The Coronary heart disease (CHD) is the most common cause of death and disability in the population of developed countries.  Atherosclerosis is a morphological basis of CVD mortality in 90% cases . In recent years, the development of atherosclerosis is considered from the perspective of the theory of immune inflammation, as evidenced by the increase of concentration of inflammatory response markers — high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), fibrinogen, tumor necrosis factor-α ( TFN-α), and others in the blood of patients with CHD. . The IL-6 plays an important role in systemic inflammation, it is a major activator of protein synthesis of liver acute phase. Also, IL-6 is a predictor of clinical manifestations of atherosclerotic vascular lesions in healthy individuals without any signs of the disease [5,6]. The TFN-α is produced predominantly by monocytes / macrophages, endothelial cells and mast cells [9,11]. It affects on the functional properties of the endothelium, coagulation, violates the lipid metabolism promoting the atherogenesis process . The role of inflammation in the pathogenesis of atherosclerosis and its complications has provided a new hypothesis of a link with risk factors with coronary heart disease cellular and molecular changes. In Accordance to it, the fundamental role of inflammation in the development of atherosclerosis may lead to a new therapeutic approaches, selectively acting on the inflammatory process, slowly evolving in atherosclerotic plaque .
Currently, the most important aspect of pharmacological treatment of patients with coronary heart disease is a reduction in total cholesterol levels in the blood plasma using the hydroxymethylglutaryl – CoA reductase inhibitors — statins . However, high doses of statins cause side effects often lead to pain in the skeletal muscle, liver and gastrointestinal tract. A promising and cost-effective direction is the combined usage of statins with plant origin lipid-lowering drugs. In the Institute of Plant Chemistry (IPCH RUz) them. Acad. S. Yunusov developed a native lipid-lowering drugs oligvon (leukomizin) on the basis of sesquiterpene lactone from whitish wormwood (Artemisia leucodes Schrenk). Since the 1995 leukomizin (Oligvon) has been approved by Pharmacological Committee of Ministry of Health of the Republic of Uzbekistan for widespread usage in medical practice as a angioprotector and lipid-lowering agent [1,2].
The aim of research
The comparative evaluation of anti-inflammatory (pleiotropic) effects of simvastatin and oligvon in patients with unstable angina (UA).
Materials and methods
The study included 92 patients with UA class IIB (E. Braunwald et al., 1989), mean age 58.7 ± 7.1 years old, of whom 23 (25%) had a history of myocardial infarction and 18 (20%) people suffering diabetes type 2. Regarding to the methods of treatment the patients were divided into groups: the first one consisted of 40 patients treated with simvastatin, the 2nd group consisted of 35 patients with UA (intolerant to statins), treated with leukomizin 60-90 mg / day, the 3 rd group consisted of 17 patients who were on the combined treatment of simvastatin (20-40 mg / day) and leukomizin (60-90 mg / day). The serum level of the cytokines was determined in 34 from 92 patients with unstable angina. Accordingly, 13 patients were examined in the first group, 11 patients in the second group and 10 patients in the third.
The exclusion criteria were: the development of acute myocardial infarction (MI) in a given period of hospitalization or suffered less than 3 months ago; severe heart failure (HF) III-IV FK; complex cardiac arrhythmias; severe violations of liver and kidneys. The study included: inpatient treatment (9-10 days) and the stages of outpatient after discharge of the patient from the hospital up to 3 months. The basic therapy included: anticoagulants (heparin or fraxiparine) in the acute period (100%), antiplatelet agents (100%), beta-blockers (bisoprolol, 100%), short-nitrates (nitroglycerin, 95%) if necessary, and ACE inhibitors (lisinopril, 95%). The hsCRP concentration was determined by a highly sensitive method of immunoturbidimetry using «Daytona» device (RANDOX, UK).
The Immunological studies were performed in the laboratory of immunopathology and immunopharmacology of Institute of Immunology, Academy of Sciences of Uzbekistan. The cytokines IL-6 and TNF-α were determined in blood serum with ELISA method using kits of «Vector-Best»ltd. (Novosibirsk, Russia) with the help of the enzyme immunoassay analyzer «Stat Fax — 2100» (USA).
The statistical processing of the results was carried out with the help of software applications for statistical processing of data Statistica® version 6.0. The significance of differences between treatment groups was evaluated by Student’s t test. The differences of compared values recognized statistically significant at p˂0,05. There was conducted the correlation analysis with the calculation of the Spearman’s coefficient.
