pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2020-8-5-304-315pmedpharm-737Research ArticleФАРМАКОЛОГИЯ И КЛИНИЧЕСКАЯ ФАРМАКОЛОГИЯPHARMACOLOGY AND CLINICAL PHARMACOLOGYКОРРЕКЦИЯ МОРФОФУНКЦИОНАЛЬНЫХ НАРУШЕНИЙ ПРИ ЭКСПЕРИМЕНТАЛЬНОЙ ПРЕЭКЛАМПСИИ СОЧЕТАННЫМ ПРИМЕНЕНИЕМ ТРИМЕТАЗИДИНА И ОЧИЩЕННОЙ МИКРОНИЗИРОВАННОЙ ФЛАВОНОИДНОЙ ФРАКЦИЕЙ, А ТАКЖЕ ИХ КОМБИНАЦИЙ С МЕТИЛДОПОЙCORRECTION OF MORPHOFUNCTIONAL DISORDERS IN EXPERIMENTAL PREECLAMPSY BY COMBINED USE OF TRIMETAZIDINE AND PURIFIED MICRONIZED FLAVONOID FRACTION AS WELL AS THEIR COMBINATIONS WITH METHYLAMPSYhttps://orcid.org/0000-0002-9456-9569АнцифероваО. Е.AntsiferovaO. E.

Анциферова Оксана Евгеньевна – аспирант кафедры фармакологии и клинической фармакологии

308015, г. Белгород, ул. Победы, 85

Oksana E. Antsiferova – postgraduate student of the Department of Pharmacology and Clinical Pharmacology 

85, Pobeda St., Belgorod, 308015

AnciferovaO@ya.ruhttps://orcid.org/0000-0003-0849-4351ТелещенкоМ. П.TeleshchenkoM. P.

Телещенко Мария Павловна – аспирант кафедры фармакологии и клинической фармакологии 

308015, г. Белгород, ул. Победы, 85

Maria P. Teleschenko – postgraduate student of the Department of Pharmacology and Clinical Pharmacology 

85, Pobeda St., Belgorod, 308015

marijastreltsowa@yandex.ruhttps://orcid.org/0000-0001-8489-247XЦуверкаловаЮ. М.TsuverkalovaYu. M.

Цуверкалова Юлия Михайловна – аспирант кафедры фармакологии и клинической фармакологии 

308015, г. Белгород, ул. Победы, 85

Yulia M. Tsuverkalova – post-graduate student of the Department of Pharmacology and Clinical Pharmacology 

85, Pobeda St., Belgorod, 308015

cvd404@mail.ruhttps://orcid.org/0000-0002-2761-6249ПокровскийМ. В.PokrovskyM. V.

Покровский Михаил Владимирович – доктор медицинских наук, профессор, профессор кафедры фармакологии и клинической фармакологии, руководитель НИИ Фармакологии живых систем 

308015, г. Белгород, ул. Победы, 85

Mikhail V. Pokrovsky – Doctor of Sciences (Medicine), Professor, Professor of the Department of Pharmacology and Clinical Pharmacology, the Head of the Research Institute of Pharmacology of Living Systems 

85, Pobeda St., Belgorod, 308015

mpokrovsky@yandex.ruhttps://orcid.org/0000-0003-1433-1225ГуреевВ. В.GureevV. V.

Гуреев Владимир Владимирович – доктор медицинских наук, доцент, профессор кафедры фармакологии и клинической фармакологии 

308015, г. Белгород, ул. Победы, 85

Vladimir V. Gureev – Doctor of Sciences (Medicine), Associate Professor, Professor of the Department of Pharmacology and Clinical Pharmacology 

85, Pobeda St., Belgorod, 308015

produmen@yandex.ruhttps://orcid.org/0000-0002-9553-1597ЗaтолокинаМ. А.ZatolokinaM. A.

Зaтолокина Мария Алексеевна – доктор медицинских наук, профессор, профессор кафедры гистологии, цитологии, эмбриологии 

305041, г. Курск, ул. Карла Маркса, 3

Maria A. Zatolokina – Doctor of Sciences (Medicine), Professor, Professor of the Department of Histology, Cytology, Embryology 

3, Karl Marx St., Kursk, 305041

marika1212@mail.ruhttps://orcid.org/0000-0003-1719-7316ГурееваА. В.GureevaA. V.

Гуреева Анастасия Владимировна – студентка 4 курса лечебного факультета 

305041, г. Курск, ул. Карла Маркса, 3

Anastasia V. Gureeva – 4th year student of Medical Department 

3, Karl Marx St., Kursk, 305041

nastasyi.207@gmail.comФедеральное государственное автономное учреждение высшего профессионального образования «Белгородский государственный национальный исследовательский университет»РоссияBelgorod State National Research UniversityRussian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Курский государственный университет»РоссияKursk State Medical UniversityRussian Federation20200203202185304315Copyright © Анциферова О.Е., Телещенко М.П., Цуверкалова Ю.М., Покровский М.В., Гуреев В.В., Зaтолокина М.А., Гуреева А.В., 20212021Анциферова О.Е., Телещенко М.П., Цуверкалова Ю.М., Покровский М.В., Гуреев В.В., Зaтолокина М.А., Гуреева А.В.Antsiferova O.E., Teleshchenko M.P., Tsuverkalova Y.M., Pokrovsky M.V., Gureev V.V., Zatolokina M.A., Gureeva A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/737Цель

Цель. Провести исследование эффективности сочетанного применения триметазидина и очищенной микронизированной флавоноидной фракцией, а также их комбинаций с метилдопой в сравнении с монотерапией этими же препаратами при коррекции морфофункциональных нарушений, возникающих в условии экспериментальной преэклампсии. Комплексный подход является наиболее эффективным способом терапии преэклампсии. Поэтому актуальной задачей современной фармакологии остается исследование эффективности новых лекарственных препаратов при комбинированном использовании, в том числе, и с препаратами, входящими в стандарты лечения.

Материалы и методы

Материалы и методы. Исследование проводилось в НИИ фармакологии живых систем ФГАОУ ВО НИУ БелГУ. Эксперимент проводили на 200 самках крыс линии Wistar, массой 250–300 г, у которых воспроизводили ADMA-подобную модель преэклампсии. Для оценки степени коррекции возникающих морфофункциональных нарушений использовали следующие параметры: артериальное давление, коэффициент эндотелиальной дисфункции, микроциркуляцию в плаценте, протеинурию, содержание жидкости в большом сальнике, морфометрические показатели плацентарных тканей и ростовесовых показателей плодов.

Результаты

Результаты. Комбинированное применение триметазидина (Предуктал® МВ) 6 мг/кг и очищенной микронизированной флавоноидной фракции (Детралекс®) 260 мг/кг, а также их сочетаное применение с метилдопой (Допегит®) 86 мг/кг, приводит к более выраженному снижению артериального давления, по сравнению со снижением коэффициента эндотелиальной дисфункции в 2,22, 2,19 и 1,94 раза соответственно по отношению к «нелеченным» животным. Происходило повышение показателей микроциркуляции в плаценте в 2,35, 2,21 и 2,03 раза соответственно. Кроме этого, наблюдалось улучшение морфологических показателей в плаценте и плодов.

