Topical combination of meldonium and N-acetyl cysteine relieves allodynia in rat models of CRPS-1 and peripheral neuropathic pain by enhancing NO-mediated tissue oxygenation.

Local microvascular dysfunction and consequent tissue ischemia/hypoxia contribute to the symptoms of complex regional pain syndrome (CRPS) and peripheral neuropathic pain. As nitric oxide (NO) is a key regulator of microvascular blood flow, compounds that increase it are potentially therapeutic for these pain conditions. This led us to hypothesize that the topical administration of drugs that modulate local tissue NO levels can alleviate the pain of CRPS and peripheral neuropathic pain. We investigated the anti-allodynic effect of a combination of two NO-modulating drugs: meldonium and N-acetylcysteine (NAC). An equimolar topical formulation of the two drugs was tested on chronic post-ischemic pain (CPIP), a rat model of CRPS, as well as chronic constriction injury (CCI) of the sciatic nerve and chemotherapy-induced painful neuropathy (CIPN), rat models of peripheral neuropathic pain. Topical meldonium-NAC produced significant anti-allodynia in CPIP, CCI, and CIPN rats. Moreover repeated application of topical meldonium-NAC produced an increase in the duration of anti-allodynia in the CPIP and CCI rats. While pre-treatment with an NO synthase inhibitor attenuated the anti-allodynic effects of meldonium-NAC, 30-min hyperbaric oxygen treatment combined with a non-effective dose of meldonium-NAC produced significant anti-allodynic effects in CPIP rats. Both experiments implicated NO in the drug combination's anti-allodynic effects. To ascertain the role played by changes in local tissue NO, we performed a quantification of plantar muscle NO in CPIP rats after hind paw topical treatment with meldonium-NAC and revealed significantly increased plantar muscle NO levels in drug-treated rats. The drug combination also reversed the reduction in tissue oxygenation normally observed in CPIP hind paws. In addition to introducing a novel topical treatment for mechanical allodynia in CRPS and peripheral neuropathic pain, this work showcases the analgesic potential of locally targeting microvascular dysfunction and tissue ischemia/hypoxia in these conditions, with emphasis on the role of NO.

Long-term mildronate treatment increased Proteobacteria level in gut microbiome, and caused behavioral deviations and transcriptome change in liver, heart and brain of healthy mice.

Mildronate is a cardiac and neuroprotective drug that is widely used in some countries. By inhibiting carnitine biosynthesis, mildronate impairs the fatty acids transport into mitochondria, thereby decreasing the ß-oxidation intensity. Since 2016, it has been prohibited by the World Anti-Doping Agency (WADA). However, the information on its safety and its influence on the athletes' health is scarce. There are no published studies on whether mildronate-induced long-term metabolism "rearrangement" may cause negative effects on high-metabolic-rate organs and on the whole organism. Here, we demonstrate that long-term mildronate treatment of healthy mice induced global metabolism change at the transcriptome level in liver, heart, and brain. Mildronate treatment also induced some behavioral changes such as anxiety-related behavior and diminished explorative behavior. We also found that mildronate induced a dysbiosis, as manifested by an increase in Proteobacteria level in gut microbiome. At the same time, the absence of a statistically significant increase in mouse strength and endurance procedures suggests that mildronate effect on productivity is negligible. The sum of our data suggests that long-term treatment of healthy mice with mildronate induces dysbiosis and behavioral deviations despite the effectiveness of mildronate for cardiac and neurological diseases. Thus, we suggest that long-term mildronate treatment is undesirable or at the very least should be accompanied by prebiotics treatments, but this issue should be studied further.

[Efficacy of Short-Term Therapy With Meldonium in Patients With Chronic Heart Failure of Ischemic Etiology and Type 2 Diabetes Mellitus].

PURPOSE: 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. RESULTS AND CONCLUSION: 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.

Meldonium use by athletes at the Baku 2015 European Games.

