EFFECTIVENESS OF SUBSTITUTED THIADIAZINE GROUP COMPOUNDS IN THE FIRST PHASE OF ACUTE PANCREATITIS
DOI: 10.22138/2500-0918-2025-22-4-353-368 (In Russ)
M.A. Rantsev¹, O.N. Chupakhin ²,³, V.L. Rusinov², T.G. Khonina³, P.A. Sarapultsev⁴, N.A. Zabokritsky ⁴, L.P. Sidorova ²
¹Ural State Medical University of the Ministry of Health of the Russian Federation, Yekaterinburg, Russian Federation;
²Ural Federal University n.a. After the First President of Russia B. N. Yeltsin, Yekaterinburg, Russian Federation;
³Institute of Organic Synthesis n.a. I. Ya. Postovsky UB RAS, Yekaterinburg, Russian Federation;
⁴Institute of Immunology and Physiology UB RAS, Yekaterinburg, Russian Federation
Abstract. Introduction. Acute biliary post-manipulation pancreatitis of severe degree remains a significant surgical challenge, associated with a high mortality rate. While surgical tactics for the second phase of the disease are well understood, there is limited evidence and consensus regarding conservative treatment options for the first phase of acute severe pancreatitis. Objective. To evaluate the effectiveness of a substituted thiadiazine compound, specifically 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrobromide (MPhTH), in an experimental obstructive model of acute post-manipulation pancreatitis, with special attention to the role of microcirculation and tissue perfusion disorders in the pathogenesis during the first phase of necrotizing pancreatitis. Materials and Methods. The study was conducted on unisex Wistar rats using an author-developed model of severe acute biliary post-manipulation pancreatitis. Animals were allocated to control (no treatment) and experimental (MPhTH administration) groups. Laboratory and morphological parameters were assessed, including total and differential leukocyte counts in peripheral blood and morphometric analysis of granulocytes and plasma cells in pancreatic inflammatory infiltrates. Results. Administration of MPhTH in the experimental model resulted in a marked reduction in the severity of the inflammatory response. On day 1, leukocyte count in the experimental group was (3,6 ± 0,4) ×10⁹/l (vs. (2,3 ± 0,1) ×10⁹/l in controls and (4,1 ± 1,4) ×10⁹/l in intact rats), and by day 7, (4,6 ± 1,1) ×10⁹/l (vs. (9,8 ± 0,9) ×10⁹/l in controls). Granulocyte levels in the pancreatic inflammatory infiltrate were significantly lower in the MPhTH group (day 1: 8,59 ± 0,73/mm²; day 7: 7,75 ± 0,98/mm²) compared to controls (day 1: 12,96 ± 0,56/mm²; day 7: 20,76 ± 1,16/mm²). On day 7, plasma cell counts in the experimental group were 0,40 ± 0,11/mm², also lower than in the controls (0,66 ± 0,11/mm²). These changes indicate that MPhTH treatment normalized leukocytic indices and attenuated both systemic and local inflammation. Conclusion. Our results identify a novel anti-inflammatory pharmacological property of MPhTH, likely mediated via effects on the serotonin transporter (SERT) and serotonin receptors. The observed antiplatelet and anticoagulant activities of MPhTH appear to be linked to its anti-inflammatory effects, supporting the concept of a unified inflammatory-coagulation response. Further studies of substituted thiadiazine compounds are warranted for the development of new therapeutic agents.
Keywords: acute pancreatitis, substituted thiadiazines, inflammatory reaction, inflammatory infiltrate
There is no conflict of interest.
Contact details of the corresponding author:
Maxim A. Rantsev
r-ma@bk.ru
Recieved 06.08.2025
For citation: Rantsev M.A., Chupakhin O.N., Rusinov V.L., Khonina T.G., Sarapultsev P.A., Zabokritsky N.A., Sidorova L.P. Effectiveness of substituted thiadiazine group compounds in the first phase of acute pancreatitis [Online] Vestn. Ural. Med. Akad. Nauki. = Journal of Ural Medical Academic Science. 2025, Vol. 22, no. 4, pp. 353–368. DOI: 10.22138/2500-0918-2025-22-4-353-368 (In Russ)
REFERENCES
1. Durleshter V.M., Andreev A.V., Kuznetsov Yu.S., Gabriel S.A., Pykhteev V.S., Shterev V.V., Remizov S.I. Minimally invasive surgical interventions in the treatment of patients with severe acute pancreatitis // Surgery. Pirogov Journal. — 2020. — No. 4. — P. 30-36. DOI: 10.17116/hirurgia202004130 (In Rus).
