{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T05:31:32Z","timestamp":1789882292494,"version":"4.0.1"},"reference-count":37,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T00:00:00Z","timestamp":1673395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Federal Target Program \u201cThe National System of Chemical and Biological Safety of the Russian Federation (2009\u20132014)\u201d"},{"name":"State assignment of State Research Centre of Virology and Biotechnology \u201cVector\u201d of Rospotrebnadzor (2018\u20132022)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Background: Since most of the modern human population has no anti-smallpox immunity, it is extremely important to develop and implement effective drugs for the treatment of smallpox and other orthopoxvirus infections. The objective of this study is to determine the main characteristics of the chemical substance NIOCH-14 and its safety and bioavailability in the body of laboratory animals. Methods: The safety of NIOCH-14 upon single- or multiple-dose intragastric administration was assessed according to its effect on the main hematological and pathomorphological parameters of laboratory mice and rats. In order to evaluate the pharmacokinetic parameters of NIOCH-14 administered orally, a concentration of ST-246, the active metabolite of NIOCH-14, in mouse blood and organs was determined by tandem mass spectrometry and liquid chromatography. Results: The intragastric administration of NIOCH-14 at a dose of 5 g\/kg body weight caused neither death nor signs of intoxication in mice. The intragastric administration of NIOCH-14 to mice and rats at doses of 50 and 150 \u00b5g\/g body weight either as a single dose or once daily during 30 days did not cause animal death or critical changes in hematological parameters and the microstructure of internal organs. The tissue availability of NIOCH-14 administered orally to the mice at a dose of 50 \u00b5g\/g body weight, which was calculated according to concentrations of its active metabolite ST-246 for the lungs, liver, kidney, brain, and spleen, was 100, 69.6, 63.3, 26.8 and 20.3%, respectively. The absolute bioavailability of the NIOCH-14 administered orally to mice at a dose of 50 \u00b5g\/g body weight was 22.8%. Conclusion: Along with the previously determined efficacy against orthopoxviruses, including the smallpox virus, the substance NIOCH-14 was shown to be safe and bioavailable in laboratory animal experiments.<\/jats:p>","DOI":"10.3390\/v15010205","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T06:18:08Z","timestamp":1673417888000},"page":"205","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Safety and Pharmacokinetics of the Substance of the Anti-Smallpox Drug NIOCH-14 after Oral Administration to Laboratory Animals"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8264-0217","authenticated-orcid":false,"given":"Larisa N.","family":"Shishkina","sequence":"first","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg Yu.","family":"Mazurkov","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolai I.","family":"Bormotov","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maksim O.","family":"Skarnovich","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga A.","family":"Serova","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia A.","family":"Mazurkova","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Skarnovich","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8362-2443","authenticated-orcid":false,"given":"Alexander A.","family":"Chernonosov","sequence":"additional","affiliation":[{"name":"The Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris A.","family":"Selivanov","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey Ya.","family":"Tikhonov","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7441-333X","authenticated-orcid":false,"given":"Svetlana G.","family":"Gamaley","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina G.","family":"Shimina","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina M.","family":"Sysoyeva","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6746-8092","authenticated-orcid":false,"given":"Oleg S.","family":"Taranov","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena D.","family":"Danilenko","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2577-0434","authenticated-orcid":false,"given":"Alexander P.","family":"Agafonov","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinat A.","family":"Maksyutov","sequence":"additional","affiliation":[{"name":"Federal Budgetary Research Institution\u2014State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,11]]},"reference":[{"key":"ref_1","unstructured":"Marennikova, S.S., and Shchelkunov, S.N. (1998). Orthopoxviruses Pathogenic for Humans, KMK Scientific Press Ltd.. (In Russian)."