Pharmacogenetics - A New Word in the Treatment of Rheumatoid Arthritis
Khalimbetova Nazira Yusufovna, Samarkand State Medical Institute. Samarkand, Uzbekistan Shukhrat Khudayberdievich Ziyadullaev, Samarkand State Medical Institute. Samarkand,
Uzbekistan
Irina Rubenovna Agababyan, Samarkand State Medical Institute. Samarkand, Uzbekistan
Jamshid Abduraimovich Ismailov, Samarkand State Medical Institute. Samarkand, Uzbekistan
Abstract
As you know, rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Over the past few years, scientists have paid special attention to the close interaction of genetic and epigenetic mechanisms of the development of the disease. Research has focused on the effects of environmental factors, as well as the mechanisms of the innate and adaptive immune systems that can influence the various stages of RA. Coverage of various aspects of the pathogenesis of RA will help improve existing diagnostic methods of research and identify new opportunities for developing more specific points of application in the treatment of this serious disease.
Introduction
Rheumatoid arthritis (RA) is a chronic immune-inflammatory (autoimmune) disease manifested by progressive joint destruction, systemic inflammation of internal organs, and a wide range of comorbid diseases associated with chronic inflammation, and often with unwanted drug reactions (ADR) [1]. The pathogenesis of RA is determined by a complex interaction of environmental factors and genetic predisposition, which lead to global disorders in the system of innate and acquired immunity and are detected long before the development of clinical symptoms of the disease [2-4].RA still belongs to diseases with an incompletely understood etiology. In the literature, the issue of its multifactorial nature is widely discussed, where genetic, immunological, infectious and other factors are actively involved. The intensive study of biomarkers in rheumatology has arisen from the need to understand the mechanisms underlying some rheumatic diseasesJoint damage in RA develops as a result of chronic inflammation of synovia during the interaction of resident cells, such as fibroblast-like synoviocytes, with cells of innate (macrophages, dendritic cells, mast cells, neutrophils) and adaptive (B- and T-lymphocytes) immunity [5, 6, 7]. Defects in RA occur at three levels, culminating in persistent inflammation: level 1 — the site of inflammation, such as the synovium, where autoreactive and inflammatory cells proliferate; level 2 - the interface of regulatory processes, for example, the mechanism of peripheral tolerance and level 3 - the central level of regulation of autoimmunity [8].These levels are arbitrary and often overlap. Another major problem is that the changes that cause the disease and the subsequent process of its development can differ between groups of patients. Presumably, changes at regulatory levels leading to persistent inflammation, as well as changes that inhibit reversible processes, may be characteristic only of RA.
Immune biomarkers.
A diagnostic biomarker, by definition, must be an objective, quantifiable characteristic of
biological processes that aids in the accurate diagnosis of a condition. Currently, autoantibodies to
rheumatoid factor (RF) and C-reactive protein (CRP) are well-known markers of RA. Numerous studies
have evaluated the usefulness of RF [16,17,22,25-27], anti-CRP [16,17,22,26-32] and their variants.
Antibodies (usually of the IgM class) to their own immunoglobulins of the IgG or RF class are one of the manifestations of a violation of tolerance to their own antigens, which characterizes the autoimmune process.It is believed that RF forms macroscopic immune complexes from IgG, which cause mechanical damage to the walls of blood vessels and synovial membranes, but this is not the only possible mechanism of RF pathogenic action.
Antibodies to cyclic citrullinated are often found in the serum of patients with rheumatoid arthritis. peptide (ACCP). Citrulline is one of the amino acids in the body, which is not encoded in DNA by a specific codon, but is formed from arginine after synthesis. Replacing arginine with citrulline affects the chemical properties of the protein and makes it more hydrophobic, which affects its spatial structure.
Such unusually folded proteins can be seen by the immune system and autoantibodies are formed to them.
Many proteins of the synovial fluid, including fibrin and fibrinogen, contain arginine residues, which are modified into citrulline under conditions of inflammation and cause an autoimmune response [11].