2. Acute pancreatitis [Electronic resource]: Russian clinical guidelines / compiled by A.Sh. Revishvili. Moscow, 2020. URL: http://xn — -9sbdbejx7bdduahou3a5d.xn — 1ai/upload/o_pankr(09_10_20)final3.doc (accessed 10/24/2021)(In Rus).
3. Cahyadi O., Tehami N., de-Madaria E., Siau K. Post-ERCP Pancreatitis: Prevention, Diagnosis and Management // Medicina. – 2022. – Vol. 58, No. 9. – Р. 1261. DOI: 10.3390/medicina58091261
4. Walkowska J., Zielinska N., Tubbs R.S., Podgórski M., Dłubek-Ruxer J., Olewnik Ł. Diagnosis and Treatment of Acute Pancreatitis // Diagnostics. – 2022. – Vol. 12, No. 8. – Р. 1974. DOI: 10.3390/diagnostics12081974
5. Hasegawa S., Koshita S., Kanno Y., Ogawa T., Sakai T., Kusunose H., Kubota K., Nakajima A., Noda Y., Ito K. Endoscopic Interventions for the Early and Remission Phases of Acute Biliary Pancreatitis: What are the More Concrete and Practical Situations for Performing Them? // Clinical Endoscopy. – 2021. – Vol. 54, No. 6. – P. 888–898. DOI: 10.5946/ce.2020.271
6. Iannuzzi J.P., King J.A., Leong J.H., Quan J., Windsor J.W., Tanyingoh D., Coward S., Forbes N., Heitman S.J., Shaheen A.A., Swain M., Buie M., Underwood F.E., Kaplan G.G. Global Incidence of Acute Pancreatitis Is Increasing Over Time: A Systematic Review and Meta-Analysis // Gastroenterology. – 2022. – Vol. 162, No. 1. – P. 122–134. DOI: 10.1053/j.gastro.2021.09.043
7. Hidalgo N.J., Pando E., Mata R., Fernandes N., Villasante S., Barros M., Herms D., Blanco L., Balsells J., Charco R. Impact of Comorbidities on Hospital Mortality in Patients with Acute Pancreatitis: a Population-based Study of 110,021 Patients // BMC Gastroenterology. – 2023. – Vol. 23, No. 1. – Р. 81. DOI: 10.1186/s12876-023-02730-6
8. Soomro I.A., Rafiq S., Otho S., Hayat M., Alam I., Rehman A. Mild to Moderate Acute Gallstone Pancreatitis: a Comparative Study of Versus Delayed Cholecystectomy // Journal of Population Therapeutics and Clinical Pharmacology. – 2024. – Vol. 31, No. 1. – P. 1215–1220. DOI: 10.53555/jptcp.v31i1.4153
9. Klochkov A., Kudaravalli P., Lim Y., Sun Y. Alcoholic Pancreatitis [electronic resource]. In: StatPearls [Internet]. Treasure Island (FL). StatPearls Publishing, 2023. URL: https://www.ncbi.nlm.nih.gov/books/NBK537191/ (date of access 01.01.2025).
10. Glabay V.P., Gridnev O.V., Bashankaev B.N., Bykov A.N., Krylov A.V., Kaprin I.A., Eldarova Z.E., Varyasova A.A. Surgical tactics in the acute stage of biliary pancreatitis // Surgery. Journal named after N.I. Pirogov. — 2019. — No. 11. — P. 37-41. DOI: 10.17116/hirurgia201911137 (In Rus).
11. Weitz G., Woitalla J., Wellhöner P., Schmidt K., Büning J., Fellermann K. Does Etiology of Acute Pancreatitis Matter? A Review of 391 Consecutive Episodes // Journal of the Pancreas. – 2015. – Vol. 16, No. 2. – P.171–175. DOI: 10.6092/1590-8577/2959
12. Bagnenko S.F., Goltsov V.R., Savello V.E., Vashetko R.V. Classification of acute pancreatitis: current state of the problem // Grekov Surgery Bulletin – 2015. – Vol. 174, No. 5. – P. 86–92. DOI: 10.24884/0042-4625-2015-174-5-86-92 (In Rus).
13. Starovoytov S.O., Efremova E.A., Tsukonova D.V. Analysis of mortality of patients with acute pancreatitis according to pathological and intravital studies of the deceased // Science Diary. — 2023. — V. 73, No. 1. — 9 p. https://dnevniknauki.ru/images/publications/2023/1/medicine/Starovoitov_Efremova_Tsukanova.pdf (In Rus).
