cardiovascular-agents and 3-(2-2-2-trimethylhydrazine)propionate

Meldonium (mildronate; 3-(2,2,2-trimethylhydrazinium)propionate; THP; MET-88) is a clinically used cardioprotective drug, which mechanism of action is based on the regulation of energy metabolism pathways through l-carnitine lowering effect. l-Carnitine biosynthesis enzyme γ-butyrobetaine hydroxylase and carnitine/organic cation transporter type 2 (OCTN2) are the main known drug targets of meldonium, and through inhibition of these activities meldonium induces adaptive changes in the cellular energy homeostasis. Since l-carnitine is involved in the metabolism of fatty acids, the decline in its levels stimulates glucose metabolism and decreases concentrations of l-carnitine related metabolites, such as long-chain acylcarnitines and trimethylamine-N-oxide. Here, we briefly reviewed the pharmacological effects and mechanisms of meldonium in treatment of heart failure, myocardial infarction, arrhythmia, atherosclerosis and diabetes.

Topics: Animals; Biomarkers; Cardiotonic Agents; Cardiovascular Agents; Cardiovascular Diseases; Humans; Methylhydrazines; Myocardium

The paper gives data on the proven efficiency of myocardial cytoprotection with the pFOX inhibitors trimetazidine and meldonium for coronary heart disease. However, no algorithm has been defined for their differentiated use at different ischemic remodeling stages in these patients in terms of the mechanism of metabolic effects. Sequential use of meldonium and trimetazidine in different periods of acute and chronic myocardial ischemia may become one of the possible ways to increase the efficacy of the pFOX inhibitors.. Представлены данные о доказанной эффективности цитопротекции миокарда р-fox-ингибиторами триметазидином и мельдонием при ишемической болезни сердца. Однако не определен алгоритм их дифференцированного назначения на различных этапах формирования ишемического ремоделирования у пациентов этой категории с учетом механизма метаболического воздействия. Одним из возможных путей увеличения эффективности использования р-fox-ингибиторов может стать последовательное назначение мельдония и триметазидина в различные периоды острой и хронической ишемии миокарда.

Topics: Cardiotonic Agents; Cardiovascular Agents; Coronary Disease; Humans; Methylhydrazines; Trimetazidine

Therapy with meldonium belongs to "metabolic direction" which is developing in cardiovascular medicine. Its purpose is restoration of impaired cellular metabolism.

Topics: Cardiotonic Agents; Cardiovascular Agents; Humans; Metabolism; Methylhydrazines; Myocardial Infarction; Randomized Controlled Trials as Topic; Treatment Outcome

Mildronate (3-(2,2,2-trimethylhydrazinium)propionate; MET-88; meldonium, quaterine) is an antiischemic drug developed at the Latvian Institute of Organic Synthesis. Mildronate was designed to inhibit carnitine biosynthesis in order to prevent accumulation of cytotoxic intermediate products of fatty acid beta-oxidation in ischemic tissues and to block this highly oxygen-consuming process. Mildronate is efficient in the treatment of heart ischemia and its consequences. Extensive evaluation of pharmacological activities of mildronate revealed its beneficial effect on cerebral circulation disorders and central nervous system (CNS) functions. The drug is used in neurological clinics for the treatment of brain circulation disorders. It appears to improve patients' mood; they become more active, their motor dysfunction decreases, and asthenia, dizziness and nausea become less pronounced. Since the brain does not utilize fatty acids as fuel other mechanisms of action of mildronate in CNS should be considered. Several reports indicate the possible existence of an alternative, non-carnitine dependent mechanism of action of mildronate. Our recent findings suggest that CNS effects of mildronate could be mediated by stimulation of the nitric oxide production in the vascular endothelium by modification of the gamma-butyrobetaine and its esters pools. It is hypothesized that mildronate may increase the formation of the gamma-butyrobetaine esters. The latter are potent cholinomimetics and may activate eNOS via acetylcholine receptors or specific gamma-butyrobetaine ester receptors. This article summarizes known pharmacological effects of mildronate, its pharmacokinetics, toxicology, as well as the proposed mechanisms of action.

Topics: Animals; Cardiovascular Agents; Drug Evaluation; Humans; Ischemia; Ketone Bodies; Methylhydrazines; Models, Biological; Neuropharmacology; Nitric Oxide; Toxicology

The authors in the article described biochemical mechanisms of Mildronat. The main mechanism of Mildronat activity is based on decreasing carnitine level in the organism, which leads to hampering oxidation of fatty acids. Mildronat is believed keeps on training myocardium pharmacologically even without physical activity by adapting cells to decreasing fat acids inflow and activating glucose oxidations. Under ischemic condition to obtain energy, cells use intensively glucose oxidation. Clinical studies have reliably showed Mildronat to have positive effect in treating patients with cardiovascular and ischemic cerebral diseases as well as for enhancing physical and mental efficiency.

Topics: Animals; Cardiovascular Agents; Carnitine; Clinical Trials as Topic; Humans; Methylhydrazines; Myocardial Ischemia; Myocardium; Oxidative Stress; Treatment Outcome

Mildronate [3-(2,2,2-trimethylhydrazinium)propionate dihydrate] ameliorates cardiac function during ischemia by modulating myocardial energy metabolism. Biochemical and pharmacological evidence supports the hypothesis that the mechanism of action of mildronate is based on its regulatory effect on carnitine concentration, whereby mildronate treatment shifts the myocardial energy metabolism from fatty acid oxidation to the more favorable glucose oxidation under ischemic conditions. Because mildronate treatment prepares cellular metabolism and membrane structures to survive ischemic stress conditions, it is possible that mildronate could be regarded as an agent of pharmacological preconditioning.

Topics: Cardiotonic Agents; Cardiovascular Agents; Carnitine; Energy Metabolism; Humans; Methylhydrazines

Partial fatty acid oxidation inhibitors have raised great interest since they are expected to counteract a dysregulated gene expression of hypertrophied cardiocytes. Some of these compounds have been developed for treating non-insulin-dependent diabetes mellitus and stable angina pectoris. A shift from fatty acid oxidation to glucose oxidation leads to a reduced gluconeogenesis and improved economy of cardiac work. An increased glucose oxidation can be achieved with the following enzyme inhibitors: etomoxir, oxfenicine, methyl palmoxirate, S-15176, metoprolol, amiodarone, perhexiline (carnitine palmitoyltransferase-1); aminocarnitine, perhexiline (carnitine palmitoyltransferase-2); hydrazonopropionic acid (carnitine-acylcarnitine translocase); MET-88 (gamma-butyrobetaine hydroxylase); 4-bromocrotonic acid, trimetazidine, possibly ranolazine (thiolases); hypoglycin (butyryl-CoA dehydrogenase); dichloroacetate (pyruvate dehydrogenase kinase). CLINICAL TRIALS with trimetazidine and ranolazine showed that this shift in substrate oxidation has an antianginal action. Etomoxir and MET-88 improved the function of overloaded hearts by increasing the density of the Ca(2+) pump of sarcoplasmic reticulum (SERCA2). The promoters of SERCA2 and alpha-myosin heavy-chain exhibit sequences which are expected to respond to transcription factors responsive to glucose metabolites and/or peroxisome proliferator-responsive element (PPAR) agonists. Further progress in elucidating novel compounds which upregulate SERCA2 expression is closely linked to the characterization of regulatory sequences of the SERCA2 promoter.

Topics: Acetanilides; Angina Pectoris; Animals; Calcium; Cardiovascular Agents; Clinical Trials as Topic; Enzyme Inhibitors; Epoxy Compounds; Fatty Acids; Gene Expression; Glucose; Heart Failure; Humans; Hypoglycemic Agents; Methylhydrazines; Myocytes, Cardiac; Oxidation-Reduction; Piperazines; Ranolazine; Rats; Rats, Wistar; Sarcoplasmic Reticulum; Trimetazidine; Up-Regulation; Vasodilator Agents

Mildronate is an agent for cardioprotection and neuroprotection. This study aimed to evaluate the pharmacokinetic (PK) profiles, safety and tolerability of mildronate injection after single escalating doses and multiple doses in healthy Chinese subjects. We performed a randomized, open-label, single- and multiple-dose phase I trial including 3 doses of mildronate: 250, 500 and 750 mg. Plasma and urine samples were collected and concentrations of mildronate were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). PK parameters were calculated using noncompartmental analysis. Safety and tolerability was assessed throughout noting subjects' vital signs and monitoring adverse events (AEs) and conduct a comprehensive physical examination and laboratory analyses before and after the study. There was no significant difference in C 0, AUC0-t, AUC0-∞ among 3 single-dose groups, whereas T 1/2 had significant statistical difference which may be caused by the inhibition of metabolic enzymes. Single- and multiple-dose intravenous injection of mildronate exhibited linear PK profiles in the range of 250-750 mg. An unconspicuous accumulation phenomenon was found after multiple-dose mildronate administration. No significant gender difference was found and mildronate is primarily excreted by the kidney. No serious AEs were observed. The formulation was safe and well tolerated from 250 to 750 mg.

Topics: Adult; Asian People; Cardiovascular Agents; China; Chromatography, Liquid; Female; Healthy Volunteers; Humans; Injections; Male; Methylhydrazines; Tandem Mass Spectrometry; Young Adult

The aim of PMICS (Postmyocardial Infarction Cardiosclerosis) patients therapy within the dispensary supervision is CCI (Chronic Cardio Insufficiency) progression prevention, life quality improvement, hospitalization number decrease and life prognosis improvement. Despite the developed approaches to the given patients treatment, CCI progression prevention, the main disease treatment ensuring and prognosis assessment are not always as much as possible effective. The search of methods improving the given patients prognosis is highly actual.. To evaluate the meldonium clinical effectiveness in the early postmyocardial infarction period.. 67 patients were included in investigation, their age ranged from 40 to 70. They survived myocardial infarction (MI) and were discharged for further ambulatory supervision. The patients were randomized into two groups: the first one consisting of 32 patients got basic therapy for ischemic heart disease (IHD). The second group consisting of 35 patients besides basic therapy got mildronate during 12 weeks.. meldonium included in standard ischemic heart disease therapy in early postmyocardial infarction cardiosclerosis reduces the rate of angina pectoris attacks (p = 0.001), decreased the number of epiventricular extrasystoles (p = 0.002) and the number of paroxysmal rhythm disturbances (p = 0.001), decreased arterial blood pressure (middle SAP and DAP) p = 0.001, improves life quality and lowered the level of anxiety (p = 0.001).. The results received are likely to depend on the use of energetically advantageous pyruvate in glycolytic cycle due to restoration of equilibrium in processes of oxygen supply and its consumption, prevention of ATA (adenozine tryphosphoric acid) transport disturbances, elimination of toxic metabolic products accumulation. No side effects were registered during the course of mildronate treatment.

Topics: Adult; Aged; Cardiovascular Agents; Dose-Response Relationship, Drug; Electrocardiography; Female; Follow-Up Studies; Heart Rate; Humans; Male; Methylhydrazines; Middle Aged; Myocardial Infarction; Prognosis; Prospective Studies; Time Factors; Treatment Outcome

To evaluate the anti-ischemic and anti-anginal efficacy of meldonium (Idrinol) in its short-term use as part of combination therapy in patients with chronic heart failure in the early post-infarction period.. The investigation enrolled 60 patients (men and women) aged 45 to 75 years at weeks 3-4 after postmyocardial infarction with symptoms of Functional Class II-III heart failure. All the patients underwent physical examination, 24-hour ECG monitoring, heart rate variability (HRV) study, and quality of life assessment using the Seattle questionnaire. After randomization of the patients into 2 groups, Group 1 (a study group) (n = 30) was given intravenous Idrinol 1000 mg/day in addition to the basic therapy of coronary heart disease. The study and control (Group 2; n = 30) groups were matched for age, gender, disease severity, and basic therapy pattern.. Following 10-14 days of treatment, both groups showed clinical improvement and the autonomically normalizing effect of meldonium (Idrinol), which were more pronounced in Group 1 patients.. Meldonium (Idrinol) was effective when parenterally administered in a dose of 1000 mg/day for 10-14 days as part of combination therapy in the early post-infarction period, which showed up as clinical improvement, a significant reduction in the frequency of angina attacks and in the need to use nitroglycerin, a decrease in the number of arrhythmia episodes, and its normalizing effect of HRV.