Заключение

Заключение. Результаты проведенного исследования показали большую эффективность комплексного применения исследуемых препаратов при экспериментальной преэклампсии по сравнению с их монотерапией. Это свидетельствует о перспективности применения триметазидина и очищенной микронизированной флавоноидной фракциии в комплексной терапии преэклампсии и необходимости проведения дальнейших исследований в этом направлении. 

The aim of the experiment was to determine the effectiveness of the combined use of trimetazidine and a purified micronized flavonoid fraction, as well as their combinations with methyldopa, in comparison with monotherapy with the same drugs in the correction of morphofunctional disorders arising in the conditions of experimental preeclampsia. An integrated/multimethodology approach is the most effective way of treatment for preeclampsia. Therefore, an urgent task of modern pharmacology is to study the effectiveness of new drugs when used in combinations, as well as the drugs included in the standards for treatment.

Materials and methods

Materials and methods. The study was carried out at the Research Institute of Pharmacology of Living Systems of Belgorod State National Research University. The experiment was performed on 200 female Wistar rats, weighing 250–300 g, in which an ADMA-like model of preeclampsia had been reproduced. To assess the degree of correction of emerging morphological and functional disorders, the following parameters were involved: blood pressure, a coefficient of endothelial dysfunction, microcirculation in the placenta, proteinuria, fluid contents in the greater omentum, morphometric indicators of placental tissues and fetal height and weight parameters.

Results

Results. The combined use of trimetazidine (Preductal® MB) 6 mg/kg and a purified micronized flavonoid fraction (Detralex®) 260 mg/kg, as well as their combination with methyldopa (Dopegit®) 86 mg/kg, leads to a more pronounced decrease in the blood pressure, compared with a decrease in the coefficient of endothelial dysfunction by 2.22, 2.19 and 1.94 times, respectively, in relation to “untreated” animals. There was an increase in microcirculation indices in the placenta by 2.35, 2.21 and 2.03 times, respectively. In addition, there was an improvement in morphological parameters in the placenta and fetuses.

Conclusion

Conclusion. The results of the study showed a greater effectiveness of the combined use of the studied drugs in experimental preeclampsia compared to their monotherapy. This indicates the prospects for the use of trimetazidine and purified micronized flavonoid fraction in the complex therapy for preeclampsia and the need for further research in this direction.

