[Cytoflavin effect on locomotor and psychoemotional status in physiological and pathological aging.]

Currently, the actual problem is the correction of motor, cognitive and psychoemotional disorders in physiological aging, as well as in various pathological processes that accompany aging and accelerate it. In this regard, it became necessary to search for drugs that can restore age-related disorders of the brain. The aim of the study was to evaluate the possibility of Cytoflavin as a pharmacological corrector of age-dependent disorders of the functions of the cerebral cortex during physiological and pathological, accelerated aging. The mouse sensorimotor cortex of the brain was the material for study. The transgenic male mice with HER2/neu overexpression at the age of 2 and 10 months were used as an experimental model, male wild-type FBV/N mice at the age of 2 and 18 months served as a control. We studied locomotor activity, orientational research behavior and the psychoemotional status of animals using the «open field¼ test and the Suok test. It was found that in old FBV/N mice, after the cytoflavin treatment, recovery of locomotor functions and orientational-research behavior is observed. Under conditions of HER2/neu overexpression after the Cytoflavin treatment, an improvement in motor functions occurs. It was also shown that the studied drug has an anxiolytic effect on both wild-type FBV/N mice and transgenic HER2/neu mice during aging. Thus, the positive effect of Cytoflavin on the dynamics of the behavior of experimental mice during physiological and pathological accelerated aging allow to suggest that in the late stages of ontogenesis, Cytoflavin restores the cerebral cortex functions and prevents neurodegeneration.

Evaluation of the Protective Effect of Ademetionine, Cytoflavin, and Dihydroquercetetine on Blood Enzymes Activity in Rats Treated with High Doses of Sodium Valproate.

We evaluated the protective effect of ademetionine, cytoflavin, and dihydroquercetin on activity of serum enzymes in rats treated with high doses of sodium valproate for 28 days. Ademetionine and cytoflavin produced the greatest protective effect, the effect of dihydroquercetin was less pronounced. In rats treated with ademetionine, AST activity decreased as soon as on day 7 and remained at this level until the end of the experiment; ALT, alkaline phosphatase, and γ-glutamyl transferase activities decreased on days 21 and 28 of the study. Cytoflavin produced similar effects, the effect of dihydroquercetin was observed on days 21 and 28 for AST, ALT, alkaline phosphatase and on day 28 for γ-glutamyl transferase. These results substantiate the use of hepatoprotective drugs in case of long-term treatment with anticonvulsants in patients with epilepsy.

[Substantiation of the drug «Cytoflavin¼ application and cognitive-behavioral therapy in complex treatment of deforming coxarthrosis in elderly patients.]

The article presents the results of a study of the effectiveness of the addition of a standard course of conservative therapy to 104 patients of the older age group with coxarthrosis deforming the drug «Cytoflavin¼ and cognitive-behavioral therapy courses. It was found that such scheme increases the effectiveness of therapeutic interventions, which manifests itself as the improvement of the mental and physical components of quality of life by reducing pain and increasing the functionality of some of the affected hip. At the heart of positive clinical effect is a decrease in processes of inflammation and reduction of tension of regulatory processes in the organism.

[Effects of cytoflavin on neuronal apoptotic processes in the murine cerebral cortex on a model of physiologicaland pathological aging]. / Vliianie tsitoflavina na protsessy apoptoza neironov kory golovnogo mozga u myshei na modeli fiziologicheskogo i patologicheskogo stareniia.