In the course of a study aimed at a comprehensive assessment of markers of inflammation in patients with rheumatoid arthritis, an increase in the level of C-reactive protein, calprotectin, IL6, IL-8, TNF-a was also revealed in comparison with the control [12].
Genetic aspect
The basis of the pathogenesis of RA is formed by a triad of genetic predisposition, environmental influences and autoimmunity, which is also rightly called the "Bermuda triangle". In this triad, a significant proportion is accounted for by heredity, as evidenced by studies on twins and monitoring of morbidity in families. To date, hundreds of genes are known whose polymorphism makes a significant contribution to the development of RA, and, as the Italian scientists C. Perricone et al. ., their discovery -
"a never-ending story" [31]
Genome-wide search for associations has shown that certain variants of genes regulating the immune system have a significant effect on the onset and development of this disease. The genes of the main histocompatibility complex affect the predisposition to rheumatoid arthritis most of all. The proteins encoded by these genes are responsible for the binding of the antigen to T-lymphocytes. Some of their variants can carry out this process more efficiently against their own antigens, thereby promoting the initiation of the autoimmune process. One of the most interesting in this regard is the HLA-DRB1 gene, whose connection with rheumatoid arthritis has long been known. Various alleles of this gene, for example, encoding proteins for the self-acid motif QKRAA, are associated with the greatest susceptibility to disease. Variants from the DRB1 * 04 family (determining the HLA-DR4 serotype) are considered to be the most "unfavorable" ones [32].
Allelic variants of the genes of many proteins involved in the activation of T-lymphocytes are also
responsible for the predisposition of their carriers to rheumatoid arthritis. Among these proteins are
molecules associated with a co-stimulating signal (CD28, CTLA-4), pro-inflammatory cytokines and
their receptors (IL2, IL2RA, IL21), which are necessary for the functioning of T cells, as well as various
enzymes that are important intracellular players in the activation of lymphocytes ( PTPN22, PRKCQ,
TAGAP). The interaction of specific allelic variants of different genes (for example, HLA-DRB1 and
PTPN22) increases the likelihood of disease [34]. Berglin et al. Tried to analyze the predictability of RA
development using a combination of an autoantibody (anti-CCP) and a common epitope allele: HLA
DRB1 * 0401 or B1 * 0404 (SE HLA DR). They demonstrated increased predictability as well as similar
specificity in predicting RA. Likewise, the combination of a single nucleotide polymorphism in the
PTPN22 gene encoding lymphoid protein tyrosine phosphatase and the presence of a detectable level of
anti-CCP demonstrated improved predictability of RA development as well as increased prediction
specificity. The presence of the PTPN22 1858T (CT + TT) variant and anti-CCP had 100% specificity with an almost 20-fold increase in the power of predictability [35]. These studies highlight the fact that the presence of susceptibility markers improves the predictive value of a positive additional test.
Epigenetic mechanisms can also regulate the immune system, increasing the risk of rheumatoid arthritis. The action of regulatory RNAs, histone or DNA modification can lead to a change in the usual
"schedule" of the work of key genes involved in pathogenesis.
Pharmacogenetics
For the best long-term results, it is very important that the patient starts taking basic anti- inflammatory drugs (DMARDs) as early as possible. These drugs have immunosuppressive properties, respectively, the autoimmune process, literally eating a joint affected by rheumatoid arthritis, can be limited at an early stage [45,48].
When using methotrexate, the best ratio of efficacy and toxicity is noted compared to the use of other basic anti-inflammatory drugs.The immunomodulatory and anti-inflammatory effect of the drug is based on the induction of apoptosis of rapidly proliferating cells (activated T-lymphocytes, fibroblasts, synoviocytes), inhibition of the synthesis of anti-inflammatory 1 cytokines (IL- a), increased synthesis of anti-inflammatory cytokines (IL-4 and IL-10), suppression of the activity of metalloproteinases.
However, the high incidence of adverse reactions, the development of resistance often become the main reason for its cancellation. [47].
