RU2602450C1 - Agent exhibiting bacteriostatic activity on multiresistant mycobacterium tuberculosis strains in experiment - Google Patents
Agent exhibiting bacteriostatic activity on multiresistant mycobacterium tuberculosis strains in experiment Download PDFInfo
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- RU2602450C1 RU2602450C1 RU2015150499/15A RU2015150499A RU2602450C1 RU 2602450 C1 RU2602450 C1 RU 2602450C1 RU 2015150499/15 A RU2015150499/15 A RU 2015150499/15A RU 2015150499 A RU2015150499 A RU 2015150499A RU 2602450 C1 RU2602450 C1 RU 2602450C1
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Изобретение относится к медицине, в частности к фармакологии, и может быть использовано для угнетения роста полирезистентных штаммов микобактерий туберкулеза в эксперименте.The invention relates to medicine, in particular to pharmacology, and can be used to inhibit the growth of multiresistant strains of mycobacterium tuberculosis in the experiment.
В последние годы повсеместно отмечается широкое распространение антибиотикорезистентных штаммов туберкулезной палочки [Lipin M.Y., Stepanshina V.N., Shemyakin I.G., Shinnick T.M. Association of specific mutations in katG, rpoB, rpsL and rrs genes with spoligotypes of multidrug-resistant Mycobacterium tuberculosis isolates in Russia. Clin. Microbiol. Infect. 2007. 13. 620-626; Ali Chaudhry L., Rambhala N., Al-Shammri A.S., Al-Tawfiq J.A. Patterns of antituberculous drug resistance in Eastern Saudi Arabia: a 7-year surveillance study from 1/2003 to 6/2010. J. Epidemiol. Glob. Health. 2012. 2(1). 57-60; Areeshi M.Y., Bisht S.C., Mandal R.K., Haque S. Prevalence of drug resistance in clinical isolates of tuberculosis from GCC: a literature review from January 2002 to March 2013. J. Infect. Dev. Ctries. 2014. 12. 8(9). 1137-1147]. Последнее диктует необходимость изыскания новых лекарственных средств, влияющих на рост данного микроорганизма.In recent years, widespread spread of antibiotic-resistant strains of tubercle bacillus [Lipin M.Y., Stepanshina V.N., Shemyakin I.G., Shinnick T.M. Association of specific mutations in katG, rpoB, rpsL and rrs genes with spoligotypes of multidrug-resistant Mycobacterium tuberculosis isolates in Russia. Clin. Microbiol. Infect. 2007. 13. 620-626; Ali Chaudhry L., Rambhala N., Al-Shammri A.S., Al-Tawfiq J.A. Patterns of antituberculous drug resistance in Eastern Saudi Arabia: a 7-year surveillance study from 1/2003 to 6/2010. J. Epidemiol. Glob. Health 2012.2 (1). 57-60; Areeshi M.Y., Bisht S.C., Mandal R.K., Haque S. Prevalence of drug resistance in clinical isolates of tuberculosis from GCC: a literature review from January 2002 to March 2013. J. Infect. Dev. Ctries. 2014.12.12 (9). 1137-1147]. The latter dictates the need to find new drugs that affect the growth of this microorganism.