Involutional changes in the cerebral cortex substantially affect the activity of the cortex itself and the function of target organs. This necessitates pharmacological correction of age-related diseases, primarily a high level of cell death. OBJECTIVE: To investigate the role of cytoflavin in mechanisms for the apoptotic regulation of cerebral cortical cells during physiological and pathological aging (in the presence of HER-2/neu overexpression). MATERIAL AND METHODS: HER-2/neu transgenic mice were used; wild-type FVB/N mice served as controls. The levels of apoptosis (TUNEL) and the expression of its associated proteins (p53, CD95, Mcl-1, p-AKT, and p-ERK) (Western blotting) were estimated in the sensorimotor cortex. RESULTS: Activation of fundamental AKT and ERK survival pathways promotes a low level of cell death in young FVB/N mice; the extrinsic receptor mechanism of apoptosis is observed to be initiated by aging. The high p-AKT levels in the cortical cells provide suppressed cell death in transgenic mice regardless of their age. After cytoflavin administration, the old wild-type mice show a lower level of apoptosis in the cortical neurons apparently due to the increased expression of the anti-apoptotic protein Mcl-1, while the old transgenic mice exhibited suppression of the AKT and ERK survival pathways and, accordingly, activation of the extrinsic receptor and p53-dependent apoptosis pathways. CONCLUSION: Thus, cytoflavin exerts a pronounced neuroprotective effect during physiological and accelerated aging, while its effect on the level of neuronal apoptosis is ambiguous and depends on the genetic line of animals. So, this is a moderate stimulation of apoptosis when its level is low in HER-2/neu mice with a high level of carcinogenesis, as well as a decrease in the high level of apoptosis in old wild-type animals, which prevents neurodegeneration.

[The intraoperative prophylaxis of local ischemical brain damage in neurosurgical patients with cerebral aneurysm]. / Intraoperatsionnaia profilaktika lokal'nogo ishemicheskogo povrezhdeniia golovnogo mozga u neirokhirurgicheskikh patsientov s tserebral'noi anevrizmoi.

AIM: To study the effectiveness of intraoperative administration of Cytoflavine for the prevention of ischemic brain injury during cerebral aneurysm (CA) clipping with temporary occlusion of the leading artery under general anesthesia. MATERIAL AND METHODS: The prospective cohort single-center study included 40 patients with CA ( the main group - 27 patients with intraoperative administration of cytoflavine; the comparison group -13 patients without use of cytoflavine), who underwent aneurism clipping with temporary occlusion of the afferent artery. We assesed the intraoperative state of the brain, the time of awakening and extubation of patients after surgery, neurological deficit and local ischemic changes in the area of surgery according to the CT of the brain in the early postoperative period, resuscitation bed-day and the relationship of these indicators with the duration of temporary occlusion of the afferent artery in the selected groups of patients. RESULTS: In intergroup comparison, patients of the main group treated with intraoperative cytoflavin showed a reduction in the time of awakening (p=0.013) and the time of extubation (p=0.01) both with temporary occlusion of the afferent artery and in patients without temporary occlusion (p<0.05). The duration of resuscitation bed-day decreased in the main group of patients receiving intraoperatively cytoflavine (p=0.01), as well as in patients in the comparison group without temporary occlusion (p<0.05). CONCLUSION: Temporary occlusion of the afferent artery with short intervals of vessel occlusion in combination with intraoperative intravenous administration of cytoflavine expands the tolerability to artery occlusion in patients operated in the 'cold' period, reduces the possibility of neurological deficit, reduces the recovery period and resuscitation bed-day after surgical clipping CA.

[Investigation of markers for myocardial remodeling during experimental hypobaric hypoxia in the correction with cytoflavin]. / Issledovanie markerov remodelirovaniia miokarda pri éksperimental'noi gipobaricheskoi gipoksii na fone korrektsii preparatom tsitoflavin.

The limited possibilities of determining myocardial morphological changes in the clinic make it necessary to investigate the effects of intermittent hypobaric hypoxia in an experiment setting. OBJECTIVE: To reveal the peculiarities of changes in the markers of myocardial remodeling in experimental hypobaric hypoxia. MATERIAL AND METHODS: The investigation was conducted on 26 mature male Wistar rats weighing 220-310 g, which were divided into 3 groups: 1) 6 intact animals; 2) 10 rats that were exposed to 30-day simulated hypobaric hypoxia without correction; 3) 10 rats that were given once-daily intraperitoneal injections of cytoflavin solution at a rate of 0.5 ml/100 g of body weight for 30 days before immersion in a hypobaric chamber. RESULTS: The early stages of myocardial remodeling in hypobaric hypoxia were found to be characterized by structural re-systematization of the components of the normal ventricular wall, which was manifested by cardiomyocyte hypertrophy and ischemia; circulatory disorders; fibroblast proliferation that dramatically enhances the extracellular expression of protein matrix, which can lead to the formation of fibrous tissue and irreversible myocardial dysfunction. Elevated matrix metalloproteinase levels are evidence for collagen degradation and cardiac remodeling. In the authors' opinion, the cyto- and angioprotective effects of cytoflavin in rats treated with the latter used in combination therapy are associated with the composition of the drug, the active components of which have mutually potentiating effects, are inducers of the major metabolic pathways in the cells and are also activators of key energy-generating processes. CONCLUSION: Identification of the molecular mechanisms of myocardial remodeling is of great practical importance. This enables remodeling markers to be considered as a potential therapeutic target in the treatment of hypoxia-induced myocardial injury.