триметазидиночищенная микронизированная флавоноидная фракцияпреэклампсиядисфункция эндотелиякрысыtrimetazidinepurified micronized flavonoid fractionpreeclampsiaendothelial dysfunctionratsДанное исследование не имело какой-либо финансовой поддержки от сторонних организацийReferencesHutcheon J.A., Lisonkova S., Joseph K.S. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy // Best Pract Res Clin Obstet Gynaecol. – 2011. – Vol. 25. – No.4. – P. 391–403. DOI: 10.1016/j.bpobgyn.2011.01.006.Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol. 2011;25(4):391–403. DOI: 10.1016/j.bpobgyn.2011.01.006.Say L., Chou D., Gemmill A., Tunçalp Ö., Moller A.B., Daniels J., Gülmezoglu A.M., Temmerman M., Alkema L. Global causes of maternal death: a WHO systematic analysis // Lancet Glob Health. 2014. – Vol. 2. – No.6. – P. 323–33. DOI: 10.1016/S2214-109X(14)70227-X.Say L, Chou D, Gemmill A, Tunçalp Ö, Moller AB, Daniels J, Gülmezoglu AM, Temmerman M, Alkema L. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014;2(6):e323-33. DOI: 10.1016/S2214–109X(14)70227-X.Клинические рекомендации (протокол лечения). Гипертензивные расстройства во время беременности, в родах и послеродовом периоде. Преэклампсия. Эклампсия // Москва, 2016. – 72 с.[Klinicheskie rekomendacii (protokol lecheniya). Gipertenzivnye rasstrojstva vo vremya beremennosti, v rodah i poslerodovom periode. Preeklampsiya. Eklampsiya]. Moskva, 2016:72. RussianGhulmiyyah L., Sibai B. Maternal mortality from preeclampsia/eclampsia // Semin Perinatol. – 2012. – Vol. 36. – No.1. – P. 56–9. DOI: 10.1053/j.semperi.2011.09.011.Ghulmiyyah L, Sibai B. Maternal mortality from preeclampsia/eclampsia. Semin Perinatol. 2012;36(1):56–9. DOI: 10.1053/j.semperi.2011.09.011.Steegers E.A., von Dadelszen P., Duvekot J.J., Pijnenborg R. Pre-eclampsia // Lancet. – 2010. – Vol. 376. – No.9741. – P. 631–44. DOI: 10.1016/S0140-6736(10)60279-6.Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376(9741):631–44. DOI: 10.1016/S0140-6736(10)60279-6.Young B., Hacker M.R., Rana S. Physicians’ knowledge of future vascular disease in women with preeclampsia // Hypertens Pregnancy. – 2012. – Vol.31. – No.1. – P. 50–8. DOI: 10.3109/10641955.2010.544955.Young B, Hacker MR, Rana S. Physicians’ knowledge of future vascular disease in women with preeclampsia. Hypertens Pregnancy. 2012;31(1):50–8. DOI: 10.3109/10641955.2010.544955.Медведь В.И., Дуда Е.М. Преэклампсия в клинике экстрагенитальной патологии // Почки. – 2013. – № 3 (5). – С. 36–38.Medved’, V.I., Duda E.M. Preeklampsiya v klinike ekstragenital’noj patologii. Pochki. 2013; 3(5):36–38. Russian.Brewster J.A., Orsi N.M., Gopichandran N., Ekbote U.V., Cadogan E., Walker J.J. Host inflammatory response profiling in preeclampsia using an in vitro whole blood stimulation model // Hypertens Pregnancy. – 2008. – Vol. 27. – No.1. – P. 1–16. DOI: 10.1080/10641950701826067.Brewster JA, Orsi NM, Gopichandran N, Ekbote UV, Cadogan E, Walker JJ. Host inflammatory response profiling in preeclampsia using an in vitro whole blood stimulation model. Hypertens Pregnancy. 2008;27(1):1–16. DOI: 10.1080/10641950701826067.Ray A., Ray S. Epidural therapy for the treatment of severe pre-eclampsia in non labouring women // Cochrane Database Syst Rev. – 2017. – Vol. 11. – No.11. – P. CD009540. DOI: 10.1002/14651858.CD009540.pub2.Ray A, Ray S. Epidural therapy for the treatment of severe pre-eclampsia in non labouring women. Cochrane Database Syst Rev. 2017 Nov 28;11(11):CD009540. DOI: 10.1002/14651858.CD009540.pub2.Babic I., Ferraro Z.M., Garbedian K., Oulette A., Ball C.G., Moretti F., Gruslin A. Intraplacental villous artery resistance indices and identification of placenta-mediated diseases // J Perinatol. – 2015. – Vol. 35. – No.10. – P. 793–8. DOI: 10.1038/jp.2015.85.Babic I, Ferraro ZM, Garbedian K, Oulette A, Ball CG, Moretti F, Gruslin A. Intraplacental villous artery resistance indices and identification of placenta-mediated diseases. J Perinatol. 2015;35(10):793–8. DOI: 10.1038/jp.2015.85.Vayssière C., Sentilhes L., Ego A., Bernard C., Cambourieu D., Flamant C., Gascoin G., Gaudineau A., Grangé G., Houfflin-Debarge V., Langer B., Malan V., Marcorelles P., Nizard J., Perrotin F., Salomon L., Senat M.V., Serry A., Tessier V., Truffert P., Tsatsaris V., Arnaud C., Carbonne B. Fetal growth restriction and intra-uterine growth restriction: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians // Eur J Obstet Gynecol Reprod Biol. – 2015. – Vol. 193. – P. 10–8. DOI: 10.1016/j.ejogrb.2015.06.021.Vayssière C, Sentilhes L, Ego A, Bernard C, Cambourieu D, Flamant C, Gascoin G, Gaudineau A, Grangé G, Houfflin-Debarge V, Langer B, Malan V, Marcorelles P, Nizard J, Perrotin F, Salomon L, Senat MV, Serry A, Tessier V, Truffert P, Tsatsaris V, Arnaud C, Carbonne B. Fetal growth restriction and intra-uterine growth restriction: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians. Eur J Obstet Gynecol Reprod Biol. 2015;193:10–8. DOI: 10.1016/j.ejogrb.2015.06.021.Ховхаева П.А., Тютюнник Н.В., Красный А.М., Сергунина О.А., Тимофеева Л.А., Кан Н.Е., Тютюнник В.Л. Оксидативный стресс и экспрессия генов ферментов антиоксидантной защиты в плаценте при преэклампсии // Фарматека. – 2016. – Т. 316. – № 3 – С. 74–76.Hovhaeva PA, Tyutyunnik NV, Krasnyj A.M, Sergunina OA, Timofeeva LA, Kan NE, Tyutyunnik VL. [Oksidativnyj stress i ekspressiya genov fermentov antioksidantnoj zashchity v placente pri preeklampsii]. Farmateka. 2016; 3(316):74-76. RussianКрасный А.М., Кан Н.Е., Тютюнник В.Л., Ховхаева П.А., Волгина Н.Е., Сергунина О.А., Тютюнник Н.В., Беднягин Л.А. Окислительный стресс при преэклампсии и при нормальной беременности // Акушерство и гинекология. – 2016. – № 5. – С. 90–95.Krasnyj AM, Kan NE, Tyutyunnik VL, Hovhaeva PA, Volgina NE, Sergunina OA, Tyutyunnik NV, Bednyagin LA. [Okislitel’nyj stress pri preeklampsii i pri normal’noj beremennosti]. Obstetrics and Gynecology. 2016; 5: 90-95. DOI:10.18565/aig.2016.5.90-94. RussianСидорова И.С., Никитина Н.А., Унанян А.Л., Рзаева А.А., Кинякин В.В. Патогенетическое обоснование дифференцированного подхода к ведению беременных с артериальной гипертензией и преэклампсией // Акушерство и гинекология. – 2013. – № 2. – С. 35–40.Sidorova IS, Nikitina NA, Unanyan AL, Rzaeva AA, Kinyakin VV. [Patogeneticheskoe obosnovanie differencirovannogo podhoda k vedeniyu beremennyh s arterial’noj gipertenziej i preeklampsiej]. Obstetrics and Gynecology. 