Introduction. Testicular hyaluronidase preparations are widely used in medical practice. Modification of native biologically active molecules by electron beam PEGylation allows to improve their pharmacokinetic properties, which determines a subsequent improvement of pharmacodynamic effects. The development of an original oral drug with a pharmacologically active core, which is hyaluronidase, is promising, but requires studying the safety of use at the preclinical stage. Aim. Ultrastructural evaluation of hepatotoxic effects of PEGylated hyaluronidase in vitro. Materials and methods. The object of a study was testicular hyaluronidase PEGylated on polyethylene oxide (PEG-HYAL) using electron beam synthesis. The culture medium is a continous culture of human liver cells Chanq liver. The cytotoxic effect was detected by the MTT assay. Ultrastructural changes were evaluated by electron microscopy. Results. The original drug PEG-HYAL in the studied concentrations of 37, 75 and 150 U/ml has no cytotoxic effect on the human liver cell culture (hepatocytes). Cell viability is virtually at the control level when PEG-HYAL administration at concentrations of 37 and 75 U/ml, and in the maximum concentration of 150 U/ml, cell proliferation is stimulated significantly, as evidenced by an increase in cell viability up to 106%. The results of evaluation of ultrastructural changes in hepatocytes showed that exposure to PEG-HYAL in all concentrations leads to the enhancement of metabolic processes in cells, development of autophagy, which is one of the main homeostatic processes. Conclusion. The drug PEG-HYAL in all studied concentrations has no toxic effect on the human hepatocyte culture. The results obtained can be used in further research in the development of PEG-HYAL.

Введение. Тромболитическая терапия с применением активаторов плазминогена достаточно эффективна, но сопряжена с риском возникновения геморрагических осложнений и реализуется только внутривенным путём введения. Существует необходимость в пероральной тромболитической терапии. Среди возможных кандидатов для эффективного перорального фибринолиза/тромболизиса следует обратить внимание на сериновые протеиназы, не вызывающие сайт-специфического гидролиза факторов свёртывания крови. Необходимо изучить их энтеральную биодоступность и тромболитическую активность. Цель исследования: изучить путь поступления сериновой протеиназы субтилизина в системный кровоток при пероральном применении, а также сравнить тромболитическую активность протеолитических ферментов трипсина, химотрипсина и субтилизина. Материалы и методы. Проведено открытое сравнительное экспериментальное исследование в параллельных группах крыс по определению тромболитической активности изучаемых препаратов in vitro. Сформировано 4 группы животных: 3 для исследования лекарственных препаратов субтилизина, трипсина, химотрипсина и 1 контрольная. В каждой группе происходила инкубация фрагментированных тромбов с предполагаемым тромболитическим агентом. Для исследования всасывания иммобилизированного субтилизина (ИС) 30 крысам после срединной лапаротомии интубировали фрагмент тощей кишки для инфузии растворов. Для ИС, меченного флуоресцеин‑5‑изотиоцианатом (ФИТЦ), определены особенности всасывания из тощей кишки в систему кровь–лимфа. Меченный ИС экстрагировали из прилегающей к области интубации интерстициальной жидкости кишечника, слизистый слой которого был удален, и из паренхимы лимфатических узлов (I и II порядка). Для визуальной детекции абсорбции ИС на эпителии тощей кишки применили метод конфокальной микроскопии. Тромболитическая активность ИС, трипсина и химотрипсина исследована на фрагментированном тромбе. Результаты. In situ установлено, что ИС через 60 мин после начала инкубации в тощей кишке детектируется и в плазме крови и в лимфе (p < 0,01). Концентрация препарата в плазме крови из v. mesenterica (223,8 ± 39,8 мЕд/мл) более чем в 10 раз выше, чем в лимфе из цистерны грудного протока (19,27 ± 2,33 мЕд/мл). Снижение концентрации препарата в v. cauda (143,7 ± 24,4 мЕд/мл) по сравнению с v. mesenterica (p < 0,01) объясняется первичным метаболизмом в печени и последующим почечным