[Possibilities of clinical use of ezetimibe Otrio (JSC "AKRIKHIN", Russia) in patients with high and very high cardiovascular risk who have not reached the target values of lipid metabolism. Conclusion of the Board of experts].

This Conclusion of the Board of experts is devoted to the analysis of the evidence base, the position in modern clinical guidelines, the efficacy and safety analysis as well as the options of combined therapy with statins and ezetimibe (Otrio, JSC "AKRIKHIN") in various categories of patients in routine clinical practice in theRussian Federation. Cardiovascular diseases (CVD) continue to lead in the structure of morbidity and mortality inRussia. Hypercholesterolemia is one of the main modifiable risk factors for CVD. Administration of HMGCo-A-reductase inhibitors (statins) remains the basis for the prevention and treatment of the main complications of atherosclerosis, but the achievement of target levels of LDL-C on of statin monotherapy in Russian practice among different categories of risk does not exceed 50%. Proportion of patients (up to 12%) does not tolerate statin therapy, which requires the search for alternative therapies. To optimize the control of the level of LDL-C, combination therapy with statins and ezetimibe is used. Ezetimibe is an effective lipid-lowering drug, an inhibitor of intestinal absorption of cholesterol, which was investigated in many international and Russian studies, the results of which have demonstrated good tolerability, safety and efficacy (reduction of LDL-C levels by 18% in monotherapy). It was noted that the combined therapy with low/medium doses of statins and ezetimibe effectively reduces the level of LDL-C by 44-53%, which is comparable to the effect of high doses of statins and reduces CV risk in patients with CKD and ACS. Otrio (INN Ezetimib) tablets 10 mg ( JSC "AKRIKHIN",Russia) has demonstrated bioequivalence to the original drug Ezetrol tablets 10 mg (Schering-plough Labo N. V,Belgium). Broad use of a new generic product Otrio in combination with different statins will significantly increase the frequency of achievement of target lipid levels in patients with high and very high CV risk, including patients with chronic renal failure, type 2 diabetes and in patients with high hypercholesterolemia (LDL-C > 5 mmol/l) and, ultimately, reduce the burden of CV disease and mortality in Russia.

A cytofluorometric study of membrane rafts in human monocyte subsets in atherosclerosis.

The peripheral blood monocytes of atherosclerotic patients are pre-activated and have some of the features of tissue macrophages. Their adhesion to the endothelium is 1.5 times higher than that of monocytes from healthy subjects, and they express a number of receptors and antigens typical of tissue macrophages. Additionally, earlier we showed that the biosynthesis of gangliosides, whose main function is the formation of membrane rafts, is significantly activated in blood monocytes from atherosclerotic patients, as well as during the in vitro differentiation of normal monocytes into macrophages. In this study, we investigated the expression of membrane rafts on various monocyte subsets from healthy subjects and atherosclerotic patients. Based on flow cytometry results, the monocytes in the examined atherosclerotic patients were found to differ from those in healthy subjects by a twofold increase in the proportion of the intermediate subset (CD14(++)/CD16(+)) and by enhancement in the expression of the fractalkine receptor CX3CR1 on the intermediate and non-classical subsets (CD14(++)/CD16(+) and CD14(+)/CD16(++)) (2.3 and 1.8 times, respectively). This suggests a pre-activated state of monocytes in atherosclerotic patients. At the same time, the expression of the membrane raft marker on the monocyte subsets was similar in both studied groups. However, a study of the in vitro differentiation of monocytes into macrophages showed that the membrane raft expression increased 2 times as early as on the 1st day of culturing and 3 times on the 7th day compared to that in freshly isolated monocytes. Therefore, it is suggested that monocytes in atherosclerosis accumulate gangliosides that are used to form membrane rafts during the macrophage differentiation after the migration of monocytes into the arterial intima.

[Comparison of the efficiency of transluminal balloon angioplasty using EucaTAX and Cypher stents in patients with stable coronary heart disease].