Topics: Administration, Oral; Aged; Cardiovascular Agents; Dose-Response Relationship, Drug; Electrocardiography; Exercise Tolerance; Female; Forkhead Transcription Factors; Humans; Male; Methylhydrazines; Middle Aged; Myocardial Infarction; Prospective Studies; Treatment Outcome

To evaluate the impact of 10-14-day intravenous administration of meldonium as part of combination therapy in patients with chronic heart failure in the early post-infarction period on the recovery period, structural and functional parameters, and heart rate variability (HRV).. The investigation enrolled 60 patients (men and women) aged 45 to 75 years at weeks 3-4 after post-myocardial infarction with symptoms of Functional Class II-III heart failure. All the patients underwent 24-hour electrochocardiography monitoring, cardiac echocardiography, and HRV study. After dividing the patients into 2 groups, Group 1 (a study group) (n = 30) was given intravenous meldonium (idrinol) 1000 mg/day in addition to the basic therapy of coronary heart disease. The patients in the study and control (Group 2; n = 30) groups were at baseline matched for age, gender, disease severity, and basic therapy pattern.. Following 10-14 days of treatment, both groups showed clinical improvement and the favorable changes in cardiac structural and functional parameters and HRV values, which were more pronounced in the patients receiving meldonium.. The patients with CHF using meldonium as part of combination therapy in the early post-infarction period were observed to have clinical improvement, a significant reduction in the rate of angina attacks and in the need for nitrates, a decrease in the number of arrhythmic and ischemic episodes, and favorable changes in cardiac structural and functional parameters and HRV values.

Topics: Aged; Cardiovascular Agents; Diastole; Drug Therapy, Combination; Female; Heart Failure; Heart Rate; Humans; Injections, Intravenous; Male; Methylhydrazines; Middle Aged; Myocardial Infarction; Systole; Treatment Outcome

Given that prolonged exposure to extreme climatic situations may play a role independent of stress factors, influencing the course of the underlying disease, the authors considered appropriate assessment of the effectiveness of additional prophylactic administration of drugs that increase the body's resistance to stress (adaptogens). The purpose of the study - to evaluate the effect of oxidative stress on meldonium, hemodynamics and quality of life of patients with cardiovascular disease (CVD) in extreme climatic conditions (summer heat). The study included 56 patients with CVD aged 38-75 years. Patients were randomized into two groups: active management (M), which in addition to basic therapy during 3 summer months received meldonium (500 mg/day), and control. The following parameters were measured: office blood pressure (BP), blood plasma malondialdehyde (MDA), erythrocyte superoxide dismutase (SOD) activity, level of oxidized low-density lipoprotein. MDA/SOD ratio was calculated. Visual analogue scale was used for assessment of quality of life. Meldonium treated patients demonstrated marked reduction of systolic BP and heart rate during heat, increased sodium level at the 2nd visit, improved quality of life. These changes corresponded to adaptive responses of healthy men. No significant dynamics of these parameters occurred in control group. MDA level during heat increased in both groups (p<0.05) but MDA/SOD ratio, which characterizes the "oxidation potential" of blood, increased significantly during the summer heat only in the control group. Meldonium can be used as an adaptogen in CVD patients during the summer heat.

Topics: Adaptation, Physiological; Adult; Aged; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Drug Monitoring; Female; Hemodynamics; Hot Temperature; Humans; Lipoproteins, LDL; Male; Malondialdehyde; Methylhydrazines; Middle Aged; Oxidative Stress; Quality of Life; Superoxide Dismutase; Treatment Outcome

Given that the effects of frost can play the role of independent stress factor influencing the course of cardiovascular disease (CVD), it is reasonable to supplementation of drugs that increase the body's resistance to cold stress. Aim: To evaluate the possibility of using meldonium to prevent unwanted seasonal changes in CVD patients in the winter. The study included 49 patients with CVD aged 38-75 years. Patients were randomized into 2 groups: active management (M), in which in addition to the basic therapy received during the winter 3 months meldonium 1000 mg/day, and a control (K). We measured office blood pressure, heart rate, blood chemistry, determination of glycosylation end products (DGP). Filled with a visual analogue scale (VAS) to assess the quality of life (QOL). During frost marked increase in blood glucose (p = 0.02) in group K, persisting throughout the winter, and an increase in tissue DGP in March (p = 0.002). In group M glucose and DGP not significantly raised. In group M at the peak of cold showed a reduction in cholesterol levels. Admission meldonium associated with improved quality of life, in the dynamics of the group K was negative [Δ +10.0 VAS scores in group M versus -7.5 points in the group K in the cold (p = 0.04) and Δ +10,0 points vs -5.0 points, respectively, in March 2014 (p = 0.055)]. Adding to the basic treatment of patients with CVD meldonium in a dose of 1000 mg/day in winter, accompanied by improved quality of life, as well as let negative changes in carbohydrate metabolism.

Topics: Adjuvants, Immunologic; Aged; Carbohydrate Metabolism; Cardiovascular Agents; Cardiovascular Diseases; Cold Temperature; Drug Monitoring; Drug Therapy, Combination; Female; Hemodynamics; Humans; Lipid Metabolism; Male; Methylhydrazines; Middle Aged; Seasons; Treatment Outcome

We examined 140 patients (mean age 54.8±3.1 years) with ST elevation acute coronary syndrome resulting in Q-wave myocardial infarction of the left ventricle. From the first hours complex therapy of these patients comprised meldonium (1 g/day intravenously for 2 weeks then orally until 1.5 months). Therapy with meldonium accelerated restoration of left ventricular diastolic function what was in agreement with lowering of NT-proBNT concentration in blood. It was established that administration of meldonium led to reduction of number of high grade ventricular extrasystoles during first 6 hours after thrombolysis, to lowering of blood concentration of lipoperoxide degradation products. Early use of meldonium decreases probability of emergence of fatal arrhythmias and improves prognosis of hospital stage of rehabilitation of patients with acute coronary syndrome resulting in Q-wave myocardial infarction.

Topics: Acute Coronary Syndrome; Cardiovascular Agents; Coronary Angiography; Diastole; Drug Administration Routes; Drug Monitoring; Electrocardiography; Female; Humans; Male; Methylhydrazines; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Treatment Outcome; Ventricular Function, Left

Topics: Adult; Atherosclerosis; Cardiovascular Agents; Carnitine; Diet; Female; HEK293 Cells; Humans; Male; Methylamines; Methylhydrazines; Organic Cation Transport Proteins; Seafood; Solute Carrier Family 22 Member 5

Mildronate, an inhibitor of carnitine-dependent metabolism, is considered to be an anti-ischemic drug. This study is designed to evaluate the efficacy and safety of mildronate injection in treating acute ischemic stroke.. We performed a randomized, double-blind, multicenter clinical study of mildronate injection for treating acute cerebral infarction. 113 patients in the experimental group received mildronate injection, and 114 patients in the active-control group received cinepazide injection. In addition, both groups were given aspirin as a basic treatment. Modified Rankin Scale (mRS) score was performed at 2 weeks and 3 months after treatment. National Institutes of Health Stroke Scale (NIHSS) score and Barthel Index (BI) score were performed at 2 weeks after treatment, and then vital signs and adverse events were evaluated.. A total of 227 patients were randomized to treatment (n = 113, mildronate; n = 114, active-control). After 3 months, there was no significant difference for the primary endpoint between groups categorized in terms of mRS scores of 0-1 and 0-2 (p = 0.52 and p = 0.07, respectively). There were also no significant differences for the secondary endpoint between groups categorized in terms of NIHSS scores of >5 and >8 (p = 0.98 and p = 0.97, respectively) or BI scores of >75 and >95 (p = 0.49 and p = 0.47, respectively) at 15 days. The incidence of serious adverse events was similar between the two groups.. Mildronate injection is as effective and safe as cinepazide injection in treating acute cerebral infarction.

Topics: Aged; Brain Ischemia; Cardiovascular Agents; Double-Blind Method; Female; Humans; Male; Methylhydrazines; Middle Aged; Stroke; Treatment Outcome

In this study, we aimed to investigate the effects of long-term administration of the cardioprotective drug mildronate on the concentrations of l-carnitine and γ-butyrobetaine in healthy volunteers.. Mildronate was administered perorally, at a dosage of 500mg, twice daily. Plasma and urine samples were collected weekly. Daily meat consumption within an average, non-vegetarian diet was monitored. l-Carnitine, γ-butyrobetaine and mildronate concentrations were measured using the UPLC/MS/MS method.. After 4 weeks, the average concentrations of l-carnitine in plasma significantly decreased by 18%. The plasma concentrations of γ-butyrobetaine increased about two-fold, and this effect was statistically significant in both the male and female groups. In urine samples, a significant increase in l-carnitine and γ-butyrobetaine levels was observed, which provides evidence for increased excretion of both substances during the mildronate treatment. At the end of the treatment period, the plasma concentration of mildronate was 20µm on average. There were no significant differences between the effects observed in female and male volunteers. Meat consumption partially reduced the l-carnitine-lowering effects induced by mildronate.. Long-term administration of mildronate significantly lowers l-carnitine plasma concentrations in non-vegetarian, healthy volunteers.

Topics: Adult; Betaine; Cardiovascular Agents; Carnitine; Diet; Female; Humans; Male; Meat; Methylhydrazines; Middle Aged; Young Adult

To assess the efficacy of various doses of Mildronate in combination with standard therapy for the exercise tolerance of patients with stable angina pectoris. The primary efficacy variable was the change in exercise time in bicycle ergometry from the baseline to 12 weeks of treatment. The secondary endpoints were the changes in maximum achieved load and time to the onset of angina from the baseline to week 12.. A total of 512 patients with chronic coronary heart disease who had ischemia as the limiting factor in the exercise test from 72 study centers in 4 countries were enrolled in this prospective, randomized, double-blind, placebo controlled phase 2 study. The patients were assigned to either 4 groups receiving standard therapy plus Mildronate at different daily doses or 1 group receiving standard therapy plus placebo.. The mean change in the total exercise time in the mildronate 100 mg and mildronate 300 mg groups was -2.12±108.45 and 11.48±62.03 seconds, respectively. The mean change for the placebo group was -7.10±81.78 seconds. The difference between Mildronate 100 mg and 300 mg and placebo groups was not significant. Patients in the Mildronate 1000 mg group showed a remarkable increase in the mean change in the total exercise time (35.18±53.29 seconds, P=0.002). Mildronate at a dose of 3000 mg caused a smaller increase as compared with a dose of 1000 mg. Similar changes in the secondary end parameters were observed.. The most effective dose of Mildronate in combination with standard therapy was found to be 500 mg twice a day.

Topics: Adult; Aged; Aged, 80 and over; Angina, Stable; Cardiovascular Agents; Dose-Response Relationship, Drug; Exercise Tolerance; Female; Humans; Male; Methylhydrazines; Middle Aged; Treatment Outcome

To clarify mildronate effects on oxidant stress and tissue oxygen in combined treatment of peripheral (sensomotor) neuropathy in patients with type 2 diabetes mellitus (DM).. An open randomized trial investigated 70 matched patients with type 2 DM and sensomotor neuropathy. They were randomized into two groups. The study group received basic anti-diabetic treatment, alpha-lipoic acid and mildronate for 3 months. Patients of the control group received the same treatment but mildronate.. Mildronate administration improved clinical condition of the study group patients vs controls by neuropathy and symptoms count scales, electrophysiological properties of the nerve fibers, optimization of oxygen tissue balance, reduced production of lipid peroxidation products and activated enzymes of antioxidant defense.. It is recommended to add 1 g/day mildronate to standard schemes of treatment for diabetes and sensomotor neuropathy.