It is known that the effectiveness and frequency of adverse reactions are determined primarily by genetic characteristics and the ability of the body to metabolize the drug. A change in the structure of a gene can influence proteins involved in pharmacodynamics and drug metabolism.
A new direction in clinical pharmacology, pharmacogenetics, allows using genotyping to determine which drug or which dose is the most effective and safe.
The methotrexate molecule alters the metabolism of folic acid by interacting with intracellular enzymes. The activity of these enzymes directly affects the entry of the drug into the cell, its intracellular metabolism and the rate of excretion from the cell, and therefore the concentration of the drug, which determines both its effectiveness and the implementation of toxic properties. [49].
It is known that, in addition to interaction with their own activators and inhibitors, the activity of enzymes is affected by conformational changes in the protein structure, in particular, the structure of the active center. The latter depends on the amino acid sequence of the linear chain, in turn, the amino acid series from gene polymorphism.
findings
A dynamic disease like RA is unlikely to have a single unique biomarker for diagnosing or predicting disease progression. The selected factor or molecule must be specific for RA, susceptible to disease progression, and cover a wide range of RA patients to qualify as a suitable biomarker.
Thus, any changes in genes affect the metabolism of methotrexate. Certain cellular components,
soluble neurotransmitters and autoantibodies contribute to the development of inflammation and
structural changes in joints and internal organs. Recently, studies at the molecular and cellular levels have
elucidated some of the mechanisms that regulate innate and adaptive immunity in RA. In particular,
genetic and immunological research has allowed us to identify new mechanisms that may explain the
development of the disease. Research aimed at improving the identification of the mechanisms underlying
the pathogenesis of RA will allow the development of new and more specific immunological parameters
of RA, and hence a new modifying therapy. Multicenter studies examining these factors should help
improve the detection of early RA biomarkers.
References
1.Smolen JS, Aletaha D, Barton A, et al. Rheumatoid arthritis. Nat Rev Dis Primers 2018;4:18001.
2.McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoidarthritis. Lancet 2017;389:2328-37.
3.Nasonov EL. Problems of the immunopathology of rheumatoid arthritis: the evolution of the disease. Scientific and practical rheumatology 2017;55(3):277-94 [Naso -nov EL. Problems of rheumatoid arthritis immunopathology:
Evolution of thedisease. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science andPractice 2017;55(3):277-94 (In Russ.)].
4.Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis.Immunity 2017;46(2):183-96.
5.Bogolyubova A. Change the composition of the joint https://biomolecula.ru/articles/revmatoidnyi-artrit-izmenit- sostav-sustavov
6.Mateen S, Zafar A, Moin S, et al. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis.
Clin Chim Acta. 2016;455:161-171. https://doi.org/10.1016/j.cca.2016.02.010.
7.Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;46(2):183- 196. https://doi.org/10.1016/j.immuni.2017.02.006.
8.Chandrashekara S. Pharmacokinetic consideration of synthetic DMARDs in rheumatoid arthritis. Expert Opin Drug Metab Toxicol. 2013;9(8):969–981.
9.Hemminki K, Li X, Sundquist J, Sundquist K. Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions. Arthritis Rheum. 2009;60(3):661-668. https://doi.org/10.1002/art.24328.
10.Kuo CF, Grainge MJ, Valdes AM, et al. Familial aggregation of rheumatoid arthritis and co-aggregation of autoimmune diseases in affected families: a nationwide population-based study. Rheumatology (Oxford).
2017;56(6):928-933. https://doi.org/10.1093/rheumatology/kew500.
11.Carolin Hecht, Matthias Englbrecht, Jürgen Rech, Sarah Schmidt, Elizabeth Araujo, et. al.. (2015). Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA. AnnRheumDis. 74, 2151-2156;
12.. Huseynova A.S. Investigation of some laboratory biomarkers of rheumatoid arthritis / BIOMEDICINEvol.17
• ¹2 • 2019
13. Alexandrova E.N., Novikov A.A., Nasonov E.L. The role of biomarkers in the diagnosis and prediction of the effectiveness of modern therapy for rheumatoid arthritis. Clinical laboratory diagnostics. 2013; 8: 3-13.
https://cyberleninka.ru/article/n/rol-biomarkerov-v-diagnostike-i-prognozirovanii-effektivnosti-sovremennoy- terapii-revmatoidnogo-artrita
14.Kopec-Medrek M., Widuchowska M., Kucharz E., Calprotectin in rheumatoid diseases: a review.
