Experimental study of toxic properties of VMU-2012-05 drug – original non-nucleeside inhibitor of HIV-1 reverse transcriptase
- Authors: Vavilova V.A.1, Shekunova E.V.1, Jain E.A.2, Balabanyan V.Y.2, Ozerov A.A.3, Makarova M.N.1, Makarov V.G.1
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Affiliations:
- «Research-and manufacturing company «НОМЕ OF РНАRМАСУ» Joint Stock Company
- Moscow State University named after M.V. Lomonosov
- Volgograd State Medical University
- Issue: Vol 9, No 3 (2021)
- Pages: 205-221
- Section: Articles
- URL: https://ogarev-online.ru/2307-9266/article/view/111685
- DOI: https://doi.org/10.19163/2307-9266-2021-9-3-205-221
- ID: 111685
Cite item
Abstract
Antiretroviral therapy is currently the main component of treatment for HIV patients. The development of new, more effective and safer drugs is an urgent task.
The aim of the research is to study the toxic properties of the finished dosage form (FDF) VMU-2012-05, a non-nucleoside reverse transcriptase inhibitor (1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil) for the HIV-1 infection treatment in single and repeated enteral administrations.
Materials and methods. The study of toxic properties in single administrations was carried out on outbred mice; the drug was administered at the limiting dose of 2000 mg/kg (by reference to the active substance). For 90 days, in repeated daily administrations, the toxic properties were studied in rats of both sexes at the doses of 0 mg/kg (placebo), 9 mg/kg (1 HTD), 45 mg/kg (5 HTD), 90 mg/kg (10 HTD). The toxic properties were also studied in rabbits of both sexes within a 28-day administration at the doses of 0 mg/kg, 4 mg/kg (1 HTD), 20 mg/kg (5 HTD), 40 mg/kg (10 HTD); the recovery period 30 days. Clinical observations and examinations, body weight registrations, physiological and clinical laboratory studies were carried out during the experiment. At the end of the administration period (50% of animals) and at the end of the recovery period, a pathological examination was performed.
Results. The LD50 of the drug is more than 2000 mg/kg. In the repeated administrations, the no observed adverse effect level (NOAEL) has been established. For rats, it is 9 mg/kg (1 HTD), for rabbits – 4 mg/kg (1 HTD). According to the results of the experiments carried out on rabbits and rats, the main target organ of the drug toxic effect is the liver. According to the data obtained in the study on rats, a toxic effect on the organs of the male reproductive system has been manifested (hypoplasia of the spermatogenic epithelium). Under the conditions of the experiment, the test drug had no effect on the gastrointestinal tract.
Conclusion. The results have manifested a favorable safety profile of the drug, not inferior to the ones of a similar pharmacological group used in clinical practice; it can be considered a promising drug candidate for the HIV-1 infection treatment.
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##article.viewOnOriginalSite##About the authors
Valeria A. Vavilova
«Research-and manufacturing company «НОМЕ OF РНАRМАСУ» Joint Stock Company
Email: vavilova.va@doclinika.ru
ORCID iD: 0000-0002-1009-3963
pharmacologist of the 1st category of the Department of Experimental Pharmacology and Toxicology
Russian Federation, Bldg. 245, 3, Zavodskaya St., Vil. Kuzmolovsky, Vsevolozhsky Dist., Leningrad Reg., Russia, 188663Elena V. Shekunova
«Research-and manufacturing company «НОМЕ OF РНАRМАСУ» Joint Stock Company
Email: shekunova.ev@doclinika.ru
ORCID iD: 0000-0002-2689-6891
Candidate of Sciences (Biology), Head of the Department of Experimental Pharmacology and Toxicology
Russian Federation, Bldg. 245, 3, Zavodskaya St., Vil. Kuzmolovsky, Vsevolozhsky Dist., Leningrad Reg., Russia, 188663Ekaterina A. Jain
Moscow State University named after M.V. Lomonosov
Author for correspondence.
Email: ekaterina.korsa@gmail.com
ORCID iD: 0000-0003-0283-8598
Postgraduate student of the Department of Pharmaceutical Chemistry, Pharmacognosy and Organization of Pharmaceutical Business, Faculty of Fundamental Medicine
Russian Federation, Bldg. 1, 27, Lomonosov Ave., Moscow, Russia, 119991Vadim Yu. Balabanyan
Moscow State University named after M.V. Lomonosov
Email: bal.pharm@mail.ru
ORCID iD: 0000-0002-5744-7060
Doctor of Sciences (Pharmacy), Associate Professor of the Department of Pharmaceutical Technology, Faculty of Fundamental Medicine
Russian Federation, Bldg. 1, 27, Lomonosov Ave., Moscow, Russia, 119991Alexander A. Ozerov
Volgograd State Medical University
Email: prof_ozerov@yahoo.com
ORCID iD: 0000-0002-4721-0959
Doctor of Sciences (Chemistry), Professor, Head of the Department of Pharmaceutical and Toxicological Chemistry
Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131Marina N. Makarova
«Research-and manufacturing company «НОМЕ OF РНАRМАСУ» Joint Stock Company
Email: makarova.mn@doclinika.ru
ORCID iD: 0000-0003-3176-6386
Doctor of Sciences (Medicine), General Director, Director of Research
Russian Federation, Bldg. 245, 3, Zavodskaya St., Vil. Kuzmolovsky, Vsevolozhsky Dist., Leningrad Reg., Russia, 188663Valery G. Makarov
«Research-and manufacturing company «НОМЕ OF РНАRМАСУ» Joint Stock Company
Email: makarov.vg@doclinika.ru
ORCID iD: 0000-0002-2447-7888
Doctor of Sciences (Medicine), Professor, Deputy General Director
Russian Federation, Bldg. 245, 3, Zavodskaya St., Vil. Kuzmolovsky, Vsevolozhsky Dist., Leningrad Reg., Russia, 188663References
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