OBJECTIVE: To compare the long-term results of transluminal balloon coronary angioplasty in patients after implantation of drug-eluting coronary artery stents with permanent or biosoluble polymer coatings. MATERIAL AND METHODS: This was a prospective, comparative, single-center trial. It enrolled patients having at least 70% stenosis who had undergone intracoronary Cypher (SES) or EucaTAX (EUPES) stent implantation. RESULTS: The trial included 602 subjects, including 282 patients with a placed EUPES stent and 320 patients with an implanted SES stent. Two years later, there was a higher rate of repeat revascularization in the EUPES group than in the SES group (16.3% versus 6.25%; p = 0.0001) and that of great unfavorable events in these groups (18.4% versus 7.8%; p = 0.001). According to the angiographic parameters of in-stent restenosis, the rate of repeat target-segment revascularization was significantly higher in the EUPES group than that in the EucaTAX group while stenting coronary arteries less than 3 mm in diameter, using stents more than 18 mm in length, as well as in residual stenosis of more than 12% as compared to the SES group. CONCLUSION: In the SES group, the clinical outcomes were better than those in the EUPES group during 2-year follow-up; the rate of target lesion revascularization was significantly higher in the EUPES group.

Association between polymorphisms of eNOS and GPx-1 genes, activity of free-radical processes and in-stent restenosis.

Our aim was to examine correlations between polymorphisms in five antioxidant enzymes genes, activity of free-radical processes, and the risk of restenosis after coronary artery stenting with bare metal stents (BMS). A total of 101 male patients who underwent intracoronary stenting using BMS and coronary angiography follow-up of 6 months were enrolled in: group with in-stent restenosis (n = 44) and without restenosis (n = 57). The content of lipoperoxides and malondialdehyde (MDA) in Low-density lipoprotein (LDL), activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) in erythrocytes, and genotypes polymorphisms of the CAT gene (-262C/T), paraoxonase-1 (PON-1) gene (163T/A and 575A/G), endothelial nitric oxide synthase (eNOS) gene (298G/T (rs#1799983) and -786T/C), GPx-1 gene (599C/T (rs#1050450)), and glutathione-S-transferase (GSTP) gene (313A/G) were determined. In carriers of the minor allele of 599C/T polymorphism of the GPx-1 gene, activity of GPx in erythrocytes was lower by 17 % than in wild allele homozygotes, while the content of lipoperoxides in LDL was higher by 74 %. T-allele of 599C/T polymorphism of the GPx-1 gene (OR = 2.9; 95 % CI: 1.23-6.82) and T-allele of 298G/T polymorphism of the eNOS gene (OR = 2.79; 95 % CI: 1.17-6.66) were associated with the risk of in-stent restenosis. Minor alleles of polymorphisms 298G/T of the eNOS gene and 599C/T of the GPx-1 gene are associated with an increased risk of in-stent restenosis. Minor allele of the GPx-1 gene 599C/T polymorphism leads to a decrease of the GPx activity and increase of the activity of free-radical processes.

Pro198Leu polymorphism of GPx-1 gene and activity of erythrocytic glutathione peroxidase and lipid peroxidation products.

We studied the relationship between the GPx-1 gene Pro198Leu polymorphism genotype and activity of free-radical processes. In patients with documented CHD, the content of lipoperoxides and MDA in LDL, activity of glutathione peroxidase in erythrocytes, and genotype of GPx-1 gene Pro198Leu polymorphism were determined. In carriers of the minor allele, activity of glutathione peroxidase in erythrocytes was lower by 17% than in wild allele homozygotes, while the content of lipoperoxides and MDA in LDL was higher by 74 and 27%, respectively. We concluded than free-radical oxidation processes are more pronounced in carriers of the minor allele of GPx-1 gene Pro198Leu polymorphism.

[Antioxidant status and restenosis after stenting of coronary arteries].

AIM: To investigate possibility of effect of antioxidant status on severity of restenosis of coronary arteries after transluminal coronary angioplasty with stenting. MATERIAL AND METHODS: Men with ischemic heart disease and coronary angiography performed in 6 months after coronary artery stenting with bare stents were included in this study. Coronary angiograms were subjected to quantitative computer analysis. Samples of venous blood were obtained before control angiography. We assessed duration of lag phase of copper induced free radical oxidation of low density lipoproteins (LDL), and measured level of lipoperoxides in LDL, content of malone dialdehyde (MDA) in LDL, activity of superoxide dismutase (SOD), glutathione peroxidase (GP), and erythrocyte catalase. RESULTS: We revealed positive correlations of lag phase duration and activity of GP with minimal artery diameter 6 months after stenting (r=0.41, p < 0.002 and r=0.24, p < 0.05, respectively), of lipoperoxide level in LDL and MDA content in LDL with degree of stenosis (r=0.32, p < 0.009, and r=0.37, p < 0002, respectively). We also found negative correlations between lag phase duration and GP activity with degree of restenosis (r= - 0.38, p < 0.04, and r= - 0.39, p < 0.001, respectively), level of lipoperoxides in LDL and MDA content in LDL with artery minimal diameter (r= - 0.33, p < 0.007, and r=0.32, p < 0.008, respectively). CONCLUSION: Our study confirms possibility of influence of antioxidant status on degree of coronary artery restenosis in patients after coronary artery stenting.