Reumatologia. 2016;54(6):306-9. DOI: 10.5114/reum.2016.64907
15Nielsen S.F., Boyesen S.E., Shnohr P., Nordestgaard B.G. Increased rheumatoid factor and long-term risk of rheumatoid arthritis: a prospective cohort study. BMJ. 2012; 345: e5244. [Free PMC article] [ PubMed ] [ Google Scholar ]
16. Berglin E, Padyukov L, Sundin U, et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther.
2004;6(4):R303–R308.
17.Johansson M, Arlestig L, Hallmans G, Rantapää-Dahlqvist S. PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease. Arthritis Res Ther. 2006;8(1):R19.
18.Markelova E.V., Zdor V.V., Romanchuk A.L., Birko O.N. Matrix metalloproteinases: relationship with cytokines system, diagnostic and prognostic potential. Immunopathology, allergology, infectology. 2017;2:11-22.
DOI: 10.14427/jipai.2016.2.11 (in Russian).
19.Mateen S., Zafar A., Moin S., KhanA.Q., Zubair S. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clinica Chimica Acta. 2016;455:161-171. DOI: 10.1016/j. cca.2016.02.010 (in Russian).
20.Yusof M.Y., Emery P. Targeting interleukin-6 in rheumatoid arthritis. Drugs. 2013;73:341-6. DOI:
10.1007/s40265-013- 0018-2.
21. Pawłowska J, Smolenska Ż, Zdrojewski Z, Witkowski JM, Bryl E. Changes in proliferation kinetics of T cells:
A new predictive cellular biomarkers for early rheumatoid arthritis? J Clin Immunol. 2012;32: 991–999.
22. Goëb V, Aegerter P, Parmar R, et al. Progression to rheumatoid arthritis in early inflammatory arthritis is associated with low IL-7 serum levels. Ann Rheum Dis. 2013;72:1032–1036.
23. Lübbers J, Brink M, van de Stadt LA, et al. The type I IFN signature as a biomarker of preclinical rheumatoid arthritis. Ann Rheum Dis. 2013;72:776–780.
24. Solanki K, Spellerberg M, Chapman P, Moller P, O’Donnell J. Anti-cyclic citrullinated antibodies:
complementary to IgM rheumatoid factor in the early diagnosis of rheumatoid arthritis. N Z Med J.
2004;117(1203):U1097.
25. Mouterde G, Lukas C, Logeart I, et al. Predictors of radiographic progression in the ESPOIR cohort: the season of first symptoms may influence the short-term outcome in early arthritis. Ann Rheum Dis. 2011;70(7):1251–1256.
26. Liu X, Jia R, Zhao J, Li Z. The role of anti-mutated citrullinated vimentin antibodies in the diagnosis of early rheumatoid arthritis. J Rheumatol. 2009;36(6):1136–1142.
27. Forslind K, Ahlmén M, Eberhardt K, Hafström I, Svensson B; BARFOT Study Group. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis. 2004;63:1090–1095.
28. Kastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann Rheum Dis. 2004;63:1085–1089.
29.Li GY, Sun XL, Li Y, Jia RL, Jia Y, Li ZG. [Significance of anti-citrullinated human papilloma virus-47 E2(345–362) peptide antibodies in diagnosis of early-stage rheumatoid arthritis]. Beijing Da Xue Xue Bao. 2013;45(3):458–463. Chinese.
