urovestВестник урологииUrology Herald2308-6424Rostov State Medical University10.21886/2308-6424-2025-13-6-27-40urovest-1142Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESНеоваскулген® и Ботокс® в сравнительном анализе влияния на структуру и функцию мочевого пузыря при интерстициальном цистите (экспериментальное исследование)Comparison of Efficacy of Neovasculgen® and Botox® in the treating Interstitial Cystitis/Bladder Pain Syndrome: experimental studyhttps://orcid.org/0000-0002-1710-0169КоганМ. И.KoganM. I.

Михаил Иосифович Коган – д-р мед. наук, профессор, заслуженный деятель науки РФ

Ростов-на-Дону

Mikhail I. Kogan – Dr.Sc.(Med), Full Prof., Hons. Sci. of the Russian Federation

Rostov-on-Don

dept_kogan@mail.ruhttps://orcid.org/0000-0003-0674-9429БелоусовИ. И.BelousovI. I.

Игорь Иванович Белоусов – д-р мед. наук, доцент

Ростов-на-Дону

lgor I. Belousov – Dr. Sc. (Med), Assoc. Prof. (Docent)

Rostov-on-Don

belrost_dept@mail.ruhttps://orcid.org/0000-0002-2996-0748МатичинаА. А.MatichinaA. A.

Алёна Алексеевна Матичина

Кузьмоловский, Ленинградская область

Alena A. Matichina

Kuzmolovsky sett., Leningrad region

matichina.aa@doclinika.ruhttps://orcid.org/0000-0001-7478-4942МатичинА. А.MatichinA. A.

Александр Алексеевич Матичин

Кузьмоловский, Ленинградская область

Aleksandr A. Matichin

Kuzmolovsky sett., Leningrad region

matichin.aa@doclinika.ruhttps://orcid.org/0000-0003-1185-1399БеляеваЕ. В.BelyaevaE. V.

Екатерина Валерьевна Беляева – канд. ветерин. наук

Кузьмоловский, Ленинградская область

Ekaterina V. Belyaeva – Cand. Sci.(Vet)

Kuzmolovsky sett., Leningrad region

belyaeva.ev@doclinika.ruРостовский государственный медицинский университетРоссияRostov State Medical UniversityRussian FederationНаучно-производственное объединение «ДОМ ФАРМАЦИИ»РоссияRMC «HOME OF PHARMACY»Russian Federation2025130120261362740Copyright © Коган М.И., Белоусов И.И., Матичина А.А., Матичин А.А., Беляева Е.В., 20262026Коган М.И., Белоусов И.И., Матичина А.А., Матичин А.А., Беляева Е.В.Kogan M.I., Belousov I.I., Matichina A.A., Matichin A.A., Belyaeva E.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.urovest.ru/jour/article/view/1142Введение

Введение. Интерстициальный цистит (ИЦ), являясь хроническим неинфекционным заболеванием, до сих пор имеет неясную этиологию и многочисленные патофизиологические теории развития. Это определяет необходимость проведения доклинических экспериментальных исследований на животных. Наиболее тождественной моделью ИЦ человека является циклофосфамид-индуцированный цистит у грызунов.

Цель исследования

Цель исследования. Изучение эффектов фармакологической активности препарата Неоваскулген® в сравнении с препаратом Ботокс® на модели ИЦ у крыс, вызванного циклофосфамидом.

Материалы и методы

Материалы и методы. Исследование выполнено на 90 самках крыс линии Wistar. Индукция ИЦ проведена препаратом Эндоксан®. В качестве терапевтических средств применяли препараты Неоваскулген® и Ботокс®. Эффективность оценивали сравнительным анализом уродинамических паттернов и морфологически. Полученные данные обрабатывали параметрическими и непараметрическими методами статистического анализа.

Результаты

Результаты. Индуцированный ИЦ развился у всех животных. Оба препарата статистически значимо улучшили изучаемые уродинамические показатели, клиническая эффективность Неоваскулген® была сравнима с Ботоксом®. Морфологическая оценка показала, что введение исследуемых препаратов сопровождалось снижением отёка тканей, меньшей выраженностью кровоизлияний и очаговой лимфогистиоцитарной инфильтрации, а также деструктивных изменений слизистой мочевого пузыря. При этом интенсивность патологических тканевых процессов на фоне введения Неоваскулгена® была наименьшей.

