SILVER NANOPARTICLES IN THE SOLUTION OF THE PROBLEM OF DRUG RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS

The goal — a scientific evaluation of the effectiveness and safety of NHS in the treatment of experimental drug-resistant tuberculosis. Materials and methods. Used silver nanoparticles obtained by an electrochemical method. With a size of 5-60 nm, 120-270 kontsentratsiey- 1 mcm² and the size of the stabilizer shell — 2-5 nm. 750 crops studied Inhibitory activity of the silver nanoparticles in an isolated form and as part of a nanocomposite with chemotherapy in concentrations of 5; 25 and 50 mcg/ml. Defines the minimum inhibitory concentration of bactericidal nanoparticles composed of a nanocomposite with isoniazid. To evaluate the morphometry M.tuberculosis used atomic force microscopy. Toxicology nanopreparations studied 83 non-linear white mice and 146 white rats. Chemotherapeutic Activity nanopreparations determined on an experimental model of tuberculosis in 65 white male mice imbrednoy line BALB/c. Infectivity dose amount 5х106 colony forming units injected into the sinus venosus animal eyes. Isoniazid, nanoparticles and nanocomposite began administered 14 days after infection by intramuscular injection daily. Treatment efficacy was determined by comparing the evaluation criteria in the experimental and control groups of animals. Evaluated the following indicators: survival index, body mass index and weight of target organ, lesions index, index smear and inoculation of affected organs. Conducted pathological examination. Results. When using isoniazid, which had resistant pathogens, with silver nanoparticles full and significant inhibition of the growth of the M.tuberculosis observed in 49,2% of cases. When the concentration of the nanoparticles 5 mcg/ml in the composite bactericidal activity reached 91,3%. The minimum inhibitory concentration of silver nanoperticles in combination with isoniazid was 2,5 mcg/ml, the minimum bactericidal — 5 mcg /ml. There have been changes in the M.tuberculosis morphometry under the influence of the nanocomposite according to atomic force microscopy. In the studied doses of isolated silver nanoparticles do not affect the basic biometrics, laboratory and functional parameters of the animals, and do not increase the toxicological parameters of isoniazid. All criteria studied the effectiveness of treatment of experimental tuberculosis had significantly priority performance using nanocomposite. Pathological studies have confirmed these results. Conclusions. Of the study provides a scientific rationale for the effectiveness of the experimental use of silver nanoparticles in treatment of drug-resistant tuberculosis. The most effective dose of silver nanoparticles in the composite in the treatment of experimental tuberculosis is 25 mcg / kg.

drug-resistant TB, silver nanoparticles, treatment of experimental tuberculosis

1. Захаров А.В., Кибрик Б.С., Павлов А.В. Эффективность лечения экспериментального туберкулёза с использованием наночастиц серебра. Туберкулёз и болезни лёгких. 2011; 4: 151-152. Zakharov A.V., Kibrik B.S., Pavlov A.V. The effectiveness of treatment of experimental tuberculosis with silver nanoparticles. Tuberculosis and lung diseases. 2011; 4: 151-152 [in Russian].

2. Кибрик Б.С., Павлов А.В., Захаров А.В. и др. Экспериментальное обоснование преодоления резистентности возбудителя туберкулёза нанокомпозитом изониазида и наночастиц серебра. Экспер. и клинич. Фармакология. 2011; 74(4): 24-26. Kibrik B.S., Pavlov A.V., Zakharov A.V. et al. Experimental substantiation of overcoming the resistance of the pathogen of tuberculosis nanocomposite of isoniazid and silver nanoparticles. Exper. and clinical. Pharmacology. 2011; 74(4): 24-26 [in Russian].

3. Кибрик Б.С., Павлов А.В., Захаров А.В. и др. Новые подходы к лечению больных туберкулёзом с лекарственной устойчивостью возбудителя с использованием наночастиц серебра. Туберкулёз и болезни лёгких. 2011; 11: 37-41. Kibrik B.S., Pavlov A.V., Zakharov A.V. et al. New approaches to the treatment of TB patients with drug-resistant with the use of silver nanoparticles. Tuberculosis and lung diseases. 2011; 11: 37-41 [in Russian].