30. Pratt AG, Charles PJ, Chowdhury M, Wilson G, Venables PJ, Isaacs JD. Serotyping for an extended anti- citrullinated peptide autoantibody panel does not add value to CCP2 testing for diagnosing RA in an early undifferentiated arthritis cohort. Ann Rheum Dis. 2011;70:2056–2058.
31.Perricone C, Ceccarelli F, Valesini G. An overview on the genetic of rheumatoid arthritis: a never-ending story.
Autoimmun Rev. 2011;10(10):599-608. https://doi.org/10.1016/j.autrev.2011.04.021.
32. Raychaudhuri S, Sandor C, Stahl EA, et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012;44:291–6.[PMC free article] [PubMed] [Google Scholar]
33.Tang GP, Hu L, Zhang QH. [PTPN22 1858C / T polymorphism is associated with rheumatoid arthritis susceptibility in Caucasian population: a meta-analysis. (In Chinese)]. Zhejiang Da Xue Xue Bao Yi Xue Ban.
2014; 43 (4): 466-473.
34. Nabi G, Akhter N, Wahid M, et al. Meta-analysis reveals PTPN22 1858C / T polymorphism confers susceptibility to rheumatoid arthritis in Caucasian but not in Asian population. Autoimmunity. 2016; 49 (3): 197- 210. https://doi.org/10.3109/08916934.2015.1134514.
35. El-Lebedy D, Raslan H, Ibrahim A, et al. Association of STAT4 rs7574865 and PTPN22 rs2476601 polymorphisms with rheumatoid arthritis and non-systemically reacting antibodies in Egyptian patients. Clin Rheumatol. 2017; 36 (9): 1981-1987. https://doi.org/10.1007/s10067-017-3632-7.
36. Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science. 2002; 296 (5573): 1634-1635.
https://doi.org/10.1126/science.1071924.
37 Chen X, Oppenheim JJ. Contrasting effects of TNF and anti-TNF on the activation of effector T cells and regulatory T cells in autoimmunity. FEBS letters. 2011; 585 (23): 3611-3618.
https://doi.org/10.1016/j.febslet.2011.04.025.
38. Hehlgans T, Pfeffer K. The intriguing biology of the tumor necrosis factor / tumor necrosis factor receptor superfamily: players, rules and the games. Immunology. 2005; 115 (1): 1-20. https://doi.org/10.1111/j.1365- 2567.2005.02143.x.
39. Nedwin GE, Naylor SL, Sakaguchi AY, et al. Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res. 1985; 13 (17): 6361-6373.
https://doi.org/10.1093/nar/13.17.6361.
40. Udalova IA, Nedospasov SA, Webb GC, et al. Highly informative typing of the human TNF locus using six adjacent polymorphic markers. Genomics. 1993; 16 (1): 180-186. https://doi.org/10.1006/geno.1993. 1156.
41. Chatzikyriakidou A, Voulgari PV, Lambropoulos A, Drosos AA. Genetics in rheumatoid arthritis beyond HLA genes: what meta-analyzes have shown? Semin Arthritis Rheum. 2013; 43 (1): 29-38.
42 McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis - shaping the immunological landscape.
Nat Rev Rheumatol. 2016; 12 (1): 63-
43. Levdansky O.D., Rodkin M.S., Danilov D.E., et al. Polymorphism of IL28B and TNF-α genes among the indigenous population of Belarus, as well as in patients with chronic hepatitis C // Molecular and Applied Genetics.
- 2016. - T. 20. - S. 80–86. [Liaudanski AD, Rodzkin MS, Danilau DE, et al. IL28B and TNF-α gene polymorphism in native Belarusians and patients with chronic hepatitis C. Molekulyarnaya i prikladnaya genetika.
2016; 20: 80-86. (InRuss.)
44.Savina N.V., Nikitchenko N.V., Kuzhir TD, et al. Frequencies of genotypes and alleles of polymorphic loci of the inflammatory response genes PTPN22, TNF-α and MIF in the children's contingent of the Republic of Belarus // Molecular and Applied Genetics ... - 2017. - T. 22. - S. 14–24. [Savina NV, Nikitchenko NV, 46. Kuzhir TD, et al. Frequencies of genotypes and alleles of polymorphic loci of inflammatory response genes PTPN22, TNF-α and MIF in children and adolescents in the Republic of Belarus. Molekulyarnaya i prikladnaya genetika. 2017; 22: 14- 24. (In Russ.)]
