A sorbent modified with melatonin and lithium: in vitro investigation of the effect on hemostatic reactions
https://doi.org/10.18699/SSMJ20240409
Abstract
Aim of the study was to evaluate the effect of lithium- and melatonin-containing sorbent based on aluminum oxide and polydimethylsiloxane on changes in the number of platelets during hemosorption modeling and on the features of the hemostatic response during dosed contact of the sorbent with blood in an in vitro experiment. Material and methods. An analysis of the effect of the porous sorbent modified with melatonin (MT, 0.15 %) and lithium (0.5 %) based on aluminum oxide and polydimethylsiloxane (Al2O3@PDMS/MT-Li) was carried out in comparison with sorbent without modifiers (Al2O3@PDMS) and modified with MT (Al2O3@PDMS/MT) on a number of donor blood clotting parameters under in vitro hemosorption conditions. Studies of the hemostatic system included assessment of platelet count, chronometric parameters, fibrinogen concentration, antithrombin activity and plasminogen content. For integral assessment, calibrated thrombography and computer thromboelastometry were used. Results and discussion. Contact of all studied sorbents with blood causes a moderate decrease in the number of platelets (by 5.3–10.1 % from initial). Comparison sorbents reduce fibrinogen concentration by 7.1–7.7 %, Al2O3@PDMS/MT-Li – by 2.6 times, which is likely due to the methodology for determining this protein against the background of the independent anticoagulant activity of lithium ions. Al2O3@PDMS and Al2O3@PDMS/MT cause the development of a hypercoagulable shift, as evidenced by a shortening of kaolin time (by 27.5 and 22.1 %, respectively) and of activated partial thromboplastin time (APTT) by 7.1 % for both sorbents. At the same time, when lithium was included in the sorbent, not only did the hypercoagulation shift not occur, but blood clotting was also inhibited, as evidenced by an increase in kaolin time and APTT by 1.2 and 1.6 times, respectively, as well as in silicone time. Conclusions. Modifying sorbents with biologically active substances, lithium and MT, makes it possible to obtain an original hemosorbent with new properties. The presented results demonstrated the absence of a hypercoagulable shift in donor blood after contact with a lithium-, MTcontaining sorbent in vitro and indicate the potential for its using as a basis for the development of safe drugs.
Keywords
About the Authors
A. P. MomotRussian Federation
Andrey P. Momot, doctor of medical sciences, professor
656045, Barnaul, Lyapidevskogo st., 1/2
L. N. Rachkovskaya
Russian Federation
Lubov N. Rachkovskaya, candidate of chemical sciences
630060, Novosibirsk, Timakova st., 2
V. V. Nimaev
Russian Federation
Vadim V. Nimaev, doctor of medical sciences
630060, Novosibirsk, Timakova st., 2
E. E. Rachkovsky
Russian Federation
Edmund E. Rachkovsky, candidate of chemical sciences
630060, Novosibirsk, Timakova st., 2
A. N. Mamaev
Russian Federation
Andrey N. Mamaev, doctor of medical sciences
656045, Barnaul, Lyapidevskogo st., 1/2
S. V. Michurina
Russian Federation
Svetlana V. Michurina, doctor of medical sciences
630060, Novosibirsk, Timakova st., 2
M. A. Kоrolev
Russian Federation
Маksim А. Kоrolev, doctor of medical sciences
630060, Novosibirsk, Timakova st., 2
D. V. Fedorov
Russian Federation
Dmitry V. Fedorov, doctor of medical sciences, professor
656038, Barnaul, Lenina ave., 40
A. Yu. Letyagin
Russian Federation
Andrey Yu. Letyagin, doctor of medical sciences, professor
630060, Novosibirsk, Timakova st., 2
A. A. Smagin
Russian Federation
Аlexander A. Smagin, doctor of medical sciences
630060, Novosibirsk, Timakova st., 2
References
1. Lopukhin Yu.M., Molodenkov M.N. Hemosorption. M.: Meditsina, 1978. 302 p. [In Russian].
2. Khoroshilov S.E., Nikulin A.V. Detoxification in critical conditions: an insight into the scientific problem in the XXI century (review). Obshchaya reanimatologiya = General Reanimatology. 2017;13(5):85–108. [In Russian]. doi: 10.15360/1813-9779-2017-5-85-108
3. Konenkov V.I., Borodin Yu.I. Lyubarsky M.S. Lymphology. Novosibirsk: Manuscript, 2012. 1104 p. [In Russian].
4. Nikolaev V.G. Activated carbons in the treatment of psychoneurological diseases. In: Method of hemocarboperfusion in experiment and clinic. Kiev: Naukova Dumka, 1984. P. 282–295. [In Russian].
