Since its licensing in 1971, the synthetic compound inosine pranobex has been effectively combating viral infections, including herpes zoster, varicella, measles, and infections caused by the herpes simplex virus, human papillomavirus, Epstein-Barr virus, cytomegalovirus, and respiratory viruses. With the emergence of SARS-CoV-2, new and existing drugs have been intensively evaluated for their potential as COVID-19 medication. Due to its potent immunomodulatory properties, inosine pranobex, an orally administered drug with pleiotropic effects, can, during early treatment, alter the course of the disease. We describe the action of inosine pranobex in the body and give an overview of existing evidence collected to support further efforts to study this drug in a rigorous clinical trial setup.

Department for Tropical Travel Medicine and Immunization Institute of Postgraduate Health Education 100 05 Prague Czech Republic

Department of Pharmacology 3rd Faculty of Medicine Charles University 100 00 Prague Czech Republic

Department of Psychology Faculty of Philosophy and Arts Trnava University 918 43 Trnava Slovakia

Zobrazit více v PubMed

Thompson R.N., Hill E.M., Gog J.R. SARS-CoV-2 incidence and vaccine escape. Lancet Infect Dis. 2021;21:913–914. doi: 10.1016/S1473-3099(21)00202-4. PubMed DOI PMC

Inchingolo A., Inchingolo A., Bordea I., Malcangi G., Xhajanka E., Scarano A., Lorusso F., Farronato M., Tartaglia G., Isacco C., et al. SARS-CoV-2 Disease through Viral Genomic and Receptor Implications: An Overview of Diagnostic and Immunology Breakthroughs. Microorganisms. 2021;9:793. doi: 10.3390/microorganisms9040793. PubMed DOI PMC

Goldman R.D., Yan T.D., Seiler M., Cotanda C.P., Brown J.C., Klein E.J., Hoeffe J., Gelernter R., Hall J.E., Davis A.L., et al. Caregiver willingness to vaccinate their children against COVID-19: Cross sectional survey. Vaccine. 2020;38:7668–7673. doi: 10.1016/j.vaccine.2020.09.084. PubMed DOI PMC

Odone A., Bucci D., Croci R., Riccò M., Affanni P., Signorelli C. Vaccine hesitancy in COVID-19 times. An update from Italy before flu season starts. Acta Biomed. 2020;91:e2020031. PubMed PMC

Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5. PubMed DOI PMC

Tichopád A., Pecen L., Sedlák V. Could the new coronavirus have infected humans prior November 2019? PLoS ONE. 2021;16:e0248255. doi: 10.1371/journal.pone.0248255. PubMed DOI PMC

Haas E.J., Angulo F.J., McLaughlin J.M., Anis E., Singer S.R., Khan F., Brooks N., Smaja M., Mircus G., Pan K., et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: An observational study using national surveillance data. Lancet. 2021;397:1819–1829. doi: 10.1016/S0140-6736(21)00947-8. Erratum in 2021, 398, 212, doi:10.1016/S0140-6736(21)01555-5. PubMed DOI PMC

Bernal J.L., Andrews N., Gower C., Gallagher E., Simmons R., Thelwall S., Stowe J., Tessier E., Groves N., Dabrera G., et al. Effectiveness of COVID-19 Vaccines against the B.1.617.2 (Delta) Variant. N. Engl. J. Med. 2021;385:585–594. doi: 10.1056/NEJMoa2108891. PubMed DOI PMC

Stowe J., Andrews N., Gower C., Gallagher E., Utsi L., Simmons R., Thelwall S., Tessier E., Groves N., Dabrera G., et al. Effectiveness of COVID-19 vaccines against hospital admission with the Delta (B.1.617.2) variant. [(accessed on 4 November 2021)];Public Health Engl. 2021 Available online: https://khub.net/web/phe-national/public-library/-/document_library/v2WsRK3ZlEig/view/479607266.