4. Кибрик Б.С., Павлов А.В., Захаров А.В. и др. Токсикологическая оценка нанокомпозита для лечения лекарственно-устойчивого туберкулёза. Токсикологический вестник. 2012; 3: 28-33. Kibrik B.S., Pavlov, A.V., Zakharov A.V. et al. Toxicological evaluation of nanocomposite for the treatment of drug-resistant tuberculosis. Poison Gazette. 2012; 3: 28-33 [in Russian].

5. Малафеева Э.В., Хохлов А.А., Хохлов А.Л. и др. Антимикробная и токсикологическая характеристика антибактериальной мази с наночастицами серебра. Ремедиум. 2011; 4: 96-97. Malafeevа E.V., Khokhlov A.A., Khokhlov A.L. et al. Antimicrobial and toxicological characterization of antibiotic ointment with silver nanoparticles. Remedium. 2011; 4: 96-97 [in Russian].

6. Муха Ю.П., Еременко А.М., Смирнова Н.П. и др. Антимикробная активность стабильных наночастиц серебра заданного размера. Прикладная биохимия и микробиология. 2013; 49(2): 215. Mucha J.P., Eremenko A.M., Smirnova N.P. et al. Antimicrobial activity of stable nanoparticles of a given size silver. Applied Biochemistry and Microbiology. 2013; 49(2): 215 [in Russian].

7. Габбасова Л.А., Касаева Т.Ч., Стерликов С.А. и др. Отраслевые и экономические показатели противотуберкулёзной работы в 2014-2015 г.г. Аналитический обзор основных показателей и статистические материалы. М.: РИО ЦНИИОИЗ, 2016. 89 с. Gabbasova L.A., Kasaeva T.Ch., Sterlikov S.A. et al. Industry and economic indicators of TB work in 2014-2015. Analytical review of key indicators and statistical material. M.: RIO FPHI, 2016. 89 p. [in Russian].

8. Пантелеев А.М. Туберкулёз с лекарственной устойчивостью МБТ у больных ВИЧ-инфекцией. В сб. Актуальные проблемы и перспективы развития противотуберкулёзной службы в российской Федерации: Матер. 1-го Конгр. Ассоциации «Национальная ассоциация фтизиатров», СПб. 2012. 281 с. Panteleev A.M. Tuberculosis drug resistance in patients with the HIV. In Proc. Actual problems and prospects of development of TB services in the Russian Federation: Mater. 1st Congreve. Association “National Association of TB specialists”, St. Petersburg. 2012. 281 p. [in Russian].

9. Правила лабораторной практики в Российской Федерации. Приказ МЗ РФ от 19.06.2003г., № 267. Terms of laboratory practices in the Russian Federation. Russian Ministry of Health Order from 19.06.2003, № 267 [in Russian].

10. Радциг М.А. Взаимодействие клеток бактерий с соединениями серебра и золота: влияние на рост, образование биоплёнок, механизмы действия, биогенез наночастиц. Автореф. дис. … канд. мед. наук. М., 2013. 24 с. Radtsig M.A. Interaction of bacterial cells with silver compounds and gold: the impact on growth, biofilm formation, mechanisms of action, biogenesis nanoparticles. Author. Dis. ... Cand. honey. Sciences. M., 2013. 24 p. [in Russian].

11. Рахманин Ю.А., Хрипач Л.В., Михайлова Р.И. и др. Сравнительный анализ влияния нано- и ионной форм серебра на биохимические показатели лабораторных животных. Гигиена и санитария. 2014; 1: 45-50. Rahmanin Y.A., Khripatch L.V., Mikhailova R.,I. et al. Comparative analysis of the effect of nano silver and ionic forms of biochemical indicators of laboratory animals. Health and Sanitation. 2014; 1: 45-50 [in Russian].

12. Руководство по экспериментальному (доклиническому) изучению новых фармакологических веществ» — 2-е изд., перераб. и доп. М.: ОАО «Издательство «Медицина», 2005: 41-53, 571-581. Manual on experimental (preclinical) study of new pharmacological substances “- 2 nd ed., Revised. and ext. M.: JSC «Publishing house» Medicine, 2005: 41-53, 571-581 [in Russian].