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/S0190-9622(00)90265-2","article-title":"Cowpox virus infection in an 11-year-old girl","volume":"42","author":"Wienecke","year":"2000","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1006\/viro.2000.0603","article-title":"An emergent poxvirus from humans and cattle in Rio de Janeiro State: Cantagalo virus may derive from Brazilian smallpox vaccine","volume":"277","author":"Damaso","year":"2000","journal-title":"Virology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1056\/NEJMoa032299","article-title":"The detection of monkeypox in humans in the Western Hemisphere","volume":"350","author":"Reed","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1159\/000331426","article-title":"Necrotic ulcerated lesion in a young boy caused by cowpox virus infection","volume":"3","author":"Favier","year":"2011","journal-title":"Case Rep. Dermatol."},{"key":"ref_6","first-page":"69","article-title":"Monkeypox: Features of spread after cancellation of mandatory pox immunization","volume":"2","author":"Borisevich","year":"2012","journal-title":"J. Microbiol. Epidemiol. Immunobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1056\/NEJMc1208124","article-title":"Variola virus in a 300-year-old Siberian mummy","volume":"367","author":"Biagini","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Olson, V.A., and Shchelkunov, S.N. (2017). Are we prepared in case of a possible smallpox-like disease emergence?. Viruses, 9.","DOI":"10.3390\/v9090242"},{"key":"ref_9","unstructured":"World Health Organization (2022, October 04). Multi-Country Outbreak of Monkeypox. External Situation Report #6\u201321 September 2022, Available online: https:\/\/www.who.int\/publications\/m\/item\/multi-country-outbreak-of-monkeypox--external-situation-report--6---21-september-2022."},{"key":"ref_10","unstructured":"(2018, July 13). FDA Approves the First Drug with an Indication for Treatment of Smallpox, FDA News Release, Available online: https:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/ucm613496.htm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13139","DOI":"10.1128\/JVI.79.20.13139-13149.2005","article-title":"An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus Challenge","volume":"79","author":"Yang","year":"2005","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1177\/095632020801900302","article-title":"Progress in the discovery of compounds inhibiting orthopoxviruses in animal models","volume":"19","author":"Smee","year":"2008","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9176","DOI":"10.1128\/JVI.02173-10","article-title":"Effective antiviral treatment of systemic orthopoxvirus disease: ST-246 treatment of prairie dogs infected with monkeypox virus","volume":"85","author":"Smith","year":"2011","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6246","DOI":"10.1128\/AAC.00977-13","article-title":"Efficacy of tecovirimat (ST-246) in nonhuman primates infected with variola virus (smallpox)","volume":"57","author":"Mucker","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chen, Y., Amantana, A., Tyavanagimatt, S.R., Zima, D., Yan, X.S., Kasi, G., Weeks, M., Stone, M.A., Weimers, W.C., and Samuel, P. (2011). Comparison of the Safety and Pharmacokinetics of ST-246\u00ae after IV Infusion or Oral Administration in Mice, Rabbits and Monkeys. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023237"},{"key":"ref_16","unstructured":"Selivanov, B.A., Tikhonov, A.Y., Belanov, E.F., Bormotov, N.I., Balakhnin, S.M., Serova, O.A., Svyatchenko, V.A., Kiselev, N.N., Kazachinskaya, E.B., and Loktev, V.B. (2011). 7-[N\u2019-4-trifluoromethylbenzyl)-hydrazinocarbonyl]-tricyclo[3.2.2.02.4]non-8-en-6-carboxylic Acid with Antiviral Activity. (No. 2412160), Patent RU, (In Russian)."},{"key":"ref_17","first-page":"58","article-title":"Estimation of therapeutic and prophylactic efficacy of chemical compound NIOCH-14 against ectromelia virus in vivo","volume":"1","author":"Kabanov","year":"2015","journal-title":"J. Microbiol. Epidemiol. Immunobiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1099\/jgv.0.000422","article-title":"The new effective chemically synthesized anti-smallpox compound NIOCH-14","volume":"97","author":"Mazurkov","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref_19","unstructured":"Shishkina, L.N., Sergeev, A.N., Agafonov, A.P., Sergeev, A.A., Kabanov, A.S., Bulychev, L.E., Sergeev, A.A., Gorbatovskaya, D.O., P\u2019yankov, O.V., and Bormotov, N.I. (2015). A Therapeutic and Prophylactic Drug against Variola Virus and Methods for Its Preparation and Use. (No. 2543338), Patent RU, (In Russian)."