Investigation of Cochlospermum religiosum leaves for antidepressant and anxiolytic activities and its synergistic effect with imipramine and fluoxetine.

The present study was conducted to evaluate the effect of Cochlospermum religiosum (CSR) in animal models of depression and anxiety. The CSR leaves are well known for their sedative, antibacterial, antifungal antioxidant, memory enhancing, anxiolytic and antidepressant potential. In present study, the extract of the leaves is used to relieve the anxiolytic and antidepressant potential. The leaves of CSR were investigated for antidepressant and anxiolytic activities in mice behavioural models namely, spontaneous locomotor activity (SLA), forced swim test (FST), tail suspension test (TST), elevated plus maze (EPM) and marble burying behaviour (MBB). The mechanism was supported by reserpine-induced hypothermia (RIH). Further, the in vivo synergistic evaluation of the CSR leaf extract was evaluated with imipramine and fluoxetine. The treatment of mice with ethanolic extract of CSR leaves for 7 days resulted significant antidepressant and anxiolytic effects (p < 0.05 for 50 mg/Kg p.o / p < 0.01 for 100 mg/kg p.o) with null impact on baseline locomotor activity. Further, the study on rat RIH model revealed that the CSR (50 mg/kg p.o) predominantly antagonized the effect (p < 0.05) of reserpine. Furthermore, synergic action was screened by co-administration of leaf extracts of CSR with fluoxetine (10 mg/Kg, i.p.) and imipramine (10 mg/Kg, i.p.) at below therapeutic dose levels using FST, TST, EPM and MBB. The synergistic effect was significant (p < 0.05) for both antidepressant and anxiolytic activities as compared to therapeutic doses of extract, imipramine and fluoxetine.

Liver mitochondrial respiratory function and coenzyme Q content in rats on a hypercholesterolemic diet treated with atorvastatin.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are effective drugs in the treatment of hypercholesterolemia, however, their undesirable actions are not fully known. We investigated the effects of atorvastatin on the oxidative phosphorylation and membrane fluidity in liver mitochondria, and also on the coenzyme Q (CoQ) content in the mitochondria, liver tissue, and plasma of rats on a standard (C) and hypercholesterolemic (HCh) diet. Atorvastatin was administered at either low (10 mg kg(-1)) or high dose (80 mg kg(-1)) for four weeks. The high dose of the drug decreased the concentrations of total cholesterol and triacylglycerols in the plasma and liver of rats on a HCh diet. Administration of atorvastatin was associated with decreased oxygen uptake (state 3), and oxidative phosphorylation rate in the mitochondria of both C and HCh rats. Further, the drug influenced mitochondrial membrane fluidity and dose-dependently reduced concentrations of oxidized and reduced forms of CoQ in the mitochondria. Our findings point to an association between in vivo administration of atorvastatin and impaired bioenergetics in the liver mitochondria of rats, regardless of diet, in conjunction with simultaneous depletion of oxidized and reduced CoQ forms from the mitochondria. This fact may play a significant role in the development of statin-induced hepatopathy.

Effects of atorvastatin on heart mitochondrial function and coenzyme Q content in the experiment.

We focused on determination of whether atorvastatin: 1) reduces CoQ content, 2) impairs mitochondrial function and 3) induces dose-dependent changes. Although the high dose of atorvastatin exerted a beneficial effect on the lipid peroxidation in plasma, coenzyme Q content was reduced and heart mitochondrial function was impaired. Physicians should be aware when prescribing statins mainly in higher doses to the patients with co-existing proved or supposed CoQ10 deficiency resulting from age-related decline, and metabolic or mitochondrial diseases (Ref. 3).

Plasma melatonin concentrations in hypertensive patients with the dipping and non-dipping blood pressure profile.