45 van Nies JA, Krabben A, Schoones JW, et al. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann Rheum Dis 2014; 73: 861-70.
46. Zhang TP, Lv TT, Xu SZ, et al. Association of interleukin-10 gene single nucleotide polymorphisms with rheumatoid arthritis in a Chinese population. PostgradMedJ. 2018; 94 (1111): 284-288.
https://doi.org/10.1136/postgradmedj-2017-135441.
47. Nasonov E.L. Pharmacotherapy of rheumatoid arthritis: Russian and international recommendations //
Scientific and practical rheumatology. 2016.Vol. 54. No. 5. P. 557–571.
Farh KK, Marson A, Zhu J, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants.
Nature. 2015; 518 (7539): 337-f343.https://doi.org/10.1038/nature13835.
48.Lopez-Olivo MA, Kakpovbia-Eshareturi V, des Bordes J, et al. Treating early undifferentiated arthritis: A systematic review and meta-analysis of direct and indirect trial vidence. Arthritis Care Res (Hoboken) 2017.doi:
10.1002 / acr.23474.
49. Yamamoto T., Shikano K., Nanki T., Kawai S. Folylpolyglutamate synthase is a major determinant of intracellular methotrexate polyglutamates in patients with rheumatoid arthritis // Sci. Rep. 2016. Vol. 6. ID 35615.
50. Nasonov E.L. Methotrexate in rheumatoid arthritis - 2015: new facts and ideas // Scientific and practical rheumatology. 2015. T. 53. No. 4. P. 421–433.
51.ShukhratZiyadullaev, Jasur RizaevAlimdjanovich, Irina AgababyanRubenovna, Jamshid IsmailovAbduraimovich, Soatboy Yuldashev JiyanboyevichThe effect of budesonide on the quality of life in patients with bronchial asthma. European Journal of Molecular & Clinical Medicine Volume 7, Issue 2, 2020 1760- 1766
52. Rizaev J.A., Ashirov Z.F., Toshev S.U., Salamova L.A., Baratova M.R. Medical and organizational measures to improve the provision of medical care in the dermatovenerology profile International Journal of Current Research and Review2020 12 (24), p. 120-122
53. Rakhmatullaevna, N.U., Utkurovna, S.G., Basirovich, S.U., Aslanovna, K.G., Hidirovna, L.Z. Arterial hypertension in central asia International Journal of Current Research and Review2020 12 (22), p. 95-99
54. Irsalieva, F., Razikova, I., Kamalov, Z., Dustbabayeva, N., Nizamov, K. Rationale for sublingual allergen- specific immunotherapy in immunocompromised patients. International Journal of Pharmaceutical Research, 2020, 12 (2), p. 230-236
55. Dustbabaeva, N., Irsalieva, F., Kamalov, Z., Ziyadullaev, S., Akhmedov, K. Research of the association of IL- 17A RS (2275913) gene polymorphism with allergic rhinitis associated with food co-sensitization. International Journal of Pharmaceutical Research, 2020, 12 (2), p. 758-762
56. Yakubova, O., Ayupova, F., Kamalov, Z., Negmatshaeva, K., Mamarasulova, D. Role of COL1A1 and G2046T genes in Uzbeks with juvenile dysmenorrhea in the presence of criteria for undifferentiated connective tissue dysplasia. Journal of Critical Reviews, 2020, 7 (2), p. 391–394
57. Tashkenbaeva, E.N, Ziyadullaev, S.K, Kamalov, Z.S, Kadirova, F.S, Abdieva, G.A. Urate regulation gene polymorphisms are correlated with clinical forms of coronary heart disease. International Journal of Pharmaceutical Research, 2019, 11 (3), p. 198–202
