APPLICATION OF QUERCETIN FOR CORRECTION OF THE IMPAIRMENT OF THE FUNCTIONAL STATE OF THE ENDOTHELIUS OF VESSELS (CLINICAL AND EXPERIMENTAL STUDY). / ZASTOSUVANNIa KVERTsETYNU DLIa KOREKTsIÏ PORUShEN' FUNKTsIONAL'NOGO STANU ENDOTELIIu SUDYN (KLINIKO-EKSPERYMENTAL'NE DOSLIDZhENNIa).

OBJECTIVE: in the experiment, to investigate the effect of Quercetin on the NO-dependent reactions of isolated vessels involving endothelium and perivascular adipose tissue (PVAT) after a single X-ray irradiation of rats at a sublethal dose. In a clinical study, to investigate the effect of long-term use of Quercetin on the functional state of themicrovascular endothelium in the elderly patients with metabolic syndrome (MS). MATERIAL AND METHODS: Experimental studies were performed on vascular fragments obtained from adult male rats(7-8 months) of the control group, in animals exposed to a single R-irradiation at a dose of 7 Gy and animals irradiated in the same dose, which received Quercetin orally for 14 days three times a week based on 10 mg/kg bodyweight. Fragments of the thoracic aorta (TA) and mesenteric artery (MA) were cleaned of perivascular adipose tissue (PVAT-) or left uncleaned (PVAT+), and then were cut into rings (up to 2 mm). The amplitude of the contractionof the rings TA and MA under the influence of phenylephrine (PE, 3 x 10-6 M), the amplitude of the contraction of therings TA and MA in the presence of a competitive blocker of NO-synthase methyl ester of N-nitro-L-arginine(L-NAME, 10-5 M), the amplitude of relaxation of the rings TA and MA in the presence of N-acetylcysteine (NAC, 10-4 M)were measured. The clinical study examined 110 patients with MS criteria in accordance with ATP III (2001).Patients in the main group for 3 months received Quercetin from the same manufacturer, 80 mg three times a day,patients in the control group received placebo. RESULTS: Single R-irradiation disrupts the regulation of the contractile function of TA and MA, which is evidenced bychanges in the contractile reactions of isolated fragments of these vessels as a response to the action of vasoactivecompounds. Course use of Quercetin in irradiated rats leads to the normalization of contractile and dilatory vascular responses due to partial correction of NO metabolism in the endothelium and PVAT. For the majority of patients(69 %) who received Quercetin, a post-occlusive hyperemia test showed a statistically significant increase of maximal volumetric velocity of the skin blood flow rate and duration of the recovery period to the baseline, which indicates about improvement of vasomotor vascular endothelial function. CONCLUSIONS: Course use of Quercetin improves the functional state of the microvascular endothelium among theelderly people with MS, normalizes contractile and dilatory vascular responses in irradiated rats due to partial correction of NO metabolism in the endothelium and PVAT.

ORGANISM REACTION TO DOSED HYPOXIC HYPOXIA IN THE HEALTHY SUBJECTS AND INDIVIDUALS WITH PREDIABETIC HYDROGEN METABOLISM DISTURBANCES.

To assess organism reaction to dosed hypoxic hypoxia in the human invividuals with pre-diabetic hydrogen metabolism disturbances.Altogether 40 subjects, age range 50-74 years, were examined, including 18 persons with pre-diabetic hydrogen metabolism disturbances and 22 essentially healthy subjects. All of them underwent dosed hypoxic test (breathing gas mixture containing 12 % of oxygen during nearly 20 min. The following monitorings were performed: blood saturation (SpO2), breathing rate, arterial blood pressure and heart rate; and standard glucose tolerance test (GTT) for blood plasma glucose and insulin concentration. The patients with prediabetic hydrogen metabolism disturbances displayed a more significant decrease of SpO2 and less effective functioning of the respiratory and cardiovascular systems during dosed hypoxic test compared with the healthy individuals without hydrogen metabolism disturbances. After redistribution of study subjects relative the degree of SpO2 decrease at dosed hypoxic test in the subgroup with satisfactory resistance to hypoxia (subgroup 1: SpO2 more than 80 %) and with reduced (subgroup 2: SpO2 80 % or less) we have found that the fasting glucose level after 2-hour GTT was significantly higher in subgroup 2 versus subgroup 1. The obtained results indicate the interrelationship between organism reaction to hypoxia, in particular between the degree of arterial hypoxemia during performance of the dosed hypoxic test and the indices of fasting glycemia and at standard GTT. The patients with pre-diabetic hydrogen metabolism disturbances are characterized with lower resistance to hypoxic hypoxia.