Заключение

Заключение. Модель циклофосфамидного ИЦ считается наиболее адекватной ИЦ человека. Проведённый эксперимент крайне важен для изучения эффективности нового лекарственного препарата, которым является Неоваскулген®. Препарат показал свою эффективность в снижении частоты мочеиспусканий и внутрипузырного давления. Внутридетрузорное введение уменьшает остроту воспалительной реакции тканей мочевого пузыря.

Introduction

Introduction. Interstitial cystitis/bladder pain syndrome (IC/BPS), being a chronic non-infectious disease, still has an unclear etiology and numerous pathophysiological theories of development. This determines the need for preclinical experimental studies on animals. The most identical model of human IC/BPS is cyclophosphamide-induced cystitis in rodents.

Objective

Objective. To study the effects of the pharmacological activity of Neovasculgen® сompared to Botox® using model of cyclophosphamide-induced IC/BPS in rats.

Materials & methods

Materials & methods. The study was performed on 90 female Wistar rats. IC/BPS was induced by Endoxan®. Neovasculgen® and Botox® were used as intradetrusor therapeutic agents. Efficiency was assessed by comparative analysis of urodynamic patterns and morphologically. The data obtained were processed by parametric and nonparametric methods of statistical analysis.

Results

Results. Cyclophosphamide-induced IC/BPS developed in all animals. Both drugs statistically significantly improved the studied urodynamic parameters, the clinical efficacy of Neovasculgen® was comparable to Botox®. Morphological assessment showed that the administration of the studied drugs was accompanied by a decrease in tissue edema, less pronounced hemorrhages and focal lymphohistiocytic infiltration, as well as destructive changes in the bladder mucosa. At the same time, the intensity of pathological tissue processes against the background of the administration of Neovasculgen® was the lowest.

Conclusions

Conclusions. The cyclophosphamide-induced IC/BPS model is considered the most adequate human IC/BPS. The experiment is extremely important for studying the effectiveness of a new drug, which is intradetrusor Neovasculgen®. The drug has shown its effectiveness in reducing the frequency of urination and intravesical pressure. Intradetrusor administration reduces the severity of the inflammatory reaction of bladder tissue.