клиренсом. При конфокальной микроскопии хорошо видно, что ИС активно абсорбируется на слизистой тонкого кишечника с накоплением в толще крипт и поступлением в сосудистую сеть. В экспериментах in vitro показано, что в условиях нормального или компенсированного кислотно-основного состояния крови достоверно наибольшую тромболитическую активность имеет препарат ИС (p < 0,05 по сравнению с контролем, трипсином и химотрипсином). За 30 мин инкубации ИС уменьшает площадь тромба более чем на 20%. Заключение. Энтеральная биодоступность ИС обеспечивается за счёт активной абсорбции на слизистой тонкого кишечника, прямого поступления в сосуды портальной системы и накопления в лимфатическом русле с дальнейшим дренажем в системный кровоток. Тромболитическое действие ИС существенно превосходит трипсин и химотрипсин, что позволяет считать малоперспективным разработку пероральных тромболитиков на основе трипсина и химотрипсина. Background. Thrombolytic therapy with plasminogen activators is quite effective, but it is associated with the risk of hemorrhagic complications and is implemented only by intravenous administration. Need for oral thrombolytic therapy exists. Among the possible options for effective oral fibrinolysis/thrombolysis, attention should be paid to serine proteinases that do notcause site-specific hydrolysis of blood coagulation factors. It is necessary to study their enteral bioavailability and thrombolytic activity. Objectives: to study the route of entry of serine proteinase subtilisin into the systemic circulation after oral administration, and also to compare the thrombolytic activity of the proteolytic enzymes trypsin, chymotrypsin, subtilisin. Materials/Methods. We carried out an open comparative experimental study in parallel groups of rats to determine the thrombolytic activity of the studied drugs in vitro. Four groups were formed: 3 groups to study subtilisin, trypsin, chymotrypsin and 1 control group. In each group, fragmented thrombi were incubated with the putative thrombolytic agent. To study the absorption of immobilized subtilisin (IS), 30 rats after midline laparotomy were intubated with a jejunum fragment for infusion of solutions. For IS labelled with fluorescein‑5‑isothiocyanate (FITC), the features of absorption from the jejunum into the blood-lymph system were determined. The labelled IS was extracted from the interstitial fluid adjacent to the intubation area, the mucous layer of which was removed, and from the parenchyma of the lymph nodes (sentinel and second-tier nodes). Confocal microscopy was used to detect visually the IS absorption on the jejunal epithelium. The thrombolytic activity of IS, trypsin, and chymotrypsin was studied on a fragmented thrombus. Results. It was found in situ that IS 60 min after the start of incubation in the jejunum was detected in both blood plasma and lymph (p < 0.01). Plasma drug concentration from the mesenteric vein (223.8 8 ± 39.8 mU/ml) is more than 10 times higher than that in the lymph from the thoracic duct cistern (19.27 ± 2.33 mU/ml). Reducing drug concentration in the caudal vena (143.7 ± 24.4 mU/ml) compared to the mesenteric vein (p < 0.01) is explained by primary hepatic metabolism and subsequent renal clearance. Confocal microscopy clearly shows that IS is actively absorbed at the mucous membrane of the small intestine with accumulation in the crypt and entering the vasculature. In vitro experiments have shown that under conditions of the normal or compensated acid-base blood state, the IS has significantly the highest thrombolytic activity (p < 0.05 compared to control, trypsin and chymotrypsin). After 30 minutes of incubation, IS reduces the thrombus area by more than 20%. Conclusions. IS enteral bioavailability is provided due to active absorption at the mucous membrane of the small intestine, direct entry into the vessels of the portal system and accumulation in the lymphatic bed with further drainage into the systemic circulation. IS thrombolytic effect is significantly superior to trypsin and chymotrypsin, which makes the development of oral thrombolytics based on trypsin and chymotrypsin unpromising.