14. Uhl W., Warshaw A., Imrie C., Bassi C., McKay C.J., Lankisch P.G., Carter R., Di Magno E., Banks P.A., Whitcomb D.C., Dervenis C., Ulrich C.D., Satake K., Ghaneh P., Hartwig W., Werner J., McEntee G., Neoptolemos J.P., Büchler M.W. IAP Guidelines for the Surgical Management of Acute Pancreatitis // Pancreatology. – 2002. – Vol. 2, No. 6. – P. 565–573. DOI: 10.1159/000071269
15. Di Martino M., Ielpo B., Pata F., Pellino G., Di Saverio S., Catena F., De Simone B., Coccolini F., Sartelli M., Damaskos D., Mole D., Murzi V., Leppaniemi A., Pisanu A., Podda M. Timing of Cholecystectomy After Moderate and Severe Acute Biliary Pancreatitis // JAMA Surgery. – 2023. – Vol. 158, No 10. – Р. e233660. DOI: 10.1001/jamasurg.2023.3660
16. Yan Q. Recent Advances in Pancreatitis. London: Intech Open, 2022. – 128 p.
17. Fedorov A.G., Davydov S.V., Klimov A.E. Complications of endoscopic transpapillary interventions and methods of their prevention and treatment. Literature review // Emergency medical care. — 2012. — No. 3. — P. 29-35. https://cyberleninka.ru/article/n/oslozhneniya-endoskopicheskih-transpapillyarnyh-vmeshatelstv-i-sposoby-ih-profilaktiki-i-lecheniya-obzor-literatury (In Rus).
18. Buxbaum J.L., Freeman M., Amateau S.K., Chalhoub J.M., Coelho-Prabhu N., Desai M., Elhanafi S.E., Forbes N., Fujii-Lau L.L., Kohli D.R., Kwon R.S., Machicado J.D., Marya N.B., Pawa S., Ruan W.H., Sheth S.G., Thiruvengadam N.R., Thosani N.C., Qumseya B.J. American Society for Gastrointestinal Endoscopy Guideline on Post-ERCP Pancreatitis Prevention Strategies: Summary and Recommendations // Gastrointestinal Endoscopy. – 2023. – Vol. 97, No. 2. – P. 153–162. DOI:10.1016/j.gie.2022.10.005
19. Van den Berg F.F., Boermeester M.A. Update on the Management of Acute Pancreatitis // Current Opinion in Critical Care. – 2023. – Vol. 29, No. 2. – P. 145–151. DOI:10.1097/MCC.0000000000001017
20. Ribeiro I.B., do Monte Junior E.S., Miranda Neto A.A., Proença I.M., de Moura D.T.H., Minata M.K., Ide E., Dos Santos M.E.L., Luz G.O., Matuguma S.E., Cheng S., Baracat R., de Moura E.G.H. Pancreatitis after Endoscopic Retrograde Cholangiopancreatography: A Narrative Review // World Journal of Gastroenterology. – 2021. – Vol. 27, No. 20. – P. 2495–2506. DOI: 10.3748/wjg.v27.i20.2495
21. Romashchenko P.N., Feklyunin A.A., Maistrenko N.A., Filin A.A., Omran V.S., Zherebtsov E.S. Transpapillary endoscopic surgeries: predictors of complications and prevention of their development // Endoscopic surgery. — 2021. — Vol. 27, No. 1. — P. 40–48. DOI: 10.17116/endoskop20212701140 (In Rus).
22. Frolov P.A., Korotkevich A.G., Pavlenko V.V., Pachgin I.V., Krasnov K.A. Current issues of prevention of acute post-manipulation pancreatitis // Experimental and clinical gastroenterology. — 2022. — Vol. 204, No. 8. — P. 141–149. DOI: 10.31146/1682-8658-ecg-204-8-141-149 (In Rus).
23. Korymasov E.A., Zhdanov A.V., Khoroshilov M.Yu. Treatment tactics for acute pancreatitis with a fulminant course after endoscopic retrograde cholangiopancreatography // Bulletin of the REAVIZ Medical Institute. — 2020. — Vol. 44, No. 2. — P. 27-31. URL: https://cyberleninka.ru/article/n/taktika-lecheniya-ostrogo-pankreatita-s-molnienosnym-techeniem-posle-endoskopicheskoy-retrogradnoy-holangiopankreatografii. (In Rus).