[Prevention of cognitive dysfunction in elderly cancer patients operated on the pelvic organs in conditions of multimodal anesthesia]. / Profilaktika kognitivnoi disfunktsii u pozhilykh onkologicheskikh bol'nykh, operirovannykh na organakh malogo taza v usloviiakh mul'timodal'noi anestezii.

The aim of the study was to evaluate the impact of various variants of multimodal anesthesia on the cognitive functions of elderly patients after surgical interventions on pelvic organs, the development of preventive measures for POCD. MATERIAL AND METHODS: A study was conducted in 76 elderly patients aged 62 to 84 years with an increased risk of developing POCD. Of these, 46 women and 30 men. Patients were divided into two groups, depending on the type of anesthesia. The 1st group consisted of 37 patients who had low-flow anesthesia with sevoflurane combined with epidural analgesia. 2nd - 39 patients who had anticipated multimodal analgesia on the basis of systemic administration of lidocaine, sulphate magnesia, verapamil. In each group, patients are divided into subgroups - the main (O) and control (K). In the main subgroups anesthetics were supplemented with 20 ml. Cytoflavin, administered 20-25 minutes before the end of surgery and on the 1-3 days of the perioperative period. Cognitive functions were assessed by standardized scales: Mini Mental State Examination (MMSE), Montreal Cognitive Evaluation Scale (MoCA), Frontal Assessment Batteries (FAB). The level of anxiety and depression was determined by the hospital scale of anxiety and depression (HADS). RESULTS: At oncological patients of advanced age in 52.5% of cases there is a moderate degree of cognitive impairment. In the perioperative period, in the study groups, when using different variants of multimodal anesthesia, there is an equivalent transient decrease in cognitive functions by 12.5 and 12.8%. The use of cytoflavin can reduce the manifestation of POCD from 1-day perioperative period, improve the cognitive status of patients. CONCLUSION: In cancer patients of advanced age, cognitive impairment is observed, aggravated after surgical treatment, regardless of the variant of multimodal anesthesia. Protection by Cytoflavin allows to restore the cognitive functions of elderly cancer patients, reduce the manifestations of POCD.

[Evaluation of bio-inverse communication and Cytoflavin effects on the dynamics of the clinical and psychophysiological condition of elderly patients with osteochondrosis].

We conducted a study of 150 patients on the basis of polyclinic № 91 in St. Petersburg. The effect of Cytoflavin and bio-inverse communication therapy on the dynamics of the condition of elderly patients with osteochondrosis was evaluated. A number of positive effects from such an addition to existing therapy, potentiating the nominal effect, were revealed.

[STRESS-PROTECTIVE EFFECT OF CYTOFLAVIN ON CHRONIC CEREBRAL ISCHEMIA IN RATS.]

Analysis of stress-releasing blood reactions (electrophoretic mobility of red blood cells, WBC count, and leukocyte ratio) in rats with experimental cerebral ischernia under the action of cytoflavin held showed that cytoflavin in combination with basic therapy leads to further activation of compensatory-adaptive reactions of the body and stimulated peripheral stress-limiting mechanisms.

[EFFECT OF CITOFLAVIN ON THE PARAMETERS OF LIPID PEROXIDATION IN BLOOD PLASMA OF RATS UNDER COLD STRESS CONDITIONS.]

