ART OF MEDICINE 2017
PROSPECTS OF TARGET ANTICYTOKINE THERAPY APPLICATION BASED ON THE CHELATE NANOCOMPLEXES
A.V. Artemov, E.S. Buryachkovsky1
Abstract. Cytokines have a leading role in the development of inflammatory reactions. In the ophthalmology, proinflammatory cytokines such as IL-1β, IL-6, TNF-α, which are the main mediators of the development, progression and therapeutic outcome of not only inflammatory diseases (uveitis, ophthalmic herpes), but also pathologies of the age-related diseases (cataract and glaucoma), where cytokines act as mediated pathogenetic factors, are intensively studied.
Despite the validity and prospects of anti-cytokine therapy, in ophthalmic practice it is hampered by the high cost, as well as the limited effectiveness of drugs created by the principle of monoclonal antibodies and aimed only at one protein receptor. Alternative may be multi-target anti-cytokine therapy using an innovative preparation MSC-428 based on chelate nanocomplexes.
The active substance MSC-428 is a low molecular weight chelating coordination compound in which the central atom of a heavy metal, mercury, is bound to two molecules of L-cysteine. The complex compound has a tetrahedral structure in which the carboxyl groups located on the periphery of the molecule (anchor molecules) allow interaction with amino groups of proteins, affecting their tertiary structure (conformation).
. The ultra-small size provides integration into the active site of the cell receptor, and the presence of the heavy metal atom, predetermines conformational changes in the spatial structure of the receptor protein.
The aim of the investigation was to study the effectiveness of multi-target anti-cytokine therapy using the innovative preparation MSC-428 by elucidating the functional and phenotypic changes in the subpopulations of blood lymphocytes in patients with various pathologies of the eye during treatment with this drug.
In connection with this, the phenotypes of blood lymphocytes were studied by expression of the activation markers CD25, CD38, CD45, CD54, CD95. A study of the therapeutic response to MSC-428 was performed in 162 patients, including 71 men (mean age 57 ± 7.3) and 91 women (mean age 59 ± 6.1). The effect of MSC-428 was evaluated by normalizing the expression of the markers.
Thus, CD25 in the study group was significantly higher than normal in 89% of patients (by 20-30%). As a result of taking the drug MSC-428 in 74% of patients it decreased to normal.
The marker of pathological activation of CD38 cells in the study group was increased in 91% of patients, the level of expression depended on the severity of the disease. After taking MSC-428, this factor was restored to normal in 78%.
CD45 before treatment was reduced in 38% of patients, in 57% was increased, which is associated with the dysregulation of Src and JAK family kinases, leading to the activation of the inflammatory process and the activation of destructive biological effects induced by a high level of pro-inflammatory cytokines. After receiving MSC-428, a smart effect on therapy was noted, which was manifested by the fact that 79% of patients with a low CD45 level had increased to normal, and 81% of patients with primarily high expression of CD45, on the contrary, experienced a decrease to the norm.
CD54 (ICAM-1) was increased in 97% of patients before receiving MSC-428. With the admission of MSC-428, 84% of patients experienced a decrease to the norm of CD54, which correlates with a decrease in inflammation, a decrease in the level of proinflammatory cytokines, and a decrease in the migration of lymphocytes to the focus of inflammation.
During the entire period of application of MSC-428, no side effects or intolerance were identified.
Thus, the innovative targeted therapy MSC-428 has proved to be an antagonist of target proteins that represent receptors for IL-1β, IL-6, TNF-α, which creates an advantage over traditional anti-cytokine therapy based on the use of monoclonal antibodies drugs.
The use of multi-target therapy based on MSC-428 in ophthalmic patients has shown its effectiveness in reducing the activity of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, which prevents from cascading destructive biological effects. This provides new therapeutic options in the complex therapy of such a common ocular pathology as uveitis, ophthalmic herpes, cataract, glaucoma, diabetic retinopathy.
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- 1. Артемов А.В. Иммунологические механизмы противоопухолевого действия ртутьсодержащих препаратов на основе хелатных нанокомплексов / А.В. Артемов, Э.С. Бурячковский // Збірник матерiалiв мiжнародної науково-практичної конференцiї «Актуальнi питання розвитку медичних наук у ХХ1 столітті», Львiв, 29-30 травня. – Львiв, 2015. – С. 109-112.
- 2. Артемов А.В. Особенности связывания ртутьсодержащих комплексов с сигнальным рецептором лимфоцитов у пациентов с различными типами злокачественных опухолей / А.В. Артемов, Э.С. Бурячковский // Збiрник тез наукових робіт учасників міжнародної науково-практичної конференції «Медична наука та практика ХХI століття», 5-6 лютого 2016р. – Київ, 2016. – С. 8-11.
- 3. Еричев В.П. Роль цитокинов в патогенезе глазных болезней / В.П. Еричев, С.Ю. Петров, А.М. Суббот и др. // Национальный журнал глаукома. – 2017. – Т. 16. – № 1. – С.85-99.
- 4. Чередниченко Л.П. Значение провоспалительных цитокинов в развитии первичной открытоугольной глаукомы / Л.П. Чередниченко, Л.Ю. Барычева, А.А. Берновская // Медицинский вестник северного Кавказа. –2013. – Т. 8. – №2. – С. 52-54.
- 5. Bradshaw RA, Dennis EA. Functioning of Transmembrane Receptors in Signaling Mechanisms // Cell Signaling Collection. – 2011. – V.1 (Apr).
- 6. Chua J., Vania M., Cheung C.M., Ang M. et al. Expression profile of inflammatory cytokines in aqueous from glaucomatous eyes. Molecular Vision 2012; 18:431-438.
- 7. Rajpal G., Arvan P. Disulfide Bond Formation. Handbook of Biologically Active Peptides.2nd Edition. 2013.
- 8. Zenkel M., Lewczuk P., Junemann A., Kruse F.E., Naumann G.O., Schlotzer-Schrehardt U. Proinflammatory cytokines are involved in the initiation of the abnormal matrix process in pseudoexfoliation syndrome/glaucoma. Am J Pathology. 2010; 176(6):2868-2879. doi:10.2353/ajpath.2010.090914.
- 9. Zhang P., Zhang X., Brown J. et al. Global healthcare expenditure on diabetes for 2010 and 2030. Diabetes Res. Clin. Pract. 2010; 87(3): 293–301.