Griffin S. COVID-19: Fully vaccinated people can carry as much delta virus as unvaccinated people, data indicate. BMJ. 2021;374:n2074. doi: 10.1136/bmj.n2074. PubMed DOI

Kumar R., Gupta N., Kodan P., Mittal A., Soneja M., Wig N. Battling COVID-19: Using old weapons for a new enemy. Trop. Dis. Travel Med. Vaccines. 2020;6:1–10. doi: 10.1186/s40794-020-00107-1. PubMed DOI PMC

Inchingolo A., Inchingolo A., Bordea I., Malcangi G., Xhajanka E., Scarano A., Lorusso F., Farronato M., Tartaglia G., Isacco C., et al. SARS-CoV-2 Disease Adjuvant Therapies and Supplements Breakthrough for the Infection Prevention. Microorganisms. 2021;9:525. doi: 10.3390/microorganisms9030525. PubMed DOI PMC

Bordea I.R., Candrea S., Sălăgean T., Pop I.D., Lucaciu O., Ilea A., Manole M., Băbțan A.-M., Sirbu A., Hanna R. Impact of COVID-19 Pandemic on Healthcare Professionals and Oral Care Operational Services: A Systemic Review. Heal. Policy Politi-Sante. 2021;14:453–463. doi: 10.2147/rmhp.s284557. PubMed DOI PMC

Hanna R., Dalvi S., Sălăgean T., Pop I.D., Bordea I.R., Benedicenti S. Understanding COVID-19 Pandemic: Molecular Mechanisms and Potential Therapeutic Strategies. An Evidence-Based Review. J. Inflamm. Res. 2021;14:13–56. doi: 10.2147/JIR.S282213. PubMed DOI PMC

Yasuhara J., Kuno T., Takagi H., Sumitomo N. Clinical characteristics of COVID-19 in children: A systematic review. Pediatr. Pulmonol. 2020;55:2565–2575. doi: 10.1002/ppul.24991. PubMed DOI

Pormohammad A., Ghorbani S., Baradaran B., Khatami A., Turner R.J., Mansournia M.A., Kyriacou D.N., Idrovo J.-P., Bahr N.C. Clinical characteristics, laboratory findings, radiographic signs and outcomes of 61,742 patients with confirmed COVID-19 infection: A systematic review and meta-analysis. Microb. Pathog. 2020;147:104390. doi: 10.1016/j.micpath.2020.104390. PubMed DOI PMC

Dotolo S., Marabotti A., Facchiano A., Tagliaferri R. A review on drug repurposing applicable to COVID-19. Brief. Bioinform. 2021;22:726–741. doi: 10.1093/bib/bbaa288. PubMed DOI PMC

Sultana J., Crisafulli S., Gabbay F., Lynn E., Shakir S., Trifirò G. Challenges for Drug Repurposing in the COVID-19 Pandemic Era. Front. Pharmacol. 2020;11:1657. doi: 10.3389/fphar.2020.588654. PubMed DOI PMC

Pawar A.Y. Combating devastating COVID-19 by drug repurposing. Int. J. Antimicrob. Agents. 2020;56:105984. doi: 10.1016/j.ijantimicag.2020.105984. PubMed DOI PMC

Jang W.D., Jeon S., Kim S., Lee S.Y. Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay. Proc. Natl. Acad. Sci. USA. 2021;118:e2024302118. doi: 10.1073/pnas.2024302118. PubMed DOI PMC

Sun D., Li H., Lu X.X., Xiao H., Ren J., Zhang F.R., Liu Z.S. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: A single center’s observational study. World J. Pediatr. 2020;16:251–259. doi: 10.1007/s12519-020-00354-4. PubMed DOI PMC

Gao Y., Li T., Han M., Li X., Wu D., Xu Y., Zhu Y., Liu Y., Wang X., Wang L. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J. Med. Virol. 2020;92:791–796. doi: 10.1002/jmv.25770. PubMed DOI PMC

Chen G., Wu D., Guo W., Cao Y., Huang D., Wang H., Wang T., Zhang X., Chen H., Yu H. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019. J. Clin. Investig. 2020;130:2620–2629. doi: 10.1172/JCI137244. PubMed DOI PMC

Ruan Q., Yang K., Wang W., Jiang L., Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46:846–848. doi: 10.1007/s00134-020-05991-x. PubMed DOI PMC

Waggoner S.N., Reighard S.D., Gyurova I.E., Cranert A.S.A., Mahl E.S.E., Karmele E.P., McNally J.P., Moran M.T., Brooks T.R., Yaqoob F., et al. Roles of natural killer cells in antiviral immunity. Curr. Opin. Virol. 2015;16:15–23. doi: 10.1016/j.coviro.2015.10.008. PubMed DOI PMC

Zhao Q., Meng M., Kumar R., Wu Y., Huang J., Deng Y., Weng Z., Yang L. Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis. Int. J. Infect. Dis. 2020;96:131–135. doi: 10.1016/j.ijid.2020.04.086. PubMed DOI PMC

Huang I., Pranata R. Lymphopenia in severe coronavirus disease-2019 (COVID-19): Systematic review and meta-analysis. J. Intensive Care. 2020;8:36. doi: 10.1186/s40560-020-00453-4. PubMed DOI PMC