Topics: Aged; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Fasting; Female; Humans; Male; Methylhydrazines; Middle Aged; Oxidative Stress

To study efficacy of the myocardial cytoprotector trimethasidine MB and metabolic drug 3-(2,2,2-trimethylhydrasine) propionate dihydrate (3-TMHP) in the treatment of chronic cardiac failure (CCF).. Sixty-five patients with CCF after myocardial infarction (> 6 months) with left ventricular ejection fraction (LV EF) <40% were randomized into 3 groups: group 1 (n=28) received basic therapy plus trimethasidine in a daily dose 70 mg; group 2 (n=25)--basic therapy plus 3-TMHP in a daily dose 1000 mg; control group (n=12) received basic therapy with ACE inhibitors, beta-blockers and diuretics. Before and after 6-month treatment all the patients have undergone stress echocardiography with dobutamine. Perfusion and myocardial metabolism were determined in 34 patients with single photon emission computed tomography of the myocardium (SPECT) with 99m-Tc-technetril and positron-emission tomography of the myocardium (PET) with F-18-fluorodesoxyglucose.. Groups 1 and 2 significantly reduced functional class of CCF and prolonged the distance of a 6-min walk. Significant improvement of life quality was observed only in the treatment with trimethasidine. According to PET, treatment with trimethasidine MB and 3-TMHP has an anti-ischemic action manifesting with a significant attenuation of glucose hypermetabolism in the ischemic segment to normal values. However, significant improvement of systolic thickening in hybernated segments by SPECT as well as a significant rise of LV EF were recorded only in the treatment with trimethasidine MB. Stress echocardiography with dobutamine had high specificity (85.7%) but low sensitivity (50.4%) in detection of hybernated myocardium.. Trimethasidine MB (preductal MB) has advantages over 3-TMHP, so it is preferable in ischemic CHF.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Chronic Disease; Combined Modality Therapy; Diuretics; Drug Administration Schedule; Female; Heart Failure; Humans; Male; Methylhydrazines; Middle Aged; Positron-Emission Tomography; Trimetazidine; Vasodilator Agents; Ventricular Dysfunction, Left

The aim of this open randomized study was to compare the clinical efficacy of mildronate in complex therapy of chronic heart failure (CHF) and basic therapy in patients with CHF and type 2 diabetes mellitus (DM2) during the postinfarction period. The subjects were 60 II to III NYHA CHF patients aged 43 to 70 yo also suffering from DM2; the patients were observed during the early postinfarction period (weeks 3 to 4 from the onset of myocardial infarction). The patients were randomized into two groups: the 30 patients of the main group received basic therapy plus mildronate in a dose of 1 g a day, while the 30 patients of the control group received basic therapy only. The observation lasted 16 weeks. The following parameters were measured dynamically: NYHA functional class (FC), 6-min walking test results, left ventricular ejection fraction (LVEF), LV isovolumic relaxation time, microalbuminuria, glomerular filtration speed (GFS), functional renal reserve (FRR), carbohydrate and lipid exchange, cardiac rhythm variability parameters, and the quality of life. The use of mildronate in addition to basic therapy was associated with a more evident decrease in CHF FC, (by 19% vs. 14%), increase in 6-min walking test distance (25.5% vs. 18%), as well as a tendency to normalization of diastolic heart function and an increase in LVEF (by 12% vs. 7%). By comparison with basic therapy, the patients in the mildronate group displayed a statistically significant improvement in renal functioning: GFS increased by 20% vs. 2% (p < 0.05), the proportion of patients with an exhausted FRR decreased (p < 0.05), the average level of MAU decreased significantly (24% vs. 9%, p < 0.05). In the main group, a significant decrease in blood triglyceride level (by 33%, p < 0.05) and total cholesterol level (by 28%, p < 0.1) was noted. A hypoglycemizing ability of mildronate was noted. The use of mildronate in the basic therapy favors the normalization of vegetative homeostasis and improves the quality of life.

Topics: Cardiovascular Agents; Chronic Disease; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Male; Methylhydrazines; Middle Aged; Myocardial Infarction; Prospective Studies

The aim of the work was to study the effect of metabolic triad with different mechanisms of acting--high-dose Glucose-Insulin-Potassium--25% polarizing solution (25% glucose, 50 IU soluble insulin and 4% 144 ml KCL-GIK), mildronat, preductal MR on the functional condition of heart during the acute myocardial infarction. 20 patients from the main group and 20 from the control one have been under the study. Patients with diabetes and heavy forms of heart failure (killip class>2) were not included in the study. Evaluation of the functional condition of heart was based on ECG and echocardiography data received before and after the treatment. It was determined that the frequency of the rhythm disorder decreases in the conditions of metabolic triad as well as during the thrombolitic reperfusion. Average period of time for normalization of S-T segment elevation made up 5.4+/-1.8 days and 7.3+/-1.2 days in case of the control group. The received data make it relevant to include the complex metabolic triad for preventive purpose during the complications followed after the acute myocardial infarction.

Topics: Adult; Aged; Cardiovascular Agents; Drug Therapy, Combination; Female; Glucose; Humans; Insulin; Male; Methylhydrazines; Middle Aged; Myocardial Infarction; Potassium; Trimetazidine; Vasodilator Agents

To assess antiischemic efficacy, safety and effect on myocardial perfusion of a course treatment with mildronate (as monotherapy and in combination with atenolol) in patients with postinfarction left ventricular dysfunction associated with moderate heart failure.. Patients (n=47) with postinfarction cardiosclerosis, angina, and decreased tolerance to physical exertion were divided into 2 groups. Patients of group 1 had functional class II angina and NYHA class I-II heart failure, patients of group 2 had functional class II-III angina and severe heart failure. Mildronate (0.75-1.0 g/day) was used as monotherapy in group 1 and in combination with atenolol (25-50 mg/day) in group 2. Duration of therapy was 3 weeks.. The use of mildronate was associated with marked antiischemic effect. Combined administration of mildronate and atenolol resulted in additional antiischemic effect without impairment of hemodynamics in patients with severe heart failure. Course use of mildronate was well tolerated. Adverse effects were registered in 4,2% of cases.

Topics: Adrenergic beta-Antagonists; Atenolol; Cardiovascular Agents; Drug Therapy, Combination; Humans; Male; Methylhydrazines; Middle Aged; Mitochondrial Trifunctional Protein; Multienzyme Complexes; Myocardial Infarction; Ventricular Dysfunction, Left

Topics: Cardiac Output; Cardiovascular Agents; Diuretics; Drug Therapy, Combination; Echocardiography; Exercise Tolerance; Follow-Up Studies; Heart Failure; Humans; Male; Methylhydrazines; Middle Aged; Safety; Treatment Outcome; Vasodilator Agents

Against placebo background 50 patients with effort stenocardia received mildronate, a new native cardioactive drug and its effects on the clinical course in conditions of spirometric bicycle ergometry were studied. It was found that monotherapy with mildronate is accompanied by an antianginal effect and an increase of the physical working capacity of patients.

Topics: Adult; Angina Pectoris; Cardiovascular Agents; Exercise Test; Humans; Male; Methylhydrazines; Middle Aged; Physical Endurance; Randomized Controlled Trials as Topic; Spirometry

Ageing is the most significant risk factor for cardiovascular diseases. l-Carnitine has a potent cardioprotective effect and its synthesis decreases during ageing. At the same time, there are pharmaceuticals, such as mildronate which, on the contrary, are aimed at reducing the concentration of l-carnitine in the heart and lead to slows down the oxidation of fatty acids in mitochondria. Despite this, both l-carnitine and mildronate are positioned as cardio protectors. We showed that l-carnitine supplementation to the diet of 15-month-old mice increased expression of the PGC-1α gene, which is responsible for the regulation of fatty acid oxidation, and the Nrf2 gene, which is responsible for protecting mitochondria by regulating the expression of antioxidants and mitophagy, in the heart. Mildronate activated the expression of genes that regulate glucose metabolism. Probably, this metabolic shift may protect the mitochondria of the heart from the accumulation of acyl-carnitine, which occurs during the oxidation of fatty acids under oxygen deficiency. Both pharmaceuticals impacted the gut microbiome bacterial composition. l-Carnitine increased the level of Lachnoanaerobaculum and [Eubacterium] hallii group, mildronate increased the level of Bifidobacterium, Rikinella, Christensenellaceae. Considered, that these bacteria for protection the organism from various pathogens and chronic inflammation. Thus, we suggested that the positive effects of both drugs on the mitochondria metabolism and gut microbiome bacterial composition may contribute to the protection of the heart during ageing.

Topics: Aging; Animals; Bifidobacterium; Cardiovascular Agents; Carnitine; DNA, Mitochondrial; Female; Gastrointestinal Microbiome; Male; Methylhydrazines; Mice; Mice, Inbred C57BL; Mitochondria, Heart

Meldonium is a metabolic drug whose inclusion in the 2016 List of Prohibited Substances and Methods followed the analysis of data collected under the 2015 World Anti-Doping Agency Monitoring Program. In the early months of 2016, anti-doping laboratories reported an unusually high number of cases in which urine samples contained high concentrations of meldonium. Consequently, the meldonium excretion period in healthy athletes and the substance's long-term urine and blood (plasma) pharmacokinetics became central questions for the anti-doping community to address, to ensure appropriate assessment of the scientific and medical situation, and also fair treatment of athletes from a result management and legal standpoint. At the present time, data on meldonium pharmacokinetics is limited to a few studies, with no known data available on long-term excretion of high oral doses. The primary objective of this open-label study was to determine long-term urine and plasma pharmacokinetic parameters of meldonium in healthy volunteers. Study design included single and repeated functional load testing and assessment of L-carnitine administration on meldonium excretion and pharmacokinetics. Thirty-two volunteers were equally divided into two groups receiving either 1.0 g or 2.0 g of oral meldonium daily for 3 weeks. The study found meldonium takes several days to attain a steady state in blood and displays an elimination period over several months after cessation of treatment. Moreover, findings demonstrate that the daily dose, periodicity and duration of treatment with meldonium are the most important factors to consider in calculating the substance's elimination and complete body clearance.

Topics: Administration, Oral; Adult; Athletes; Cardiovascular Agents; Doping in Sports; Female; Healthy Volunteers; Humans; Male; Methylhydrazines; Substance Abuse Detection; Young Adult

L-carnitine is important for the catabolism of long-chain fatty acids in the mitochondria. We investigated how the triacylglycerol (TAG)-lowering drug 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA) influenced lipid metabolism in carnitine-depleted, 3-(2,2,2-trimethylhydrazinium)propionate dehydrate (Mildronate; meldonium)-treated male Wistar rats. As indicated, carnitine biosynthesis was impaired by Mildronate. However, TAG levels of both plasma and liver were decreased by 1-triple TTA in Mildronate-treated animals. This was accompanied by increased gene expression of proteins involved in mitochondrial activity and proliferation and reduced mRNA levels of Dgat2, ApoB and ApoCIII in liver. The hepatic energy state was reduced in the group of Mildronate and 1-triple TTA as reflected by increased AMP/ATP ratio, reduced energy charge and induced gene expression of uncoupling proteins 2 and 3. The increase in mitochondrial fatty acid oxidation was observed despite low plasma carnitine levels, and was linked to strongly induced gene expression of carnitine acetyltransferase, translocase and carnitine transporter, suggesting an efficient carnitine turnover. The present data suggest that the plasma TAG-lowering effect of 1-triple TTA in Mildronate-treated rats is not only due to increased mitochondrial fatty acid oxidation reflected by increased mitochondrial biogenesis, but also to changes in plasma clearance and reduced TAG biosynthesis.

Topics: Animals; Cardiovascular Agents; Carnitine; Fatty Acids; Liver; Male; Methylhydrazines; Mitochondria; Oxidation-Reduction; Rats; Rats, Wistar; Triglycerides

to assess efficacy and endotheliotropic properties of short-term addition of meldonium to basic therapy of patients with chronic ischemic heart failure and type 2 diabetes.. The study demonstrated the ability of meldonium to significantly improve endothelial function and the state of microcirculatory vascular bed, as well as to influence beneficially heart rate variability.