2013;2: 35-40. RussianСидорова И.С., Никитина Н.А., Унанян А.Л., Рзаева А.А., Кинякин В.В. Оценка эффективности терапии преэклампсии в зависимости от тяжести гестационной дисфункции эндотелия // Российский вестник акушера-гинеколога. – 2013. – Т. 13. № 3. – С. 4–8.Sidorova I.S., Nikitina N.A., Unanian A.L., Rzaeva A.A., Kiniakin V.V. Evaluation of the efficiency of preeclampsia therapy in relation to the severity of gestational endothelial dysfunction. Rossijskij vestnik akushera-ginekologa. 2013; 13(3):4-8.Shamshirsaz A.A., Paidas M., Krikun G. Preeclampsia, hypoxia, thrombosis, and inflammation // J Pregnancy. – 2012. – Vol. 2012. – No.374047. DOI: 10.1155/2012/374047.Shamshirsaz AA, Paidas M, Krikun G. Preeclampsia, hypoxia, thrombosis, and inflammation. J Pregnancy. 2012;2012:374047. DOI: 10.1155/2012/374047.Zou Y., Zuo Q., Huang S., Yu X., Jiang Z., Zou S., Fan M., Sun L. Resveratrol inhibits trophoblast apoptosis through oxidative stress in preeclampsia-model rats // Molecules. – 2014. – Vol. 19. – No.12. – P. 20570–9. DOI: 10.3390/molecules191220570.Zou Y, Zuo Q, Huang S, Yu X, Jiang Z, Zou S, Fan M, Sun L. Resveratrol inhibits trophoblast apoptosis through oxidative stress in preeclampsia-model rats. Molecules. 2014;19(12):20570–9. DOI: 10.3390/molecules191220570.Stupakova E.G., Lazareva G.A., Gureev V.V. Correction of morphofunctional disturbances arising when modelling Preeclampsia with resveratrol and nicorandil // Research Results in Pharmacology. – 2018. – Vol. 4. – No.1. – P. 59–71. DOI:10.3897/rrpharmacology.4.25528Stupakova EG, Lazareva GA, Gureev VV. Correction of morphofunctional disturbances arising when modelling Preeclampsia with resveratrol and nicorandil. Research Results in Pharmacology. 2018;4(1):59–71. doi:10.3897/rrpharmacology.4.25528Гуреев В.В., Алехин С.А., Должиков А.А., Мостовой А.С. Коррекция ADMA-подобного гестоза в эксперименте // Курский научно-практический вестник Человек и его здоровье. – 2012. – № 1. – С. 14–19.Gureev VV, Alekhin SA, Dolzhikov AA, Mostovoy AC. Correction of experimental adma-like pre-eclampsy. Kurskij nauchno-prakticheskij vestnik CHelovek i ego zdorov’e. 2012;1:14–19. RussianYoshikawa K., Umekawa T., Maki S., Kubo M., Nii M., Tanaka K., Tanaka H., Osato K., Kamimoto Y., Kondo E., Ikemura K., Okuda M., Katayama K., Miyoshi T., Hosoda H., Ma N., Yoshida T., Ikeda T. Tadalafil Improves L-NG-Nitroarginine Methyl Ester-Induced Preeclampsia With Fetal Growth Restriction-Like Symptoms in Pregnant Mice // Am J Hypertens. – 2017. – Vol. 31. – No.1. – P. 89–96. DOI: 10.1093/ajh/hpx130.Yoshikawa K, Umekawa T, Maki S, Kubo M, Nii M, Tanaka K, Tanaka H, Osato K, Kamimoto Y, Kondo E, Ikemura K, Okuda M, Katayama K, Miyoshi T, Hosoda H, Ma N, Yoshida T, Ikeda T. Tadalafil Improves L-NG-Nitroarginine Methyl Ester-Induced Preeclampsia With Fetal Growth Restriction-Like Symptoms in Pregnant Mice. Am J Hypertens. 2017;31(1):89–96. DOI: 10.1093/ajh/hpx130.Покровский М.В., Гуреев В.В., Должиков А., Полянская О.С., Мостовой А.С., Алехин С.А. Коррекция экспериментального гестоза тадалафилом // Научные ведомости Белгородского государственного университета. Серия: Медицина. Фармация. – 2012. – Т. 18. № 10–2 (129). – С. 146–151.Pokrovskij MV, Gureev VV, Dolzhikov A, Polyanskaya OS, Mostovoj AS, Alekhin SA. Korrekciya eksperimental’nogo gestoza tadalafilom Nauchnye vedomosti Belgorodskogo gosudarstvennogo universiteta. Seriya: Medicina. Farmaciya. 2012;18(10-2 (129)):146–151. RussianАнциферова О.Е., Юракова А.В., Локтева Т.И., Северинова О.В., Гуреев В.В. Комплексная оценка коррекции триметазидином морфофункциональных нарушений при ADMA-подобной преэклампсии // Вестник Смоленской государственной медицинской академии. – 2019. – Т. 18. – №1. – С. 103–108.Antsiferova O.E., Yurakova A.V., Lokteva T.I., Severinova O.V., Gureev V.V Comprehensive assessment of the correction of morphofunctional disorders in adma preeclampsia by trimetazidine. VESTNIK OF Smolensk state medical academy. 2019;18(1). 103–108. RussianАнциферова О.Е., Гуреев В.В., Гуреева А.В., Авдеева Е.В., Михайлова Ю.А., Кузьмин Д.Б. Комплексная оценка коррекции очищенной микронизированной флавоноидной фракцией нарушений при ADMA-подобной преэклампсии в эксперименте // Научные результаты биомедицинских исследований. – 2020. – Т. 6. – №1. – С. 78–93. DOI:10.18413/2658-6533-2020-6-1-0-7Antsiferova OE, Gureev VV, Gureeva AV, et al. Comprehensive assessment of using micronised purified flavonoid fraction in the correction of disorders associated with ADMA-like preeclampsia in experiment. Research Results in Biomedicine. 2020;6(1):78–93. DOI: 10.18413/2658-6533-2020-6-1-0-7. RussianAntsiferova O.E., Yurakova A.V., Lukyanova Y.S., Gureev V.V., Korokin M.V., Gureeva A.V., Pokrovskaya T.G., Gudyrev O.S. Correction of asymmetric dimethylarginine-like pre-eclampsia in rats by micronized purified flavonoids fraction // Drug Invention Today. – 2019. – Vol. 12. – No.11. – P. 2709–12.Antsiferova OE, Yurakova AV, Lukyanova YS, Gureev VV, Korokin MV, Gureeva AV, Pokrovskaya TG, Gudyrev OS. Correction of asymmetric dimethylarginine-like pre-eclampsia in rats by micronized purified flavonoids fraction Drug Invention Today. 2019;12(11):2709–12.Stupakova E.G., Lazareva G.A., Gureev V.V., Dolzhikova I.N., Zhilinkova L.A., Gureeva A.V. L-NAME-induced Preeclampsia: correction of functional disorders of the hemostasis system with Resveratrol and Nicorandil // Research Results in Pharmacology. – 2019. – Vol. 5. – No.2. – P. 1–12. DOI:10.3897/rrpharmacology.5.35316Stupakova EG, Lazareva GA, Gureev VV, Dolzhikova IN, Zhilinkova LA, Gureeva AV L-NAME-induced Preeclampsia: correction of functional disorders of the hemostasis system with Resveratrol and Nicorandil. Research Results in Pharmacology. 