Relationship between free-radical lipid oxidation and efficiency of coronary angioplasty in coronary patients.

Low-dose (250 mg daily) oral probucol produces a significant antioxidant effect in coronary patients: increases activity of glutathione peroxidase (enzyme utilizing lipoperoxides) and reduces the content of free-radical oxidation products in the blood. Probucol therapy for 7 days before and for 6 months after coronary angioplasty significantly reduces the severity of coronary artery stenosis.

[Effect of atorvastatin therapy on the level of secretory phospholipase A2 group IIA and on the modification of low density lipoproteins in patients with ischemic heart disease].

We studied effect of atorvastatin on secretory phospholipase A2 group IIA (sPLA2-IIA) in blood serum of patients with ischemic heart disease (IHD), lipid composition of low density lipoproteins (LDL) and process of modification of LDL induced by sPLA2-IIA in 20 patients taking 20 mg/day of atorvastatin for 3 months. In patients with initially high level of sPLA2-IIA ( > 8 mcg/l) its concentration significantly decreased. Amount of total cholesterol, triglyceride, lecithin, and lysolecithin remained unchanged, however in equimolar relations there occurred decrease of amount of total cholesterol and increase of cholesterol esters. At incubation of LDL, extracted from patient s plasma before initiation of the study, with human sPLA2-IIA from cardiac myxoma, 3.5 nmol of lysolecithin per 1 mg of LDL protein was formed while at incubation of LDL of same patients, extracted after 3 months of atorvastatin administration, amount of lysolecithin was 1.54 nmol/mg LDL protein. Thus atorvastatin therapy causes lowering of sPLA2-IIA in patients with initially high blood level of the enzyme and to a great extent precludes sPLA2-IIA induced LDL modification.

Effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor atorvastatin on contractility of the isolated rat heart under normal conditions and during oxidative stress.

Long-term administration of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor atorvastatin to rats was accompanied by an increase in the relative weight of the heart and decrease in the rate of pressure development in the isovolumic heart. During oxidative stress induced by addition of 100 microM H2O2 to the perfusate, the decrease in contractile function was more pronounced that in the control. Our results indicate that administration of atorvastatin is accompanied by a decrease in myocardial contractility, which becomes more pronounced under conditions of oxidative stress.

Effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors and antioxidant vitamins on free radical lipid oxidation in rat liver.

We studied the effects of two inhibitors of beta-hydroxy-beta-methylglutaryl coenzyme A reductase, simvastatin and lovastatin, on the lag phase of ascorbate-dependent lipid oxidation in rat liver. Oxidizability of liver biological membranes significantly increased in intact animals and rats with induced hypercholesterolemia after peroral administration of these statins. The lag phase of ascorbate-dependent lipid oxidation in liver biomembranes decreased by 2.1 times in hypercholesterolemic rats. In animals of the lovastatin group this parameter decreased by 4.4 times compared to the control. In intact rats receiving simvastatin, the lag phase of oxidation in biomembranes from the liver decreased practically by 2 times. At the same time, in animals receiving simvastatin in combination with antioxidant vitamins (vitamins E and C, provitamin A) and selenium, the period of induction of oxidation increased by 3.3 times. Our results indicate that beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors produce a prooxidant effect on the liver, which can be prevented by administration of antioxidant agents.

Effect of ubiquinone Q(10) and antioxidant vitamins on free radical oxidation of phospholipids in biological membranes of rat liver.

We studied the effects of 30-day peroral treatment with beta-carotene, a complex of antioxidant vitamins (vitamins C and E and provitamin A) and selenium, and solubilized ubiquinone Q(10) on the antioxidant potential in rat liver (ascorbate-dependent free radical oxidation of unsaturated membrane phospholipids). beta-Carotene irrespective of the administration route increased antioxidant potential of the liver by 2-3.5 times. The complex of antioxidant vitamins and selenium increased this parameter by more than 15 times. Antiradical activity in rat liver was extremely high after administration of solubilized ubiquinone Q(10) (increase by more than by 36 times). It can be expected that reduced ubiquinone Q(10) in vivo should produce a more pronounced protective effect due to activity of the system for bioregeneration of this natural antioxidant.