BACKGROUND: The aim of this report was to estimate the prevalence of meldonium use in athletes competing in the Baku 2015 European Games to contribute to the surveillance of substances on the 2015 World Anti-Doping Agency (WADA) Monitoring Program. Meldonium is reported to be used by athletes to potentially enhance personal performance and shorten the recovery period after physical activity. METHODS: Three sources of data were reviewed to determine the prevalence of meldonium use during the Games including: (1) athlete self-reported declarations of drug and supplement use; (2) declarations from National Olympic Committee medical teams of the list of medicines that they imported into Azerbaijan as part of their stock of drugs for administration; (3) results from the antidoping laboratories reporting the detection of meldonium. RESULTS: Meldonium was declared as imported into Azerbaijan by 2 of 50 National Olympic Committee medical teams at the Games, but athletes from 6 countries declared the use of meldonium. Only 23 of the 662 (3.5%) athletes tested from 8 to 28 June 2015 declared the personal use of meldonium, which included 13 competition winners. However, 66 of the total 762 (8.7%) athlete urine samples analysed during the Games and during precompetition tested positive for meldonium. Meldonium use was detected in athletes competing in 15 of the 21 sports during the Games. CONCLUSIONS: This study highlights the widespread and inappropriate use and prescribing of this prescription drug in a generally healthy athlete population. Subsequent to these findings, WADA has included meldonium as a prohibited substance on the 2016 List of Prohibited Substances.

Pharmaceutical Composition for Improving Physical Working Capacity.

For development of a pharmaceutical composition improving physical performance, effects of various drugs and their combinations on forced swimming test performance were studied on laboratory rats. Maximum increase in animal performance was produced by a 3-component composition asparcam+mildronate+metaprote in proportion of 5.0, 10.7, and 14.3 mg/kg, respectively. No changes in blood serum biochemistry and morphological composition of the peripheral blood were detected after single intragastric administration of the composition.

[Effects of Meldonium in Early Postmyocardial Infarction Period].

UNLABELLED: 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. THE AIM: To evaluate the meldonium clinical effectiveness in the early postmyocardial infarction period. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

[Unsolved problems of cytoprotective therapy in patients with coronary heart disease].

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.

[Efficiency of meldonium in the complex therapy of acute coronary syndrome].

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.

[Cardioprotective capabilities of drug meldonium in secondary prevention after percutaneous coronary intervention in patients with documented myocardial ischemia].

The purpose of research ­ analysis of capabilities in cytoprotective drug mеldonium, in complex in the cardioprotective effect of secondary prevention after percutaneous coronary intervention (PCI). Patients with stable coronary heart disease (n=35 ) aged ≤65 years with incomplete revascularization at 6 months after PCI and positive exercise test (SFI) were randomized 1:1 to groups controlled physical training (CPT) with intensity 80% and a duration of 2 weeks (10 SFI): group 1 (n=17; 53,9±6,2 years) and group 2 (n=18; 56,1±4,8 years). Patients in Group 1, in addition to SFI mеldonium administered at a dose of 1000 mg/ml intravenously. In the 1st group on the background mеldonium adjunctive therapy showed a significant increase in the duration from 15±2 to 32±7 min for the 10th CPT (p<0.05). Index of maximum oxygen consumption after 10 intense CPT increased to 20.8±1.06 ml/kg/min compared to baseline (18.6±1.1 ml/kg/min, p<0.05) and the control group (18.5±1.5 ml/kg/min, p<0.05). Use of meldonium was also associated with decrease of maximum ST-segment depression (from -0.18±0.1 to 0.10±0.2 mV), increases of exercise duration (from 364±22 to 556±29 s) threshold heart rate (from 118±12 to 132±5 bpm), decrease of time of ST segment recovery to baseline (from 385±32 to 242±22 s, p<0.05). Final level of free fatty acids in the meldonium group was significantly lower than that in the control group (0.248±0.047 vs. 0.265±0.031 mg/dl). Inclusion of meldonium in complex treatment after PCI potentiates cardioprotective effect of intensive CPT as evidenced by the positive dynamics of ECG and biochemical markers of myocardial ischemia.

[The ability to use meldonium as adaptogen in winter in patients with cardiovascular disease].

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.

[Clinical experience of application mildronate at recovery treatment of patients with displazia connecting fabric].

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).

[Using meldonium to improve the adaptation of patients with cardiovascular disease to the effects of heat and correction of associated oxidative stress].

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.

[Role of pFox inhibitors in the treatment of patients with acute myocardial ischemia].

AIM: 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. SUBJECTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[Use of meldonium in the combination treatment of patients with heart failure in the early postinfarction period].

AIM: 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). SUBJECTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[Effect of sanatorium treatment on endothelial function in children with primary arterial hypertension].