Topics: Aged; Cardiovascular Agents; Chronic Disease; Diabetes Mellitus, Type 2; Female; Heart Failure; Heart Rate; Humans; Male; Methylhydrazines; Middle Aged; Myocardial Ischemia

Topics: Cardiovascular Agents; Doping in Sports; Humans; Methylhydrazines; Performance-Enhancing Substances; Substance Abuse Detection

Topics: Athletes; Cardiovascular Agents; Carnitine; Doping in Sports; Female; Heart; Humans; Methylhydrazines; Muscle, Skeletal; Performance-Enhancing Substances; Tennis

Topics: Animals; Cardiovascular Agents; Doping in Sports; Humans; Methylhydrazines; Solute Carrier Family 22 Member 5

Topics: Adjuvants, Immunologic; Animals; Cardiovascular Agents; Cardiovascular Diseases; Carnitine; Humans; Methylhydrazines; Randomized Controlled Trials as Topic

to analyze clinical and economical effectiveness of meldonium as component of integrated program of cardio-rehabilitation in patients with ischemic heart disease (IHD) in the early period after percutaneous coronary intervention (PCI) with incomplete revascularization.. A program of controlled physical training (CPT) was carried out in patients with stable IHD and positive post PCI exercise test (n=48, age less or equal 65 years) starting 8-10 days after PCI. CRT program consisted of 2 phases - inhospital (exercise on treadmill with max heart rate [HR] 80% of that achieved in initial test, 10 times during 2 weeks) and home (exercise on treadmill with max HR 60% of HR achieved in initial test, 3 times a week for 2 months). Before initiation of CRT patients were distributed into 2 groups: CRT without (n=23; 56.7+/-7.1 years) and with (n=25; 54.6+/-6.8 years) administration of meldonium (1000 mg/day intravenously). Control group (n=24; 50+/-8.4 years) consisted of patients who were under outpatient observation, received similar drug therapy, but were not subjected to CRT. After completion of CRT (in 2.5 months) all patients underwent clinical-instrumental examination with determination of exercise tolerance.. Exercise duration and metabolic equivalent (MET) increased by 43.9, 36.6, 4.1% and 42.1, 34.8, 3.4% in CRT+ meldonium, CRT only, and control groups, respectively.. In patients with documented ischemia after PCI inclusion of meldonium in the scheme of rehabilitation was associated with improved physical performance and optimal cost-effectiviness.

Topics: Cardiovascular Agents; Coronary Disease; Exercise Test; Exercise Tolerance; Female; Humans; Male; Methylhydrazines; Middle Aged; Myocardial Ischemia; Percutaneous Coronary Intervention; Treatment Outcome

The extremely high hygroscopicity (solubility in water ≥2 g/ml) of the pharmaceutical preparation mildronate defines specific requirements to both packaging material and storage conditions. To overcome the above mentioned inconveniences, microencapsulated form of mildronate was developed using polystyrene (PS) and poly (lactic acid) (PLA) as watertight coating materials. Drug/polymer interaction as well as influence of the microencapsulation process variables on microparticle properties was studied in detail. Water-in-oil-in-water double emulsion technique was adapted and applied for the preparation of PS/mildronate microparticles with total drug load up to 77 %wt and PLA/mildronate microparticles with total drug load up to 80 %wt. The repeatability of the microencapsulation process was ±4% and the encapsulation efficiency of the active ingredient reached 60 %wt. The drug release kinetics from the obtained microparticles was evaluated and it was found that drug release in vivo could be successfully sustained if polystyrene matrix has been used.

Topics: Animals; Capsules; Cardiovascular Agents; Kinetics; Lactic Acid; Male; Methylhydrazines; Polyesters; Polymers; Polystyrenes; Rabbits

The dehydration kinetics of mildronate dihydrate [3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propionate dihydrate] was analyzed in isothermal and nonisothermal modes. The particle size, sample preparation and storage, sample weight, nitrogen flow rate, relative humidity, and sample history were varied in order to evaluate the effect of these factors and to more accurately interpret the data obtained from such analysis. It was determined that comparable kinetic parameters can be obtained in both isothermal and nonisothermal mode. However, dehydration activation energy values obtained in nonisothermal mode showed variation with conversion degree because of different rate-limiting step energy at higher temperature. Moreover, carrying out experiments in this mode required consideration of additional experimental complications. Our study of the different sample and experimental factor effect revealed information about changes of the dehydration rate-limiting step energy, variable contribution from different rate limiting steps, as well as clarified the dehydration mechanism. Procedures for convenient and fast determination of dehydration kinetic parameters were offered.

Topics: Cardiovascular Agents; Kinetics; Methylhydrazines; Particle Size; Water

In order to evaluate the effectiveness mildronate in rehabilitative treatment in connective tissue dysplasia examined 240 patients (24,41 ± 7,62 years, 130 men). All patients were treated with 5 ml of mildronate 10% intravenously for 10 days, then 1 capsule (250 mg), 2 times per day for 4 months. The therapy showed a significant decrease in asthenic complaints, reducing the incidence of violations repolarization I (p<0.05) and II infarction (p<0.05), a significant increase in end-diastolic volume (p<0.05), stroke volume (p<0.05), left ventricular ejection fraction (p<0.05) by echocardiography, increased exercise tolerance with the normalization of reaction to physical stress on a dystonic normotonichesky, improved quality of life. During the treatment was not recorded adverse events in patients receiving the drug. Portability mildronate majority of patients described as good to very good (average 8.67 points).

Topics: Adult; Asthenia; Cardiovascular Agents; Connective Tissue Diseases; Drug Administration Routes; Drug Monitoring; Exercise Tolerance; Female; Heart Diseases; Heart Function Tests; Humans; Male; Methylhydrazines; Myocardial Contraction; Treatment Outcome

The aim of the present study was to investigate the effects of vascular tissue levels of l-carnitine and its precursor, γ-butyrobetaine (GBB), on the development of endothelial dysfunction induced by 5 μmol/L lysophosphatidylcholine (LPC), 10 mmol/L triglycerides (TG) or a high glucose concentration (44 mmol/L). Changes in vascular tissue levels of l-carnitine and GBB were induced by administration of l-carnitine (100 mg/kg), mildronate (100 mg/kg; an inhibitor of l-carnitine synthesis) or their combination to male Wistar rats for 2 weeks. Treatment with l-carnitine elevated vascular tissue levels of l-carnitine, whereas administration of mildronate reduced l-carnitine levels and increased GBB levels. Experimental animals that received the combination of both drugs showed elevated tissue levels of GBB. The results from organ bath experiments demonstrated that increased GBB levels with preserved l-carnitine content in vascular tissues attenuated the development of endothelial dysfunction induced by high glucose. However, changes in vascular tissue l-carnitine and GBB levels had no impact on endothelial dysfunction induced by TG or LPC. The results demonstrate that increased levels of GBB with preserved l-carnitine content in vascular tissue attenuate the development of endothelial dysfunction induced by high glucose concentrations.

Topics: Animals; Aorta; Betaine; Cardiovascular Agents; Carnitine; Drug Therapy, Combination; Endothelium, Vascular; Glucose; Male; Methylhydrazines; Rats; Rats, Wistar

Under experimental myocardial ischemia in rats of 10 months treatment with mildronate resulted in essential changes in metabolism of cardiomyocites. This includes stimulation of aerobic and anaerobic ways of power supply of heart cells: activation of glycolysis, oxidative phosphorylation and oxidative pyruvate decarboxylation with restoration of adenosine triphosphate pool to intact rats level in myocardium, serum and erythrocytes with signs of stabilization of cardiomyocytes membranes and essential decrease of tissue hypoxia. Introduction of mildronate to old rats (24 months) with an experimental myocardium ischemia was accompanied by lesser expressed changes of metabolism: activation of glycolysis and oxidative pyruvate decarboxylation without stimulation of Crebs' cycle enzymes. This became sufficient for restoration of adenosine triphosphate pool in myocardium without change of its quantity in serum and erythrocytes with signs of stabilization of cardiomyocytes membranes and moderate reduction of tissue hypoxia degree.

Topics: 2,3-Diphosphoglycerate; Adenosine Triphosphate; Age Factors; Animals; Cardiovascular Agents; Creatine Kinase; Decarboxylation; Energy Metabolism; Glycolysis; Isoenzymes; L-Lactate Dehydrogenase; Male; Methylhydrazines; Myocardial Ischemia; Myocytes, Cardiac; Pyruvates; Rats; Rats, Wistar

An aim of the present study was to evaluate the treatment efficacy of the antioxidant mildronate in patients with transitory ischemic attacks. We studied the dynamics of clinical status, psychometric data and indices of free-radical lipid oxidation in 40 patients. The improvement in the subjective state, memory and attention was seen in 24 patients.

Topics: Attention; Cardiovascular Agents; Disease Progression; Free Radical Scavengers; Humans; Ischemic Attack, Transient; Lipid Peroxidation; Magnetic Resonance Imaging; Memory; Methylhydrazines; Psychometrics; Treatment Outcome; Ultrasonography, Doppler, Transcranial

The article presents data of literature review on potential use of cytoprotectors in sports medicine (exemplified by Mildronat medication). This group of medications improve metabolism and energy supply in tissues. One of leading indications to Mildronat use is state of low mental and physical performance, including that of athletes.

Topics: Adaptation, Physiological; Athletes; Biological Availability; Cardiovascular Agents; Cytoprotection; Energy Metabolism; Humans; Mental Fatigue; Methylhydrazines; Nitric Oxide; Physical Endurance; Psychomotor Performance

Under observation were 40 hypertensive patients with coronary heart disease, gout and obesity I and II degree. Patients with hypertension in combination with coronary heart disease, gout and obesity, syndrome of early vascular aging is shown by increased stiffness of arteries, increased peak systolic flow velocity, pulse blood presure, the thickness of the intima-media complex, higher level endotelinemia and reduced endothelial vasodilation. Obtained evidence that losartan in complex combination with basic therapy and metamaks in complex combination with basic therapy positively affect the elastic properties of blood vessels and slow the progression of early vascular aging syndrome.

Topics: Antihypertensive Agents; Blood Flow Velocity; Blood Pressure; Cardiovascular Agents; Carotid Arteries; Coronary Disease; Elasticity; Endothelium, Vascular; Female; Gout; Humans; Hypertension; Losartan; Male; Methylhydrazines; Middle Aged; Obesity; Severity of Illness Index; Tunica Intima; Tunica Media; Vascular Stiffness

Mildronate, an inhibitor of L-carnitine biosynthesis and uptake, is a cardioprotective drug whose mechanism of action is thought to rely on the changes in concentration of L-carnitine in heart tissue. In the present study, we compared the cardioprotective effect of mildronate (100 mg/kg) and a combination of mildronate and L-carnitine (100 + 100 mg/kg) administered for 14 days with respect to the observed changes in l-carnitine level and carnitine palmitoyltransferase I (CPT-I)-dependent fatty acid metabolism in the heart tissues. Concentrations of L-carnitine and its precursor γ-butyrobetaine (GBB) were measured by ultraperformance liquid chromatography with tandem mass spectrometry. In addition, mitochondrial respiration, activity of CPT-I, and expression of CPT-IA/B messenger RNA (mRNA) were measured. Isolated rat hearts were subjected to ischemia-reperfusion injury. Administration of mildronate induced a 69% decrease in L-carnitine concentration and a 6-fold increase in GBB concentration in the heart tissue as well as a 27% decrease in CPT-I-dependent mitochondrial respiration on palmitoyl-coenzyme A. In addition, mildronate treatment induced a significant reduction in infarct size and also diminished the ischemia-induced respiration stimulation by exogenous cytochrome c. Treatment with a combination had no significant impact on L-carnitine concentration, CPT-I-dependent mitochondrial respiration, and infarct size. Our results demonstrated that the mildronate-induced decrease in L-carnitine concentration, concomitant decrease in fatty acid transport, and maintenance of the intactness of outer mitochondrial membrane in heart mitochondria are the key mechanisms of action for the anti-infarction activity of mildronate.