Results and discussion
To assess the significance of immune responses in the development of coronary artery disease destabilization studied hsCRP, fibrinogen, leukocytes, ESR indicators and proinflammatory cytokines before and during the treatment with lipid-lowering drugs.
The values of inflammatory mediators before and in dynamics (3 months) in the treatment groups (M ± SD)
|Indicators||simvastatin (n = 40)||oligvon (n = 35)||oligvon + simvastatin (n = 17)|
|outcome||after treatment||outcome||after treatment||outcome||after treatment|
|hsCRP, g / l||5,1±2,7||2,1±0,7^^^||5,0±2,6||2,7±1,9^^^||5,5±2,6||2,0±1,9^^^|
|White blood cells (10’9 / l)||6,9±1,9||6,6±1,8||5,7±1,3||5,6±1,7||6,0±0,9||5,7±1,5|
|ESR, mm / h||8,9±5,1||5,7±3,9^^||6,7±4,7||5,8±3,2||7,6±6,7||6,4±4,4|
|Fibrinogen, g / l||3,1±1,2||2,8±1,0||3,1±1,3||3,0±0,9||3,1±0,7||2,6±0,3^|
Note: * P <0.05, P ^^ <0.01 ^^^ P <0.001 — significance relative to the initial value; (In case of nonparametric distribution — Wilcoxon test); * P <0.05, ** P <0.01, *** P <0.001 — significance relative to the group receiving oligvon (in the case of non-parametric distribution — Wilcoxon test);
According to the obtained data level of leukocytes and ESR had no significant difference between the groups, but in the 1group of patients showed a significant decrease in erythrocyte sedimentation rate (P <0,001) in relation to the source data. The hsCRP concentration substantially and significantly reduced in patients of all three groups (P <0,001), which confirms the presence of pleiotropic properties of simvastatin and indicates the presence of those of oligvon (Table 1). The anti-inflammatory activity of the combination therapy confirms the dynamics of other biochemical markers of inflammation — fibrinogen: there was a significant decline (P <0,05) in patients of the 3rd group,whereas a declining trend was observed in the other groups. In randomized studies was found that hsCRP being acute phase protein synthesized in the liver in response to interleukin-1 (IL-1), interleukin-6 and tumor necrosis factor α (TNF-α), is present in atheromatous plaques and may be a clinical marker of atherosclerosis .
During the in the study of the level of pro-inflammatory cytokines IL-6 and TFN-α revealed that in healthy individuals the average of their level significantly lower than in patients with unstable angina.
The values of IL-6 and TNF-alpha in the treatment groups (M ± SD)
|Indicators||The control group (n=15)||simvastatin (n=13)||oligvon (n=11)||oligvon + simvastatin (n=10)|
|outcome||After treatment||outcome||After treatment||outcome||After treatment|
|IL-6 (pg / ml)||3,42±0,28||80,6±51,2||45,1±31,4*||13,5±2,7^^||8,6±1,1**||27,4±10,5^||11,9±2,6***|
|TFN-α (pg / ml)||4,58±0,81||25,3±13,6||21,8±12,9||10,4±2,7^||9,4±1,1||13,0±4,1^||9,3±1,1*|
Note: *, **, *** — p <0.05, P <0.01, P <0.001 significance of differences with respect to baseline; ^, ^^ — P <0.05, P <0.001 significance of differences between the outcome and the control group.
As seen from Table 2 in patients taking oligvon IL-6 levels decreased in 1.6-times (P <0.01) and TFN-α in 1.6-times compared to before treatment. In the group of patients taking simvastatin IL-6, indicators decreased by 1.8 times (P <0.05), and TFN-α 1.2 times in relation to baseline values. The best authentic result was found in the group of patients with combined treatment: the levels of IL-6 decreased in 2.3 times (P <0.001), and TFN-α 1.4 times (P <0.05) relative to baseline values. The results of our study showed that the usage of lipid-lowering therapy significantly reduced the levels of proinflammatory cytokines, which in turn indicates the presence of pleiotropic (anti-inflammatory) effect from these drugs. Our data are consistent with the results of several studies in which the anti-inflammatory effect of statins is carried out through the suppression of the activity of a number of cytokines (TFN-α, γ interferon, interleukin-6, etc.) and the level of hsCRP [8,12,15]. Due to this aseptic inflammation of unstable atherosclerotic plaque and prevents the risk of cardiovascular disease suppressed in the short term (4-16 weeks) .