Фармакологический тромболизис широко применяется для ликвидации жизнеугрожающих тромбозов. Эта медицинская технология постоянно усовершенствуется. Разрабатываются гибридные фармако-хирургические технологии. Наиболее широко применяется системный тромболизис на основе активаторов плазминогена. Также внедряются новые технологии систем-ного тромболизиса на основе новых препаратов — не активаторов плазминогена. Разработана концепция неплазминового фибринолиза. На её основе предложен метод фармакологического тромболизиса на основе ферментов субтилизинов. Pharmacological thrombolysis is widely used to eliminate life-threatening thrombosis. This medical technique is constantly improved. Hybrid pharmaco-surgical technologies are developed. The most widely used thrombolysis is the systemic thrombolysisbased on plasminogen activators. New technologies of systemic thrombolysis based on new drugs being non-plasminogen activators are also introduced. The concept of non-plasmin fibrinolysis has been developed. On the basis of this concept a methodof pharmacological thrombolysis based on subtilisins enzymes is proposed.

АННОТАЦИЯДля определения эффективности и безопасности лекарственного препарата на основе иммобилизированного субтилизина (СУБТ) проведены экспериментальные (с использованием крыс-самцов линии Wistar и Balb/C) и клиническое (VETTER-1 -Venous Thrombosis Therapy) исследования.Экспериментальные исследования показали прямое тромболитическое действие СУБТ на 1-, 2-и 24-часовые тромбы (in vitro) и отсутствие локальных изменений у крыс с κ-каррагинановым тромбозом (in vivo).В ходе клинического исследования у пациентов, получавших СУБТ, увеличение кровотока на 5 % от исходного либо реканализацию вены наблюдали в 1.5-1.6 раза чаще по сравнению с пациентами, получавшими плацебо.Таким образом, лекарственный препарат на основе СУБТ может быть использован в терапии венозных тромбозов.

Введение. Таргетная терапия тромбозов заключается в тромболитической терапии. В настоящий момент в подавляющем большинстве случаев терапия тромбозов у пациента сводится к назначению антикоагулянтов в расчете на механизм собственного фибринолиза/тромболизиса. Применение активаторов плазминогена эффективно, но сопряжено с опасностью тяжелых кровотечений и проводится только в условиях стационара. Очень перспективно для лечения тромбозов выглядит применение лекарственных препаратов на основе иммобилизированных субтилизинов, которые имеют прямое тромболитическое действие при пероральном приеме. В России зарегистрирован лекарственный препарат на основе иммобилизированных субтилизинов Тромбовазим, который имеет показание лечение хронической венозной недостаточности. Основой фармакодинамики препарата является тромболитическое действие. Цель исследования: показать, что включение лекарственного препарата Тромбовазим в комплексную терапию тромбозов венозного русла нижних конечностей улучшает результаты лечения. Материалы и методы. Проведено многоцентровое рандомизированное плацебоконтролируемое двойное слепое клиническое исследование. В настоящий момент лекарственный препарат Тромбовазим зарегистрирован к медицинскому применению в дозе 1600 ЕД/сут. Клиническое исследование было проведено по двум протоколам: Протокол 1 включение Тромбовазима в комплексную терапию тромбоза в суточной дозе 1600 ЕД Протокол 2 включение Тромбовазима в комплексную терапию тромбоза в более высоких дозах 3200 и 4800 ЕД/сут. Результаты. У пациентов, принимающих лекарственный препарат Тромбовазим в дозе 1600 3200 ЕД/сут, увеличение кровотока либо реканализацию вены наблюдали в 1,6 раза чаще (на 60 больше), чем среди пациентов, получающих плацебо. Эффективная тромболитическая доза препарата Тромбовазим 1600 3200 