Some patients with hypertension exhibit disturbed circadian organization in the cardiovascular system. Hormone melatonin can synchronize circadian rhythms and its repeated administration can improve synchronization of rhythmicity in blood pressure (BP). In our study we measured endogenous melatonin production in patients with essential hypertension exhibiting a dipping and non-dipping BP profile. Blood pressure was monitored for at least 24-hr with an automatic ambulatory BP monitor and patients with no decline in BP were classified as non-dippers. Plasma melatonin was measured in the middle of the daytime and night-time by radioimmunoassay. As expected night-time systolic (P <0.05), diastolic (P <0.001) and mean arterial (P <0.001) BP was higher in non-dippers than in dippers. No significant difference was found between both groups in BP during the day. Mean melatonin concentrations were higher during the night than during the day in both dippers and non-dippers. When patients were divided into dippers and non-dippers on the basis of mean arterial or diastolic BP a lower ratio of night/day concentration was determined in non-dippers than in dippers. Our study showed a blunted night/day difference in plasma melatonin concentrations in hypertensive patients with the non-dipping profile in diastolic BP indicating disturbances in the circadian system of these patients.

Trimetazidine in geriatric patients with stable angina pectoris: the tiger study.

This study aims to assess the efficacy and tolerance of the metabolic antianginal agent trimetazidine, a 3-KAT inhibitor, in 141 stable angina patients aged 65-86 years. Efficacy was assessed with exercise tests and clinical evaluation after 12 weeks of treatment. The main outcome was an increase in exercise duration by 52 +/- 92 sec (p < 0.001). Other exercise test parameters also improved, with no change in rate-pressure product. Angina attacks and short-acting nitrate consumption significantly decreased, indicating an improvement in quality of life. Two adverse events were reported (gastric pain and dyspepsia) but they were mild and transient. In conclusion, in elderly stable angina patients, trimetazidine improves exercise stress tests and angina symptoms. Because of its metabolic effect, free from any haemodynamic action, trimetazidine proved to be beneficial in elderly patients and with an excellent tolerance profile.

[The significance of aldosterone in chronic heart failure: the RALES study]. / Význam aldosterónu pri chronickom zlyhaní srdca: stúdia RALES.

Reduction of excessive neurohumoral activation in chronic heart failure (CHF) improves the prognoses. In addition to reduction of angiotensin production or angiotensin II action and the influence of the sympathoadrenal system also blocking of aldosterone effects becomes part of the therapeutic procedure in patients with CHF. Excessive systemic and probably also local aldosterone production promotes undesirable fluid retention, hypokalaemia and hypomagnesaemia, induction of hypertrophy and fibrosis of the heart muscle and blood vessels and the development of endothelial dysfunction, peripheral vasoconstriction and depression of the baroreflex. In addition to classical effects also the existence of a rapid, so-called non-genomic effect of aldosterone is assumed. Adding a blocker of aldosterone receptors to ACE inhibition was not recommended due to possibility development of hyperkalaemia. Later it was revealed that ACE inhibitors are unable to block sufficiently the action of aldosterone and that addition of spironolactone in small amounts to ACE inhibition and diuretics does not cause in patients with CHF a major increase of the potassium level. In the RALES study (Randomized Aldacton Evaluation Study) comprising 1663 patients with serious heart failure (NYHA III, IV) addition of 25 mg spironolactone to standard treatment with ACE inhibitor, diuretic and as rule also digoxin reduced the mortality by another 30% as compared with the addition of placebo. Undesirable effects were minimal. As to potential protective mechanisms of spironolactone the greatest importance is ascribed to the reduction of excessive fibrosis of the heart muscle. Spironolactone reduces the level of the circulating N-terminal aminopeptide procollagen type III the high level of which is associated with deterioration of the prognosis.

[The effect of streptozotocin-induced diabetes in the neonatal period on hepatic mitochondrial bioenergetics in adult rats]. / Vplyv streptozotocínového diabetu vyvolaného v neonatálnom období na bioenergetiku mitochondrií pecene dospelých potkanov.