The possibility of correcting free radical oxidation of lipid membranes by the administration of cytoflavin was experimentally studied in rats. It is established that daily cold exposure for 3 h leads to increase in the level of lipid hydroperoxides, diene conjugates, and malonic dialdehyde on the background of decrease in activity of the antioxidant system in the blood of experimental animals. The introduction of cytoflavin (100 mg/kg, i.p.) for 21 day immediately prior to cold exposure leads to reliable (p < 0.05) decrease in the blood level of lipid hydroperoxides (by 13 - 21%), diene conjugates (by 24 - 25%), and malonic dialdehyde (by 20 - 33%) in comparison to rats of the control group. Analysis of the effect of cytoflavin on activity of the antioxidant system components showed that the level of ceruloplasmin and vitamin E in the blood of animals was reliably (p < 0.05) higher by 10 - 33% than analogous indicator in rats of the control group. Thus, the application of cytoflavin under conditions of long-term influence of cold on the organism of animals leads to stabilization of the processes of lipid peroxidation on the background of increased activity of the blood antioxidant system.

[MORPHOLOGICAL CHANGES IN RAT MYOCARDIUM EXPOSED TO HEMIC HYPOXIA AND TREATED WITH CYTOFLAVIN.]

This study was aimed at determining the influence of cytoflavin on the morphological features of contractile cardiomyocytes in female rats after gestation and in newborn rats exposed to hemic hypoxia induced by sodium nitrite (NaNO(2)). The experiment was performed on 28 three-month-old female Wistar albino rats and their offspring (24 seven-day-old newborns). Throughout pregnancy and during 7 days of suckling period, all animals divided into two groups were daily injected intraperitoneally with NaNO(2) at a dose of 5 mg/100 g body weight. Animals in the second test group were additionally injected intraperitoneally with. cytoflavin at a dose of 0.5 mL/100 g body weight. It was found that hemid hypoxia had a strong pathogenic effect on the contractile cardiomyocytes and hemomicrocirculatory bed vessels, which was manifested by the hypoxic and ischernic damage involving violation of the integrity of cellular and mitochondrial membranes. Histological and morphometric studies in animals of the first group showed a significant decrease in the length and area of contractile cardiomyocytes: up to 16.9 and 36.04%, respectively (p = 0.05). In the second group of animals (treated with cytoflavin), these changes were less pronounced: reduction in length and area on the average was 8.2 and 18.6%, respectively (p = 0.05). The administration of cytoflavin reduces the degree of cardiomyocyte damage in female rats after gestation and in newborns, presumably due to the antioxidant and membrane-protective properties of this drug.

[PHARMACOLOGICAL CORRECTION OF APOPTOSIS LEVEL OF CORTICAL NEURONS IN AGED HER2/NEU TRANSGENIC MICE].

Neurodegenerative changes and neuronal death are the basis for development of the nervous system aging. We investigated the mechanism of apoptosis of the sensorimotor cortex neurons of transgenic mice HER2/neu during aging, changes in the cortex function and the participation of exogenous neurometabolites (cytoflavin, piracetam) in regulation of neuronal death and locomotor and psycho-emotional status of mice. The level of apoptosis and expression of apoptosis markers (TUNEL, immunohistochemistry, Western blotting) in HER2/neu transgenic mice as compared to wild type mice (FBV line) were determined. In aging FBV mice the basal activity was shown to decrease and anxiety to increase correlating with the high level of neuronal apoptosis. We identified behavioral characteristics of transgenic HER2/neu mice and found that their low basal activity does not change with aging. Previously we have shown that in this strain of mice the apoptosis level is low, without any age-related changes, due to the suppression, first of all, of the p53-dependent pathway by HER2 (tyrosine kinase receptor) overexpression. Cytoflavin and piracetam were revealed to possess a marked neuroprotective effect, preserving and restoring functions of the nervous system (improving locomotion and psychological status) in both strains of mice. The effect of neurometabolites studied on neuronal apoptosis is ambiguous. In case of its low level it is a moderate stumulation of apoptosis via the external p53-dependent pathways with activation of caspase-3 in transgenic HER2/neu mice with high carcinogenesis level that can possibly prevent tumor development. On the contrary, in old wild-type animals we observed a significant decrease of age-dependent apoptosis level (by stimulating expression of the anti-apoptotic protein Mcl-1), which prevents neurodegeneration.

[Effect of cytoflavin on the clinical and autonomic-psychological manifestations of hypertensive disease].