Препарат фотодитазин, выпускаемый фирмой "Вета-Гранд" (Россия), представляет собой диметилглюкаминовую соль хлорина Е6 и используется в настоящее время в качестве фотосенсибилизатора для флюоресцентной диагностики и фотодинамической терапии злокачественных опухолей [Рагулин Ю.А., Капинус Н.В., Каплан М.А. и др. Возможности фотодинамической терапии с фотосенсибилизатором фотодитазин в лечении центрального рака легких. Российский биотерапевтический журнал. 2005. 3. 58-61; Белый Ю.А., Терещенко А.В., Володин П.Л. и др. Лечение меланом сосудистой оболочки глаза большого размера методом фотодинамической терапии с препаратом фотодитазин (клинический случай). Российский биотерапевтический журнал. 2008. 4. 53-56; Странадко Е.Ф., Волгин В.Н., Ламоткин М.В. и др. Фотодинамическая терапия базально-клеточного рака кожи с фотосесибилизатором фотодитазином. Российский биотерапевтический журнал. 2008. 4. 7-11].Photoditazine manufactured by Veta-Grand (Russia) is a dimethylglucamine salt of chlorin E6 and is currently used as a photosensitizer for fluorescence diagnostics and photodynamic therapy of malignant tumors [Ragulin Yu.A., Kapinus N.V., Kaplan M.A. et al. The possibilities of photodynamic therapy with a photosensitizer photoditazine in the treatment of central lung cancer. Russian biotherapeutic magazine. 2005.3.58-61; Bely Yu.A., Tereshchenko A.V., Volodin P.L. et al. Treatment of melanoma of the choroid of the large eye with photodynamic therapy with photoditazine (a clinical case). Russian biotherapeutic magazine. 2008.4.55-56; Stranadko E.F., Volgin V.N., Lamotkin M.V. et al. Photodynamic therapy of basal cell skin cancer with photosensitizer photoditazine. Russian biotherapeutic magazine. 2008. 4. 7-11].
Нами впервые установлено ингибирующее влияние фотодитазина на рост полирезистентных штаммов микобактерий туберкулеза.We first established the inhibitory effect of photoditazine on the growth of multiresistant strains of mycobacterium tuberculosis.
Лекарственно-устойчивые штаммы микобактерий туберкулеза были получены при посеве респираторного материала (мокрота), полученного от больных, проходящих лечение в ГБУЗ «Тамбовский областной клинический противотуберкулезный диспансер». Профили лекарственной устойчивости (ЛУ) были получены с использованием стандартной методики оценки лекарственной устойчивости микобактерий на плотной яичной питательной среде Левенштейна-Йенсена, не содержащей крахмал (HiMedia, Индия), методом абсолютных концентраций (приказ МЗ РФ от 21 марта 2003 г. N 109 «О совершенствовании противотуберкулезных мероприятий в Российской Федерации»), а ЛУ к рифампицину и изониазиду дополнительно оценивали с помощью постановки полимеразной цепной реакции (ПЦР) и последующей гибридизации генетического материала М. tuberculosis на биочипах «ТБ-БИОЧИП» (ООО «Биочип-ИМБ», Россия) по методике, рекомендованной производителем. Все штаммы М. tuberculosis были множественно лекарственно-устойчивыми (МЛУ), т.е. резистентными к основным противотуберкулезным препаратам - изониазиду, рифампицину, стрептомицину, этамбутолу и чувствительными к пиразинамиду.Drug-resistant strains of mycobacterium tuberculosis were obtained by sowing respiratory material (sputum) obtained from patients undergoing treatment at the Tambov Regional Clinical Tuberculosis Dispensary. Drug resistance profiles (LU) were obtained using the standard methodology for assessing the drug resistance of mycobacteria on dense starch-free egg medium Levenshtein-Jensen (HiMedia, India) using the absolute concentration method (order of the Ministry of Health of the Russian Federation dated March 21, 2003 No. 109 “ On the improvement of anti-tuberculosis measures in the Russian Federation ”), and LU to rifampicin and isoniazid was additionally evaluated using the polymerase chain reaction (PCR) and subsequent hybridization of genetic material and M. tuberculosis biochips on "TB-Biochip" (LLC "Biochip-IMB", Russia) by the method recommended by the manufacturer. All M. tuberculosis strains were multidrug-resistant (MDR), i.e. resistant to the main anti-TB drugs - isoniazid, rifampicin, streptomycin, ethambutol and sensitive to pyrazinamide.