[Metabolic syndrome and cognitive impairment in aging patients with dyscirculatory encephalopathy].

The relationship between metabolic syndrome and its individual components, leptin levels and the severity of cognitive impairment in patients of different age with dyscirculatory encephalopathy (DE) and metabolic syndrome (MS) was studied. There were 503 patients aged 45-89 years with DE enrolled into the study, who were divided into two groups: patients without MS (n=198) and with MS (n=305). All patients were divided into three age subgroups. All patients underwent clinical-neurological examination, laboratory tests, high resolution B-mode ultrasound examination, MRI. Cognitive functions were assessed by Mini Mental State Examination (MMSE). In middle age and elderly patients a significant inverse relationship between the total score of MMSE and the level of blood pressure, blood glucose level was found. A direct significant correlation between blood pressure level and a total score of MMSE was revealed in senile patients. The duration of hypertension significantly influenced on the severity of cognitive impairment in patients of middle and old age. The results obtained indicate a definite relationship between the level of leptin in the blood of patients with MS and the state of their cognitive functions. The influence of leptin level on cognitive function in patients with the metabolic syndrome increases with age. Timely and adequate correction of blood pressure, blood glucose and triglycerides may have a positive effect on cognitive function in patients with MS.

[Age features of hemostatic system in people with insulin resistance and pre-diabetes carbohydrate metabolism disorders].

In pre-diabetes disorders in which pathogenesis the insulin resistance (IR) plays a leading role, the risk of thrombosis due to increased coagulation factors, decreased concentration of physiological anticoagulants and inhibition of fibrinolysis is increased. Similar changes in the hemostatic system with aging are observed. We investigated the characteristics of the hemostatic system in middle-aged and elderly people with IR in the absence and presence of impaired glucose tolerance (IGT). It is shown that IR in middle-aged and elderly people is accompanied by increased content of plasminogen activator inhibitor type-1, which may lead to potential inhibition of fibrinolysis. An indication of significant prothrombotic changes associated with IR in the elderly are reduced a clotting time of blood plasma in the APTT test and elevated levels of soluble fibrin and D-dimer. Intensity of these changes in the hemostatic system is enhanced in the presence of IGT. The results substantiate need for correction of hemostasis by reducing the IR.

[The tetrapeptide pankragen forte efficiency in elderly people with prediabetic state].

The aim of this study was to investigate the effectiveness of tetrapeptide pankragen-forte in older people with prediabetic state. A total of 150 healthy people of different ages, including 39 young people (20-39 years), 42 people. middle-aged (40-59 years) and 69 older adults (60 years and older). As a result of screening, 69 seniors were selected 12 patients with impaired glucose tolerance, which, for the correction of glucose metabolism used Pankragen-forte as follows: 500 mkg 2 times a day (morning and evening) for 4 weeks. All included surveyed was defined indicator of glycosylated hemoglobin, conducted a standard oral glucose tolerance test with determination of glucose, insulin in plasma glucose and venous blood at 30, 60 and 120 min after ingestion of 75 g glucose. Pro-insulin levels were determined in plasma, venous blood glucose and 30-min OGTT. Also calculated an index of insulin resistance (HOMA-IR), insulin sensitivity index (Matsuda index) and functional activity of ß cells of the pancreas (HOMA- %). In 50 percent older people with impaired glucose tolerance use of pankragen forte led to a significant decrease in the concentration of plasma glucose during a standard oral glucose tolerance test, which indicates the normalizing effect of peptide drug in the violation of carbohydrate metabolism, which is consistent with the improvement of the lipid composition of serum blood, endothelial function, decreased platelet aggregation. The use of peptide drug pankragen forte is promising correction prediabetic status in the elderly.