BACKGROUND: Previous experimental studies focused on the liver mitochondrial bioenergetic changes in diabetes mellitus type I induced in adult animals. Information about the effects of persisting neonataly induced diabetes mellitus type I on the mitochondrial bioenergetics are missing. AIM: The aim of the study was to assess the degree of diabetes mellitus compensation and parameters of oxidative phosphorylation in rats aged 3 months with DM persisting from neonatal period. METHODS: DM was induced in male Wistar rats by repeated intraperitoneal administration of streptozotocine 45 mg/kg on 2nd and 9th day after birth. The concentrations of glucose, glycosylated haemoglobin, fructosamine were detected in the blood and the concentration of cholesterol and triacylglycerols in the blood and liver tissue, respectively. After mitochondria isolation from the liver we measured parameters of oxidative phosphorylation by polarography using Clark oxygen electrode. RESULTS: In the group of neonataly induced DM the concentration of glucose (23.10 +/- 1.55 vs 8.3 +/- 0.56 mmol/l), glycosylated haemoglobin (6.04 +/- 1.17 vs 3.99 +/- 0.44%) and blood cholesterol concentration (2.15 +/- 0.11 vs 1.83 +/- 0.09 mmol/l) increased significantly (p < 0.001 and p < 0.005 for cholesterol) comparing to a group of healthy rats. No statistically significant differences were found in the remaining parameters when comparing these two groups. The parameters of oxidative phosphorylation were significantly (p < 0.001) decreased in the group with DM comparing to control group of healthy animals--the index of respiratory control (4.87 +/- 0.25 vs 9.57 +/- 0.34), the rate of oxygen consumption in the stage 3 in ADP presence (88.61 +/- 4.62 vs 165.08 +/- 4.5 natO.mg/protein/min) and phosphorylation rate (203.54 +/- 7.26 vs 332.87 +/- 7.39 nmolATP.mg/protein/min) with NAD substrate glutamate. Similar trend was also seen with FAD substrate succinate. The index of oxidative phosphorylation ADP:0 was not changed in both groups. CONCLUSIONS: In 3 months old rats with neonataly induced DM the development of steatosis was not observed and uncoupling of oxidative processes from phosphorylation did not appear. Energy production was sufficient enough for normal functions of the liver and to ensure all needs of the organism. (Tab. 4, Ref. 51.)

[Secondary prevention in patients after a myocardial infarct]. / Moznosti sekundárnej prevencie u pacientov po prekonanom infarkte myokardu.

The confirmation of ischaemic disease of the heart increases the probability of death due to cardiovascular causes to more than 80%. The overcoming of myocardial infarction increases, according to the past AHA data, the risk of the origin of a new coronary episode 5 or 7-fold. The necessity of decreasing this risk in the frame of secondary prevention is therefore very urgent. The first assumption of success in secondary prevention resides in optimal therapy in the acute phase of myocardial infarction. The thrombolytic therapy is accompanied by risks of re-perfusion lesion implying from the increased production of free oxygen radicals, activation of leukocytes, intracellular calcium overload at a current deficit in potassium and magnesium, the defects of coronary microcirculation, increased sympathetic activities, general disturbances of energetic reserves in myocardium. Very significant is an early stratification of patients after MI to those indicated to intervention/in case that the mass of ischaemic myocardium exceeds 20%, or if EF is below 40%, and to patients who regarding the low risk are manageable by conservative procedure. Both groups profit from the modification of classical risk factors (hypertension, smoking, hypercholesterolaemia). The values of cholesterol measured within the acute phase of myocardial infarction are not indicative, very often they are low. Finally, also in the later period with so-called adequate values of the total cholesterol, the patient after overcoming IM is increasingly under threat. The aim of secondary prevention is to reduce the chief pathogen, namely LDL cholesterol below 2.6 mmol/l, the level of HDL cholesterol on the opposite should be above 1.0 mmol/l. It is necessary to re-emphasize that the bioactive capacity is borne but by the oxidated form of LDL. Oxidative stress has a direct negative effect on vascular endothelium, and haemocoagulation potential, it participates in the metabolic X syndrome (insulin resistance, hyperinsulinaemia, defects in glucose tolerance, hypertriglyceridaemia, hypertension). (Ref. 41.)

Moznosti sekundarnej prevencie u pacientov po prekonanom infarkte myokardu.