интерстициальный циститциклофосфамид-индуцированный циститэкспериментальный циститНеоваскулгенЭндоксанБотоксуродинамикаиммуногистохимиярецепторы к ЦОГ-2EP4interstitial cystitiscyclophosphamide-induced cystitisexperimental cystitisNeovasculgenEndoxanBotoxurodynamicsimmunohistochemistryreceptors for COX-2EP4Исследование выполнено в рамках договорных обязательств между АО «НПО «Дом фармации» и АО «НекстГен» (Договор 0298-ДФ/2021 от 24 ноября 2021 года).The study was conducted in accordance with the contractual obligations between RMC «HOME OF PHARMACY» and JSC «Nextgen» (contract № 0298-ДФ/2021 of November 24, 2021).ReferencesHanno PM, Erickson D, Moldwin R, Faraday MM; American Urological Association. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(5):1545-1553. DOI: 10.1016/j.juro.2015.01.086Hanno PM, Erickson D, Moldwin R, Faraday MM; American Urological Association. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(5):1545-1553. DOI: 10.1016/j.juro.2015.01.086Parsons CL. The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology. 2007;69(4 Suppl):9-16. DOI: 10.1016/j.urology.2006.03.084Parsons CL. The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology. 2007;69(4 Suppl):9-16. DOI: 10.1016/j.urology.2006.03.084de Groat WC, Griffiths D, Yoshimura N. Neural control of the lower urinary tract. Compr Physiol. 2015;5(1):327-396. DOI: 10.1002/cphy.c130056de Groat WC, Griffiths D, Yoshimura N. Neural control of the lower urinary tract. Compr Physiol. 2015;5(1):327-396. DOI: 10.1002/cphy.c130056Karamali M, Shafabakhsh R, Ghanbari Z, Eftekhar T, Asemi Z. Molecular pathogenesis of interstitial cystitis/bladder pain syndrome based on gene expression. J Cell Physiol. 2019;234(8):12301-12308. DOI: 10.1002/jcp.28009Karamali M, Shafabakhsh R, Ghanbari Z, Eftekhar T, Asemi Z. Molecular pathogenesis of interstitial cystitis/bladder pain syndrome based on gene expression. J Cell Physiol. 2019;234(8):12301-12308. DOI: 10.1002/jcp.28009Akiyama Y. Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome with and without Hunner Lesion: A Review and Future Perspectives. Diagnostics (Basel). 2021;11(12):2238. DOI: 10.3390/diagnostics11122238Akiyama Y. Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome with and without Hunner Lesion: A Review and Future Perspectives. Diagnostics (Basel). 2021;11(12):2238. DOI: 10.3390/diagnostics11122238Shah AM, Vodovotz Y, Yoshimura N, Chermansky CJ, Fitzgerald J, Tyagi P. Temporally complex inflammatory networks in an animal model reveal signatures for interstitial cystitis and bladder pain syndrome phenotype. Neurourol Urodyn. 2023;42(8):1839-1848. DOI: 10.1002/nau.25267Shah AM, Vodovotz Y, Yoshimura N, Chermansky CJ, Fitzgerald J, Tyagi P. Temporally complex inflammatory networks in an animal model reveal signatures for interstitial cystitis and bladder pain syndrome phenotype. Neurourol Urodyn. 2023;42(8):1839-1848. DOI: 10.1002/nau.25267Akiyama Y, Luo Y, Hanno PM, Maeda D, Homma Y. Interstitial cystitis/ bladder pain syndrome: The evolving landscape, animal models and future perspectives. Int J Urol. 2020;27(6):491-503. DOI: 10.1111/iju.14229Akiyama Y, Luo Y, Hanno PM, Maeda D, Homma Y. Interstitial cystitis/ bladder pain syndrome: The evolving landscape, animal models and future perspectives. Int J Urol. 2020;27(6):491-503. DOI: 10.1111/iju.14229Chang YC, Yu CY, Dong C, Chen SL, Sung WW. Divergent histopathological and molecular patterns in chemically induced interstitial cystitis/bladder pain syndrome rat models. Sci Rep. 2024;14(1):16134. DOI: 10.1038/s41598-024-67162-yChang YC, Yu CY, Dong C, Chen SL, Sung WW. Divergent histopathological and molecular patterns in chemically induced interstitial cystitis/bladder pain syndrome rat models. Sci Rep. 2024;14(1):16134. DOI: 10.1038/s41598-024-67162-yFowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci. 2008;9(6):453-466. DOI: 10.1038/nrn2401Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci. 2008;9(6):453-466. DOI: 10.1038/nrn2401Garzon S, Laganà AS, Casarin J, Raffaelli R, Cromi A, Sturla D, Franchi M, Ghezzi F. An update on treatment options for interstitial cystitis. Prz Menopauzalny. 