Topics: Animals; Betaine; Cardiovascular Agents; Carnitine; Carnitine O-Palmitoyltransferase; Chromatography, Liquid; Drug Interactions; Fatty Acids; Male; Methylhydrazines; Mitochondria, Heart; Mitochondrial Membranes; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Rats, Wistar; Tandem Mass Spectrometry; Vitamin B Complex

Cerebrovascular pathology has long moved from the category of a single medical problem in the social problem. Progression of vascular lesions of the brain results in significant disability, and in the later stages interfere with the ability to self-service and significantly reduces the quality of life. The key link is ischemic brain damage, or glutamate cascade, which many researchers believe trigger excitotoxic damage and a major cause of neuronal death. One important component of effective control of the effects of ischemic disorders is complex neuro-cytoprotective therapy. To correct for the effects of both acute and chronic ischemia of the brain need to effectively act in several directions simultaneously, normalizing metabolic changes, eliminating the cytokine imbalance transcription violations, reducing the severity of oxidative stress and excitotoxicity.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Circulation; Cerebrovascular Disorders; Energy Metabolism; Humans; Hypoxia; Ischemia; Methylhydrazines; Randomized Controlled Trials as Topic

Hypertension is a well established risk factor for the development of cardiovascular diseases and increased mortality. This study was performed to investigate the effects of the administration of L-carnitine or mildronate, an inhibitor of L-carnitine biosynthesis, or their combination on the development of hypertension-related complications in Dahl salt-sensitive (DS) rats fed with a high salt diet. Male DS rats were fed laboratory chow containing 8% NaCl from 7 weeks of age. Experimental animals were divided into five groups and treated for 8 weeks with vehicle (water; n = 10), L-carnitine (100 mg/kg, n = 10), mildronate (100 mg/kg, n = 10) or a combination of L-carnitine and mildronate at the doses above (n = 10). During the experiment, control group animals continued to consume a diet with normal salt content. Administration of the combination significantly improved the survival rate for 50% of the population. None of the tested compounds or their combination influenced high salt intake-induced hypertension, while treatment with mildronate and the combination for 8 weeks significantly decreased resting heart rate by 12% and 10%, respectively. Feeding with high salt diet had no influence on systolic function of the heart, but it induced thickening of the ventricular walls and development of heart hypertrophy that was not improved by the administration of tested compounds. In addition, administration of the combination attenuated the development of endothelial dysfunction in isolated aortic rings. In conclusion, our results demonstrate that treatment with a combination of L-carnitine and mildronate is protective against hypertension-induced complications in an experimental model of salt-induced hypertension.

Topics: Animals; Cardiovascular Agents; Carnitine; Endothelium, Vascular; Hypertension; Male; Methylhydrazines; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Survival Rate; Vitamin B Complex

Mildronate (3-[2,2,2-trimethylhydrazinium] propionate dihydrate) traditionally is a well-known cardioprotective drug. However, our recent studies convincingly demonstrated its neuroprotective properties. The aim of the present study was to evaluate the influence of mildronate on the expression of proteins that are involved in the differentiation and survival of the nigrostriatal dopaminergic neurons in the rat model of Parkinson's disease (PD). The following biomarkers were used: heat shock protein 70 (Hsp70, a molecular chaperone), glial cell line-derived nerve growth factor (GDNF, a growth factor promoting neuronal differentiation, regeneration, and survival), and neural cell adhesion molecule (NCAM).. PD was modeled by 6-hydroxydopamine (6-OHDA) unilateral intrastriatal injection in rats. Mildronate was administered at doses of 10, 20, and 50 mg/kg for 2 weeks intraperitoneally before 6-OHDA injection. Rat brains were dissected on day 28 after discontinuation of mildronate injections. The expression of biomarkers was assessed immunohistochemically and by western blot assay.. 6-OHDA decreased the expression of Hsp70 and GDNF in the lesioned striatum and substantia nigra, whereas in mildronate-pretreated (20 and 50 mg/kg) rats, the expression of Hsp70 and GDNF was close to the control group values. NCAM expression also was decreased by 6-OHDA in the striatum and it was totally protected by mildronate at a dose of 50 mg/kg. In contrast, in the substantia nigra, 6-OHDA increased the expression of NCAM, while mildronate pretreatment (20 and 50 mg/kg) reversed the 6-OHDA-induced overexpression of NCAM close to the control values.. The obtained data showed that mildronate was capable to regulate the expression of proteins that play a role in the homeostasis of neuro-glial processes.

Topics: Animals; Cardiovascular Agents; Corpus Striatum; Disease Models, Animal; Glial Cell Line-Derived Neurotrophic Factor; HSP70 Heat-Shock Proteins; Male; Methylhydrazines; Neural Cell Adhesion Molecules; Neuroprotective Agents; Oxidopamine; Parkinson Disease, Secondary; Protein Biosynthesis; Rats; Rats, Wistar; Substantia Nigra

A simple, rapid and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the determination of mildronate in human plasma. Following a simple protein precipitation with methanol, the analyte was separated on a C(18) column by isocratic elution with methanol and 10 mM ammonium acetate (55:45; v/v), and then analyzed by mass spectrometry in the positive ion MRM mode. Good linearity was achieved over a wide range of 0.01-20 microg/mL. The intra- and inter-batch precisions (as RSD, %) were less than 7.1%. The average extraction recovery was 87.5%. The method described above has been used, for the first time, to reveal the pharmacokinetics of mildronate injection in healthy subjects. After single intravenously administration of 250, 500 and 1000 mg mildronate, the elimination half-life (t(1/2)) were (5.56+/-1.55), (6.46+/-1.07) and (6.55+/-1.17) h, respectively. The Student-Newman-Keuls test results showed that peak plasma concentration (C(max)) and the area under the plasma concentration versus time curve from time 0 to 24h (AUC(0-24)) were both linearly related to dose. The pharmacokinetics of mildronate fitted the linear dynamic feature over the dose range studied. The essential pharmacokinetic parameters of multidoses administration intravenously (500 mg, b.i.d) were as follows: t(1/2) was (15.34+/-3.14) h; C(max) was (25.50+/-3.63) microg/mL; AUC(0-24) was (58.56+/-5.57) mgh/L. The t(1/2) and AUC of multidoses administration intravenously were different from those of single-dose administration significantly. These findings suggested that accumulation of mildronate in plasma occurred.

Topics: Cardiovascular Agents; Chromatography, Liquid; Humans; Linear Models; Methylhydrazines; Sensitivity and Specificity; Tandem Mass Spectrometry

Mildronate, an inhibitor of L-carnitine biosynthesis and transport, is used in clinics as a modulator of cellular energy metabolism and is a cardioprotective drug. L-Carnitine is a pivotal molecule in fatty acid oxidation pathways and its regulation in vasculature might be a promising approach for antiatherosclerotic treatment. This study was performed to evaluate the effects of mildronate treatment on the progression of atherosclerosis and the content of L-carnitine in the vascular wall.. ApoE/LDLR(-/-) mice received mildronate at doses of 30 and 100 mg/kg for 4 months. Lipid profile was measured in plasma and atherosclerotic lesions were analyzed in whole aorta and aortic sinus. L-Carnitine concentration was assessed in rat aortic tissues after 2 weeks of treatment with mildronate at a dose of 100 mg/kg.. The chronic treatment with mildronate at a dose of 100 mg/kg significantly reduced the size of atherosclerotic plaques in the aortic roots and in the whole aorta, and slightly decreased the free cholesterol level. In addition, mildronate treatment decreased L-carnitine concentration in rat aortic tissues.. Long-term mildronate treatment decreases L-carnitine content in aortic tissues and attenuates the development of atherosclerosis in apoE/LDLR(-/-) mice.

Topics: Animals; Aorta; Atherosclerosis; Betaine; Cardiovascular Agents; Carnitine; Energy Metabolism; Female; Lipids; Male; Methylhydrazines; Mice; Mice, Knockout; Rats; Rats, Wistar

The aim of the study was to examine effect of cardioversion (CV) on the subjective and objective status of patients with persistent atrial fibrillation (AF) receiving different therapy. The study included 4 groups of patients (n = 85). Group 1 (n = 30) were given standard treatment. In group 2 (n = 25), standard therapy was supplemented by i.v. injections of emoxipin (200 mg/day). Treatment of group 3 (n = 10) included mildronat (50 mg/day, i.v.), patients of group 4 (n = 20) were given riboxin (200 mg/day, i.v.). It was shown that the recovery of sinus rhythm improved the quality of life and parameters of cardiovascular function in all the treated patients.

Topics: Atrial Fibrillation; Cardiovascular Agents; Echocardiography, Doppler; Electric Countershock; Electrocardiography, Ambulatory; Female; Follow-Up Studies; Heart Rate; Humans; Injections, Intravenous; Inosine Diphosphate; Male; Methylhydrazines; Middle Aged; Quality of Life; Stroke Volume; Treatment Outcome

Mildronate [3-(2,2,2-trimethylhydrazinium) propionate] is an anti-ischaemic drug whose mechanism of action is based on its inhibition of L-carnitine biosynthesis and uptake. As L-carnitine plays a pivotal role in the balanced metabolism of fatty acids and carbohydrates, this study was carried out to investigate whether long-term mildronate treatment could influence glucose levels and prevent diabetic complications in an experimental model of type 2 diabetes in Goto-Kakizaki (GK) rats.. GK rats were treated orally with mildronate at doses of 100 and 200 mg.kg(-1) daily for 8 weeks. Plasma metabolites reflecting glucose and lipids, as well as fructosamine and beta-hydroxybutyrate, were assessed. L-carnitine concentrations were measured by ultra performance liquid chromatography with tandem mass spectrometry. An isolated rat heart ischaemia-reperfusion model was used to investigate possible cardioprotective effects. Pain sensitivity was measured with a tail-flick latency test.. Mildronate treatment significantly decreased L-carnitine concentrations in rat plasma and gradually decreased both the fed- and fasted-state blood glucose. Mildronate strongly inhibited fructosamine accumulation and loss of pain sensitivity and also ameliorated the enhanced contractile responsiveness of GK rat aortic rings to phenylephrine. In addition, in mildronate-treated hearts, the necrosis zone following coronary occlusion was significantly decreased by 30%.. These results demonstrate for the first time that in GK rats, an experimental model of type 2 diabetes, mildronate decreased L-carnitine contents and exhibited cardioprotective effects, decreased blood glucose concentrations and prevented the loss of pain sensitivity. These findings indicate that mildronate treatment could be beneficial in diabetes patients with cardiovascular problems.

Topics: 3-Hydroxybutyric Acid; Administration, Oral; Animals; Blood Glucose; Cardiovascular Agents; Carnitine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Fructosamine; Heart; Hyperalgesia; Hypoglycemic Agents; In Vitro Techniques; Lipids; Male; Methylhydrazines; Myocardial Ischemia; Pain Threshold; Rats; Rats, Wistar

Mildronate is a cardioprotective drug that improves cardiac function during ischaemia and functions by lowering l-carnitine concentration in body tissues and modulating myocardial energy metabolism. The aim of the present study was to characterise cardiovascular function and liver condition after long-term mildronate treatment in rats. In addition, changes in the plasma lipid profile, along with changes in the concentration of mildronate, l-carnitine and gamma-butyrobetaine were monitored in the rat tissues. Wistar rats were perorally treated daily with a mildronate dose of either 100, 200 or 400 mg/kg for 4, 8 or 12 weeks. The l-carnitine-lowering effect of mildronate was dose-dependent. However, the carnitine levels reached a plateau after about four weeks of treatment. During the additional weeks of treatment, the carnitine levels were not considerably changed. The obtained results provide evidence that even a high dose of mildronate does not alter cardiovascular parameters and the function of isolated rat hearts. Furthermore, the histological evaluation of liver tissue cryosections and measurement of biochemical markers of hepatic toxicity showed that all the measured values were within the normal reference range. Our results provide evidence that long-term mildronate administration induces significant changes in carnitine homeostasis, but it is not associated with cardiac impairment or disturbances in liver function.