Zheng M., Gao Y., Wang G., Song G., Liu S., Sun D., Xu Y., Tian Z. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell. Mol. Immunol. 2020;17:533–535. doi: 10.1038/s41423-020-0402-2. PubMed DOI PMC

Zheng Q., Li Y.-Z., Huang G., Wu W., Dong S.-Y., Xu Y. Mortality of COVID-19 Is Associated with Cellular Immune Function Compared to Immune Function in the Chinese Han Population. [(accessed on 30 August 2021)]. Available online: https://www.medrxiv.org/content/10.1101/2020.03.08.20031229v2. DOI

Tan L., Wang Q., Zhang D., Ding J., Huang Q., Tang Y., Wang Q., Miao H. Lymphopenia predicts disease severity of COVID-19: A descriptive and predictive study. Signal. Transduct. Target Ther. 2020;5:33. doi: 10.1038/s41392-020-0148-4. PubMed DOI PMC

Jafarzadeh A., Jafarzadeh S., Nozari P., Mokhtari P., Nemati M. Lymphopenia an important immunological abnormality in patients with COVID-19: Possible mechanisms. Scand. J. Immunol. 2021;93:e12967. doi: 10.1111/sji.12967. PubMed DOI

Thevarajan I., Nguyen T.H.O., Koutsakos M., Druce J., Caly L., van de Sandt C.E., Jia X., Nicholson S., Catton M., Cowie B., et al. Breadth of concomitant immune responses prior to patient recovery: A case report of non-severe COVID-19. Nat. Med. 2020;26:453–455. doi: 10.1038/s41591-020-0819-2. PubMed DOI PMC

Doesschate T.T., Moorlag S.J.C.F.M., van der Vaart T.W., Taks E., Debisarun P., Oever J.T., Bleeker-Rovers C.P., Verhagen P.B., Lalmohamed A., ter Heine R., et al. Two Randomized Controlled Trials of Bacillus Calmette-Guérin Vaccination to reduce absenteeism among health care workers and hospital admission by elderly persons during the COVID-19 pandemic: A structured summary of the study protocols for two randomised controlled trials. Trials. 2020;21:481. doi: 10.1186/s13063-020-04389-w. PubMed DOI PMC

Loo J., Spittle D.A., Newnham M. COVID-19, immunothrombosis and venous thromboembolism: Biological mechanisms. Thorax. 2021;76:412–420. doi: 10.1136/thoraxjnl-2020-216243. PubMed DOI

Mirzaei R., Goodarzi P., Asadi M., Soltani A., Aljanabi H.A.A., Jeda A.S., Dashtbin S., Jalalifar S., Mohammadzadeh R., Teimoori A., et al. Bacterial co-infections with SARS-CoV-2. IUBMB Life. 2020;72:2097–2111. doi: 10.1002/iub.2356. PubMed DOI PMC

Trivedi N., Verma A., Kumar D. Possible treatment and strategies for COVID-19: Review and assessment. Eur. Rev. Med. Pharmacol. Sci. 2020;24:12593–12608. PubMed

Wybran J., Govaerts A., Appelboom T. Inosiplex, a stimulating agent for normal human T cells and human leukocytes. J. Immunol. 1978;121:1184–1187. PubMed

Wybran J., Appelboom T. Immunomodulation. Springer International Publishing; Berlin/Heidelberg, Germany: 1984. Isoprinosine (Inosiplex): Immunological and Clinical Effects; pp. 363–374.

O’Neill B.B., Robins D.S. Isoprinosine in the treatment of genital warts. Cancer Detect. Prev. 1988;12:497–501. PubMed

Georgala S., Katoulis A.C., Befon A., Georgala C. Rigopoulos, D. Oral inosiplex in the treatment of cervical condy-lomata acuminata: A randomised placebo-controlled trial. BJOG. 2006;113:1088–1091. doi: 10.1111/j.1471-0528.2006.01041.x. PubMed DOI

Sundar S.K., Barile G., Menezes J. Isoprinosine enhances the activation of sensitized lymphocytes by Epstein-Barr virus antigens. Int. J. Immunopharmacol. 1985;7:187–192. doi: 10.1016/0192-0561(85)90025-6. PubMed DOI