Oxidative stress in atherosclerosis and diabetes.

We measured the content of lipid peroxides in plasma LDL from patients with chronic CHD not accompanied by hypercholesterolemia; CHD and hypercholesterolemia; type 2 diabetes mellitus and decompensation of carbohydrate metabolism; and CHD, circulatory insufficiency, and type 2 diabetes mellitus (without hypercholesterolemia). The content of lipid peroxides in LDL isolated from blood plasma by differential ultracentrifugation in a density gradient was estimated by a highly specific method with modifications (reagent Fe(2+) xylene orange and triphenylphosphine as a reducing agent for organic peroxides). The content of lipid peroxides in LDL from patients was much higher than in controls (patients without coronary heart disease and diabetes). Hypercholesterolemia and diabetes can be considered as factors promoting LDL oxidation in vivo. Our results suggest that stimulation of lipid peroxidation in low-density lipoproteins during hypercholesterolemia and diabetes is associated with strong autooxidation of cholesterol and glucose during oxidative and carbonyl (aldehyde) stress, respectively. These data illustrate a possible mechanism of the progression of atherosclerosis in patients with diabetes mellitus.

Low daily dose of antioxidant probucol decreases incidence and severity of restenosis after transluminal coronary balloon angioplasty.

Antioxidant probucol in both high (1000 mg) and low (250 mg) daily doses effectively reduced manifestations of oxidative stress in patients with atherosclerosis (assessed by in vivo accumulation of lipoperoxides in atherogenic LDL). When probucol was administered in a dose of 250 mg/day for 7-10 days before transluminal balloon coronary angioplasty and then for 6 months after surgery, the incidence of restenosis decreased to 25% compared to 45% in the control (without probucol therapy). In the group of operated patients receiving probucol (250 mg/day for 6 months) the minimal artery lumen was significantly higher, and the degree of artery occlusion significantly lower than in the control group not treated with probucol.

Changes in antioxidant status of myocardium during oxidative stress under the influence of coenzyme Q10.

Changes in myocardium were studied during oxidative stress induced by infusion of hydrogen peroxide in the coronary vessels of isolated rat heart. Moderate concentrations of H2O2 increased the heart rate but decreased the contractile force, whereas higher concentrations of H2O2 decreased both parameters and increased the end diastolic pressure. The effect of H2O2 was stable, cumulative, and was associated with disturbance in respiration of mitochondria, increased production of ROS in them, and decrease in activities of antioxidant enzymes in the myocardium. Changes in the antioxidant status of the myocardium induced by long-term addition of coenzyme Q(10) into food was accompanied by decrease in the negative inotropic effect of H2O2, whereas the levels of superoxide dismutase and glutathione peroxidase after oxidative stress were virtually unchanged. The activities of these enzymes displayed a high positive correlation with the cardiac function. The findings suggest that coenzyme Q(10) should increase resistance of the myocardium to oxidative stress not only by a direct antioxidant mechanism but also indirectly, due to increased protection of antioxidant enzymes.

[Serum level of secretory phospholipase A2 (sPLA2) as a predictor of restenosis after coronary angioplasty]. / Uroven' sekretornoi fosfolipazy A2 v syvorotke krovi kak prediktor restenoza posle koronarnoi angioplastiki.

AIM: To elucidate whether secretory phospholipase A2 (sPLA2) level in the blood and catalytic activity are significant predictors of restenosis after coronary angioplasty (CAP). MATERIAL AND METHODS: Samples of venous blood were obtained from 24 patients before CAP and 1, 3, 6 days and 6 months after it. sPLA2 was measured with enzyme immunoassay, catalytic activity--using aqueous emulsion of 14C-labelled phosphatidylcholine. Control coronarography was performed in all the examinees 6 months after CAP. RESULTS: Restenosis was detected in 13 patients. In the serum of their blood sPLA2 rose significantly after CAP and persisted for 6 days after it. If restenosis was not registered, this rise was insignificant and disappeared by day 6 after CAP. Catalytic activity of sPLA2 on day 6 after CAP was significantly higher in patients who later developed restenosis. CONCLUSION: Elevated concentrations of sPLA2 in blood serum of patients after CAP may predict restenosis. Moreover, sPLA2 may not only mark inflammation but directly participate in development of restenosis.