24. Frolov P.A., Korotkevich A.G., Pavlenko V.V., Pachgin I.V., Krasnov K.A. Prevention of acute post-manipulation pancreatitis // Experimental and clinical gastroenterology. — 2023. — Vol. 213, No. 5. — P. 114–121. DOI: 10.31146/1682-8658-ecg-213-5-114-121 (In Rus).
25. Teterin Yu.S., Blagovestnov D.A., Gendurkaev L.L., Yartsev P.Ya. Prevention of acute pancreatitis in patients with complex cannulation after transpapillary interventions // Bulletin of surgical gastroenterology. — 2021. — No. 1. — P. 11-18. URL: https://cyberleninka.ru/article/n/profilaktika-ostrogo-postmanipulyatsionnogo-pankreatita (In Rus).
26. Perdigoto D.N., Gomes D., Almeida N., Mendes S., Rita Alves A., Camacho E., Tomé L. Risk Factors for Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis in the Indomethacin Era – A Prospective Study // GE Portuguese Journal of Gastroenterology. – 2019. – Vol. 26, No. 3. – P. 176–183. DOI: 10.1159/000492313
27. Popova M.A., Leontyev A.S., Korotkevich A.G., Merzlyakov M.V., Shestak I.S. Post-manipulation pancreatitis: relevance of the problem, diagnostic difficulties and unresolved issues // Polytrauma. — 2018. — No. 3. — P. 86-109. URL: https://poly-trauma.ru/index.php/pt/article/view/100/272 (In Rus).
28. Logvinova Yu.S., Vasilyeva T.M., Makarov V.A., Chupakhin O.N., Sidorova L.P., Perova N.M., Rusinov V.L. Effect of new compounds of the 1,3,4-thiadiazine class on platelet aggregation in vitro and ex vivo // Experimental and Clinical Pharmacology. — 2010. — Vol. 73, No. 8. — P. 21-25.(In Rus)
29. Patent 2259371 Russian Federation, IPC C 07 D 417/12. Substituted 5R1,6R2 1,3,4-thiadiazin-2 amines and pharmaceutical compositions containing them as pharmacologically active agents with anticoagulant and antiplatelet action: No. 2003113145/04: declared 05.05.2003: published 27.08.20005 / O.N. Chupakhin, L.P. Sidorova, N.M. Perova, V.N. Charushin, V.L. Rusinov, A.G. Mulyar. – 20 p.(In Rus)
30. Patent 6028068A United States of America, C07D 417/12. Substituted 6H-1,3,4-Thiadiazie-2-Amines, the Use thereof Anaesthetizing, Cardiovascularand Hypometabolic Agents, and a Pharmaceutical Compotiion Containing them: 6313111: Date of filing: 28.12.1995: Date of publication: 11.11.1998 / O.N. Chupakhin, L.P. Sidorova, E.A. Tarakhty, A.P. Novikova, N.M. Perova, V.A. Vinogradov. – 11 p.
31. Sarapultsev P.A., Chupakhin O.N., Sarapultsev A.P., Rantsev M.A., Medvedeva S.Yu., Sidorova L.P., Danilova I.G. Effect of a compound from the group of substituted 5R1-6H2-1,3,4-thiadiazin-2-amines on the course of systemic inflammation // Cytokines and Inflammation. — 2013. — Vol. 12, No. 3. — P. 40-45.(In Russ)
32. Sarapultsev A. P., Chupakhin O. N., Sarapultsev P. A., Sidorova L. P., Tseitler T. A. Pharmacologic Evaluation of Antidepressant Activity and Synthesis of 2-Morpholino-5-phenyl-6H-1,3,4 thiadiazine Hydrobromide // Pharmaceuticals. – 2016. – Vol.9, No 27. – C. 1-11. DOI:10.3390/ph9020027
33. Patent 2400820 Russian Federation, IPC G 09B 23/28. Method for creating an experimental model of pancreatic necrosis in rats: No. 2008100816/14: declared 09.01.2008: published 27.09.2010 / M. A. Rantsev, P. A. Sarapultsev, A. N. Dmitriev, K. V. Plaksin, A. P. Malkov, S. Yu. Medvedeva. – 5 p.(In Russ)
34. Gribunov Yu.P., Baranov G.A., Davydovskaya T.I., Skalozub O.I. Pathomorphological assessment of the effectiveness of modern immunotherapy of surgical sepsis // Kremlin Medicine. Clinical Bulletin. — 2012. — No. 2. — P. 69-74.(In Russ)
35. Sarapultsev A., Chupakhin O., Rantsev M., Sarapultsev P., Danilova I., Medvedeva S., Sidorova L, Tseitler T, Brilliant S, Tseǐlikman V. Effects of 1,3,4-Thiadiazine Compound with Antidepressant Properties in Ligation Model of Acute Pancreatitis // General Physiology and Biophysics. – 2018. – Vol. 37, No. 5. – P. 549–562. DOI: 10.4149/gpb_2018012