5. Kozyrev V.V., Naumtsev S.A., Malin D.I. Clinical and pathogenetic dependencies in extracorporeal hemosorption in patients with paranoid schizophrenia with resistance to psychopharmacotherapy. Sotsial’naya i klinicheskaya psikhiatriya = Social and Clinical Psychiatry. 2002;12(1):58–62. [In Russian].
6. Davydov V.G., Agishev V.G. Strategy and tactics of choosing treatment methods in psychiatric practice (the role and place of psychopharmacotherapy). Obzory po klinicheskoy farmakologii i lekarstvennoy terapii = Reviews on Clinical Pharmacology and Drug Therapy. 2004;3(4):42–54. [In Russian].
7. Abritalin E.Yu., Shamrey V.K., Belskikh A.N. The application of methods of extracorporal blood purification in therapy of treatment-resistant depression. Kubanskiy nauchnyy meditsinskiy vestnik = Kuban Scientific Medical Bulletin. 2009;(7):7–11. [In Russian].
8. Russian Society of Psychiatrists. Therapy of critical conditions in psychiatry. Clinical recommendations (project). Moscow, 2015. 31 p. [In Russian].
9. Fountoulakis K.N., Tohen M., Zarate C.A. Jr. Lithium treatment of Bipolar disorder in adults: A systematic review of randomized trials and meta-analyses. Eur. Neuropsychopharmacol. 2022:54:100–115. doi: 10.1016/j.euroneuro.2021.10.003
10. Plotnikov E.Yu., Silachev D.N., Zorova L.D., Pevsner I.B., Yankauskas S.S., Zorov S.D., Babenko V.A., Skulachev M.V. Lithium salts are simple but magical (review). Biokhimiya = Biochemistry. 2014;79(8):932–943. [In Russian].
11. Decker B.S., Goldfarb D.S., Dargan P.I., Friesen M., Gosselin S., Hoffman R.S., Lavergne V., Nolin T.D., Ghannoum M.; EXTRIP Workgroup. Extracorporeal treatment for lithium poisoning: systematic review and recommendations from the EXTRIP workgroup. Clin. J. Am. Soc. Nephrol. 2015;10(5):875–887. doi: 10.2215/CJN.10021014
12. Adityanjee А., Munshi K.R., Thampy A. The syndrome of irreversible lithium-effectuated neurotoxicity. Clin. Neuropharmacol. 2005;28(1):38–49. doi: 10.1097/01.wnf.0000150871.52253.b7
13. Borodin Yu.I., Rachkovskaya L.N., Darneva I.S., Novoselova T.I. Enterosorbent Noolite. For physical and psychological rehabilitation of the body. Novosibirsk: Sova, 2006. 228 p. [In Russian].
14. Korolev M.A. Pharmacoholic properties of a drug based on lithium citrate immobilized on a matrixnoxite made of aluminum oxide and an organosilicon polymer (experimental study: abstract of thesis … doct. med. sci. Tomsk, 2021. [In Russian].
15. Rachkovskaya L.N., Momot A.P., Rachkovsky E.E., Smagin A.A., Nimaev V.V., Terekhov S.S., Fedorova N.N., Mamaev A.N., Korolev M.A., Letyagin A.Yu. A method for obtaining a hemosorbent with normotimic properties based on porous aluminum oxide. Patent 2797212 RF; published 05.31.2023. [In Russian].
16. Michurina S.V., Rachkovskaya L.N., Ishchenko I.Yu., Rachkovsky E.E., Klimontov V.V., Konenkov V.I. Porous sorbent with chronotropic properties based on aluminum oxide. Patent 2577580 RF; published 20.03.2016. [In Russian]. 17. Hannanova A.N., Bykov Yu.V., Bekker R.A. Melatonin: perspectives in therapy of different psychiatric disorders (a literature review). V mire nauchnykh otkrytiy = In the World of Scientific Discovery. 2017;9(1):131–149. doi: 10.12731/wsd-2017-1-131-149
17. Zavyalov E.L., Michurina S.V., Rachkovskaya L.N., Pozmogova T.N., Letyagin A.Yu. Composition based on lithium citrate and melatonin with antiglioblastoma action. Patent 2787883 RF; published 01.13.2023. [In Russian].