The confirmation of ischaemic disease of the heart increases the probability of death due to cardiovascular causes to more than 80%. The overcoming of myocardial infarction increases, according to the past AHA data, the risk of the origin of a new coronary episode 5 or 7 fold. The necessity of decreasing this risk in the frame of secondary prevention is therefore very urgent. The first assumption of success in secondary prevention resides in optimal therapy in the acute phase of myocardial infarction. The thrombolytic therapy is accompanied by risks of re-perfusion lesion implying from the increased production of free oxygen radical, activation of leukocytes, intracellular calcium overload at a current deficit in potassium and magnesium, the defects of coronary microcirculation, increased sympathetic activities general disturbances of energetic reserves in myocardium. Very significantly is an early stratification of patients after MI to those indicated to intervention / in case that the mass of ischaemic myocardium exceeds 20%, or if EF is below 40%, and to patients who regarding the low risk are manageable by conservative procedure. Both groups profit from the modification of classical risk factors (hypertension, smoking, hypercholesterolaemia). The values of cholesterol measured within the acute phase of myocardial infarction are not indicative, very often they are low. Finally, also in the later period with so-called adequate values of the total cholesterol, the patient after overcoming IM is increasingly under threat. The aim of secondary prevention is to reduce the chief pathogen, namely LDL cholesterol below 2.6 mmol/l, the level of HDL cholesterol on the opposite should be above 1.0 mmol/l. It is necessary to re-emphasize that the bioactive capacity is borne but by the oxidated form of LDL. Oxidative stress has a direct negative effect on vascular endothelium, and haemocoagulation potential, it participates in the metabolic X syndrome (insulin resistance, hyperinsulinaemia, defects in glucose tolerance, hypertriglyceridaemia, hypertension). (Ref. 41.)

[Trends in alcohol consumption in relation to liver diseases in Slovakia 1973-1994]. / Vývoj spotreby alkoholu vo vztahu k ochoreniam pecene na Slovensku v rokoch 1973-1994.

The World Health Organisation warns before the increase in alcohol consumption and the proportional increase in ethyltoxic diseases which have taken place in past decades. Slovakia is included into the countries with the highest consumption of alcohol in Europe. The authors present a retrospective analysis of alcohol consumption from 1973 to 1994 in Slovakia according to the kinds of alcohol beverages, in a selected district and according to profession and family status. The epidemiologic analysis of the situation of alcohol consumption that is currently present in Slovakia is based on the data from wholesale and retail sale in relation to the prevalence and the mortality due to hepatic cirrhosis. The presented data was investigated by the Slovak Statistical Institute and the Institute of Medical Statistics of the Slovak Republic. Mortality due to hepatic cirrhosis has increased during the past 40 years 10-fold in men, and 4-fold in women. A severely increasing trend in alcohol consumption which had taken place prior to 1990 was succeeded by an abrupt decrease in pure alcohol consumption after 1990 (as much as by 21.2%). This decrease corresponds with the proportional decrease in the prevalence of chronic hepatopathies (by 35%) and with the decrease in mortality due to hepatic cirrhosis (by 20%). This phenomenon may be explained by the proportional increase in prices of alcoholic beverages. According to average yearly consumption of pure alcohol (p.a.) per capita, the consumption of spirits dominates when compared with the consumption of beer and wine. It is desirable to continue in the begun decreasing trend in alcohol consumption which is crucial in the procurement of primary, secondary as well as of tertiary preventions on both individual and population levels. (Tab. 1, Fig. 6, Ref. 19.)

Effect of captopril on the development of left ventricular hypertrophy in rabbits with aortic insufficiency.

We investigated the effect of captopril on the growth of the left ventricle in an experimental model of aortic insufficiency. Four groups of rabbits were studied 28 days after experimental intervention: 1. control, 2. control with captopril (10 mg/kg/day), 3. aortic insufficiency, 4. aortic insufficiency with captopril (10 mg/kg/day). Aortic insufficiency induced hypertrophic growth of the left ventricle demonstrated by increased weight and ribonucleic acid (RNA) concentration. Administration of captopril only slightly attenuated the weight increase of the left ventricle and the increase in concentration of left ventricular RNA. However, captopril reduced the concentration of left ventricular deoxyribonucleic acid (DNA) both in the control and even more in the group with aortic insufficiency. The chronic haemodynamic overload enhanced mitochondrial respiration in the left ventricle which was not influenced by captopril. We conclude that captopril in the dose 10 mg/kg/day did not prevent hypertrophy of the left ventricle but reduced left ventricular DNA concentration.