[Tissue oxygen exchange and oxidative processes in long-livers: age peculiarities].

This work was undertaken to study tissue oxygen exchange and oxidative processes in the long-lived individuals who were assumed as the physiologically aging individuals. Oxygen tension was assessed in forearm subcutaneous cellular tissue by means of the polarographic method while performing 10 min oxygen inhalation tests (with spontaneous oxygemogram recording) and a 10 min clamping of vessels. The obtained data served as the tissue oxygen exchange indicator. This approach made us possible to evaluate the oxygen delivery and oxygen uptake. To study qualitative characteristics of oxidative processes, we assessed vacat-oxygen of the blood and urine and estimated the underoxidation coefficient proposed by Muller. We have found that tissue respiration intensity falls, the amount of underoxidated products of the blood and urine rises, and the underoxidation coefficient increases in aging. The decrease of tissue oxygen respiration intensity in subcutaneous cellular tissue reflects the development of tissue hypoxia associated with reduced activity of the enzymes, being involved in oxygen exchange. An age-related decrease of tissue perfusion leads to the formation of circulatory hypoxia and also contributes considerably to tissue hypoxia formation. The revealed changes in the tissue oxygen exchange and oxidative processes in the long-livers are generally correspondent to those that can be seen in the people of 80-89 years. This finding speaks in favor of the physiological aging in the long-livers.

[Relationship of enzyme activity of the gastric mucosa with microcirculation and acid output].

The aim was to study the gastric blood flow due to acid output and enzyme systems of GM. The study included 14 healthy young and 20 healthy elderly people without atrophic changes in GM. Blood flow in microvessels GM was determined by laser Doppler flowmeter, acid output was assessed by 24-hours pH-monitoring, the activity of H(+)-K(+)-ATPase and nitric oxide synthase in biopsies GM was determined by standard biochemical methods. In normal elderly people a significant reduction in blood flow in the microvessels of the secretory zone of GM (large curvature, front and back wall in the body stomach) accompanied by a decrease in the activity of NO-synthase was found. Acid output and activity of H(+)-K(+)-ATPase of parietal cells in the same area do not decreases with age. However, older patients demonstrated a higher level of blood flow in the secretory zone combined with a higher acid output, which indicates that the increase in the level of blood flow values for hydrochloric acid secretion in older people.

[Insulin resistance and physical performance in middle age and elderly people].

In 43 middle age and elderly people without obesity (body mass index of less than 30 kg/m2) we studied the relationship between insulin resistance (IR) and physical performance. It is shown that in healthy elderly IR is associated with a moderate increase of insulin and a small increase in the level of glucose in the blood plasma. In the middle age people, IR has no effect on physical performance. IR in the elderly people is accompanied by the decrease in physical performance due to less economical for hemodynamic load and oxygen consumption. A lower exercise tolerance in elderly people without obesity can be considered not only as a risk factor for insulin resistance, but also as its consequence.

Prospects of using pancragen for correction of metabolic disorders in elderly people.

We examined two groups of older persons: 30 healthy and 33 patients with type 2 diabetes mellitius. Nocturnal melatonin production was significantly reduced by 70% in patients with DM2 compared to healthy individuals of the corresponding age. In patients with DM2, pancragen significantly decreased glucose level on an empty stomach and in standard glucose tolerance test and reduced plasma concentrations of insulin and insulin resistance index. In patients receiving no pancragen, no changes in carbohydrate metabolism indices were observed. Thus, disturbances in the melatonin-producing function of the pineal gland in elderly individuals contribute to the development of insulin resistance. Administration of the tetrapeptide pancragen is a promising approach to the correction of insulin resistance in elderly individuals.

Peptide geroprotector from the pituitary gland inhibits rapid aging of elderly people: results of 15-year follow-up.