18. Arushanyan E.B. Effect of melatonin on the thrombocyte hemostasis and its circadian organization. Eksperimental’naya i klinicheskaya farmakologiya = Experimental and Clinical Pharmacology. 2013;76(5):32–36. [In Russian].
19. Greg S. Adsorption, specific surface area, porosity. Moscow: Mir, 1984. 310 р. [In Russian].
20. Thompson M. Guide to spectrometric analysis with inductively coupled plasma. Moscow: Nedra, 1988. 288 p. [In Russian].
21. Shvetsova A., Rachkovskaya L., Rachkovsky E., Madonov P., Miroshnikov P., Yaroslavtsev D. Studies of melatonin releasing into solution from the surface of porous carrier based on aluminum oxide and polydimethylsiloxane. 2023 IEEE Ural-Siberian conference on computational technologies in cognitive science, genomics and biomedicine (CSGB): coll. thes. conf., Novosibirsk–Yekaterinburg, September 28–30, 2023. P. 037–040. doi: 10.1109/CSGB60362.2023.10329852
22. Rachkovskaya L.N., Momot A.P., Smagin A.A., Nimaev V.V., Rachkovsky E.E., Fedorova N.N., Mamaev A.N., Korolev M.A., Letyagin A.Yu. Lithiummodified sorbent: Effects on hemostatic responses in vitro. Bull. Exp. Biol. Med. 2023;175(5):690–694. doi: 0.1007/s10517-023-05927-7
23. Barkagan Z.S., Momot A.P. Diagnosis and controlled therapy of hemostasis disorders. Moscow: Newdiamed, 2008. 292 p. [In Russian].
24. Hemker H., Giesen P., AlDieri R., Regnault V., de Smedt E., Wagenvoord R., Lecompte T., Béguin S. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol. Haemost. Thromb. 2003;33(1):4–15. doi: 10.1159/000071636
25. Korolev M.A., Rachkovskaya L.N., Madonov P.G., Shurlygina A.V., Rachkovsky E.E., Letyagin A.Yu., Konenkov V.I., Churin A.A., Dubskaya T.Yu., Vetoshkina T.V., Sandrikina L.A., Fomina T.I., Fedorova E.P. Assessment of acute toxicity of a drug based on a complex lithium citrate, polymethylsiloxane, aluminum oxide. Sibirskiy nauchnyy meditsinskiy zhurnal = Siberian Scientific Medical Journal. 2020;40(5):46–52. [In Russian]. doi: 10.15372/SSMJ20200505
26. Shirinkin S.V. Microelements and their role in the pathogenesis of pneumonia. Pul’monologiya = Pulmonology. 2003;(4):104–108. [In Russian].
27. Robinson M.V., Kotlyarova A.A., Shurlygina A.V., Rachkovskaya L.N., Letyagin A.Yu. Mechanisms of action of lithium compounds. Sibirskiy nauchnyy meditsinskiy zhurnal = Siberian Scientific Medical Journal. 2019;39(5):19–28. [In Russian]. doi: 10.15372/SSMJ20190503
28. Alda M. Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol. Psychiatry. 2015;20(6):661–670. doi: 10.1038/mp.2015.4
29. McCarthy M.J., Nievergelt C.M., Shekhtman T., Kripke D.F., Welsh D.K., Kelsoe J.R. Functional genetic variation in the Rev-Erbα pathway and lithium response in the treatment of bipolar disorder. Genes Brain Behav. 2011;10(8):852–861. doi: 10.1111/j.1601-183X.2011.00725.x
30. Ludwig B., Dwivedi Y. Dissecting bipolar disorder complexity through epigenomic approach. Mol. Psychiatry. 2016;21(11):1490–1498. doi: 10.1038/mp.2016.123
Review
For citations:
Momot A.P., Rachkovskaya L.N., Nimaev V.V., Rachkovsky E.E., Mamaev A.N., Michurina S.V., Kоrolev M.A., Fedorov D.V., Letyagin A.Yu., Smagin A.A. A sorbent modified with melatonin and lithium: in vitro investigation of the effect on hemostatic reactions. Сибирский научный медицинский журнал. 2024;44(4):85-95. (In Russ.) https://doi.org/10.18699/SSMJ20240409