2019;5(2):1–12. DOI:10.3897/rrpharmacology.5.35316Korokin M., Gureev V., Gudyrev O., Golubev I., Korokina L., Peresypkina A., Pokrovskaia T., Lazareva G., Soldatov V., Zatolokina M., Pobeda A., Avdeeva E., Beskhmelnitsyna E., Denisyuk T., Avdeeva N., Bushueva O., Pokrovskii M. Erythropoietin Mimetic Peptide (pHBSP) Corrects Endothelial Dysfunction in a Rat Model of Preeclampsia // Int J Mol Sci. – 2020. – Vol. 21. – No.18. – P. E6759. DOI: 10.3390/ijms21186759.Korokin M, Gureev V, Gudyrev O, Golubev I, Korokina L, Peresypkina A, Pokrovskaia T, Lazareva G, Soldatov V, Zatolokina M, Pobeda A, Avdeeva E, Beskhmelnitsyna E, Denisyuk T, Avdeeva N, Bushueva O, Pokrovskii M. Erythropoietin Mimetic Peptide (pHBSP) Corrects Endothelial Dysfunction in a Rat Model of Preeclampsia. Int J Mol Sci. 2020 Sep 15;21(18):E6759. DOI: 10.3390/ijms21186759. PMID: 32942669.Gureev V.V., Pokrovskii M.V., Korokin M.V., Gudyrev O.S., Philippova O.V., Dolzhikov A.A., Lazareva G.A. Correction of ADMA-induced preeclampsia with use of tetrahydrobiopterin and selective inhibitor of arginase II ZB49-0010 // Research Journal of Pharmaceutical, Biological and Chemical Sciences. – 2015. – Vol. 6. – No.5. – P. 1538–1541.Gureev VV, Pokrovskii MV, Korokin MV, Gudyrev OS, Philippova OV, Dolzhikov AA, Lazareva GA. Correction of ADMA-induced preeclampsia with use of tetrahydrobiopterin and selective inhibitor of arginase II ZB49-0010. Research Journal of Pharmaceutical, Biological and Chemical Sciences. 2015;6(5):1538–1541.Korokin M., Pokrovskiy M., Gudyrev O., Korokina L., Pokrovskaia T., Lazarev A., Philippenko N., Gureev V. Pharmacological correction of endothelial dysfunction in rats using e-NOS cofactors // Research Journal of Pharmaceutical, Biological and Chemical Sciences. – 2015. – Vol. 6. – P. 1548–1552.Korokin M, Pokrovskiy M, Gudyrev O, Korokina L, Pokrovskaia T, Lazarev A, Philippenko N, Gureev V. Pharmacological correction of endothelial dysfunction in rats using e-NOS cofactors. Research Journal of Pharmaceutical, Biological and Chemical Sciences. 2015;6:1548–1552.Lokteva T.I., Rozhkov S., Gureev V.V., Gureeva A.V., Zatolokina M.A., Avdeeva E.V., Zhilinkova L.A., Prohoda E.E., Yarceva E.O. Correction of morphofunctional disorders of the cardiovascular system with asialized erythropoietin and arginase II selective inhibitors KUD 974 and KUD 259 in experimental preeclampsia // Research Results in Pharmacology. – 2020. – Vol. 6. – No.1. – P. 29–40. DOI: 10.3897/rrpharmacology.6.50851Lokteva TI, Rozhkov S, Gureev VV, Gureeva AV, Zatolokina MA, Avdeeva EV, Zhilinkova LA, Prohoda EE, Yarceva EO. Correction of morphofunctional disorders of the cardiovascular system with asialized erythropoietin and arginase II selective inhibitors KUD 974 and KUD 259 in experimental preeclampsia. Research Results in Pharmacology. 2020;6(1):29-40. DOI: 10.3897/rrpharmacology.6.50851Yalamati P., Bhongir A.V., Karra M., Beedu S.R. Comparative Analysis of Urinary Total Proteins by Bicinchoninic Acid and Pyrogallol Red Molybdate Methods // J Clin Diagn Res. – 2015. – Vol. 9. – No.8. – P. BC01–4. DOI: 10.7860/JCDR/2015/13543.6313.Yalamati P, Bhongir AV, Karra M, Beedu SR. Comparative Analysis of Urinary Total Proteins by Bicinchoninic Acid and Pyrogallol Red Molybdate Methods. J Clin Diagn Res. 2015;9(8):BC01–4. DOI: 10.7860/JCDR/2015/13543.6313.Тюренков И.Н., Перфилова В.Н., Иванова Л.Б., Карамышева В.И. Влияние производных ГАМК на антитромботическую функцию эндотелия и состояние микроциркуляции у животных с экспериментальным гестозом // Региональное кровообращение и микроциркуляция. – 2012. – T. 11. № 2(42). – С. 61–65.Tyurenkov IN, Perfilova VN, Ivanova LB, Karamysheva VI. Vliyanie proizvodnyh GAMK na antitromboticheskuyu funkciyu endoteliya i sostoyanie mikrocirkulyacii u zhivotnyh s eksperimental’nym gestozom. Regionarnoe krovoobrashchenie i mikrocirkulyaciya. 2012;11(2):61–65. DOI: 10.24884/1682-6655-2012-11-2-61-65. RussianРуководство по проведению доклинических исследований лекарственных средств [Текст] / М-во здравоохранения и соц. развития, Науч. центр экспертизы средств мед. применения; под ред. А.Н. Миронова [и др.]. – Москва: Гриф и К, 2012. – Ч. 1. – 944 с.Mironova AN et al. Rukovodstvo po provedeniyu doklinicheskih issledovanij lekarstvennyh sredstv. Part 1. Moscow: Grif i K; 2012. Russian.Kantor P.F., Lucien A., Kozak R., Lopaschuk G.D. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase // Circ Res. – 2000. – Vol. 86. – No.5. – P. 580–8. DOI: 10.1161/01.res.86.5.580. PMID: 10720420.Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000;86(5):580–8. DOI: 10.1161/01.res.86.5.580. PMID: 10720420.Dalal J.J., Mishra S. Modulation of myocardial energetics: An important category of agents in the multimodal treatment of coronary artery disease and heart failure // Indian Heart J. – 2017. – Vol. 69. – No.3. – P. 393–401. DOI: 10.1016/j.ihj.2017.04.001.Dalal JJ, Mishra S. Modulation of myocardial energetics: An important category of agents in the multimodal treatment of coronary artery disease and heart failure. Indian Heart J. 2017;69(3):393–401. DOI: 10.1016/j.ihj.2017.04.001.Belardinelli R., Solenghi M., Volpe L., Purcaro A. Trimetazidine improves endothelial dysfunction in chronic heart failure: an antioxidant effect // Eur Heart J. – 2007. – Vol. 28. – No.9. – P. 1102–8. DOI: 10.1093/eurheartj/ehm071.Belardinelli R, Solenghi M, Volpe L, Purcaro A. Trimetazidine improves endothelial dysfunction in chronic heart failure: an antioxidant effect. Eur Heart J. 2007;28(9):1102–8. DOI: 10.1093/eurheartj/ehm071.Wei J., Xu H., Shi L., Tong J., Zhang J. Trimetazidine protects cardiomyocytes against hypoxia-induced injury through ameliorates calcium homeostasis // Chem Biol Interact. – 2015. – Vol. 236. – P. 47–56. DOI: 10.1016/j.cbi.2015.04.022.Wei J, Xu H, Shi L, Tong J, Zhang J. Trimetazidine protects cardiomyocytes against hypoxia-induced injury through ameliorates calcium homeostasis. Chem Biol Interact. 2015;236:47–56. DOI: 10.1016/j.cbi.2015.04.022.Steggall A., Mordi I.R., Lang C.C. Targeting Metabolic Modulation and Mitochondrial Dysfunction in the Treatment of Heart Failure // Diseases. – 2017. – Vol. 5. – No.2. – P. 14. DOI: 10.3390/diseases5020014.Steggall A, Mordi IR, Lang CC. Targeting Metabolic Modulation and Mitochondrial Dysfunction in the Treatment of Heart Failure. Diseases. 2017 May 10;5(2):14. DOI: 10.3390/diseases5020014.Shi W., Shangguan W., Zhang Y., Li C., Li G. Effects of trimetazidine on mitochondrial respiratory function, biosynthesis, and fission/fusion in rats with acute myocardial ischemia // Anatol J Cardiol. – 2017. – Vol. 18. – No.3. – P.175–181. DOI: 10.14744/AnatolJCardiol.2017.7771.Shi W, Shangguan W, Zhang Y, Li C, Li G. Effects of trimetazidine on mitochondrial respiratory function, biosynthesis, and fission/fusion in rats with acute myocardial ischemia. Anatol J Cardiol. 