13. Савин Е.И., Субботина Т.И., Хадарцев А.А. и др. Экспериментальное исследование антибактериальной активности наночастиц серебра на модели перитонита и менинго- энцефалита in vivo // Вестник новых медицинских технологий (Электронный журнал). 2014; 1: 1-6. URL:http://www.medtsu.tula. ru/VNMT/Bulletin/E2014-1/4793.pdf Savin E.I., Subbotina T.I., Khadartsev A.A. et al. Experimental study of the antibacterial activity of silver nanoparticles on the model of peritonitis and meningoencephalitis in vivo. Herald of new medical technologies (electronic magazine). 2014; 1: 1-6. URL: http: //www. medtsu.tula.ru/VNMT/Bulletin/E2014-1/4793.pdf [in Russian].

14. Сердюк А.М., Михиенкова А.И. Наночастицы серебра: характеристика и стабильность антимикробного действия композиции на основе высокодисперсного кремнезема. Environment&Health. 2011; 3: 8-11. Serdyuk A.M., Mihienkova A.I. Silver Nanoparticles: characterization and stability of the antimicrobial action of a composition based on highly dispersed silica. Environment & Health. 2011; 3: 8-11 [in Russian].

15. Хохлов А.Л., Крейцберг Г.Н., Завойстый И.В. и др. Исследование антибактериальной эффективности коллоидных растворов наночастиц серебра. Новости здравоохранения. 2007; 2: 55-59. Khokhlov A.L., Kreuzberg G.N., Zavoysty I.V. et al. The study of antibacterial efficiency of silver nanoparticles colloidal solutions. Health News. 2007; 2: 55-59 [in Russian].

16. Шульгина Т.А., Норкин И.А., Пучиньян Д.М. Изучение антибактериальной активности водных дисперсий наночастиц серебра и меди. Вест. новых мед. технологий. 2012; XIX(4): 131-132. Shulginа T.A., Norkin I.A., Puchinyan D.M. Study of aqueous dispersions of antimicrobial activity of silver and copper nanoparticles. Fed. new medical. Technologies. 2012; XIX(4): 131-132 [in Russian].

17. Яминский И.В. Взгляд в микромир: от атомов и молекул — до живых клеток. М., Наука, 2006. 106 с. Yaminsky I.V. Look into microworld: from atoms and molecules — to living cells. Nauka, 2006. 106 p. [in Russian].

18. Amin M. Green Synthesis of Silver Nanoparticles: Structural Features and In vivo and In vitro therapeutic effects against Helicobacter pylori Induced Gastritis. Bioinorganic Chemistry and Applications. 2014; 2014: 1-11.

19. Bahador A., Esmaeili D., Khaledi A. et al. An in vitro assessment of the antibacterial propertiesof nanosilver Iranian MTA against Porphyromonas gingivalis. Journal of Chemical and Pharmaceutical Reseach. 2013; 10(5): 65-71.

20. Niakan S., Niakan M., Hesaraki S. et al. Comparison of the Antibacterial Effects of Nanosilver With 18 Antibiotics on Multidrug Resistance Clinical Isolates of Acinetobacter baumannii. Jundishapur Journal of Microbiology. 2013; 6(5): 1-5.

21. Radzig M.A., Nadtochenko V.A., Koksharova O.A. et al. Antibacterial effects of silver nanoparticles on gram-negative bacterial: Influence on the growth and biofilms formation, mechanisms of action. Colloids and Surfaces B: Biointerfaces, 2013; 102: 300-306.

22. Radzig M.A., Khmel I.A. Effect of silver nanoparticles on growth and biofilm formation of Gram-negative bacterial, mechanisms of action. IIInternational Conference on Antimicrobial Research (ICAR2012). Lisbon, Portugal, 21-23 november 2012.

23. World Health Organization. Global tuberculosis report 2015. Geneva, 2015.//WHO/HTM/TB/2015.22.

24. Zhao J., Castranova V. Toxicology of nanomaterials used in nanomedicine. J. Toxicol. Environ Health B. Grit. Rev., 2011; 14: 593-632.