Topics: Animals; Betaine; Biomarkers; Blood Glucose; Body Weight; Cardiovascular Agents; Carnitine; Carnitine O-Palmitoyltransferase; Dose-Response Relationship, Drug; Glucose; Heart; Hemodynamics; Lipids; Liver; Liver Glycogen; Male; Methylhydrazines; Myocardium; Rats; Rats, Wistar; Time Factors; Toxicity Tests, Chronic

Carnitine acetyltransferase (CrAT; EC 2.3.1.7) catalyzes the reversible transfer of acetyl groups between acetyl-coenzyme A (acetyl-CoA) and L-carnitine; it also regulates the cellular pool of CoA and the availability of activated acetyl groups. In this study, biochemical measurements, saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, and molecular docking were applied to give insights into the CrAT binding of a synthetic inhibitor, the cardioprotective drug mildronate (3-(2,2,2-trimethylhydrazinium)-propionate). The obtained results show that mildronate inhibits CrAT in a competitive manner through binding to the carnitine binding site, not the acetyl-CoA binding site. The bound conformation of mildronate closely resembles that of carnitine except for the orientation of the trimethylammonium group, which in the mildronate molecule is exposed to the solvent. The dissociation constant of the mildronate CrAT complex is approximately 0.1 mM, and the K(i) is 1.6 mM. The results suggest that the cardioprotective effect of mildronate might be partially mediated by CrAT inhibition and concomitant regulation of cellular energy metabolism pathways.

Topics: Animals; Binding Sites; Biocatalysis; Cardiovascular Agents; Carnitine O-Acetyltransferase; Columbidae; Dose-Response Relationship, Drug; Energy Metabolism; Enzyme Inhibitors; Magnetic Resonance Spectroscopy; Methylhydrazines; Molecular Dynamics Simulation; Structure-Activity Relationship; Substrate Specificity

To study fractional composition of red cell membrane (RCM) lipids in patients with severe iron-deficiency anemia (IDA) complicated by myocardiodystrophy prior to treatment and after 1-month combined treatment with sorbifer and mildronate.. Fatty acid composition of RCM lipids was studied in 12 patients with severe chronic posthemorrhagic IDA complicated by myocardiodystrophy and in 15 healthy subjects. Extraction of lipids from blood red cells and methylation of fatty acids were performed according to K.M. Sinyak et al. (1976). Relative content of fatty acids was determined at chromatography.. The study detected increased content of saturated fatty acids, especially palmitic and decreased content of unsaturated fatty acids especially fraction of omega6-polyunsaturated fatty acids: arachidonic and gamma-linolenic.. Sorbifer in combination with mildronate improved fatty acid composition of blood red cells in patients with iron-deficiency anemia.

Topics: Anemia, Iron-Deficiency; Cardiomyopathies; Cardiovascular Agents; Drug Therapy, Combination; Erythrocytes; Fatty Acids; Follow-Up Studies; Humans; Methylhydrazines; Middle Aged; Treatment Outcome; Vitamin E; Vitamins

A sensitive and selective analytical method based on liquid chromatography-triple-quadrupole mass spectrometer has been developed to determine mildronate in human plasma and urine. The aim of this work was to find a valid method to study the pharmacokinetic profiles of mildronate in humans. Mildronate is a heart protection medicine, a carnitine's structural analogue, so levocarnitine was used as an internal standard for quantification. Under the electrospray ionization source positive ion mode, calibration curves with good linearities (r=0.9998 for plasma sample and r=0.9999 for urine sample) were obtained in the range of 1.0-20,000 ng ml(-1) for mildronate. The detection limit was 1 ng ml(-1). Recoveries were around 90% for the extraction from human plasma, and good precision and accuracy were achieved. This method is feasible for the evaluation of pharmacokinetic profiles of mildronate in humans, and to the best of our knowledge, this is the first report on LC-MS-MS analysis of mildronate in plasma and urine.

Topics: Cardiotonic Agents; Cardiovascular Agents; Chromatography, High Pressure Liquid; Humans; Methylhydrazines; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry

To date, the uptake of drugs into the human heart by transport proteins is poorly understood. A candidate protein is the organic cation transporter novel type 2 (OCTN2) (SLC22A5), physiologically acting as a sodium-dependent transport protein for carnitine. We investigated expression and localization of OCTN2 in the human heart, uptake of drugs by OCTN2, and functional coupling of OCTN2 with the eliminating ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein).. Messenger RNA levels of OCTN2 and ABCB1 were analyzed in heart samples by quantitative polymerase chain reaction. OCTN2 was expressed in all auricular samples that showed a pronounced interindividual variability (35 to 1352 copies per 20 ng of RNA). Although a single-nucleotide polymorphism in OCTN2 (G/C at position -207 of the promoter) had no influence on expression, administration of beta-blockers resulted in significantly increased expression. Localization of OCTN2 by in situ hybridization, laser microdissection, and immunofluorescence microscopy revealed expression of OCTN2 mainly in endothelial cells. For functional studies, OCTN2 was expressed in Madin-Darby canine kidney (MDCKII) cells. Using this system, verapamil, spironolactone, and mildronate were characterized both as inhibitors (EC50=25, 26, and 21 micromol/L, respectively) and as substrates. Like OCTN2, ABCB1 was expressed preferentially in endothelial cells. A significant correlation of OCTN2 and ABCB1 expression in the human heart was observed, which suggests functional coupling. Therefore, the interaction of OCTN2 with ABCB1 was tested with double transfectants. This approach resulted in a significantly higher transcellular transport of verapamil, a substrate for both OCTN2 and ABCB1.. OCTN2 is expressed in the human heart and can be modulated by drug administration. Moreover, OCTN2 can contribute to the cardiac uptake of cardiovascular drugs.

Topics: Aged; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cardiovascular Agents; Cell Line; Dogs; Endothelial Cells; Female; Genotype; Humans; Male; Methylhydrazines; Middle Aged; Myocardium; Organic Cation Transport Proteins; Polymerase Chain Reaction; Promoter Regions, Genetic; RNA, Messenger; Solute Carrier Family 22 Member 5; Spironolactone; Transfection; Verapamil

We used antiischemic cardiovascular preparation mildronat as neuroprotective and cytoprotective therapy to treat and prevent glaucomatous optic neuropathy. Prescription of mildronat was given to 35 patients. From 35 patients 20 were women and 15 men, at the age 40-75, visual acuity 0.1-1.0, Pt=18-24, treatment course 2,5-3 months. Before and after treatment patients were observed with routine methods (visometry, tonometry, determinig visual field on goldman spheroperymeter) and besides that on automated static perimetry Humphrey (30-2; 24-2; Armally) and Medmont studio (Glaucoma test; Full test). Also we used method of biomicroophtalmoscopy by positive lens +83 dptr on slit lamp and described optic nerve head with our scheme. According to the subjective and objective data positive dynamics were signed in 34 patients (63 eyes), negative dynamics in 1 patient (2 eyes). Glaucoma is medical and social problem in many countries. With the difference of expensive methods in prevention and treatment of glaucomatous optic neuropathy, using a mildronat as neuroprotective and cytoprotective drug is available for the majority of glaucoma patients. We recommend using mildronat in patients with primary open angle glaucoma with normolised intraocular pressure and in patients with normal tension glaucoma.

Topics: Adult; Aged; Cardiovascular Agents; Female; Glaucoma; Humans; Intraocular Pressure; Lipid Peroxidation; Male; Methylhydrazines; Middle Aged; Optic Nerve; Optic Neuropathy, Ischemic

Mildronate is a fatty acid oxidation inhibitor approved as an antianginal drug in parts of Europe. We carried out the first study to determine whether a 10-day course of mildronate could reduce myocardial infarct size (IS) during acute myocardial ischemia. Sprague Dawley rats received 200 mg/kg/d of mildronate (treated group, n = 16) or sterile water (control group, n = 14) subcutaneously for 10 days before ischemia-reperfusion. Rats were then subjected to 45 minutes of left coronary artery occlusion and 2 hours of reperfusion. The 2 groups had identical areas at risk: treated 38 +/- 3%; controls 38 +/- 2%. The amount of necrosis was smaller in the mildronate group at 16 +/- 2% of the left ventricle versus controls, 22 +/- 2% (P = 0.05); and for any amount of risk >25%, necrosis was smaller in the treated group (P = 0.0035). Myocardial IS (% of risk zone) was 43+/-3% in the mildronate-treated rats, and 57+/-4% in controls (P = 0.004). During occlusion, there were no differences between the 2 groups in heart rate (216 +/- 12 bpm, mildronate and 210 +/- 9 bpm, control), in mean arterial pressure (60 +/- 2 mm Hg, mildronate and 64 +/- 3 mm Hg, control) or in the frequency of arrhythmias. Our study for the first time demonstrated that a 10-day treatment with mildronate reduced myocardial IS in an experimental model of acute myocardial ischemia, without any effect on hemodynamics.

Topics: Angina Pectoris; Animals; Blood Pressure; Body Weight; Cardiovascular Agents; Fatty Acids; Female; Heart Rate; Methylhydrazines; Myocardial Infarction; Oxidation-Reduction; Rats; Rats, Sprague-Dawley

Alcoholic cardiomyopathy is specific cardial pathology characteristic for chronic consumption of alcohol. Endothelin-1 is an endothelium-derived potent vasoconstrictor peptide, which level directly influence the severity of this condition. Mildronate is an antiischemic drug. It inhibits carnitine biosynthesis (suppress beta-oxidation of the fatty acids) and increases the production of nitric oxide in the vascular endothelium. The aim of the study was to establish how Mildronate influences concentration of ET-1 in blood of rats on a background of chronic consumption of alcohol and at abstinence. White rats (n=28) instead of drinking water were taking 15% ethanol with the following regimens: A) three-week alcohol consumption, B) after 3 weeks of alcohol consumption on a background of alcohol they took mildronate, C) four-week alcohol consumption; D) after 4 weeks alcohol consumption they took only mildronate. Concentration of ET-1 in the group A was 6,00 +/- 0,35 fmol/ml, in the group B - 4,82 +/- 0,31 fmol/ml, in the group C - 13,25 +/- 0,49 fmol/ml and in the group D - 9,17 +/- 0,17 fmol/ml. Consumption of alcohol concentration ET-1 in blood high, for this purpose it is enough also 3-week alcohol consumption; the concentration of ET-1 progressively elevates with increase of duration of alcohol consumption; mildronate lowers concentration of ET-1 both on the background of alcohol consumption and on the background of acceptance of alcohol; under influence of mildronate the condition is improved in parallel the with complete alcohol consumption and acceptance of alcohol.

Topics: Alcohol Drinking; Animals; Cardiomyopathy, Alcoholic; Cardiovascular Agents; Endothelin-1; Ethanol; Male; Methylhydrazines; Rats; Rats, Inbred Strains

Mildronate is an antiischemic drug. It inhibits carnitine biosynthesis (suppresses beta-oxidation of fatty acid) The aim of the study was to establish how Mildronate influences the concentration of L-carnitine in blood and in some tissues in rats with various stages chronic consumption of alcohol. 28 white rats instead of drinking water were taking 15 % ethanol. In the group A the rats were on the three-week alcohol consumption, in the group B--after 3 weeks of alcohol consumption on a background of alcohol they were taking the mildronate, group C--four-week alcohol consumption; D--after 4 weeks of alcohol consumption only mildronate was administered. The concentration of L-carnitine in the group A was as follows: in the liver 136.11+/-2.44; in heart 74.3+/-3.15; in brain 60.44+/-5.21; in blood 45.8+/-2.32. In the group B: in liver 115.7+/-4.69; in heart 72.11+/-4.23; in brain 59.23+/-2.44; in blood 62.5+/-1.99. In the group C: in liver 107.71+/-1.43; in heart 52.57+/-0.95; in brain 71.5+/-1.08; in blood 38.8+/-2.32. And in group D: in liver 106.94+/-1.81; in heart 42.04+/-0.88; in brain 56.84+/-2.75; in blood 2.37+/-0.69 (nmol/l). During the chronic use of alcohol the decrease of concentration of L-carnitine is marked. The level of L-carnitine is reduced under influence of alcohol, but at the same time it suppressed also all steps of metabolism of the cells. Mildronate not only suppresses carnitine-dependent oxidation, but also switches metabolism to more favorable aerobic glycolysis. Under the influence of mildronate general condition of the body is improved both during complete acceptance of alcohol, and on the background of continuation of consumption of alcohol.