ЕД/сут. Заключение. Лекарственный препарат на основе иммобилизированных субтилизинов Тромбовазим обладает тромболитическим действием при пероральном применении. Тромбовазим в составе комплексной терапии больных с тромбозом венозных сосудов быстро восстанавливает кровоток в зоне скомпрометированного кровообращения. Introduction. The target therapy of thrombosis consists of thrombolytic therapy. At present in most of cases, the therapy of thromboses in patient is reduced to the prescribing of anticoagulants based on mechanism of own fibrinolysis/thrombolysis. The use of plasminogen activators is effective, but is associated with the risk of severe bleeding and is carried out only in hospital. The administration of drugs that based on immobilized subtilisins looks very promising for thromboses treatment. The immobilized subtilisins have a direct thrombolytic effect under oral administration. The drug Trombovazim is based on immobilized subtilisins and has been registered in Russia. Trombovazim has an indication treatment of chronic venous insufficiency thrombolytic action is the basis of its pharmacodynamics. Aim: to show that Trombovazim in complex therapy of venous thromboses of the lower extremities improves the treatment outcomes. Materials and methods. A multicenter randomized doubleblind placebocontrolled clinical trial was carried out. At present Trombovazim is registered for medical use at a dose of 1600 U/day. The clinical study was undertaken according to 2 protocols: Рrotocol 1 Trombovazim inclusion in complex therapy of thrombosis at a dose of 1600 U/day Рrotocol 2 Trombovazim inclusion in complex therapy of thrombosis in higher doses 3200 and 4800 U/day. Results. In patients taking Trombovazim at a dose of 1600 3200 U/day increased blood flow or vein recanalization was observed 1.6 times more often (60 more) than in patients receiving placebo. The effective thrombolytic dose of Trombovazim is 1600 3200 U/day. Conclusion. Trombovazim has a thrombolytic action under oral administration. Thrombovazim in complex therapy of patients with venous thrombosis quickly restores the blood flow in a zone of compromised blood circulation.

The article presents the results of investigation of the electron-beam processing effect by a stream of accelerated electrons on coronary stents with a drug coating. Experiments on the visualization of the polymer coating have been carried out, the parameters of the kinetics of the antiproliferative substance as a function of the radiation dose have been determined. Integrity of the drug-coated stents has been visually assessed by scanning electron microscopy and optical microscopy. The release kinetic have been evaluated by high-performance liquid chromatography method. It has been established that electron beam treatment by the stream of accelerated electrons leads to non-dangerous deformations of the coronary stents drug coating and to the increased yield of antiproliferative substance. Deformation sites of the elution system appear on the surface of the drug-eluting stents after electron-beam treatment by the stream of accelerated electrons at a dose of 1.5 and 3 Mrad. Prolonged diffusion of rapamycin from the treated stent creates concentrations greater than those when used untreated stent and depends on the radiation load in a dose-dependent manner. Stent electron beam treatment by the stream of accelerated electrons provides a high gradient of release of the antiproliferative substance from the elution system, exceeding that without treatment, for 10 days. Comparison of efficiency and safety allows us to consider the technology of electron beam processing as promising for the introduction into coronary stents production.