Pedersen B.K., Tvede N., Diamant M., Gerstoft J., Hansen M.B., Haahr P.M., Hørding M., Käppel M., Klokker M., Søeberg B., et al. Effects of Isoprinosine Treatment of HIV-Positive Patients on Blood Mononuclear Cell Subsets, NK- and T-Cell Function, Tumour Necrosis Factor, and Interleukins 1, 2, and 6. Scand. J. Immunol. 1990;32:641–649. doi: 10.1111/j.1365-3083.1990.tb03206.x. PubMed DOI

Wiranowska-Stewart M., Hadden J.W. Effects of isoprinosine and NPT 15392 on interleukin-2 (IL-2) production. Int. J. Immunopharmacol. 1986;8:63–69. doi: 10.1016/0192-0561(86)90074-3. PubMed DOI

Milano S., Dieli M., Millott S., Miceli M.D., Maltese E., Cillari E. Effect of isoprinosine on IL-2, IFN-γ and IL-4 production in vivo and in vitro. Int. J. Immunopharmacol. 1991;13:1013–1018. doi: 10.1016/0192-0561(91)90055-C. PubMed DOI

Petrova M., Jelev D., Ivanova A., Krastev Z. Isoprinosine Affects Serum Cytokine Levels in Healthy Adults. J. Interf. Cytokine Res. 2010;30:223–228. doi: 10.1089/jir.2009.0057. PubMed DOI

Lasek W., Janyst M., Wolny R., Zapała Ł., Bocian K., Drela N. Immunomodulatory effects of inosine pranobex on cytokine production by human lymphocytes. Acta Pharm. 2015;65:171–180. doi: 10.1515/acph-2015-0015. PubMed DOI

Gordon P., Brown E.R. The anti-viral activity of isoprinosine. Can. J. Microbiol. 1972;18:1463–1470. doi: 10.1139/m72-224. PubMed DOI

Chang T.W., Weinstein L. Antiviral activity of isoprinosine in vitro and in vivo. Am. J. Med. Sci. 1973;265:143–146. doi: 10.1097/00000441-197302000-00005. PubMed DOI

Linhares R.E.C., Wigg M.D., Lagrota M.H.C., Nozawa C.M. The in vitro anti-viral activity of isoprinosine on simian rotavirus (SA-11) Braz. J. Med. Biol. Res. 1989;22:1095–1103. PubMed

Sliva J., Pantzartzi C.N., Votava N. Inosine Pranobex: A Key Player in the Game against a Wide Range of Viral Infections and Non-Infectious Diseases. Adv. Ther. 2019;36:1878–1905. doi: 10.1007/s12325-019-00995-6. PubMed DOI PMC

You Y., Wang L., Li Y., Wang Q., Cao S., Tu Y., Li S., Bai L., Lu J., Wei Z. Multicenter randomized study of inosine pranobex versus acyclovir in the treatment of recurrent herpes la-bialis and recurrent herpes genitalis in Chinese patients. J. Dermatol. 2015;42:596–601. doi: 10.1111/1346-8138.12845. PubMed DOI

Galli M., Lazzarin A., Moroni M., Zanussi C. Immunomodulation. Springer; Boston, MA, USA: 1984. Treatment of Recurrent Viral Infectious Diseases by Methisoprinol; pp. 385–397.

Galli M., Lazzarin A., Moroni M., Zanussi C. Inosiplex in recurrent herpes simplex infections. Lancet. 1982;2:331–332. doi: 10.1016/S0140-6736(82)90300-2. PubMed DOI

Talbot D., Menday A., Saurat J.-H. Inosine Pranobex in Mucocutaneous Herpes. Lancet. 1985;325:877. doi: 10.1016/S0140-6736(85)92239-1. PubMed DOI

Byrne M.A.A., Lawrence A., Walker G.D., O’Neill B., Csonka G., John J., Shanson D., Jeffries D., Harris J. Suppression of recurrent genital herpes by inosine pranobex: Effects of episodic and continuous treatment. Curr. Ther. Res.-Clin. Exp. 1988;43:681–688.