2017;18(3):175–181. DOI: 10.14744/AnatolJCardiol.2017.7771.Mahfoudh-Boussaid A., Hadj Ayed Tka K., Zaouali M.A., Roselló-Catafau J., Ben Abdennebi H. Effects of trimetazidine on the Akt/eNOS signaling pathway and oxidative stress in an in vivo rat model of renal ischemia-reperfusion // Ren Fail. – 2014. – Vol. 36. – No.9. – P. 1436–42. DOI: 10.3109/0886022X.2014.949765.Mahfoudh-Boussaid A, Hadj Ayed Tka K, Zaouali MA, Roselló-Catafau J, Ben Abdennebi H. Effects of trimetazidine on the Akt/eNOS signaling pathway and oxidative stress in an in vivo rat model of renal ischemia-reperfusion. Ren Fail. 2014;36(9):1436–42. DOI: 10.3109/0886022X.2014.949765.Wu Q., Qi B., Liu Y., Cheng B., Liu L., Li Y., Wang Q. Mechanisms underlying protective effects of trimetazidine on endothelial progenitor cells biological functions against H2O2-induced injury: involvement of antioxidation and Akt/eNOS signaling pathways // Eur J Pharmacol. – 2013. – Vol. 707. – No.1–3. – P. 87–94. DOI: 10.1016/j.ejphar.2013.03.027.Wu Q, Qi B, Liu Y, Cheng B, Liu L, Li Y, Wang Q. Mechanisms underlying protective effects of trimetazidine on endothelial progenitor cells biological functions against H2 O2 -induced injury: involvement of antioxidation and Akt/eNOS signaling pathways. Eur J Pharmacol. 20135;707(1–3):87–94. DOI: 10.1016/j.ejphar.2013.03.027.Danikiewicz A., Szkodziński J., Hudzik B., Korzonek-Szlacheta I., Gąsior M., Zubelewicz-Szkodzińska B. Effects of trimetazidine on interleukin-2 and interleukin-8 concentrations in patients with coronary artery disease // Can J Physiol Pharmacol. – 2017. – Vol. 95. – No.6. – P. 759–762. DOI: 10.1139/cjpp-2016-0424.Danikiewicz A, Szkodziński J, Hudzik B, Korzonek-Szlacheta I, Gąsior M, Zubelewicz-Szkodzińska B. Effects of trimetazidine on interleukin-2 and interleukin-8 concentrations in patients with coronary artery disease. Can J Physiol Pharmacol. 2017;95(6):759–762. DOI: 10.1139/cjpp-2016-0424.Szkodzinski J., Danikiewicz A., Hudzik B., Szewczyk M., Gąsior M., Zubelewicz-Szkodzinska B. Effect of trimetazidine on serum interleukin-6 and C-reactive protein concentrations in patients with stable coronary artery disease // J Biol Regul Homeost Agents. – 2015. – Vol. 29. – No.1. – P. 63–72.Szkodzinski J, Danikiewicz A, Hudzik B, Szewczyk M, Gąsior M, Zubelewicz-Szkodzinska B. Effect of trimetazidine on serum interleukin-6 and C-reactive protein concentrations in patients with stable coronary artery disease. J Biol Regul Homeost Agents. 2015;29(1):63–72.Yoon J.W., Cho B.J., Park H.S., Kang S.M., Choi S.H., Jang H.C., Shin H., Lee M.J., Kim Y.B., Park K.S., Lim S. Differential effects of trimetazidine on vascular smooth muscle cell and endothelial cell in response to carotid artery balloon injury in diabetic rats // Int J Cardiol. – 2013. – Vol. 167. – No.1. – P. 126–33. DOI: 10.1016/j.ijcard.2011.12.061.Yoon JW, Cho BJ, Park HS, Kang SM, Choi SH, Jang HC, Shin H, Lee MJ, Kim YB, Park KS, Lim S. Differential effects of trimetazidine on vascular smooth muscle cell and endothelial cell in response to carotid artery balloon injury in diabetic rats. Int J Cardiol. 2013;167(1):126–33. DOI: 10.1016/j.ijcard.2011.12.061.Zhang L., Ding W.Y., Wang Z.H., Tang M.X., Wang F., Li Y., Zhong M., Zhang Y., Zhang W. Early administration of trimetazidine attenuates diabetic cardiomyopathy in rats by alleviating fibrosis, reducing apoptosis and enhancing autophagy // J Transl Med. – 2016. – Vol. 14. – No.1. – P. 309. DOI: 10.1186/s12967-016-0849-1.Zhang L, Ding WY, Wang ZH, Tang MX, Wang F, Li Y, Zhong M, Zhang Y, Zhang W. Early administration of trimetazidine attenuates diabetic cardiomyopathy in rats by alleviating fibrosis, reducing apoptosis and enhancing autophagy. J Transl Med. 2016;14(1):109. DOI: 10.1186/s12967-016-0849-1.Cтаценко М.Е., Фабрицкая С.В., Рындина Ю.А. Влияние терапии триметазидином на состояние магистральных сосудов и микроциркуляцию у больных ХСН и СД 2-го типа // Медицинский совет. – 2018. – №5. – С. 65–69.Statsenko ME, Fabritskaya SV, Ryndina UA. Influence of therapy with trimetazidine on the state of the main vessels and microcirculation in patients with CHF and DM type 2. The results of the original study. Meditsinskiy sovet: Medical Council. 2018;(5):65–69. DOI:10.21518/2079-701X-2018-5-65-69. RussianMilinković I., Rosano G., Lopatin Y., Seferović P.M. The Role of Ivabradine and Trimetazidine in the New ESC HF Guidelines // Card Fail Rev. – 2016. – Vol. 2. – No.2. – P. 123–129. DOI: 10.15420/cfr.2016:13:1.Milinković I, Rosano G, Lopatin Y, Seferović PM. The Role of Ivabradine and Trimetazidine in the New ESC HF Guidelines. Card Fail Rev. 2016 Nov;2(2):123–129. DOI: 10.15420/cfr.2016:13:1.Трухан Д.И., Давыдов Е.Л., Мазуров А.Л. Миокардиальный цитопротектор триметазидин МВ – препарат, повышающий эффективность лечения пациентов с хронической сердечной недостаточностью и ишемической болезнью сердца // Медицинский совет. – 2017. – №7. – С. 75–83.Trukhan DI, Mazurov AL, Davydov EL. Myocardial cytoprotector trimetazidine MB-preparat, increases the effectiveness of treatment of chronic heart failure and coronary heart disease. Meditsinskiy sovet: Medical Council. 2017;(7):75–83. DOI: 10.21518/2079-701X-2017-7-75-83. RussianPatel K., Gadewar M., Tahilyani V., Patel D.K. A review on pharmacological and analytical aspects of diosmetin: a concise report // Chin J Integr Med. – 2013. – Vol. 19. – No.10. – P. 792–800. DOI: 10.1007/s11655-013-1595-3.Patel K, Gadewar M, Tahilyani V, Patel DK. A review on pharmacological and analytical aspects of diosmetin: a concise report. Chin J Integr Med. 2013;19(10):792–800. DOI: 10.1007/s11655-013-1595-3.Wei D., Ci X., Chu X., Wei M., Hua S., Deng X. Hesperidin suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model // Inflammation. – 2012. – Vol. 35. – No.1. – P. 114–21. DOI: 10.1007/s10753-011-9295-7.Wei D, Ci X, Chu X, Wei M, Hua S, Deng X. Hesperidin suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model. Inflammation. 2012;35(1):114–21. DOI: 10.1007/s10753-011-9295-7.Maneesai P., Bunbupha S., Potue P., Berkban T., Kukongviriyapan U., Kukongviriyapan V., Prachaney P., Pakdeechote P. Hesperidin Prevents Nitric Oxide Deficiency-Induced Cardiovascular Remodeling in Rats via Suppressing TGF-β1 and MMPs Protein Expression // Nutrients. – 2018. – Vol. 10. – No.10. – P. 1549. DOI: 10.3390/nu10101549.Maneesai P, Bunbupha S, Potue P, Berkban T, Kukongviriyapan U, Kukongviriyapan V, Prachaney P, Pakdeechote P. Hesperidin Prevents Nitric Oxide Deficiency-Induced Cardiovascular Remodeling in Rats via Suppressing TGF-β1 and MMPs Protein Expression. Nutrients. 