The paper presents the results of randomized comparative study of the efficiency of peptide geroprotector from the pituitary gland in elderly patients with rapidly aging cardiovascular system. Over three years 39 coronary patients received, in addition to basic therapy, regular courses of epithalamin (peptide drug), while 40 coronary patients (control group) received basic therapy alone. Long-term treatment with epithalamin (6 courses over 3 years) decelerated aging of the cardiovascular system, prevented age-associated impairment of physical endurance, normalized circadian rhythm of melatonin production and carbohydrate and lipid metabolism. A significantly lower mortality in the group of patients treated with epithalamin in parallel with basic therapy also indicated a geroprotective effect of the peptide preparation from the pineal gland.

[Effect of positive expiratory pressure on pulmonary gas exchange in elderly people with accelerated aging].

The reaction of cerebral blood flow during breathing with positive end expiratory pressure in elderly people with physiological (24 pers.) and accelerated (26 pers.) aging of the respiratory system were studied. It is shown that in people with accelerated aging of the respiratory system some resistance to expiration improves the efficiency of gas exchange in the lungs. However, breathing with considerable resistance to expiration (15 mm water column) in people with accelerated aging of the respiratory system, causing depression of gas exchange in the lungs. Found that people with accelerated aging of the respiratory system decreased pulmonary gas exchange response to breathing resistance expiration.

[Effectiveness of intermittent normabaric hypoxic trainings in elderly patients with coronary artery disease].

The intermittent normabaric hypoxic training (IHT) is a non-pharmacological method, which due to several positive effects, has been used successfully in treating patients with cardiovascular diseases (CVD). However, the application of this method in the elderly has its own peculiarities because of age-related changes of organism. The article presents the indications and limitations of IHT in elderly people with coronary artery disease, the method of the mode of training in the elderly, as well as displaying the results of our clinical study of the safety and efficacy of IHT in 45 elderly patients with stable angina of I and II functional classes. It is shown that IHT is a safe method, leading to reduction in clinical symptoms of angina and duration of daily myocardial ischemia, normalization of lipid metabolism and increase exercise tolerance. Mechanisms of positive effects of IHT in patients with stable angina of I and II functional classes are an economical functioning of the cardiovascular system, optimization of oxygen consumption, improvement of vasomotor endothelial function due to increased formation of nitric oxide, normalization of microcirculation.

[Normalizing effect of the pineal gland peptides on the daily melatonin rhythm in old monkeys and elderly people].

In the course of aging both monkeys and people reveal decreased night and average daily level of melatonin in the blood plasma and reduced hormone circadian rhythm amplitude, which evidence the disorder of the pineal gland melatonin releasing function. Peptide preparations of the pineal gland (Epithalamin--a complex of peptides isolated from the pineal gland and Epitalon--synthetic tetrapeptide) recover night release of endogenous melatonin and lead to the normalization of the hormone circadian rhythm in the blood plasma. In elderly people Epithalamin and Epitalon modulate pineal gland functional state: people with pineal gland functional insufficiency report an increase of night melatonin level. The preparations of the pineal gland, effectively increasing melatonin concentration and having no side effects, can be used in clinical geriatric practice.

[Individual characteristics of human adaptation to intermittent hypoxia: possible role of genetic mechanisms].

The majority of the adaptation processes to hypoxia is based on transcriptional regulation by hypoxia-inducible factors--HIFs. Recently the allele polymorphism of oxygen-dependent degradation domain of HIF-lalpha has been described. It consists in the replacement of cytosine for thymine in 1772 location (C1772-->T). The physiological significance of such replacement is obscure. In the investigation of 26 healthy elderly subjects (58.5 +/- 0.7 yr) we tried to verify whether HIF-lalpha polymorphism in exon 12 may identify individual features of adaptation to intermittent hypoxia training (IHT) (isocapnic hypoxic rebreathing technique, 5-min sessions with 5 min rest intervals, 3 times daily during 10 days). The distribution of HIF-l alpha genotypes for C1772-->T were studied by using the polymerase chain reaction and restriction analysis. We detected that all subjects from the group had C/C genotype. Meanwhile, the broad spectrum of adaptive reactions to IHT was observed, from the best adaptation up to disadaptation. IHT enhanced HVRs in the range of 167% - 5%, blood malon dialdehyde content varied from a decrease by 46% up to an increase by 88%, the changes of superoxide dismutase activity varied from +64% to -56% etc. These results suggest that the C1772-->T polymorphism in HIF- 1alpha does not contribute to individual peculiarities of adaptation to IHT. Because the activity of HIF-lalpha is regulated by multiple steps including the transcriptional level, the effect of the polymorphism in enother exons on the adaptive reactions remains to be elucidated.