Mindel A., Carney O., Sonnex C., Freris M., Patou G., Williams P. Suppression of frequently recurring genital herpes: Acyclovir v inosine pranobex. Sex. Transm. Infect. 1989;65:103–105. doi: 10.1136/sti.65.2.103. PubMed DOI PMC

Kinghorn G.R., Woolley P.D., Thin R.N., De Maubeuge J., Foidart J.M., Engst R. Acyclovir vs isoprinosine (immunovir) for suppression of recurrent genital herpes simplex infection. Sex. Transm. Infect. 1992;68:312–316. doi: 10.1136/sti.68.5.312. PubMed DOI PMC

Huttenlocher P.R., Mattson R.H. Isoprinosine in subacute sclerosing panencephalitis. Neurology. 1979;29:763. doi: 10.1212/WNL.29.6.763. PubMed DOI

Haddad F.S., Risk W.S. Isoprinosine treatment in 18 patients with subacute sclerosing panencephalitis: A controlled study. Ann. Neurol. 1980;7:185–188. doi: 10.1002/ana.410070216. PubMed DOI

Silverberg R., Brenner T., Abramsky O. Inosiplex in the Treatment of Subacute Sclerosing Panencephalitis. Arch. Neurol. 1979;36:374–375. doi: 10.1001/archneur.1979.00500420084012. PubMed DOI

Jones C., Huttenlocher P., Dyken P., Jabbour J., Maxwell K. Inosiplex Therapy in Subacute Sclerosing Panencephalitis. Lancet. 1982;319:1034–1037. doi: 10.1016/S0140-6736(82)92097-9. PubMed DOI

DuRant R.H., Dyken P.R., Swift A.V. The influence of inosiplex treatment on the neurological disability of patients with subacute sclerosing panencephalitis. J. Pediatr. 1982;101:288–293. doi: 10.1016/S0022-3476(82)80143-1. PubMed DOI

Anlar B., Yalaz K., Öktem F., Köse G. Long-term follow-up of patients with subacute sclerosing panencephalitis treated with intraventricular α-interferon. Neurology. 1997;482:526–528. doi: 10.1212/WNL.48.2.526. PubMed DOI

Anlar B., Yalaz K., Köse G., Saygi S. β-Interferon Plus Inosiplex in the Treatment of Subacute Sclerosing Panencephalitis. J. Child Neurol. 1998;13:557–559. doi: 10.1177/088307389801301106. PubMed DOI

Yalaz K., Anlar B., Oktem F., Aysun S., Ustacelebi S., Gurcay O., Gucuyener K., Renda Y. Intraventricular interferon and oral inosiplex in the treatment of subacute sclerosing panencephalitis. Neurology. 1992;42:488. doi: 10.1212/WNL.42.3.488. PubMed DOI

Sobczyk W., Kulczycki J., Piłkowska E., Iwińska B., Milewska D., Szmigielski S. Comparison of the results of the treatment of patients with SSPE using various immunomodulating preparations. Neurol. Neurochir. Polska. 1991;25:626–633. PubMed

Gascon G., Yamani S., Crowell J., Stigsby B., Nester M., Kanaan I., Jallu A. Combined oral isoprinosine-intraventricular α-interferon therapy for subacute sclerosing panencephalitis. Brain Dev. 1993;15:346–355. doi: 10.1016/0387-7604(93)90120-W. PubMed DOI

Khakoo R.A., Watson G.W., Waldman R.H., Ganguly R. Effect of inosiplex (isoprinosine) on induced human in-fluenza infection. J. Antimicrob. Chemother. 1981;7:389–397. doi: 10.1093/jac/7.4.389. PubMed DOI

Beran J., Šalapová E., Špajdel M. 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 Infect. Dis. 2016;16:1–10. doi: 10.1186/s12879-016-1965-5. PubMed DOI PMC

Waldman R.H., Ganguly R. Therapeutic efficacy of inosiplex (isoprinosine®) in rhinovirus infection. Ann. N. Y. Acad. Sci. 1977;284:153–160. doi: 10.1111/j.1749-6632.1977.tb21946.x. PubMed DOI

Bekesi J.G., Tsang P.H., Wallace I.J., Roboz J.P. Immunorestorative properties of isoprinosine in the treatment of patients at high risk of developing ARC or AIDS. J. Clin. Lab. Immunol. 1987;24:155–161. PubMed

Wallace J.I., Bekesi J. A double-blind clinical trial of the effects of inosine pranobex in immunodepressed patients with prolonged generalized lymphadenopathy. Clin. Immunol. Immunopathol. 1986;39:179–186. doi: 10.1016/0090-1229(86)90218-7. PubMed DOI

Kovacs A.J., Powell F., Voeller D., Allegra C.J. Inhibition of Pneumocystis carinii dihydropteroate synthetase by para-acetamidobenzoic acid: Possible mechanism of action of isoprinosine in human immunodeficiency virus infection. Antimicrob. Agents Chemother. 1993;37:1227–1231. doi: 10.1128/AAC.37.6.1227. PubMed DOI PMC