AIM: To evaluate the impact of incorporating cytoflavin in a treatment regimen for patients with different stages of hypertensive disease (HD). SUBJECTS AND METHODS: The results of treatment were analyzed in 140 patients with HD (53 with Stage I, 50 with Stage II, and 37 with Stage III). According to the treatment regimen, the patients were divided into 2 groups. A study group (n=74) received combination treatment involving antihypertensive therapy and cytoflavin intravenously dropwisely in a single dose of 200 ml of 5% glucose solution for 10 days, then 2 tablets twice daily for 60 days, with a total cycle time being 70 days. A comparison group (n=66) had antihypertensive therapy only. Thirty apparently healthy individuals (a control group) were examined to have reference values. All the patients were examined using conventional clinical and laboratory studies. The patients' complaints and neurological status were assessed using respective questionnaires over time - before and after treatment. RESULTS: The incorporation of cytoflavin in a treatment regimen was ascertained to reduce the degree of anxiety, depressive, dissomnic, and cognitive disorders, improves quality of life in patients with Stage I HD, and lowers the degree of asthenic and autonomic disorders in all disease stages. CONCLUSION: The found efficacy and safety of the drug may recommend its incorporation in combination therapy regimens for Stages I-III HD.

Cardio and cytoprotective effect of cytoflavin in terms of experimental perinatal hemic hypoxia.

The purpose: The purpose of research is to study cardiocytoprotective effect of cytoflavin in terms of aperinatal hypoxia in experiment. Methods: During research the offspring (22 pups) of 15 females of white Wistar line rats aged 3-4 months were involved. The hypoxia was recreated by daily intraperitoneal introduction of sodium nitrite (NaNO2) in a dose of 5 mg/100 g of the body weight causing a moderately severe hypoxia. To females of the first group, and also their posterity medicamental correction wasn't carried out. To females of the second group (8 females) after administration of sodium nitrite Cytoflavin was injected intraperitoneally. For an assessment of consequences of a perinatal hypoxia pups aged 7 days were slaughtered by means of a fast decapitation under ethereal anesthesia. Results: It is taped that the hypoxia induced by nitrobonds has the expressed damaging effect on cardiomyocytes of newborn infant rats which is shown in the form of the hypoxemic and ischemic changes caused, first of all, by disturbance of integrity of cellular and mitochondrial membranes causes formation of hypoxemic type of a metabolism in a cardiac muscle, disturbance of energy balance in it found reflection in disturbance of automatism of a myocardium of experimental animals. Cytoflavin at pregnant females in experiment allows to lower a damage rate of cardiomyocytes at newborn animals, first of all, at the expense of his protective properties. Conclusion: Membrane-protective properties of the drug along with its anti-hypoxic and antioxidant effects can put Cytoflavin in a number of promising drugs with cardiological and cytological protective action, leading to the optimization of energy metabolism in ischemic myocardium and allows it to take its rightful place among the modern drugs which are used to correct disorders of energy metabolism in the ischemic myocardium including pathologies in the neonatal period.

[Comparative experimental study of the influence of drugs that improve brain metabolism (angiogen, cytoflavin) on neuronal apoptosis and function of cerebral cortex during aging].

The safety of cortical neurons and their functional activity is essential for organism at all stages of ontogenesis. However, aging changes leading to an increase in apoptosis level may cause considerable damage to cerebral cortex function, including sensorimotor. We have studied the role of exogenous neurometabolites (angiogen, cytoflavin) in apoptosis regulation and correction of age-related motor and behavioral disturbances. To study the regulation of neuronal morphofunctional activity, we used accelerate-senescent transgenic HER2 mice in comparison to wild type FBV mice. Functional changes in cerebral cortex were studied by the Suok test and open field test, the level of neuronal apoptosis was assessed by TUNEL method, the expression of apoptosis-modulating proteins was detected by immunohistochemistry and Western blotting. We have revealed differences in psycho-emotional and locomotor activity of these strains of mice. In addition, results of our study showed morphological differences: increase in the apoptosis level of cortical neurons in aged FBV type mice, but no changes in aged HER2 mice. The investigated drugs induce cell death of cortical neurons in transgenic mice of both ages and in young wild-type mice by p53-dependent pathway. Increased apoptosis in the cortex of old transgenic mice has important clinical implications, because reduced apoptosis during aging is one of the causes of cancer. The treatment of old wild-type animals reduces elevated neuronal apoptosis, which decreases risk of age neurodegeneration. Thus, revealed morphological changes in the cerebral cortex are the basis for involutional disabilities (including reduced locomotor activity and increased anxiety level). The use of angiogen and cytoflavin treatment improves functional activity of the cortex and protects normal structure of nervous tissue.