[Efficacy of treatment-and-prophylactic diets including soya-based food in elderly patients with atherogenic dislipidemia and glucose intolerance].

47 elderly patients aged 60-74 with stable exertional angina of I-II functional classes and 2a type dislipidemia have been observed. The authors studied the efficacy of hypocholesteremic diet (HD) including soya-based food in comparison with the use of HD without soya-based food. Patients of the main group were prescribed HD, soya-based food (29 g of soya protein per day) and medications of a based therapy during four weeks. Patients of the control group were given HD and medications of a based therapy during the same period. The use of HD with soya-based food decreased considerably frequency and duration of exertional angina attack, increased the tolerance to physical activity resulted in more considerable decrease in concentration of blood serum common cholesterin and cholesterin of low density lipoprotein in comparison with indices of patients of the control group. Soya-based food together with HD in patients with disturbed tolerance to glucose normalized the tolerance test to glucose.

Effect of epithalamin on the rhythm of immune and endocrine systems functioning in patients with chronic coronary disease.

In contrast to young people, changes in the rhythms of parameters manifested in elderly and senile chronic coronary patients in inversion (decreased T cell count in the peripheral blood, values of lymphocyte blastogenesis test with phytohemagglutinin, and phagocytic index in the fall), monotony (B cell count in the peripheral blood), decreased amplitude of serum hydrocortisone, and desynchronization. The levels of thymic serum factor and IgG were higher in the fall than in the spring, but the seasonal difference leveled after 2.5 years of observation. On the other hand, the rhythms of changes in the thymic serum factor and hydrocortisone were retained in patients with chronic coronary disease after 6 courses of epithalamin by the optimal protocol (period of observation 30 months) and blood T cell count increased in the fall. Improvement of the rhythms of the parameters was associated with a benign clinical course of the disease.

Geroprotective effect of epithalamine (pineal gland peptide preparation) in elderly subjects with accelerated aging.

A 12-year randomized clinical study of epithalamine (pineal gland peptide preparation) was carried out in elderly patients with coronary disease and accelerated aging of the cardiovascular system. Long-term treatment with epithalamine decreased the functional age and degree of cardiovascular aging; exercise tolerance increased. After 12 years the number of elderly subjects dead in the group treated by epithalamine was 28% lower than in the control group, despite the same basic therapy. Cardiovascular mortality was 2-fold lower in patients treated by epithalamine; the incidence of cardiovascular failure and respiratory diseases was 2-fold lower in this group. Long-term treatment with epithalamine was associated with a geroprotective effect on the long-term life prognosis in elderly subjects with accelerated aging.

[Age peculiarities of cardiorespiratory system reaction to hypoxia].

Age peculiarities of cardiorespiratory system reactions on isocapnic hypoxia (inhalation of gas mixture of 12% O2) have been investigated. It has been stated that breathing with hypoxic mixture resulted in more significant shift of O2 blood saturation, AP and autonomic balance in the elderly people (p < 0.05) comparing to the young people. It testifies to a greater intensity of sympathoadrenal system at hypoxic stress in elderly people that confirms the decrease of their tolerance to hypoxia.

Effect of epithalamin on circadian relationship between the endocrine function of the thymus and melatonin-producing function of the pineal gland in elderly people.

The effect of epithalamin on circadian rhythms of thymic serum factor titers and melatonin concentrations in the blood of elderly people was studied. Course treatment with epithalamin modulated the rhythm of the thymic endocrine function. The increase in the titer of thymic serum factor at night coincided with the increase in blood melatonin concentration and shift of its acrophase to 3.00, which was characteristic of young people. In elderly people with preserved nocturnal peak of the thymic serum factor titer before therapy the nocturnal (3.00) concentration of melatonin was high and did not change after drug therapy. The correlation between melatonin concentration and titer of thymic serum factor increased after epithalamin treatment.