Assessment of The Toxicological Profile of The New Dioxidine Dosage Form (Solution for Topical and External Use, 0.025%)

The general toxicity was studied with an assessment of local tolerability, immunotoxicity, and pharmacological safety of the new medicine Dioxidine®, a solution for topical and external use, 0.25 mg/ml (0.025%) for the treatment of acute tonsillopharyngitis (JSC «Valenta Pharm», Russia). The experiment included 48 rabbits (divided in equal proportion by sex) randomized into 3 groups (n=16 in each group), whose back wall of the pharynx was irrigated with the studied substances for 28 days. Group 1 — control (aqueous solution of NaCl 0.9% for infusions at a daily dose of 4.0 ml/animal); group 2 — dioxidine (1.8 ml/animal); group 3 — dioxidine (4.0 ml/animal). The animals were observed for the entire period of drug administration — up to the 28^th day of the experiment, as well as during the delayed observation period — up to the 58^th day. The following indicators were recorded: lethality, daily monitoring of general condition and behavior, weight, feed and water consumption, respiratory rate, heart rate, blood pressure, electrocardiogram, mass coefficients of internal organs. Immunotoxicity, poisoning symptoms, adrenal insufficiency, as well as animal autopsy results were assessed. Clinical and biochemical blood tests, blood coagulation system analysis, urine analysis, macroscopic and histological examination of internal organs were performed. The absence of statistically significant differences in all evaluated indicators between the group of animals receiving dioxidine solution for topical and external use, 0.25 mg/ml (0.025%) at a dose of 1.8 ml/animal (equivalent to 15 therapeutic doses for humans), the group receiving dioxidine at a dose of 4.0 ml/animal (equivalent to 35 therapeutic doses for humans) and the control group allowed us to draw conclusions concerning the absence of signs of general toxicity, including toxic effects on the adrenal glands, cardiotoxicity, immunotoxicity, and toxic effects on other organs and organ systems, as well as local irritant and toxic effects after repeated irrigation of dioxidine on the back wall of the pharynx in rabbits for 28 days and during the period of delayed observation.

1. Prikaz ministerstva zdravoohraneniya SSSR ot 29 iyunya 1976 g. № 647 «O razreshenii k medicinskomu primeneniyu novyh lekarstvennyh sredstv». (In Russian). Available at: https://doznko.ru/ (Accessed: 10.09.22).

2. Shamkina P.A., Krivopalov A.A., Panchenko P.I., Ryazancev S.V. Vozmozhnosti topicheskoj terapii bakterial'nyh LOR-infekcij. Medicinskij Sovet. 2021; 18: 44–54. https://doi.org/10.21518/2079-701X-2021-18-44-54. (in Russian)

3. Padejskaya E. N. Antibakterial'nyj preparat dioksidin: osobennosti biologicheskogo dejstviya i znachenie v terapii razlichnyh form gnojnoj infekcii. Infekcii i Antimikrob Ter. 2001; 5: 150–155. (in Russian)

4. Kryukov A.I., Kunel'skaya N.L., Gurov A.V., Izotova G.N., Romanenko S.G., Pavlihin O.G. et al. Vozmozhnosti antisepticheskih sredstv v laringeal'noj i tonzillyarnoj patologii. Medicinskij Sovet. 2016; 6: 36–40. Available at: https://www.elibrary.ru/item.asp?id=26103969 (Accessed: 10.09.22). (in Russian)

5. Svistushkin V.M., Nikiforova G.N., SHevchik E.V., Zolotova A.V., Volkova K.B. Vozmozhnosti mestnogo etiotropnogo lecheniya bol'nyh hronicheskim tonzillitom. Medicinskij Sovet. 2016; 18: 116–120. Available at: https://www.elibrary.ru/item.asp?id=27474984 (Accessed: 10.09.22). (in Russian)