[THE PHARMACOTHERAPEUTIC EFFICIENCY OF CYTOFLAVIN IN PATIENTS WITH DIABETIC FOOT SYNDROME: IMMEDIATE AND LONG-TERM RESULTS].

Immediate and long-term results of parenteral and oral administration of cytoflavin to patients with diabetic foot complicated by grade I and II trophic ulcers (Wagner classification) are considered with special reference to the assessment of reparative processes, normalization of the serum pro oxidant-antioxidant system, and improvement of clinical and instrumental bloodflow characteristics.

[The study of the effectiveness of drug prevention mechanisms of cardiovascular aging by cytoflavin].

The aim of the research was the search of the mechanism of Cytoflavin action in patients with isolated systolic arterial hypertension (ISAH) as the aging model. The following research methods were applied: the assessment of complaints, 24-hour arterial pressure monitoring, ultrasound diagnostic, volume sphygmography, lipid profiles and coagulogram, molecular phenotyping by MALDI-TOF-TOF-MS. The combination of Cytoflavin with standard therapy of ISAH led to the most expressed return development of clinical symptoms, the restoration of the haemodynamics, structural and geometrical parameters of cardiovascular system, indicators lipid profiles and coagulogram in the comparison with patients with ISAH, who accepted standard therapy and those of the control groups. Molecular mechanisms of Cytoflavin action, including regulation of the activity of cell signaling pathways through intermolecular interactions were found. We recommend using Cytoflavin together with the standard therapy in treatment of ISAH, which provides the action of geroprotectors for cardiovascular system.

[The influence of cytoflavin and cardioxipin on the indices of lipid peroxidation and antioxidant protection in the blood of rat with dyslipidemia].

Comparative tests on nonlinear rats of both sex with model violation of lipid metabolism have been performed in order to study the effects of cytoflavin (1.75 ml/kg or 175 mg/kg with respect to succinic acid) and cardioxipin (52.5 mg/kg) on lipid peroxidation and antioxidant protection indices in the blood. It is established that these preparations cause a decrease in the content of malonic dialdehyde (MDA) in erythrocytes that results in increased antioxidant activity and lipid reserves for peroxidation in the blood.

[Cytoflavin® effect on endothelium function and cerebral hemodynamics in patients with hypertensive enceplalopathy].

One hundred forty patients (the average age of 46.7 ± 7.7 years) with hypertensive encephalopathy (HE) were observed. 74 patients of the main group received Cytoflavin in a dose of 2 tablets twise a day in the standard basic therapy. 66 patients of the reference group received the basic therapy alone. The arterial endothelium function was estimated and ultrasonic examination of the hemodynamics at five structurally functional levels of the cerebral vascular course was used. All the patients with HE had endothelial dysfunction, bloodstream depression in the arterial course of the brain vascular system, decreased reactivity of the intracranial veins, difficulty in venous outflow. In the course of the therapy with Cytoflavin restotation of the arterial endothelial function in the patients with HE I stage, the linear and volume speed of bloodstream in the main and intracranial cerebral arteries in the patients with HE I-II stages, restoration of the intracranial veins reactivity, the linear speed of bloodstream in intracranial veins in the patients with all three stages of HE, the linear speed of bloodstream in the main veins up to the control values in the patients with I-III stages of HE were observed. Interrelation between the values of the cerebral hemodynamics and the state of the endothelium function was shown.

[Protective effect of cytoflavin and its components in mice with acute alloxan intoxication].

We have studied the protective effect of cytoflavin and its components (meglumine sodium succinate, riboflavin, inosine and nicotinamide) in mice with acute alloxan intoxication. It is established that cytoflavin and its components possessing in vitro antioxidant activity (riboflavin, inosine and nicotinamide) significantly decrease the hyperglycemic effect of alloxan. The protective effect of cytoflavin in animals with behavioral disorders caused by acute alloxan intoxication is related to the effect of meglumine sodium succinate and inosine, but does not depend on the influence of these substances on free-radical oxidation processes.