2020;19(1):35-43. DOI: 10.5114/pm.2020.95334Garzon S, Laganà AS, Casarin J, Raffaelli R, Cromi A, Sturla D, Franchi M, Ghezzi F. An update on treatment options for interstitial cystitis. Prz Menopauzalny. 2020;19(1):35-43. DOI: 10.5114/pm.2020.95334Хамедов Р.Г., Горгоцкий И.А., Шкарупа А.Г., Шкарупа Д.Д., Гаджиев Н.К. Использование обогащённой тромбоцитами плазмы при интерстициальном цистите и эректильной дисфункции. Вестник урологии. 2022;10(1):121-127.Khamedov R.G., Gorgotsky I.A., Shkarupa A.G., Shkarupa D.D., Gadzhiev N.K. Platelet-rich plasma: application for interstitial cystitis and erectile dysfunction. Urology Herald. 2022;10(1):121-127. (In Russian). DOI: 10.21886/2308-6424-2022-10-1-121-127Chen YH, Man KM, Chen WC, Liu PL, Tsai KS, Tsai MY, Wu YT, Chen HY. Platelet-Rich Plasma Ameliorates Cyclophosphamide-Induced Acute Interstitial Cystitis/Painful Bladder Syndrome in a Rat Model. Diagnostics (Basel). 2020;10(6):381. DOI: 10.3390/diagnostics10060381Chen YH, Man KM, Chen WC, Liu PL, Tsai KS, Tsai MY, Wu YT, Chen HY. Platelet-Rich Plasma Ameliorates Cyclophosphamide-Induced Acute Interstitial Cystitis/Painful Bladder Syndrome in a Rat Model. Diagnostics (Basel). 2020;10(6):381. DOI: 10.3390/diagnostics10060381Brandolini L, Aramini A, Bianchini G, Ruocco A, Bertini R, Novelli R, Angelico P, Valsecchi AE, Russo R, Castelli V, Cimini A, Allegretti M. Inflammation-Independent Antinociceptive Effects of DF2755A, a CXCR1/2 Selective Inhibitor: A New Potential Therapeutic Treatment for Peripheral Neuropathy Associated to Non-Ulcerative Interstitial Cystitis/Bladder Pain Syndrome. Front Pharmacol. 2022;13:854238. DOI: 10.3389/fphar.2022.854238Brandolini L, Aramini A, Bianchini G, Ruocco A, Bertini R, Novelli R, Angelico P, Valsecchi AE, Russo R, Castelli V, Cimini A, Allegretti M. Inflammation-Independent Antinociceptive Effects of DF2755A, a CXCR1/2 Selective Inhibitor: A New Potential Therapeutic Treatment for Peripheral Neuropathy Associated to Non-Ulcerative Interstitial Cystitis/Bladder Pain Syndrome. Front Pharmacol. 2022;13:854238. DOI: 10.3389/fphar.2022.854238Sakata T, Smith RA, Garland EM, Cohen SM. Rat urinary bladder epithelial lesions induced by acrolein. J Environ Pathol Toxicol Oncol. 1989;9(2):159-169. PMID: 2732910.Sakata T, Smith RA, Garland EM, Cohen SM. Rat urinary bladder epithelial lesions induced by acrolein. J Environ Pathol Toxicol Oncol. 1989;9(2):159-169. PMID: 2732910.Bjorling DE, Elkahwaji JE, Bushman W, Janda LM, Boldon K, Hopkins WJ, Wang ZY. Acute acrolein-induced cystitis in mice. BJU Int. 2007;99(6):1523-1529. DOI: 10.1111/j.1464-410X.2007.06773.xBjorling DE, Elkahwaji JE, Bushman W, Janda LM, Boldon K, Hopkins WJ, Wang ZY. Acute acrolein-induced cystitis in mice. BJU Int. 2007;99(6):1523-1529. DOI: 10.1111/j.1464-410X.2007.06773.xГосударственный реестр лекарственных средств. Регистрационное удостоверение препарата Неоваскулген®. (Дата обращения 03.01.2025)State Register of Medicines. Registration certificate of the drug Neovasculgen ® (Accessed 03.01.2025). (In Russian). URL: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=fbd48945-f006-43d5-b67d-99825a786c08Червяков Ю.В., Староверов И.Н., Нерсесян Е.Г., Власенко О.Н., Исаев А.А. Возможности генной терапии при хронических облитерирующих заболеваниях артерий нижних конечностей. Хирургия. Журнал им. Н.И. Пирогова. 2014;(4):40 45.Cherviakov IuV, Staroverov IN, Nersesian EG, Vlasenko ON, Isaev AA. The opportunities for genic therapy of chronic obliterating diseases of lower limbs arteries. Pirogov Russian Journal of Surgery. 2014;(4):40-45. (In Russian). eLIBRARY ID: 21568109; EDN: SDZIWNLucioni A, Bales GT, Lotan TL, McGehee DS, Cook SP, Rapp DE. Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU Int. 2008;101(3):366-370. DOI: 10.1111/j.1464-410X.2007.07312.xLucioni A, Bales GT, Lotan TL, McGehee DS, Cook SP, Rapp DE. Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU Int. 2008;101(3):366-370. DOI: 10.1111/j.1464-410X.2007.07312.xBirder L, Andersson KE. Animal Modelling of Interstitial Cystitis/Bladder Pain Syndrome. Int Neurourol J. 2018;22(Suppl 1):S3-9. DOI: 10.5213/inj.1835062.531Birder L, Andersson KE. Animal Modelling of Interstitial Cystitis/Bladder Pain Syndrome. Int Neurourol J. 2018;22(Suppl 1):S3-9. DOI: 10.5213/inj.1835062.531Gad SC, Spainhour CB, Shoemake C, Pallman DR, Stricker-Krongrad A, Downing PA, Seals RE, Eagle LA, Polhamus K, Daly J. Tolerable Levels of Nonclinical Vehicles and Formulations Used in Studies by Multiple Routes in Multiple Species With Notes on Methods to Improve Utility. Int J Toxicol. 2016;35(2):95-178. DOI: 10.1177/1091581815622442Gad SC, Spainhour CB, Shoemake C, Pallman DR, Stricker-Krongrad A, Downing PA, Seals RE, Eagle LA, Polhamus K, Daly J. Tolerable Levels of Nonclinical Vehicles and Formulations Used in Studies by Multiple Routes in Multiple Species With Notes on Methods to Improve Utility. Int J Toxicol. 2016;35(2):95-178. DOI: 10.1177/1091581815622442Ruengwanichayakun P. Histochemical scoring assessment (H-score). Asian Arch Pathol. 2021;3(1):13–14.Ruengwanichayakun P. Histochemical scoring assessment (H-score). Asian Arch Pathol. 2021;3(1):13–14.Tay C, Grundy L. Animal models of interstitial cystitis/bladder pain syndrome. Front Physiol. 2023;14:1232017. DOI: 10.3389/fphys.2023.1232017Tay C, Grundy L. Animal models of interstitial cystitis/bladder pain syndrome. Front Physiol. 2023;14:1232017. DOI: 10.3389/fphys.2023.1232017Mykoniatis I, Tsiakaras S, Samarinas M, Anastasiadis A, Symeonidis EN, Sountoulides P. Monoclonal Antibody Therapy for the Treatment of Interstitial Cystitis. Biologics. 2022;16:47-55. DOI: 10.2147/BTT.S290286Mykoniatis I, Tsiakaras S, Samarinas M, Anastasiadis A, Symeonidis EN, Sountoulides P. Monoclonal Antibody Therapy for the Treatment of Interstitial Cystitis. Biologics. 2022;16:47-55. DOI: 10.2147/BTT.S290286Ha JY, Lee EH, Chun SY, Lee JN, Ha YS, Chung JW, Yoon BH, Jeon M, Kim HT, Kwon TG, Yoo ES, Kim BS. The Efficacy and Safety of a Human Perirenal Adipose Tissue-Derived Stromal Vascular Fraction in an Interstitial Cystitis Rat Model. Tissue Eng Regen Med. 2023;20(2):225-237. DOI: 10.1007/s13770-022-00505-wHa JY, Lee EH, Chun SY, Lee JN, Ha YS, Chung JW, Yoon BH, Jeon M, Kim HT, Kwon TG, Yoo ES, Kim BS. The Efficacy and Safety of a Human Perirenal Adipose Tissue-Derived Stromal Vascular Fraction in an Interstitial Cystitis Rat Model. Tissue Eng Regen Med. 2023;20(2):225-237. DOI: 10.1007/s13770-022-00505-wJhang JF, Yu WR, Kuo HC. Comparison of the Clinical Efficacy and Adverse Events between Intravesical Injections of Platelet-Rich Plasma and Botulinum Toxin A for the Treatment of Interstitial Cystitis Refractory to Conventional Treatment. Toxins (Basel). 2023;15(2):121. DOI: 10.3390/toxins15020121Jhang JF, Yu WR, Kuo HC. Comparison of the Clinical Efficacy and Adverse Events between Intravesical Injections of Platelet-Rich Plasma and Botulinum Toxin A for the Treatment of Interstitial Cystitis Refractory to Conventional Treatment. Toxins (Basel). 2023;15(2):121. DOI: 10.3390/toxins15020121Lee YK, Jiang YH, Jhang JF, Ho HC, Kuo HC. Changes in the Ultrastructure of the Bladder Urothelium in Patients with Interstitial Cystitis after Intravesical Injections of Platelet-Rich Plasma. Biomedicines. 2022;10(5):1182. DOI: 10.3390/biomedicines10051182Lee YK, Jiang YH, Jhang JF, Ho HC, Kuo HC. Changes in the Ultrastructure of the Bladder Urothelium in Patients with Interstitial Cystitis after Intravesical Injections of Platelet-Rich Plasma. Biomedicines. 2022;10(5):1182. DOI: 10.3390/biomedicines10051182Danacioglu YO, Erol B, Ozkanli S, Yildirim A, Atis RG, Silay MS, Caskurlu T. Comparison of Intravesical Hyaluronic Acid, Chondroitin Sulfate, and Combination of Hyaluronic Acid-Chondroitin Sulfate Therapies in Animal Model of Interstitial Cystitis. Int Neurourol J. 2021;25(1):42-50. DOI: 10.5213/inj.1938176.088Danacioglu YO, Erol B, Ozkanli S, Yildirim A, Atis RG, Silay MS, Caskurlu T. Comparison of Intravesical Hyaluronic Acid, Chondroitin Sulfate, and Combination of Hyaluronic Acid-Chondroitin Sulfate Therapies in Animal Model of Interstitial Cystitis. Int Neurourol J. 2021;25(1):42-50. DOI: 10.5213/inj.1938176.088

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