Topics: Alcoholism; Animals; Cardiovascular Agents; Carnitine; Ethanol; Male; Methylhydrazines; Rats; Rats, Inbred Strains; Tissue Distribution

Azidothymidine, a nucleoside-analogue reverse transcriptase inhibitor (NRTI), is a commonly used antiretroviral drug in AIDS treatment, however its use is limited by severe toxic side effects due to its influence on mitochondria that result in myopathy, particularly affecting the cardiac muscle. We suggest that effective protection of azidothymidine-induced cardiopathology can be expected from drugs that are capable of targeting mitochondria. Therefore the present study in mice was carried out with mildronate, a cardioprotective drug of the aza-butyrobetaine class, which previously has been shown to act as a highly potent protector of mitochondrial processes. In our study, saline (control), azidothymidine (50 mg/kg), mildronate (50, 100 and 200 mg/kg), and azidothymidine + mildronate (at the doses mentioned) were injected intraperitoneally daily in separate groups of mice for two weeks. At the termination of the experiment, mice were sacrificed, the hearts were removed and cardiac tissue was examined morphologically and immunohistochemically. It was found that azidothymidine, compared to control and mildronate groups, induced major morphologic changes in cardiac tissue, which were manifestated as degeneration and inflammation. These changes were prevented when mildronate was co-administered with azidothymidine. Mildronate also reduced the azidothymidine-induced expression of nuclear factor kappaBp65 (NF-kappaBp65). The obtained data demonstrate a high ability of mildronate of preventing azidothymidine-induced cardiopathologic changes, and suggest mildronate's indirect action on azidothymidine-caused oxidative stress reactions leading to mitochondrial dysfunction. This offers a rational combination of mildronate with azidothymidine or other anti-HIV drugs for beneficial application in AIDS therapy.

Topics: Animals; Cardiovascular Agents; Disease Models, Animal; Heart Diseases; Methylhydrazines; Mice; Mice, Inbred ICR; Mitochondria; Zidovudine

To study efficacy of mildronate in the treatment of elderly patients with cardiac failure (CF).. A total of 91 patients with chronic CF (NYHA FC I-III) entered the study. The study group of 63 patients received standard therapy for a month and mildronate in a dose 750 mg/day. The control group of 28 patients was treated conventionally. Subjective and objective assessment of the patients' condition, quality of life questionnaire, ECG, 6-min walk test were used for evaluation of the treatment efficacy.. In the study group daily frequency of anginal attacks reduced from 1.6 to 0.7 (in the control group from 1.46 to 1.25, p > 0.05), intensity of the attacks--from 1.4 to 0.7 points by 7-score scale (p < 0.05). Crepitation disappeared in 8 (12.8%) patients, edema of the legs--in 3 (4.8%) patients. Systolic blood pressure went down by 8 mmHg, diastolic one--by 4 mmHg. In the control group clinical changes were insignificant.. Elderly patients tolerated mildronate well. It was a safe drug attenuating CF symptoms, increasing exercise tolerance and improving quality of life.

Topics: Age Factors; Aged; Aged, 80 and over; Blood Pressure; Cardiovascular Agents; Female; Follow-Up Studies; Heart Failure; Humans; Male; Methylhydrazines; Middle Aged; Myocardial Contraction; Quality of Life; Treatment Outcome

The inhibition of gamma-butyrobetaine (GBB) hydroxylase, a key enzyme in the biosynthesis of carnitine, contributes to lay ground for the cardioprotective mechanism of action of mildronate. By inhibiting the biosynthesis of carnitine, mildronate is supposed to induce the accumulation of GBB, a substrate of GBB hydroxylase. This study describes the changes in content of carnitine and GBB in rat plasma and heart tissues during long-term (28 days) treatment of mildronate [i.p. (intraperitoneal) 100 mg/kg/daily]. Obtained data show that in concert with a decrease in carnitine concentration, the administration of mildronate caused a significant increase in GBB concentration. We detected about a 5-fold increase in GBB contents in the plasma and brain and a 7-fold increase in the heart. In addition, we tested the cardioprotective effect of mildronate in isolated rat heart infarction model after 3, 7, and 14 days of administration. We found a statistically significant decrease in necrotic area of infarcted rat hearts after 14 days of treatment with mildronate. The cardioprotective effect of mildronate correlated with an increase in GBB contents. In conclusion, our study, for the first time, provides experimental evidence that the long-term administration of mildronate not only decreases free carnitine concentration, but also causes a significant increase in GBB concentration, which correlates with the cardioprotection of mildronate.

Topics: Animals; Betaine; Cardiovascular Agents; Carnitine; Chromatography, High Pressure Liquid; Coronary Circulation; gamma-Butyrobetaine Dioxygenase; In Vitro Techniques; Injections, Intraperitoneal; Male; Methylhydrazines; Myocardial Infarction; Myocardium; Rats; Rats, Wistar

Mildronate (3-(2,2,2,-trimethylhydrazinium)propionate), is a butyrobetaine analogue that is known to inhibit gamma-butyrobetaine hydroxylase, the enzyme catalyzing the last step of carnitine biosynthesis. When administered to adult rats it determines a systemic carnitine deficiency and may therefore serve as an animal model for human carnitine depletion. The aim of this study was to evaluate the effect of mildronate administration to pregnant and lactating rats on tissue carnitine concentrations in 4- and 13-day-old rat pups. At 14 days of gestation female rats began to receive mildronate in the diet (200 mg/kg/d) and this continued for entire lactation period. Mildronate treatment determined a large reduction of carnitine levels in the milk of lactating dams. Because organ carnitine concentrations in neonatal rats are directly related to dietary supply, pups from mildronate group had significantly depleted levels of total carnitine in serum, heart, liver, muscle, brain and pancreas relative to controls, at 4 and 13 days of age. Correspondingly, an increase in triglyceride levels was observed in liver, heart and muscle of mildronate pups. This is in agreement with a reduction of basal rate of oxidation of [U-(14)C]-palmitate to (14)CO(2) and (14)C-acid-soluble products observed in liver homogenates from carnitine-deficient pups. All functional and biochemical modifications were compatible with a carnitine deficiency status. In conclusion our results describe a model of carnitine depletion in pups, suitable for the investigation of carnitine deficiency in fetal-neonatal nutrition, without any concomitant mildronate-mediated metabolic alterations.

Topics: Animals; Animals, Newborn; Cardiovascular Agents; Carnitine; Female; Heart; Lactation; Liver; Methylhydrazines; Milk; Muscles; Palmitates; Pregnancy; Rats; Rats, Sprague-Dawley; Tissue Distribution; Triglycerides

The metabolic and genic effects induced by a 20-fold lowering of carnitine content in the heart were studied in mildronate-treated rats. In the perfused heart, the proportion of palmitate taken up then oxidized was 5-10% lower, while the triacylglycerol (TAG) formation was 100% greater than in controls. The treatment was shown to increase the maximal capacity of heart homogenates to oxidize palmitate, the mRNA level of carnitine palmitoyltransferase I (CPT-I) isoforms, the specific activity of CPT-I in subsarcolemmal mitochondria and the total carnitine content of isolated mitochondria. Concomitantly, the increased mRNA expression of lipoprotein lipase, fatty acid translocase and enzymes of TAG synthesis was associated with a 5- and 2-times increase in serum TAG and free fatty acid contents, respectively. The compartmentation of carnitine at its main functional location was expected to allow the increased CPT-I activity to ensure in vivo correct fatty acid oxidation rates. All the inductions related to fatty acid transport, oxidation and esterification most likely stem from the abundance of blood lipids providing cardiomyocytes with more fatty acids.

Topics: Animals; Biological Transport; Cardiovascular Agents; Carnitine; Carnitine O-Palmitoyltransferase; Esterification; Fatty Acids; Gene Expression Regulation; In Vitro Techniques; Lipoprotein Lipase; Male; Methylhydrazines; Mitochondria, Heart; Myocardium; Oxidation-Reduction; Oxygen Consumption; Palmitic Acid; Perfusion; Rats; Rats, Wistar; RNA, Messenger; Triglycerides

Topics: Acute Disease; Adjuvants, Immunologic; Autoantibodies; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Cardiovascular Agents; Chronic Disease; DNA; Humans; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Methylhydrazines; Myocarditis; Myocardium; Recurrence; T-Lymphocytes; Virus Diseases

Myocardial ischemia can cause myocardial infarction and as a consequence, heart failure. 3-(2,2,2-trimethylhydrazinium) propionate (MET-88) inhibits gamma-butyrobetaine hydroxylase and has cardioprotective effects on the ischemic heart. We now examined the effects of MET-88 in rats with congestive heart failure following myocardial infarction. Congestive heart failure was produced by left coronary artery ligation in rats. MET-88 at 100 mg/kg/day was orally administered from the 2nd day after surgery. We performed a survival study for 181 days, and measured ventricular remodeling, cardiac function, and myocardial high-energy phosphate levels after treatment for 20 days. MET-88 prolonged survival with a median 50% survival of 103 days compared to 79 days for the heart-failure control rats. The expansion of the left ventricular cavity (ventricular remodeling) in heart-failure rats was prevented by treatment with MET-88, and the effect of MET-88 was similar to that of captopril at 20 mg/kg. MET-88 attenuated the rise in right atrial pressure in heart-failure rats and augmented cardiac functional adaptability against an increased load. Also, MET-88 improved the myocardial energy state in heart-failure rats. The present results indicate that MET-88 improves the pathosis in rats with heart failure induced by myocardial infarction.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Body Weight; Cardiovascular Agents; gamma-Butyrobetaine Dioxygenase; Heart Failure; Heart Ventricles; Hemodynamics; Lactic Acid; Male; Methylhydrazines; Mixed Function Oxygenases; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Survival Rate

In this study, we examined the disposition, metabolism, and excretion of a novel cardioprotective agent, 3-(2,2, 2-trimethylhydrazinium)propionate dihydrate (MET-88), in rats. The disposition of MET-88 after oral and i.v. administration of 2, 20, and 60 mg/kg indicated that the pharmacokinetics of MET-88 were nonlinear. The profiles of radioactive MET-88 and total radioactivity in plasma were consistent at doses of 20 and 60 mg/kg. However, at 2 mg/kg, the plasma MET-88 levels were obviously lower than the total. The excretion of radioactivity after oral administration of MET-88 indicated that increasing doses led to a shift from exhaled CO(2) to urinary excretion as the major excretion route. Major metabolites in plasma after oral administration of MET-88 were glucose, succinic acid, and 3-hydroxypropionic acid, and in vitro studies revealed that MET-88 was converted to 3-hydroxypropionic acid by gamma-butyrobetaine hydroxylase (EC 1.14. 11.1). An isolated liver perfusion system modified to trap CO(2) gas was used to examine the excretion pathway of MET-88. [(14)C]CO(2) gas was decreased by the addition of iodoacetic acid, DL-fluorocitric acid, or gamma-butyrobetaine to this system, and subsequent thin-layer chromatography analyses of perfusates revealed that MET-88 was first converted to 3-hydroxypropionic acid by gamma-butyrobetaine hydroxylase and then was biosynthesized to glucose and metabolized to CO(2) gas via the glycolytic pathway and tricarboxylic acid cycle.