[The cytoprotective effect of magnesium in global myocardial ischemia]. / Cytoprotectívny úcinok magnézia v podmienkach globálnej ischémie myokardu.

BACKGROUND: Administration of magnesium in the therapy of ischaemic heart diseases does not belong to the standard procedures. The results of clinical trials with application of this cation are mutually contradictive, mechanisms of its effect are not solved yet. Many physicians consider magnesium to represent a classical placebo, or an uncertain light sedative. MAIN PURPOSE AND OBJECTIVES: The study is aimed at proving the direct effect of magnesium on the heart muscle under ischaemic conditions which exclude the placebo effects. These conditions are mostly fulfilled by the model of isolated heart. MATERIAL AND METHODS: The authors used isolated rabbit hearts according to Langedorff with Krebs-Henseleit (KH) perfusion solution, the only variable of which is represented by concentration of magnesium. The following groups of patients were formed: 1. Control group-30-minute perfusion with normal Mg concentration (0.5 mmol/l) in KH solution. 2. Hypomagnesemia-30-minute perfusion with KH solution Mg-free. 3. Normomagnesemia+ischaemia-30-minute perfusion with normal concentration succeeded by a 60-minute global ischaemia. 4. Hypomagnesiaemia+ischaemia-30-minute perfusion with KH solution magnesium-free succeeded by a 60-minute global ischaemia. 5. Hypermagnesiemia +ischaemia-30-minute perfusion with increased Mg concentration in KH solution to 2.0 mmol/l succeeded by a 60-minute global ischaemia. The investigated parameters: after completion of perfusion the authors isolated mitochondria and evaluated individual parameters of oxidative phosphorylation by means of oxygraph/Gilson/with Clark's oxygen electrode. The calcium uptake by mitochondria was observed by means of calcium-sensitive electrode Orion (oxygraph Gilson). The formation of free oxygen radicals was observed indirectly by spectrophotometric assessment of malondialdehyde production. Concentration of mitochondrial nucleotides (AMP, ADP, ATP) was assessed by using HPLC. RESULTS: Hypomagnesemia lasting 30 minutes had a negative effect on the index of oxidative phosphorylation (ADP:O p < 0.005) the uptake of calcium (p < 0.002), ATP concentration in mitochondrial ATP (p < 0.05) and the production of free radicals significantly increased (p < 0.001). Normomagnesemia indicated practically no cytoprotective effect before global ischaemia of myocardium lasting for 60 minutes. Hypermagnesemia indicated a direct cytoprotective effect before global ischaemia affecting respiration of isolated heart mitochondria in state of S3 (p < 0.001), respiration control index RCI (p < 0.001), the rate of oxidative phosphorylation OPR (p < 0.001) and on the index of oxidative phosphorylation ADP:O (p < 0.05) on the uptake of calcium by mitochondria (p < 0.002) and on concentration of mitochondrial nucleotides ATP (p < 0.002). It was remarkable that also under conditions of moderate hypomagnesemia the production of malondialdehyde increased. CONCLUSIONS: Under our experimental conditions it was confirmed that magnesium yields direct cytoprotective effect on the subcellular level of the myocardium prior to global ischaemia, providing the process takes place under the condition of hypermagnesemia. (Tab. 1, Fig. 12, Ref. 45.) Key words: hypomagnesemia, normomagnesemia, hypermagnesemia, Langendorff's global ischaemia, mitochondrial metabolism, cytoprotective effect.

[Cardiomyopathies from the aspect of clinical and experimental cardiology]. / Problematika kardiomyopatií z hladiska klinickej a experimentálnej kardiológie.