2018;10(10):1549. DOI: 10.3390/nu10101549.Shaban N.Z., Ahmed Zahran A.M., El-Rashidy F.H., Abdo Kodous A.S. Protective role of hesperidin against γ-radiation-induced oxidative stress and apoptosis in rat testis // J Biol Res (Thessalon). – 2017. – Vol. 24. – P. 5. DOI: 10.1186/s40709-017-0059-x.Shaban NZ, Ahmed Zahran AM, El-Rashidy FH, Abdo Kodous AS. Protective role of hesperidin against γ-radiation-induced oxidative stress and apoptosis in rat testis. J Biol Res (Thessalon). 2017;24:5. DOI: 10.1186/s40709-017-0059-x. PMID: 28265554; PMCID: PMC5333452.Ali T.M., Abo-Salem O.M., El Esawy B.H., El Askary A. The Potential Protective Effects of Diosmin on Streptozotocin-Induced Diabetic Cardiomyopathy in Rats // Am J Med Sci. – 2020. – Vol. 359. – No.1. – P. 32–41. DOI: 10.1016/j.amjms.2019.10.005.Ali TM, Abo-Salem OM, El Esawy BH, El Askary A. The Potential Protective Effects of Diosmin on Streptozotocin-Induced Diabetic Cardiomyopathy in Rats. Am J Med Sci. 2020 Jan;359(1):32–41. doi: 10.1016/j.amjms.2019.10.005.Yarmolinsky L., Budovsky A., Yarmolinsky L., Khalfin B., Glukhman V., Ben-Shabat S. Effect of Bioactive Phytochemicals from Phlomis viscosa Poiret on Wound Healing // Plants (Basel). – 2019. – Vol. 8. – No.12. – P. 609. DOI: 10.3390/plants8120609.Yarmolinsky L, Budovsky A, Yarmolinsky L, Khalfin B, Glukhman V, Ben-Shabat S. Effect of Bioactive Phytochemicals from Phlomis viscosa Poiret on Wound Healing. Plants (Basel). 2019;8(12):609. DOI: 10.3390/plants8120609.Lin J.T., Chang Y.Y., Chen Y.C., Shen B.Y., Yang D.J. Molecular mechanisms of the effects of the ethanolic extract of Muntingia calabura Linn. fruit on lipopolysaccharide-induced pro-inflammatory mediators in macrophages // Food Funct. – 2017. – Vol. 8. – No.3. – P. 1245–1253. DOI: 10.1039/c6fo01735e.Lin JT, Chang YY, Chen YC, Shen BY, Yang DJ. Molecular mechanisms of the effects of the ethanolic extract of Muntingia calabura Linn. fruit on lipopolysaccharide-induced pro-inflammatory mediators in macrophages. Food Funct. 2017;8(3):1245–1253. DOI: 10.1039/c6fo01735e.Ağır M.S., Eraslan G. The effect of diosmin against liver damage caused by cadmium in rats // J Food Biochem. – 2019. – Vol. 43. – No.9. – P. e12966. DOI: 10.1111/jfbc.12966.Ağır MS, Eraslan G. The effect of diosmin against liver damage caused by cadmium in rats. J Food Biochem. 2019;43(9):e12966. DOI: 10.1111/jfbc.12966.Elhelaly A.E., AlBasher G., Alfarraj S., Almeer R., Bahbah E.I., Fouda M.M.A., Bungău S.G., Aleya L., Abdel-Daim M.M. Protective effects of hesperidin and diosmin against acrylamide-induced liver, kidney, and brain oxidative damage in rats // Environ Sci Pollut Res Int. – 2019. – Vol. 26. – No.34. – P. 35151–35162. DOI: 10.1007/s11356-019-06660-3.Elhelaly AE, AlBasher G, Alfarraj S, Almeer R, Bahbah EI, Fouda MMA, Bungău SG, Aleya L, Abdel-Daim MM. Protective effects of hesperidin and diosmin against acrylamide-induced liver, kidney, and brain oxidative damage in rats. Environ Sci Pollut Res Int. 2019;26(34):35151-35162. DOI: 10.1007/s11356-019-06660-3.Berkoz M. Diosmin suppresses the proinflammatory mediators in lipopolysaccharide-induced RAW264.7 macrophages via NF-κB and MAPKs signal pathways // Gen Physiol Biophys. – 2019. – Vol. 38. – No.4. – P. 315–324. DOI: 10.4149/gpb_2019010.Berkoz M. Diosmin suppresses the proinflammatory mediators in lipopolysaccharide-induced RAW264.7 macrophages via NF-κB and MAPKs signal pathways. Gen Physiol Biophys. 2019 Jul;38(4):315–324. doi: 10.4149/gpb_2019010. Epub 2019 Jun 26. PMID: 31241043.Kalinin R.E., Suchkov I.A., Kamaev A.A., Zvyagina V.I., Krylov A.A. Éndoteliotropnye éffekty venotoniziruiushchikh preparatov pri lechenii bol’nykh s varikoznoĭ bolezn’iu [Endotheliotropic effects of venotonic drugs in treatment of patients with varicose veins]. Angiol Sosud Khir. – 2018. – Vol. 24. – No.4. – P. 72–74. Russian.Kalinin RE, Suchkov IA, Kamaev AA, Zvyagina VI, Krylov AA. Éndoteliotropnye éffekty venotoniziruiushchikh preparatov pri lechenii bol’nykh s varikoznoĭ bolezn’iu [Endotheliotropic effects of venotonic drugs in treatment of patients with varicose veins]. Angiol Sosud Khir. 2018;24(4):72–74. Russian. PMID: 30531772.Gurfinkel’ I.I., Sasonko M.L., Talov N.A. Korrektsiia parametrov mikrotsirkuliatsii krovi i funktsii éndoteliia pri khronicheskoĭ venoznoĭ nedostatochnosti nizhnikh konechnosteĭ [Correction of blood microcirculation parameters and endothelial function in chronic venous insufficiency of lower limbs] // Angiol Sosud Khir. – 2017. – Vol. 23. – No.2. – P. 89–95. Russian.Gurfinkel’ II, Sasonko ML, Talov NA. Korrektsiia parametrov mikrotsirkuliatsii krovi i funktsii éndoteliia pri khronicheskoĭ venoznoĭ nedostatochnosti nizhnikh konechnosteĭ [Correction of blood microcirculation parameters and endothelial function in chronic venous insufficiency of lower limbs]. Angiol Sosud Khir. 2017;23(2):89–95. Russian.Zudin A.M., Gritsenko A.G., Hadzhishvili I.T. Vozdeĭstvie diosmina i gesperidina na kapilliarnyĭ krovotok verkhnikh konechnosteĭ u patsientov s vtorichnym sindromom Reĭno [The effects of diosmin and hesperidin on capillary blood flow of upper limbs in patients with secondary Raynaud’s syndrome] // Khirurgiia (Mosk). – 2017. – Vol. 5. – P. 60–66. DOI: 10.17116/hirurgia2017560-66. Russian.Zudin AM, Gritsenko AG, Hadzhishvili IT. Vozdeĭstvie diosmina i gesperidina na kapilliarnyĭ krovotok verkhnikh konechnosteĭ u patsientov s vtorichnym sindromom Reĭno [The effects of diosmin and hesperidin on capillary blood flow of upper limbs in patients with secondary Raynaud’s syndrome]. Khirurgiia (Mosk). 2017;(5):60–66. DOI: 10.17116/hirurgia2017560-66. Russian.Paredes M.D., Romecín P., Atucha N.M., O’Valle F., Castillo J., Ortiz M.C., García-Estañ J. Moderate Effect of Flavonoids on Vascular and Renal Function in Spontaneously Hypertensive Rats // Nutrients. – 2018. – Vol. 10. – No.8. – P. 1107. DOI: 10.3390/nu10081107.Paredes MD, Romecín P, Atucha NM, O’Valle F, Castillo J, Ortiz MC, García-Estañ J. Moderate Effect of Flavonoids on Vascular and Renal Function in Spontaneously Hypertensive Rats. Nutrients. 