Topics: Animals; Carbon Radioisotopes; Cardiovascular Agents; Liver; Male; Metabolic Clearance Rate; Methylhydrazines; Perfusion; Protective Agents; Rats; Rats, Sprague-Dawley

We previously reported that MET-88, 3-(2,2,2-trimethylhydrazinium) propionate, improved left ventricular diastolic dysfunction induced by congestive heart failure (CHF) in rats. The present study was designed to investigate the mechanism by which MET-88 improved the cardiac relaxation impaired in CHF rats. The left coronary artery of the animals was ligated, and the rats were then orally administered vehicle (control), MET-88 at 50 or 100 mg/kg or captopril at 20 mg/kg for 20 days. Myocytes were isolated from the non-infarcted region in the left ventricle, and cell shortening and [Ca2+]i transients were measured with a video-edge detector and by fluorescence analysis, respectively. In CHF control rats, the diastolic phase of cell shortening was prolonged compared with that of the sham-operated (sham) rats. This prolongation was prevented by treatment with MET-88 at 100 mg/kg or captopril at 20 mg/kg. CHF control rats also showed an increase in the decay time of [Ca2+]i transients compared with sham rats. MET-88 at 100 mg/kg and captopril at 20 mg/kg attenuated the increase in decay time of [Ca2+]i transients. Ca2+ uptake activity of the sarcoplasmic reticulum (SR) isolated from the non-infarcted region in the left ventricle was measured, and Lineweaver-Burk plot analysis of the activity was performed. CHF control rats revealed a decrease in the Vmax for SR Ca2+ uptake activity without alteration in Kd. MET-88 at 100 mg/kg significantly prevented the decrease in Vmax, but had no effect on Kd. Also, treatment with MET-88 at 100 mg/kg improved myocardial high-energy phosphate levels impaired in CHF rats. These results suggest that one of the mechanisms by which MET-88 improved cardiac relaxation in CHF rats is based on the amelioration of [Ca2+]i transients through increase of SR Ca2+ uptake activity.

Topics: Adenine Nucleotides; Animals; Calcium; Captopril; Cardiovascular Agents; Energy Metabolism; Enzyme Inhibitors; gamma-Butyrobetaine Dioxygenase; Heart; Heart Failure; In Vitro Techniques; Male; Methylhydrazines; Mixed Function Oxygenases; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum

It was previously reported that inhibition of carnitine synthesis by 3-(2,2,2-trimethyl-hydrazinium) propionate (MET-88) restores left ventricular (LV) systolic and diastolic function in rats with myocardial infarction (MI). Preservation of the calcium uptake function of sarcoplasmic reticulum Ca2+-ATPase (SERCA2) is one of the possible mechanisms by which MET-88 alleviates hemodynamic dysfunction. To test this hypothesis, the effects of MET-88 on protein content of SERCA2 were evaluated using the same rat model of heart failure. Myocardial protein content of hexokinase, which is one of the key enzymes of glucose utilization, was also measured. Either MET-88 (MET-88 group) or a placebo (MI group) was administered for 20 days to rats with MI induced by coronary artery ligation. The control group underwent sham surgery (no ligation) and received placebo. In LV myocardial homogenates, the myocardial SERCA2 protein content was 32% lower (p<0.05) in the MI group than in the control group. However, in the MET-88 group myocardial SERCA2 content was the same as in the control group. Hexokinase I protein content was 29 % lower (p<0.05) in the MI group compared with the control. In contrast, hexokinase II protein content did not differ significantly among the three groups. Consequently, inhibition of carnitine synthesis ameliorates depression of SERCA2 and hexokinase I protein content which may reduce tissue damage caused by MI.

Topics: Animals; Calcium-Transporting ATPases; Cardiovascular Agents; Carnitine; Hexokinase; Isoenzymes; Male; Methylhydrazines; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum Calcium-Transporting ATPases

The site of action of 3-(2,2,2-trimethylhydrazinium) propionate (THP), a new cardioprotective agent, was investigated in mice and rats. I.p. administration of THP decreased the concentrations of free carnitine and long-chain acylcarnitine in heart tissue. In isolated myocytes, THP inhibited free carnitine transport with a Ki of 1340 microM, which is considerably higher than the observed serum concentration of THP. The major cause of the decreased free carnitine concentration in heart was found to be the decreased serum concentration of free carnitine that resulted from the increased renal clearance of carnitine by THP. The estimated Ki of THP for inhibiting the reabsorption of free carnitine in kidneys was 52.2 microM, which is consistent with the serum THP concentration range. No inhibition of THP on the carnitine palmitoyltransferase activity in isolated mitochondrial fractions was observed. These results indicate that the principal site of action of THP as a cardioprotective agent is the carnitine transport carrier in the kidney, but not the carrier in the heart.

Topics: Animals; Cardiovascular Agents; Carnitine; Carnitine O-Palmitoyltransferase; Fibroblasts; In Vitro Techniques; Kidney; Male; Methylhydrazines; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Myocardium; Rats; Rats, Sprague-Dawley

To study quality of life (QL) of patients with chronic heart failure (CHF) and QL changes resultant from mildronate therapy.. QL was studied in 30 IHD patients with CHF of NYHA class II-IV, ejection fraction > 45%; 40 IHD patients without CHF and 30 healthy subjects. CHF patients were treated for 30 days with oral mildronate (250 mg 4 times a day). QL was assessed according to the method SF-36 Health Status Survey.. QL in CHF patients is much lower than that of the controls. Objective severity of the disease and subjective satisfaction with life do not always coincide. Mildronate in a dose 1 g/day per os may be beneficial for LQ of CHF patients.. It is thought desirable to include QL in analysis of efficiency of managing patients with CHF. SF-36 is a tool able to follow up changes in QL of CHF patients within a short-term treatment period.

Topics: Administration, Oral; Adult; Cardiovascular Agents; Chronic Disease; Female; Heart Failure; Humans; Male; Methylhydrazines; Middle Aged; Myocardial Ischemia; Patient Satisfaction; Quality of Life; Stroke Volume; Treatment Outcome

We examined the effects of MET-88 on haemodynamics and cardiac hypertrophy in rats with an aortocaval shunt (A-V shunt). On the day of surgery, an A-V shunt was produced by using an 18-gauge needle in Wistar rats as described by Garcia and Diebold. MET-88 and captopril were orally administered to rats 1 week after surgery, and the administration was continued for 3 weeks. Four weeks after the surgery, A-V shunt-operated rats had biventricular hypertrophy and higher right atrial pressure (RAP) and left ventricular end-diastolic pressure (LVEDP) than sham-operated rats. Compared with untreated A-V shunt rats, those treated with MET-88 showed significant attenuation of the development of left ventricular (LV) hypertrophy and of the increased LVEDP. Captopril-treated A-V shunt rats also failed to show increases in LV weight and LVEDP. In in vitro studies, MET-88 had no effect on renin and angiotensin-converting enzyme (ACE) activities in the plasma of normal rats. These results suggest that MET-88 improved LV hypertrophy and LV dysfunction in rats with an A-V shunt. Furthermore, the data indicate that the beneficial effects of MET-88 may be attributed to some pathway, not involving the renin-angiotensin system, such as myocardial energy metabolism, venous return, etc. We conclude that MET-88 may be a novel agent for the therapy of chronic heart failure.

Topics: Animals; Body Weight; Cardiac Volume; Cardiomegaly; Cardiovascular Agents; Heart; Hemodynamics; Male; Methylhydrazines; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Renin; Ventricular Dysfunction, Left

3-(2,2,2-trimethylhydrazinium) propionate (MET-88) is an inhibitor of carnitine synthesis. This study was carried out to investigate whether or not reduction of carnitine content could attenuate hypoxic damage in isolated perfused rat hearts. Rats were divided into four groups: 1) vehicle control; 2) pretreatment with MET-88 (MET-88); 3) application of insulin (500 muU/mL) in the perfusate (insulin); and 4) pretreatment with MET-88 and application of insulin (MET-88 + insulin). MET-88 (100 mg/kg) was orally administered once a day for 10 days until the day before the experiments. Hearts were initially perfused for a 10 min period under normoxia, followed by a 30 min period under hypoxia. Hearts were frozen at the end of hypoxia for the measurement of high-energy phosphates, carnitine derivatives, and glycolysis intermediates. In a separate series of untreated and MET-88 treated hearts, exogenous glucose and palmitate oxidation was measured. MET-88 decreased the extent of the depression of cardiac contractility (+dP/dt), and aortic flow during the hypoxic state. Insulin also improved cardiac function, and co-treatment of MET-88 and insulin additionally improved cardiac function during hypoxia. MET-88 prevented the decrease of high-energy phosphate and the increase of long-chain acylcarnitine after 30 min of hypoxic perfusion. In addition, MET-88 increased the steady state of glucose oxidation in hypoxic perfused rat hearts. These results indicate that MET-88 has cardioprotective effects on contractile function and energy metabolism of isolated perfused rat hearts in a hypoxic condition. Preventing the accumulation of long-chain acylcarnitine may serve to protect hypoxic hearts.

Topics: Administration, Oral; Animals; Cardiovascular Agents; Carnitine; Coronary Circulation; Glucose; Glycolysis; Heart; Hypoglycemic Agents; Hypoxia; In Vitro Techniques; Insulin; Lactic Acid; Male; Methylhydrazines; Myocardial Contraction; Oxidation-Reduction; Palmitates; Phosphates; Rats; Rats, Sprague-Dawley

Topics: Adult; Aged; Cardiovascular Agents; Chronic Disease; Drug Therapy, Combination; Erythrocytes; Heart Failure; Hemodynamics; Humans; Male; Methylhydrazines; Middle Aged; Myocardial Ischemia

A study is presented of the clinico-hemodynamic efficacy of mildronate in 38 patients with ischemic stroke. The drug produces a positive inotropic effect on the myocardium, improves the cerebral hemodynamics in patients with stroke and postischemic hypo- and hyperperfusion of the brain tissue. It is concluded that mildronate may be recommended for the complex treatment of ischemic disorders of the cerebral circulation.

Topics: Aged; Brain Ischemia; Cardiovascular Agents; Drug Evaluation; Female; Hemodynamics; Humans; Male; Methylhydrazines; Middle Aged; Remission Induction; Time Factors

Central hemodynamic parameters under the effect of mildronate were examined in 62 patients suffering from coronary heart disease, 35 of these with acute myocardial infarction complicated by acute left-ventricular insufficiency and 20 with atherosclerotic cardiosclerosis with chronic cardiac insufficiency. The drug effect was assessed in two groups of patients after a single intravenous injection of 0.5-3 g. In group 1 (n = 53) mildronate effect on central hemodynamic parameters was assessed in spontaneous cardiac rhythm. Variously directed statistically unreliable hemodynamic shifts were revealed, related to heart rhythm changes. In group 2 (n = 9) the drug effect on heart rhythm was eliminated with the use of two-chamber electrocardiostimulation, and various hemodynamic regimens with hypo-, eu-, and hyperkinetic circulation types were artificially created by changing the A-V interval. Mildronate had no effect on the hemodynamics during two-chamber electrocardiostimulation.

Topics: Adult; Aged; Aged, 80 and over; Cardiac Pacing, Artificial; Cardiovascular Agents; Coronary Disease; Electrocardiography; Female; Heart Rate; Hemodynamics; Humans; Male; Methylhydrazines; Middle Aged

Topics: Aged; Cardiovascular Agents; Coronary Disease; Heart Failure; Hemoglobins; Humans; Ligands; Male; Methemoglobin; Methylhydrazines; Middle Aged; Oxyhemoglobins

The method of the study of medical agent influence and biological active substances on duration of small laboratory animals swimming has been worked out excluding the air. For this purpose the animals were placed into altitude chamber, filled with water by 1/3 (one-third) of its volume being in antiorthostatic position on dipping into water. It has been established that at the altitude of 4000 (four thousand) meters high the rat swimming duration became shorter in comparison with their work under normal pressure in 2.5-4 times. Bemitil stimulating work in hypobaric hypoxia depresses it sharply. Bemitil stimulating influence on the rat efficiency did not appear with rising. Antioxidant substance ionol increased efficiency in normal conditions and in hypoxia AKS-85 adaptogenic compound increased swimming in the height duration to a greater degree, mildronat substance for efficiency restoration produced actoprotective influence.

Topics: Amphetamine; Animals; Antioxidants; Atmosphere Exposure Chambers; Atmospheric Pressure; Benzimidazoles; Butylated Hydroxytoluene; Cardiovascular Agents; Hypoxia; Methylhydrazines; Mice; Physical Endurance; Posture; Swimming