Фотодитазин разводили в дистиллированной воде до конечной концентрации 4·10-5 моль/л. Бактериальную взвесь М. tuberculosis с титром 100000 КОЕ/мл питательной среды Middlebrook 7Н9 смешивали с раствором фотосенсибилизатора в соотношении 1:9 (итоговый объем образца равен 5 мл) в пластиковых чашках Петри диаметром 10 см и инкубировали в течение 15 мин при температуре 37°C. В качестве контроля использовали взвесь М. tuberculosis каждого штамма, которую вместо раствора сенсибилизатора разводили дистиллированной водой, сохраняя объемное соотношение 1:9.Photoditazine was diluted in distilled water to a final concentration of 4 · 10 -5 mol / L. A bacterial suspension of M. tuberculosis with a titer of 100,000 CFU / ml of Middlebrook 7H9 nutrient medium was mixed with a photosensitizer solution in a ratio of 1: 9 (the final sample volume was 5 ml) in 10 cm diameter plastic Petri dishes and incubated for 15 min at 37 ° C . As a control, a suspension of M. tuberculosis of each strain was used, which was diluted with distilled water instead of a sensitizer solution, maintaining a volume ratio of 1: 9.
Посев производили на жидкую питательную среду Middlebrook 7Н9 в индикаторные пробирки MGIT автоматизированной системы ВАСТЕС™ MGIT™ 960 (Becton Dickinson, Sparks, MD). В каждую пробирку вносили по 0,5 мл каждого образца из чашек Петри. Выполняли по пять повторных посевов, учитывая возможность случайных колебаний роста культур микобактерий. Наблюдения проводили в течение месяца. Результат фиксировался автоматической системой при достижении стандартного титра микобактерий в пробирке и выражался в сутках после посева.Sowing was performed on Middlebrook 7H9 liquid nutrient medium in MGIT indicator tubes of the BASTEC ™ MGIT ™ 960 automated system (Becton Dickinson, Sparks, MD). 0.5 ml of each sample from Petri dishes was added to each tube. Five repeated crops were performed, taking into account the possibility of random fluctuations in the growth of cultures of mycobacteria. Observations were carried out for a month. The result was recorded by the automatic system when the standard titer of mycobacteria in vitro was reached and was expressed in days after seeding.
Статистическая обработка результатов экспериментов проводилась с использованием программы GraphPad Prism-5. Различия с контролем признавались достоверными при p<0,05.Statistical processing of the experimental results was carried out using the GraphPad Prism-5 program. Differences with control were considered significant at p <0.05.
Результаты наблюдений представлены в таблице.The results of the observations are presented in the table.
Как видно из таблицы, воздействие фотодитазина в 1,32 раза замедляет скорость роста микобактерий туберкулеза в жидкой среде, т.е. оказывает отчетливый бактериостатический эффект.As can be seen from the table, the effect of photoditazine 1.32 times slows the growth rate of mycobacterium tuberculosis in a liquid medium, i.e. It has a distinct bacteriostatic effect.
Следовательно, данный препарат может быть использован по новому назначению, а именно как средство, угнетающее рост Mycobacterium tuberculosis в эксперименте.Therefore, this drug can be used for a new purpose, namely, as an agent that inhibits the growth of Mycobacterium tuberculosis in the experiment.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20110053880A1 (en) * | 2007-12-21 | 2011-03-03 | Martin Fussenegger | Composition for treatment of tuberculosis |
| RU2468802C2 (en) * | 2010-12-20 | 2012-12-10 | Открытое акционерное общество "Химико-фармацевтический комбинат "АКРИХИН" (ОАО "АКРИХИН") | Combined antituberculous composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110053880A1 (en) * | 2007-12-21 | 2011-03-03 | Martin Fussenegger | Composition for treatment of tuberculosis |
| RU2468802C2 (en) * | 2010-12-20 | 2012-12-10 | Открытое акционерное общество "Химико-фармацевтический комбинат "АКРИХИН" (ОАО "АКРИХИН") | Combined antituberculous composition |
Non-Patent Citations (1)
| Title |
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| М.А. Каплан и др. ""Фотодитазин - эффективный фотосенсибилизатор для фотодинамической терапии, Материалы III Всероссийской научно-практической конференции "Отечественные противоопухолевые препараты", Москва, 17-19 марта 2004 г, найдено в Интернет на сайте:http://xn--80ahkcc4aba9adq.xn--p1ai/doctors/kaplan/36-fotoditazin-effektivnyy-fs-dlya-fdt.html. * |
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