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1134\/S0012496611060135","article-title":"Tricyclo[3.2.2.02,4]non-8-en-6,7-Dicarbonic acid derivatives efficiently inhibits the replication of different orthopoxvirus species","volume":"441","author":"Selivanov","year":"2011","journal-title":"Dokl. Biol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1177\/0897190012456366","article-title":"Bioterrorism: Pathogens as weapons","volume":"25","author":"Anderson","year":"2012","journal-title":"J. Pharm. Pract."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1021\/jm061484y","article-title":"N-(3,3a,4,4a,5,5a,6,6a-Octahydro-1,3-dioxo-4,6- ethenocycloprop[f]isoindol-2-(1H)-yl)carboxamides: Identification of novel orthopoxvirus egress inhibitors","volume":"50","author":"Bailey","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_23","unstructured":"Sanitary Rules and Norms SanR&N 3.3686-21 \u201cSanitary and Epidemiological Requirements for the Prevention of Infectious Diseases\u201d, Mini Type."},{"key":"ref_24","unstructured":"National Research Council of the National Academies (2022, January 09). Guidelines on Laboratory Animal Care and Use, Available online: https:\/\/grants.nih.gov\/grants\/olaw\/guide-for-the-care-and-use-of-laboratory-animals.pdf."},{"key":"ref_25","unstructured":"SIGA Technologies Inc (2018, May 01). FDA Advisory Committee Briefing Document. Tecovirimat for the Treatment of Smallpox Disease. Antimicrobial Division Advisory Committee Meeting 1 May 2018. 83p. Final Advisory Committee Briefing Materials: Available for Public Release, Available online: https:\/\/www.fda.gov\/media\/112808\/download."},{"key":"ref_26","unstructured":"Mironov, A.N. (2012). Guidelines for Conducting Preclinical Studies of Drugs, Grif and K. (In Russian)."},{"key":"ref_27","unstructured":"Menshikov, V.V. (1987). Laboratory Research Methods in the Clinic, Medicine. (In Russian)."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.cmpb.2010.01.007","article-title":"PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel","volume":"99","author":"Zhang","year":"2010","journal-title":"Comput. Methods Programs Biomed."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"105182","DOI":"10.1016\/j.antiviral.2021.105182","article-title":"Benefit-risk assessment for brincidofovir for the treatment of smallpox: U.S. Food and Drug Administration\u2019s Evaluation","volume":"195","author":"Harrington","year":"2021","journal-title":"Antivir. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1177\/135965350701200802","article-title":"Activity of the anti-orthopoxvirus compound ST-246 against vaccinia, cowpox and camelpox viruses in cell monolayers and organotypic raft cultures","volume":"12","author":"Duraffour","year":"2007","journal-title":"Antivir. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1128\/AAC.00879-06","article-title":"Efficacy of delayed treatment with ST-246 given orally against systemic orthopoxvirus infections in mice","volume":"51","author":"Quenelle","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"768","DOI":"10.4269\/ajtmh.2007.76.768","article-title":"Efficacy of the antipoxvirus compound ST-246 for treatment of severe orthopoxvirus infection","volume":"76","author":"Sbrana","year":"2007","journal-title":"Am. J. Trop. Med. Hygiene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.1128\/AAC.00021-09","article-title":"Nonhuman primates are protected from smallpox virus or monkeypox virus challenges by the antiviral drug ST-246","volume":"53","author":"Huggins","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1128\/AAC.01596-08","article-title":"ST-246 antiviral efficacy in a nonhuman primate monkeypox model: Determination of the minimal effective dose and human dose justification","volume":"53","author":"Jordan","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1128\/AAC.01303-07","article-title":"Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor","volume":"52","author":"Jordan","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1128\/AAC.00959-12","article-title":"Pharmacokinetic and pharmacodynamic modeling to determine the dose of ST-246 to protect against smallpox in humans","volume":"57","author":"Leeds","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.antiviral.2012.02.005","article-title":"Evaluation of disease and viral biomarkers as triggers for therapeutic intervention in respiratory mousepox\u2014An animal model of smallpox","volume":"94","author":"Parker","year":"2012","journal-title":"Antivir. Research."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/1\/205\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:03:07Z","timestamp":1760119387000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/1\/205"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,11]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["v15010205"],"URL":"https:\/\/doi.org\/10.3390\/v15010205","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,11]]}}}