Introduction. The target therapy of thrombosis consists of thrombolytic therapy. At present in most of cases, the therapy of thromboses in patient is reduced to the prescribing of anticoagulants based on mechanism of own fibrinolysis/thrombolysis. The use of plasminogen activators is effective, but is associated with the risk of severe bleeding and is carried out only in hospital. The administration of drugs that based on immobilized subtilisins looks very promising for thromboses treatment. The immobilized subtilisins have a direct thrombolytic effect under oral administration. The drug Trombovazim is based on immobilized subtilisins and has been registered in Russia. Trombovazim has an indication — treatment of chronic venous insufficiency; thrombolytic action is the basis of its pharmacodynamics. Aim: to show that Trombovazim in complex therapy of venous thromboses of the lower extremities improves the treatment outcomes. Materials and methods. A multicenter randomized double-blind placebo-controlled clinical trial was carried out. At present Trombovazim is registered for medical use at a dose of 1600 U/day. The clinical study was undertaken according to 2 protocols: Рrotocol 1 — Trombovazim inclusion in complex therapy of thrombosis at a dose of 1600 U/day; Рrotocol 2 — Trombovazim inclusion in complex therapy of thrombosis in higher doses — 3200 and 4800 U/day. Results. In patients taking Trombovazim at a dose of 1600–3200 U/day increased blood flow or vein recanalization was observed 1.6 times more often (60% more) than in patients receiving placebo. The effective thrombolytic dose of Trombovazim is 1600–3200 U/day. Conclusion. Trombovazim has a thrombolytic action under oral administration. Thrombovazim in complex therapy of patients with venous thrombosis quickly restores the blood flow in a zone of compromised blood circulation. REFERENCES Savelev V.S., Kirienko A.I., Andriiashkin V.V. et al. Prevention of venous thromboembolism: the results of Safety Zone project. [Itogi proekta «Territoriya bezopasnosti ot venoznyh tromboem- bolicheskih oslozhnenij»]. Flebologiya. 2011;5(4):4–9 (in Russ.). KirienkoA.I.,Leont’evS.G.,GusevL.L.etal.Theconservative treatment of the patients with acute venous thrombosis. [Konser- vativnoe lechenie bol’nyh s ostrym venoznym trombozom]. Fle- bologiya. 2012;6(2):40–4 (in Russ.). Stoyko Yu.M., Kirienko A.I., Ilyukhin E.A. et al. Diagnosis and treatment of superficial thrombophlebitis. Guidelines of the Rus- sian Phlebological Association. [Diagnostika i lechenie trombo- flebita poverhnostnyh ven konechnostej. Rekomendacii Associa- cii flebologov Rossii]. Flebologiya. 2019;13(2):78–97 (in Russ.). DOI: 10.17116/flebo20191302178. Lobastov K.V., Dementieva G.I., Laberko L.A. Current insights on the etiology and pathogenesis of venous thrombosis: Virchow’s triad. [Sovremennye predstavleniya ob etiologii i patogeneze ve- noznogo tromboza: pereosmyslenie triady Virhova]. Flebologiya. 2019;13(3):227–35 (in Russ.). DOI: 10.17116/flebo201913031227. Son’kin I.N., Krylov D.V., Mel’nik V. Yu., Atabekov A.I. The sever- ity of manifestations of the post-thrombotic syndrome following different variants of conservative treatment of deep vein throm- bosis in the lower extremities. [Vyrazhennost’ proyavlenij post- tromboticheskoj bolezni posle primeneniya razlichnyh varian- tov konservativnogo lecheniya tromboza glubokih ven nizhnih konechnostej]. Flebologiya. 2018;12(3):118–22 (in Russ.). DOI: 10.17116/flebo2018123118. Shaydakov E.V., Tsarev O.I. Thrombolysis in treatment of the lower limbs deep veins acute thrombosis. [Trombolizis v lechenii ostrogo tromboza glubokih ven nizhnih konechnostej]. Novosti hirurgii. 2011;19(5):128–37 (in Russ.). Watson L., Broderick C., Armon M.P. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev. 2016;2016(11): CD002783. DOI: 10.1002/14651858.CD002783.pub4. Comerota A.J., Kagan S.A. Catheter-directed thrombolysis for the treatment of acute iliofemoral deep venous thrombosis. Phlebology. 2000;15:149–55. DOI: 10.1177/026835550001500314. 9. Mewissen M.W., Seabrook G.R., Meissner M.H. et al. Catheter- directed thrombolysis for lower extremity deep venous throm- bosis: report of a national multicenter registry. Radiology. 1999;211(1):39–49. DOI: 10.1148/radiology.211.1.r99ap4739. 10. Bulatov V.L., Ilyukhin E.A., Fomin K.N. et al. Immediate and early results of catheter-directed thrombolysis for lower extremity deep vein thrombosis: a pilot study. [Rannie rezul’taty kateternogo trom- bolizisa pri tromboze glubokih ven nizhnih konechnostej: pilotnoe issledovanie]. Flebologiya. 2019;13(3):211–9 (in Russ.). DOI: 10.17116/flebo201913031211.11. Vedantham S., Goldhaber S.Z., Julian J.A. et al. Pharmacome-chanical catheter-directed thrombolysis for deep-vein thrombo- sis. N Engl J Med. 2017;377(23):2240–52. DOI: 10.1056/NEJ- Moa1615066. 12. Chupin A.V., Katorkin S.E., Katelnitsky I.I. et al. Sulodexide in treatment of chronic venous insufficiency. Results of the All- Russian multicenter programme ACVEDUCT. [Sulodeksid v lech- enii hronicheskoj venoznoj nedostatochnosti. Itogi Vserossijskoj mul’ticentrovoj programmy ACVEDUCT]. Angiologiya i sosudis- taya hirurgiya. 2018;24(1):47–54 (in Russ.). 13. Madonov P.G., Mishenina S.V., Kinsht D.N., Kikhtenko N.V. Chem- ical and pharmacological properties of subtilisins. [Himicheskie i farmakologicheskie svojstva subtilizinov]. Sibirskij nauchnyj medicinskij zhurnal. 2016;36(3):13–22 (in Russ.). 14. Madonov P.G., Mishenina S.V., Kinsht D.N., Kikhtenko N.V. Tar- geted pharmacodynamics of subtilisins. [Targetnaya farmako- dinamika subtilizinov]. Sibirskij nauchnyj medicinskij zhurnal. 2016;36(4):15–24 (in Russ.). 15. Mishenina S.V., Yershov K.I., Madonov P.G., Baykalov G.I. Throm- bolytic effects of subtilizin drug on experimental models. [Trom- boliticheskoe dejstvie subtilizinovogo lekarstvennogo preparata na eksperimental’nyh modelyah]. Sibirskij nauchnyj medicinskij zhurnal. 2017;37(3):27–31 (in Russ.). 16. Roitman E.V., Mishenina S.V., Madonov P.G. Another way of fibri- nolysis, the Nobel Prize and the possibility of thrombolytic ther- apy. [Drugoj put’ fibrinoliza, nobelevskaya premiya i vozmozh- nosti tromboliticheskoj terapii]. Rossijskij kardiologicheskij zhurnal. 2018;(3):15–7 (in Russ.). 17. Artamonov A.V., Bekarev A.A., Kinsht D.N. et al. A method for treatment of patients with acute venous thrombosis of the lower extremities. [Sposob lecheniya bol’nyh s ostrymi trombozami ve- noznogo rusla nizhnih konechnostej]. Patent RF No 2613155 ot 15.03.2017. Byul. No 8. 9 s (in Russ.). 18. Madonov P.G., Mishenina S.V., Ufimtsev M.S., Baikalov G.I. New pharmacological technology for treatment of vienna diseases. [No- vaya farmakologicheskaya tekhnologiya lecheniya zabolevanij ven]. Sovremennaya medicina. 2018;(2):203–6 (in Russ.). 19. Kuznetsov M.R., Sapelkin S.V., Boldin B.V. et al. Recanaliza- tion of lower-limb deep veins as an index of the efficacy of treat- ment for acute venous thrombosis. [Rekanalizaciya glubokih ven nizhnih konechnostej kak pokazatel’ effektivnosti lecheniya ost- rogo venoznogo tromboza]. Angiologiya i sosudistaya hirurgiya. 2016;22(3):82–7 (in Russ.). 20. Wang H., Chow S.-C. Sample size calculation for comparing proportions. In: Wiley encyclopedia of clinical trials. Eds. R. D’Agostino, J. Massaro, L. Sullivan. Hoboken, NJ: John Wiley & Sons, Inc., 2007. DOI: 10.1002/9780471462422.eoct005. 21. Rosner B.A. Fundamentals of Biostatistics. 7th ed. Boston, MA: Brooks/Cole, Cengage Learning, 2011. 859 s. 22. Levine M., Ensom M.H. Post hoc power analysis: an idea whose time has passed? Pharmacotherapy. 2001;21(4):405–9. DOI: 10.1592/phco.21.5.405.34503.