2018;10(8):1107. DOI: 10.3390/nu10081107.Paredes M.D., Romecín P., Atucha N.M., O’Valle F., Castillo J., Ortiz M.C., García-Estañ J. Beneficial Effects of Different Flavonoids on Vascular and Renal Function in L-NAME Hypertensive Rats // Nutrients. – 2018. – Vol. 10. – No.4. – P. 484. DOI: 10.3390/nu10040484.Paredes MD, Romecín P, Atucha NM, O’Valle F, Castillo J, Ortiz MC, García-Estañ J. Beneficial Effects of Different Flavonoids on Vascular and Renal Function in L-NAME Hypertensive Rats. Nutrients. 2018;10(4):484. DOI: 10.3390/nu10040484.Liu X., Zhang X., Zhang J., Kang N., Zhang N., Wang H., Xue J., Yu J., Yang Y., Cui H., Cui L., Wang L., Wang X. Diosmin protects against cerebral ischemia/reperfusion injury through activating JAK2/STAT3 signal pathway in mice // Neuroscience. – 2014. – Vol. 268. – P. 318–27. DOI: 10.1016/j.neuroscience.2014.03.032.Liu X, Zhang X, Zhang J, Kang N, Zhang N, Wang H, Xue J, Yu J, Yang Y, Cui H, Cui L, Wang L, Wang X. Diosmin protects against cerebral ischemia/reperfusion injury through activating JAK2/STAT3 signal pathway in mice. Neuroscience. 2014;268:318–27. DOI: 10.1016/j.neuroscience.2014.03.032.Kilicoglu S.S., Tanrikulu Y., Kismet K., Devrim E., Erel S., Tanrikulu C.S., Aydogan A., Tasova V., Sabuncuoglu M.Z., Kilicoglu B. The effect of diosmin on pancreatic injury induced by hepatic ischemia reperfusion in rats // Bratisl Lek Listy. – 2013. – Vol. 114. – No.3. – P. 119–24. DOI: 10.4149/bll_2013_026.Kilicoglu SS, Tanrikulu Y, Kismet K, Devrim E, Erel S, Tanrikulu CS, Aydogan A, Tasova V, Sabuncuoglu MZ, Kilicoglu B. The effect of diosmin on pancreatic injury induced by hepatic ischemia reperfusion in rats. Bratisl Lek Listy. 2013;114(3):119–24. DOI: 10.4149/bll_2013_026.Mastantuono T., Battiloro L, Sabatino L., Chiurazzi M., Di Maro M., Muscariello E., Colantuoni A., Lapi D. Effects of Citrus Flavonoids Against Microvascular Damage Induced by Hypoperfusion and Reperfusion in Rat Pial Circulation // Microcirculation. – 2015. – Vol. 22. – No.5. – P. 378–90. DOI: 10.1111/micc.12207.Mastantuono T, Battiloro L, Sabatino L, Chiurazzi M, Di Maro M, Muscariello E, Colantuoni A, Lapi D. Effects of Citrus Flavonoids Against Microvascular Damage Induced by Hypoperfusion and Reperfusion in Rat Pial Circulation. Microcirculation. 2015;22(5):378–90. DOI: 10.1111/micc.12207.Mansilha A., Sousa J. Pathophysiological Mechanisms of Chronic Venous Disease and Implications for Venoactive Drug Therapy // Int J Mol Sci. – 2018. – Vol. 19. – No.6. – P. 1669. DOI: 10.3390/ijms19061669.Mansilha A, Sousa J. Pathophysiological Mechanisms of Chronic Venous Disease and Implications for Venoactive Drug Therapy. Int J Mol Sci. 2018;19(6):1669. DOI: 10.3390/ijms19061669.Cacchio A., Di Carlo G., Vincenza C., De Blasis E. Effectiveness and safety of a mixture of diosmin, coumarin and arbutin (Linfadren®) in addition to conventional treatment in the management of patients with posttrauma/surgery persistent hand edema: a randomized controlled trial // Clin Rehabil. – 2019. – Vol. 33. – No.5. – P. 904–912. DOI: 10.1177/0269215519829797.G, Vincenza C, De Blasis E. Effectiveness and safety of a mixture of diosmin, coumarin and arbutin (Linfadren®) in addition to conventional treatment in the management of patients with post-trauma/surgery persistent hand edema: a randomized controlled trial. Clin Rehabil. 2019;33(5):904–912. DOI: 10.1177/0269215519829797.Cacchio A., Prencipe R., Bertone M., De Benedictis L., Taglieri L., D’Elia E., Centoletti C., Di Carlo G. Effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy on management of breast cancer-related lymphedema // Support Care Cancer. – 2019. – Vol. 27. – No.4. – P. 1471–1480. DOI: 10.1007/s00520-018-4514-5.Cacchio A, Prencipe R, Bertone M, De Benedictis L, Taglieri L, D’Elia E, Centoletti C, Di Carlo G. Effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy on management of breast cancer-related lymphedema. Support Care Cancer. 2019 ;27(4):1471–1480. DOI: 10.1007/s00520-018-4514-5.Feldo M., Wójciak-Kosior M., Sowa I., Kocki J., Bogucki J., Zubilewicz T., Kęsik J., Bogucka-Kocka A. Effect of Diosmin Administration in Patients with Chronic Venous Disorders on Selected Factors Affecting Angiogenesis // Molecules. – 2019. – Vol. 24. – No.18. – P. 3316. DOI: 10.3390/molecules24183316.Feldo M, Wójciak-Kosior M, Sowa I, Kocki J, Bogucki J, Zubilewicz T, Kęsik J, Bogucka-Kocka A. Effect of Diosmin Administration in Patients with Chronic Venous Disorders on Selected Factors Affecting Angiogenesis. Molecules. 2019;24(18):3316. DOI: 10.3390/molecules24183316.Дроговоз С.М., Штрыголь С.Ю., Щекина Е.Г., Матвеева Е.В., Волощук Н.И., Тржецинский С.Д., Заморский И.И., Олещук А.М., Подплетняя Е.А., Штробля А.Л., Иванцик Л.Б., Дроговоз В.В. Фармакология в помощь врачу, провизору и студенту // Х.: Титул. – 2018. – 640 с.Drogovoz SM, SHtrygol’ SYu, SHCHekina EG, Matveeva EV, Voloshchuk NI, Trzhecinskij SD, Zamorskij II, Oleshchuk AM, Podpletnyaya EA, SHtroblya AL, Ivancik LB, Drogovoz VV. Farmakologiya v pomoshch’ vrachu, provizoru i studentu. Har’kov; 2018.Xu B., Charlton F., Makris A., Hennessy A. Antihypertensive drugs methyldopa, labetalol, hydralazine, and clonidine improve trophoblast interaction with endothelial cellular networks in vitro // J Hypertens. – 2014. – Vol. 32. – No.5. – P. 1075–83; discussion 1083. DOI: 10.1097/HJH.0000000000000134.Xu B, Charlton F, Makris A, Hennessy A. Antihypertensive drugs methyldopa, labetalol, hydralazine, and clonidine improve trophoblast interaction with endothelial cellular networks in vitro. J Hypertens. 2014;32(5):1075–83; discussion 1083. DOI: 10.1097/HJH.0000000000000134.Xu B., Bobek G., Makris A., Hennessy A. Antihypertensive methyldopa, labetalol, hydralazine, and clonidine reversed tumour necrosis factor-α inhibited endothelial nitric oxide synthase expression in endothelial-trophoblast cellular networks // Clin Exp Pharmacol Physiol. – 2017. – Vol. 44. – No.3. – P. 421–427. DOI: 10.1111/1440-1681.12712.Xu B, Bobek G, Makris A, Hennessy A. Antihypertensive methyldopa, labetalol, hydralazine, and clonidine reversed tumour necrosis factor-α inhibited endothelial nitric oxide synthase expression in endothelial-trophoblast cellular networks. Clin Exp Pharmacol Physiol. 2017;44(3):421–427. DOI: 10.1111/1440-1681.12712.

The authors declare that there are no conflicts of interest present.