World Health Organization Influenza: BRaVe Call to Action. 2013. [(accessed on 5 September 2021)]. Available online: http://www.who.int/influenza/patient_care/clinical/call_to_action/en/

Guo Y., Patil N.K., Luan L., Bohannon J.K., Sherwood E.R. The biology of natural killer cells during sepsis. Immunology. 2017;153:190–202. doi: 10.1111/imm.12854. PubMed DOI PMC

Trinchieri G. Biology of Natural Killer Cells. Adv. Immunol. 1989;47:187–376. doi: 10.1016/s0065-2776(08)60664-1. PubMed DOI PMC

Vivier E., Tomasello E., Baratin M., Walzer T., Ugolini S. Functions of natural killer cells. Nat. Immunol. 2008;9:503–510. doi: 10.1038/ni1582. PubMed DOI

Diaz-Salazar C., Sun J.C. Natural killer cell responses to emerging viruses of zoonotic origin. Curr. Opin. Virol. 2020;44:97–111. doi: 10.1016/j.coviro.2020.07.003. PubMed DOI PMC

Cerwenka A., Lanier L.L. Natural killer cells, viruses and cancer. Nat. Rev. Immunol. 2001;1:41–49. doi: 10.1038/35095564. PubMed DOI

Jost S., Altfeld M. Control of Human Viral Infections by Natural Killer Cells. Annu. Rev. Immunol. 2013;31:163–194. doi: 10.1146/annurev-immunol-032712-100001. PubMed DOI

Vivier E., Nunès J.A., Vély F. Natural Killer Cell Signaling Pathways. Science. 2004;306:1517–1519. doi: 10.1126/science.1103478. PubMed DOI

Ahmed S.R., Newman A.S., O’Daly J., Duffy S., Grafton G., Brady C.A., Curnow S.J., Barnes N.M., Gordon J. Inosine Acedoben Dimepranol promotes an early and sustained increase in the natural killer cell component of circulating lymphocytes: A clinical trial supporting anti-viral indications. Int. Immunopharmacol. 2017;42:108–114. doi: 10.1016/j.intimp.2016.11.023. PubMed DOI

Ma Y., Li X., Kuang E. Viral Evasion of Natural Killer Cell Activation. Viruses. 2016;8:95. doi: 10.3390/v8040095. PubMed DOI PMC

Moretta A., Marcenaro E., Parolini S., Ferlazzo G., Moretta L. NK cells at the interface between innate and adaptive immunity. Cell Death Differ. 2007;15:226–233. doi: 10.1038/sj.cdd.4402170. PubMed DOI

Smyth M.J., Cretney E., Kelly J.M., Westwood J.A., Street S.E., Yagita H., Takeda K., van Dommelen S.L., Degli-Esposti M.A., Hayakawa Y. Activation of NK cell cytotoxicity. Mol. Immunol. 2005;42:501–510. doi: 10.1016/j.molimm.2004.07.034. PubMed DOI

Gayoso I., Sanchez-Correa B., Campos C., Alonso C., Pera A., Casado J.G., Morgado S., Tarazona R., Solana R. Immunosenescence of Human Natural Killer Cells. J. Innate Immun. 2011;3:337–343. doi: 10.1159/000328005. PubMed DOI

Hazeldine J., Lord J.M. The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res. Rev. 2013;12:1069–1078. doi: 10.1016/j.arr.2013.04.003. PubMed DOI PMC

McCarthy M.T., Lin D., Soga T., Adam J., O’Callaghan C.A. Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression. Eur. J. Immunol. 2020;50:130–137. doi: 10.1002/eji.201847948. PubMed DOI PMC

Beran J., Špajdel M., Katzerová V., Holoušová A., Malyš J., Finger Rousková J., Slíva J. Inosine pranobex significantly decreased the case-fatality rate among PCR positive elderly with SARS-CoV-2 at three nursing homes in the Czech Republic. Pathogens. 2020;9:1055. doi: 10.3390/pathogens9121055. PubMed DOI PMC

Kennelly S.P., Dyer A.H., Noonan C., Martin R., Kennelly S.M., Martin A., O’Neill D., Fallon A. Asymptomatic carriage rates and case fatality of SARS-CoV-2 infection in residents and staff in Irish nursing homes. Age Ageing. 2021;50:49–54. doi: 10.1093/ageing/afaa220. PubMed DOI PMC

Borges M., Borges J., Bastidas R. Estudio experimental: Manejo del metisoprinol en pacientes con COVID-19. Univ. Cienc. Tecnol. 2020;24:41–50. doi: 10.47460/uct.v24i103.356. DOI