Введение. В современной клинической медицине технология фармакологического тромболизиса в подавляющем большинстве случаев реализуется посредством применения активаторов плазминогена. Плазминовый фибринолиз ограничен ввиду ингибирования плазмина продуктами деградации фибрина. Фибринолиз субтилизинами может рассматриваться как альтернативная технология фармакологического тромболизиса. Цель исследования: изучить особенности фибринолитического действия иммобилизированных субтилизинов in vitro. Материалы и методы. В соответствии с задачами исследования было проведено 5 серий экспериментов: со специфичным к плазмину хромогенным субстратом с очищенным препаратом фибринмономера с оценкой наличия прямой фибринолитической активности с оценкой торможения полимеризации (самосборки) фибринмономера со сравнением тромболитической активности препарата иммобилизированных субтилизинов по отношению к аналогичной активности плазмина и трипсина in vitro. Результаты. Проведенные исследования продемонстрировали высокую фибринолитическую активность иммобилизированных субтилизинов. Показано, что действие последних на фибрин реализуется напрямую и с четким дозозависимым эффектом. Заключение. Фибринолитическая активность субтилизинов представляет собой феномен экзогенного неплазминового фибринолиза. Introduction. Pharmacological thrombolysis is traditionally using plasminogen activators. Followed fibrinolysis can become limited in some time due to plasmin depletion and its inhibition by fibrin/fibrinogen degradation products. We assumed the subtilisin can perform alternative mode of fibrinolysis. Aim: to study features of fibrinolytic activity of immobilized subtilisins in vitro. Materials and methods. Subtilisin fibrinolytic activity, and fibrinmonomer selfassembling deceleration, and comparing thrombolytic activities immobilized subtilisins, plasmin and trypsin each to other were examined with five in vitro experiments using plasminspecific chromogenic substrates and purified fibrinmonomer. Results. Immobilized subtilisins have shown high direct fibrinolytic activity which seems having dosedependent manner. Conclusion. Exogenous immobilized subtilisins are plasmin/plasminogen bypassing agents. Their proteolytic action at fibrin might be considered as a phenomenon of nonplasmin fibrinolysis.

Within the framework of the multicenter randomized placebo-controlled double-blind clinical trial "VETTER-1" the authors carried out assessment of therapeutic efficacy and safety of oral drug Thrombovasim® possessing a thrombolytic effect in comprehensive treatment of lower-extremity deep vein thrombosis (LEDVT). The clinical study comprised a total of 154 patients. All patients received standard therapy accepted in LEDVT. The patients were subdivided into 4 groups. Patients from the three study groups received Thrombovasim® at a daily dose of 1,600, 3,200, and 4,800 IU. The control group patients were given placebo. Efficacy was assessed by the results of ultrasound duplex scanning first performed before treatment commenced and then after it terminated. The relative frequency of positive dynamics according to the findings of instrumental methods of study in patients taking Thrombovasim® amounted to 0.728 and in the group of patients receiving placebo to 0.585, p=0.0031. Comparing the degree of blood flow normalization in the zone of the compromised blood flow revealed a pronounced dose-dependent effect: in patients taking the drug at a daily dose of 1,600 IU, the relative frequency of positive dynamics amounted to 0.707 corresponding to an increase in therapeutic efficacy by 21%, for a dose of 3,200 IU these parameters amounted to 0.0257 and 24% and for 4,800 IU - 0.747 and 28%, respectively. In patients taking Thrombovasim® there were no cases of negative dynamics observed. Of the patients taking Thrombovasim®, none developed undesirable or severe adverse events. Inclusion of Thrombovasim® into the composition of comprehensive therapy for LEDVT increases efficacy of treatment at the expense of a spontaneous thrombolytic effect. The most effective dose amounted to 4,800 IU daily. Thrombovasim® turned out to be an efficient and safe agent in treatment of venous thromboses.