (4): 318–322. doi:10.1054/ijom.2001.0066.
  13. ^ a b Sliva, Jiri; Pantzartzi, Chrysoula N.; Votava, Martin (2019-08-01). "Inosine Pranobex: A Key Player in the Game Against a Wide Range of Viral Infections and Non-Infectious Diseases". Advances in Therapy. 36 (8): 1878–1905. doi:10.1007/s12325-019-00995-6. ISSN 1865-8652. PMC 6822865. PMID 31168764.
  14. ^ Pachuta, Donald M.; Togo, Yasushi; Hornick, Richard B.; Schwarts, Andrew R.; Tominaga, Suketami (April 1974). "Evaluation of Isoprinosine in Experimental Human Rhinovirus Infection". Antimicrobial Agents and Chemotherapy. 5 (4): 403–408. doi:10.1128/aac.5.4.403. ISSN 0066-4804.
  15. ^ Beran, Jiří; Šalapová, Eva; Špajdel, Marian; on behalf of the Isoprinosine Study (EWO ISO-2014/1) Team (2016-11-07). "Inosine pranobex is safe and effective for the treatment of subjects with confirmed acute respiratory viral infections: analysis and subgroup analysis from a Phase 4, randomised, placebo-controlled, double-blind study". BMC Infectious Diseases. 16 (1): 648. doi:10.1186/s12879-016-1965-5. ISSN 1471-2334. PMC 5100179. PMID 27821093.{{cite journal}}: CS1 maint: numeric names: authors list (link) CS1 maint: unflagged free DOI (link)
  16. ^ Beran, Jiří; Špajdel, Marián; Slíva, Jiří (2021-11-09). "Inosine Pranobex Deserves Attention as a Potential Immunomodulator to Achieve Early Alteration of the COVID-19 Disease Course". Viruses. 13 (11): 2246. doi:10.3390/v13112246. ISSN 1999-4915. PMC 8619495. PMID 34835052.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  17. ^ C R, Jayanthi; Swain, Ashok K; Ganga, Ranganath T; Halnor, Dnyaneshwar; Avhad, Ajit; Khan, Mohd. Saif; Ghosh, Ayan; Choudhary, Sumer Sanjiv; Yannawar, Anand Namdevrao; Despande, Shubhangi; Patel, Manish; Anne, Krishna Prasad; Bangar, Yogesh (December 2022). "Efficacy and Safety of Inosine Pranobex in COVID‐19 Patients: A Multicenter Phase 3 Randomized Double‐Blind, Placebo‐Controlled Trial". Advanced Therapeutics. 5 (12). doi:10.1002/adtp.202200159. ISSN 2366-3987. PMC 9539257. PMID 36246300.
  18. ^ Indries, Mirela (December 2013). "Clinical and histological corelations in chronic viral hepatitis C". BMC Infectious Diseases. 13 (S1). doi:10.1186/1471-2334-13-s1-p52. ISSN 1471-2334.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ Pardo, M.; Carreño, V. (January 1994). "Lack of efficacy of inosine pranobex in the treatment of chronic hepatitis C". Journal of Hepatology. 21 (2): 278. doi:10.1016/s0168-8278(05)80410-6. ISSN 0168-8278.
  20. ^ www.MeDitorial.cz. "Největší informační zdroj pro lékaře". www.prolekare.cz (in Czech). Retrieved 2024-05-01.
  21. ^ Diaz-Mitoma, Francisco; Turgonyi, Eva; Kumar, Ashok; Lim, Wilfred; Larocque, Louise; Hyde, Byron M. (January 2003). "Clinical Improvement in Chronic Fatigue Syndrome Is Associated with Enhanced Natural Killer Cell-Mediated Cytotoxicity: The Results of a Pilot Study with Isoprinosine®". Journal of Chronic Fatigue Syndrome. 11 (2): 71–95. doi:10.1300/J092v11n02_06. ISSN 1057-3321.
  22. ^ Campling, Frankie; Sharpe, Michael (2008-07-03), "Some myths about CFS/ME", Chronic fatigue syndrome (CFS/ME), Oxford University PressOxford, pp. 57–60, ISBN 978-0-19-923316-8, retrieved 2024-05-01
  23. ^ Huttenlocher, Peter R.; Mattson, Richard H. (June 1979). "Isoprinosine in subacute sclerosing panencephalitis". Neurology. 29 (6): 763–763. doi:10.1212/WNL.29.6.763. ISSN 0028-3878.
  24. ^ Glasky, A J; Gordon, J F (1987-01-01). "Isoprinosine (inosine pranobex BAN, INPX) in the treatment of AIDS and other acquired immunodeficiencies of clinical importance". Cancer detection and prevention Supplement. 1: 597–609. ISSN 1043-6995. PMID 2446760.
  25. ^ You, Yi; Wang, Li; Li, Yafei; Wang, Qianqiu; Cao, Shuanglin; Tu, Yating; Li, Shenqiu; Bai, Li; Lu, Jianyun; Wei, Zhiping; Chen, Wenchieh; Hao, Fei (June 2015). "Multicenter randomized study of inosine pranobex versus acyclovir in the treatment of recurrent herpes labialis and recurrent herpes genitalis in Chinese patients". The Journal of Dermatology. 42 (6): 596–601. doi:10.1111/1346-8138.12845. ISSN 0385-2407.
  26. ^ Campoli-Richards, Deborah M.; Sorkin, Eugene M.; Heel, Rennie C. (1986-11-01). "Inosine Pranobex". Drugs. 32 (5): 383–424. doi:10.2165/00003495-198632050-00001. ISSN 1179-1950.
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