- Yielding to simvastatin on lipid-lowering effect native product oligvon at 3 months of treatment equally reduce the level of hsCRP and pro-inflammatory cytokines (IL-6 and TFN-α), which indicates the presence of pleiotropic effect of these drugs.
- A more marked reduction of the levels of inflammatory mediators noted during the combined use of simvastatin and oligvon: hsCRP by 55% (P <0.001), IL-6 at 56.6% (P <0.001) and TFN-α by 37.7% (P <0.05)
- Oligvon during the combined using with simvastatin has also anti-fibrinogen effect that expands the possibilities of its usage in clinical practice, particularly in patients with high risk of cardiovascular complications.
- Aksartov R.M. The lipid-lowering properties and pharmacokinetics of sesquiterpene lactone leukomizin.- Diss … MD, Astana, 2004 (in Russian language)
- Alimardanov L. The application of oligvon in complex treatment of patients with myocardial infarction. Abstract for the degree of candidate of medical science. Tashkent 1997. (in Russian language)
- Alekperov E.Z., Najafov R.N. The modern concepts of the role of inflammation in atherosclerosis. // Cardiology. — 2010. — №6. — pp. 88-91. (in Russian language)
- Aronov D.M. The pleiotropic effects of statins at the present stage of their study: focus on atorvastatin. Part III.// Kardiosomatika. — 2013. — №2. — pp. 20-26. (in Russian language)
- Gordeeva E.K., Kade A.Kh. The change of cytokine status with stable angina. // Medical bulletin of the South of Russia. — 2016. — №1. – pp. 15-21. (in Russian language)
- Paleev F.N., Abudeeva I.S., Moscalets O.V. Belokopytova I.S. Changes of interleukin-6 in various forms of ischemic heart disease. // Cardiology. — 2010. — №2. — pp. 69-72. (in Russian language)
- Paleyev F.N., Belokopytova I.S., Minchenko B.I., Moscalets O.V. rol of cytokines in the pathogenesis of ischemic heart disease. // Creative cardiology. — 2011. — №1. — pp. 75-80. (in Russian language)
- Fichtischerer S., Schmidt-Lucke C. et al. Differencial effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD evidence for «pleotropic» functions of statin therapy. Eur Heart J 2006; 27 (10): 1182-90.
- Libby P. Inflammation in aterosclerosis // Nature. — 2002. — Vol. 420. — P. 868-874.
- Marcovina S.M., Crea F., Davignon J. et al. Biochemical and bioimaging markers for risk assessment and diagnosis in major cardiovascular diseases: a road to integration of complementary diagnostic tools // J. Int. Med. — 2007. — Vol. 261. — P.214-234.
- McGill H.C., Herderic E.E., McMahan C.A. et al. Atherosclerosis in youth // Minerva Pediatr / — 2002. — Vol.54, №5. — P. 437-447.
- Morrow D.A., de Lemos J.A. et al. Clinical relevance of C-reactive protein during gollow-ur of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation 2006; 25 (114): 281-288.
- Reiner S., Catapano A., De B acker G. et al. ESC / EAS G uidelines for the management of dyslipidaemias The T ask Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Developed with the special contribution of: European Association for cardiovascular P revention & Rehabilitation . European Heart Journal (2011) 32, 1769-1818.
- Ridker P.M. Clinical application of C-reactive protein for cardiovascular disease detection and prevention // Circulation. — 2003. — Vol. 107 (3). — P. 363-369.
- Ridker P.M. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). // J. Thromb. Heamost 2009; (Suppl.7) 1: P. 332-339.THE INFLUENCE OF OLIGVON AND SIMVASTATIN ON THE IMMUNOLOGICAL PARAMETERS IN PATIENTS WITH CORONARY ARTERY DISEASE WITH DESTABILIZATION OF ANGINA.Written by: Kasimova Mukhlisakhon SaidakbarkhodjaevnaPublished by: БАСАРАНОВИЧ ЕКАТЕРИНАDate Published: 02/14/2017Edition: ЕВРАЗИЙСКИЙ СОЮЗ УЧЕНЫХ_30.01.2017_1(34)Available in: Ebook