The study represents a summary of the latest experience, definitions, classification and diagnostics in cardiomyopathologic diseases. The main attention is drawn to the pathogenesis of cardiomyopathies, especially regarding the metabolic disturbances of the cardiac muscle on the mitochondrial level: the disturbances of oxidative and related energetic processes which the authors have registered in coincidence with the cardiomyopathological alcohol and smoking experimental model. The conclusion includes a notice about the prospective possibility for human cardiology to study these metabolic disturbances in endomyocardial biopsies in order to assess the diagnosis in early thus still reversible stages.

[The effect of an alpha-tocopherol analog, MDL 73404, on myocardial bioenergetics]. / Vplyv analógu alfatokoferolu MDL 73,404 na bioenergetiku myokardu.

The authors investigated the effect of the synthetic analogue of MDL 73,404 alpha-tocopherol on bioenergetic processes of the cardiac muscle in a control group of rats. After a 10-day application of the presented preparation they analyzed the following parameters of energetic metabolism: ATP, ADP, AMP and inorganic phosphorus. Beside these, the authors investigate the levels of main indicators of the purine metabolism (xanthine, hypoxanthine, inosine and uric acid) in the myocardium. Under the influence of the given analogue of alpha-tocopherol a significant increase in ATP, ADP and hypoxanthine took place in the myocardium. Also the total concentration of adenine nucleotide and relative ATP/ADP ratio increased in the cardiac muscle. On the basis of the gained results the authors came to a conclusion that the synthetic analogue of alpha-tocopherol MDL 73,404 has a favourable effect on the bioenergetic conditions in the myocardium. MDL 73,404 has a favourable cardioprotective effect on the cardiac muscle assumedly by means of stabilization of mitochondrial membranes on the myocardium with a subsequent impact on cellular ATP concentration.

[Cardiomyopathies and myocarditis]. / Kardiomyopatie a myokarditídy.

The authors discuss recent findings regarding cardiomyopathies, assembled recently due to the association of clinical and experimental cardiology. The main attention is paid to the pathogenesis of cardiomyopathies from the aspect of metabolic disorders of the heart muscle at the cellular and subcellular level. The differential diagnosis in relation to myocarditis is still a serious problem in cardiology: acute myocarditis is not a myocardiopathy, there exists, however, a close relationship between viral myocarditis and the development of dilatation cardiomyopathies. Echocardiography is one of the most important diagnostic examinations.

[New findings on cardiomyopathies]. / Novsie poznatky o kardiomyopatiách.

In this review the authors summarize the newest knowledge on cardiomyopathies, which was obtained during the last ten years due to joint experimental and clinical in this field. It concerns the pathogenesis of cardiomyopathies from the point of view of metabolic damage of the heart on the cellular and subcellular level, the diagnosis--mainly by means of echocardiographic investigation, as well as the therapy of cardiomyopathies--medicamental and surgical (transplantation of the heart). (Ref. 6.)

[Smokers' mitochondrial cardiomyopathy]. / Fajciarska mitochondríálna kardiomyopatia.

The authors analyze the metabolic background of mitochondrial myopathies of the skeletal musculature in humans. They summarize their results assembled over years pertaining to functional disorders of mitochondria of the heart muscle in experimental models of passive smoking in rabbits. Based on comparison of these disorders with disorders in mitochondrial myopathies they reach the conclusion that the concept of smokers' mitochondrial myopathy is justified.

[Treatment of enuresis by the epidural infiltration of distilled water. Clinico-statistical and therapeutic considerations in a series of 48 treated cases]. / Tratamentul enurezisului prin infiltratie epidurala cu apa distilata. Consideratii clinico-statistice si terapeutice asupra unei serii de 48 cazuri tratate.

The clinical results in a series of 48 children with enuresis treated by a new therapeutical approach based on the epidural distilled water infiltration associated with drug therapy and hygienic and dietary measures are presented. After 1-3 treatment courses, cures were obtained in 89.5% of the children, improvements in 6.2% and in 4.1% the treatment failed. The neuropsychic disturbances, found at presentation in 25% of the children, improved or were no longer present in 58.3% of the children in the 3 months interval following the clinical cure of enuresis. No accidents due to infiltration, except some minor incidents, were recorded.