6. Ovchinnikov A. Yu., Egiyan S. S. Nash opyt etiotropnogo lecheniya vospalitel'nyh zabolevanij naruzhnogo i srednego uha. Rossijskaya Otorinolaringologiya. 2021; 20 (6): 115–124. https://doi.org/10.18692/1810-4800-2021-6-115-124. (in Russian)

7. Instrukciya po medicinskomu primeneniyu lekarstvennogo preparata Dioksidin® (reg.№ LP-N(000404)-(RG-RU)-281021). Available at: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=6d853302-58bb-4044-817c-016b45808420. (Accessed: 10.09.22). (in Russian)

8. Prikaz ministerstva zdravoohraneniya Rossijskoj Federacii ot 13 fevralya 2013 goda № 66 «Ob utverzhdenii Strategii lekarstvennogo obespecheniya naseleniya Rossijskoj Federacii na period do 2025 goda i plana ee realizacii». (In Russian). Available at: https://base.garant.ru/70317532/ (Accessed: 10.09.22). (in Russian)

9. Federal'nyj zakon ot 12.042010 g. № 61-FZ «Ob obrashchenii lekarstvennyh sredstv» (s izmeneniyami i dopolneniyami). Available at: http://ivo.garant.ru/#/document/12174909/paragraph/25019:0 (Accessed: 10.09.22). (in Russian)

10. Mironov A.N. Rukovodstvo po doklinicheskim issledovaniyam lekarstvennyh sredstv. T. 1. Moscow: FGBU «NCEMSP», 2012; 942. (in Russian)

11. Reshenie Soveta EEK №81 «Ob utverzhdenii pravil nadlezhashchej laboratornoj praktiki Evrazijskogo ekonomicheskogo soyuza v sfere obrashcheniya lekarstvennyh sredstv» ot 03.11.2016 g.. Available at: http://docs.cntd.ru/document/456026101 (Accessed: 10.09.22). (in Russian)

12. Reshenie Kollegii EEK № 202 «Ob utverzhdenii Rukovodstva po doklinicheskim issledovaniyam bezopasnosti v celyah provedeniya klinicheskih issledovanij i registracii lekarstvennyh preparatov» ot 26.11.2019 g. Available at: https://sudact.ru/law/reshenie-kollegii-evraziiskoi-ekonomicheskoi-komissii-ot-26112019_4/rukovodstvopo-doklinicheskim-issledovaniiam-bezopasnosti (Accessed: 10.09.22). (in Russian)

13. Reshenie Soveta EEK №78 «O Pravilah registracii i ekspertizy lekarstvennyh sredstv dlya medicinskogo primeneniya» ot 03.11.2016 g. Available at: http://docs.cntd.ru/document/552305024 (Accessed: 10.09.22). (in Russian)

14. Globally harmonized system of classification and labeling pf chemicals (GHS). 5th revised edition // United Nations. – 2013. – 536 p. Доступно по: https://unece.org/fileadmin/DAM/trans/danger/publi/ghs/ghs_rev05/English/ST-SG-AC10-30-Rev5e.pdf (Ссылка активна на 10.09.22).

15. OECD guidelines for testing of chemicals: Repeated dose dermal toxicity: 21/28-day study. OECD guideline for testing chemicals Publishing, Paris. 1981, 410: 1–8. https://doi.org/10.1787/9789264070745-en

16. Direktiva 2010/63/EU Evropejskogo Parlamenta i Soveta Evropejskogo Soyuza po ohrane zhivotnyh, ispol'zuemyh v nauchnyh celyah / per. s angl. Pod red. M.S. Krasil'shchikovoj, I.V. Belozercevoj. SPb.: 2012; 48. (in Russian)

17. Washington I.M., Van Hoosier G. (2012). Clinical biochemistry and hematology. In: The laboratory rabbit, Guinea pig, hamster, and other rodents, pp. 57–116. doi:10.1016/B978-0-12-380920-9.00003-1.

18. Melillo A. Rabbit clinical pathology. J Exot Pet Med. 2007; 16 (3): 135–145. doi:10.1053/j.jepm.2007.06.002. Epub 2007 Sep 18.