36. Sarapultsev A., Vassiliev P., Grinchii D., Kiss A., Mach M., Osacka J., Balloova A., Paliokha R., Kochetkov A., Sidorova L., Sarapultsev P., Chupakhin O., Rantsev M., Spasov A., Dremencov E. Combined in Silico, ex vivo, and in vivo Assessment of L-17, a Thiadiazine Derivative with Putative Neuro- and Cardioprotective and Antidepressant Effects // International Journal of Molecular Sciences. – 2021. – Vol. 22, No. 24. – Р. 13626. DOI: 10.3390/ijms222413626
37. Rasina L.N., Chupakhin O.N. Evaluation of the prospects of thiadiazine derivatives as means of protecting healthy tissues during radiation therapy of malignant tumors // Radiation biology. Radioecology. — 2005. — V. 45, No. 6. — P. 1-5.(In Russ)
38. Bleibel L., Sokołowska P., Henrykowska G., Owczarek J., Wiktorowska-Owczarek A. Unveiling the Anti-Inflammatory Effects of Antidepressants: A Systematic Review of Human Studies over the Last Decade // Pharmaceuticals (Basel). – 2025. – Vol.18, No. 6. P. 867. DOI: 10.3390/ph18060867
39. Lu Y., Xu X., Jiang T., Jin L., Zhao X.D., Cheng J.H., Jin X.J., Ma J., Piao H.N., Piao L.X. Sertraline ameliorates inflammation in CUMS mice and inhibits TNF-α-induced inflammation in microglia cells // International Immunopharmacology. – 2019. – Vol.67. P. 119-128. DOI: 10.1016/j.intimp.2018.12.011
40. Patel S., Keating B.A., Dale R.C. Anti-inflammatory properties of commonly used psychiatric drugs // Frontiers in Neuroscience. – 2023. – Vol.16. P. 1039379. DOI: 10.3389/fnins.2022.1039379
Authors
Maxim A. Rantsev
Ural State Medical University of the Ministry of Health of the Russian Federation
Candidate of Medical Sciences, Associate Professor, Associate Professor of the Department of Surgical Diseases of the Institute of Surgery
r-ma@bk.ru
Yekaterinburg, Russian Federation
Oleg N. Chupakhin
I. Ya. Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Sciences
Doctor of Chemical Sciences, Academician of the Russian Academy of Sciences, Professor, Scientific Director of the Institute
chupakhin@ios.uran.ru
Yekaterinburg, Russian Federation
Vladimir L. Rusinov
Ural Federal University named after the first President of Russia B.N. Yeltsin"
Doctor of Chemical Sciences, Corresponding Member of the Russian Academy of Sciences, Professor, Head of the Department of Organic and Biomolecular Chemistry
v.l.rusinov@urfu.ru
Yekaterinburg, Russian Federation
Tatyana G. Khonina
Federal State Budgetary Scientific Institution Institute of Organic Synthesis named after I. Ya. Postovsky, Ural Branch of the Russian Academy of Sciences
Doctor of Chemical Sciences, Professor, Leading Researcher, Laboratory of Organic Materials
khonina@ios.uran.ru
Yekaterinburg, Russian Federation
Petr A. Sarapultsev
Federal State Budgetary Institution of Science Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences
Doctor of Medical Sciences, Professor, Honored Scientist of Russia, Senior Researcher, Laboratory of Immunopathophysiology
p.sarapultsev@gmail.com
Yekaterinburg, Russian Federation
Nikolay A. Zabokritsky
Federal State Budgetary Institution of Science Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences
Doctor of Medical Sciences, Associate Professor, Leading Researcher, Laboratory of Immunopharmacology
pharmusma@rambler.ru
Yekaterinburg, Russian Federation
Larisa P. Sidorova
Federal State Autonomous Educational Institution of Higher Education «Ural Federal University named after the first President of Russia B.N. Yeltsin»
Candidate of Chemical Sciences, Senior Researcher, Department of Organic and Biomolecular Chemistry
v.l.rusinov@urfu.ru
Yekaterinburg, Russian Federation