To study the effect of sanatorium treatment (ST) using sodium chloride baths and metabolic drug mildronat on the dynamics of the ambulatory blood pressure monitoring (ABPM), markers of endothelial function in children with primary arterial hypertension (PAH). ABPM and held defined level of asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1) and nitric oxide (NO) in the serum of 114 children with PAH aged 12-17. The positive dynamics of ABPM in all groups, but significantly (P < 0.05) decrease in mean BP was noted in the group with combined ST using sodium chloride baths. When analyzing the level of NO a positive trend (P < 0.01) in the group was using metabolic therapy, but significantly (P < 0.001) pronounced effect was observed when it is combined balneotherapy and metabolic therapy. Analysis of ET-1 and ADMA at ST in conjunction with therapy and metabolic rate of sodium chloride baths there was a significant (P < 0.01) decrease in these parameters in comparison with those before treatment. In children with PAH have been identified violations of the functional activity of the endothelium, which is reflected in increased levels of ET-1, ADMA and reducing NO. Conducting rehabilitation inclusion complex balneotherapy and metabolic therapy helps to reduce average daily blood pressure, normalization of functional activity of the endothelium as a normalization of the synthesis of NO (P < 0.,001), a significant decrease of ET-1 (P < 0.01) and ADMA (P < 0.01).

[Parallel pharmacological correction of myocardial dysfunction, cognitive and psychopathological disordres in patients with congestive heart failure].

Was examined 92 patients with congestive heart failure III-IV FC with fraction of emission left ventricle < 45% against coronary artery disease. Patients of control group received basic therapy (according to recommendations of the Ukrainian society of cardiology), the 1 group--in addition received a preparation of Vazonat within 15 days intravenously in a dose of 1000 mg a day further are out-patient within 1 month on 250 mg 3 times per os; the 2 group--under the same scheme a preparation of Vazonat and a day tranquilizer of Adapto in a dose of 500 mg twice a day throughout all term of supervision. It is established that addition of Vazonat to basic treatment leads to additional effect concerning improvement of indicators cardio-hemodynamic, to improvement congestive functions. Joint appointment of preparations of Vazonat and Adaptol against basic treatment leads to more expressed improvement congestive functions, to progressive reduction of degree of trouble, depression.

Elevated vascular γ-butyrobetaine levels attenuate the development of high glucose-induced endothelial dysfunction.

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.

Influence of mildronat on left ventricular systolic, diastolic functional parameters, pulmonary arterial flow and systolic dyssynchrony in patients with congestive heart failure.

The aim of the study was to investigate the influence of metabolic treatment with Mildronat on left and right ventricular function, pulmonary flow and systolic synchrony in patient with heart failure. We studied 16 persons with 2-3-d NYHA class Heart Failure, 8 male and 8 female (age 69.2±9.3). All where in stable condition at last for 3 months and take traditional medical treatment (ACE inhibitors or AT2-blockers, beta-blockers, Furosemide, Spirolactone). It was added Mildronat (500 mg 2x daily per os) for 2 months. All patient undergone standard EchoCG, PW and Color Tissue Doppler (TD) examination before and after 2 months of treatment with Mildronat. It was noted significant decrease LV end systolic volume and increase of Ejection Fraction and Fractional Shortening of LV after 2 month treatment with Mildronat. LV Tissue Doppler parameters did not change significantly, it was noted only tendency of increasing Right Ventricular systolic velocity. Pulmonary Arterial Acceleration Time significantly increased, right ventricular (RV) isovolumic relaxation time and RV TEI index (Systolic-Diastolic Index) on Tissue Doppler was significantly decreased after the treatment, which indicates improvement of RV function and decrease of Pulmonary Arterial Pressure. There was improvement of Intraventricular synchrony, systolic delay time between intraventricular septum and lateral wall became shorter after 2 month treatment with Mildronat but interventricular delay did not change significantly. Addition of Mildronat to traditional medical treatment improves left ventricular systolic function in patients with Heart Failure. Mildronat improves left ventricular systolic dissynchroni in patients with Heart Failure. Mildronat increases the pulmonary arterial flow acceleration time and shortens Right Ventricular isovolumic relaxation time and TEI index, this means that it reduces the Pulmonary Arterial Pressure and improves right ventricular function.

[Microcirculatory effects of fluctophoresis series in patient with moderate chronic periodontal disease].

The results of fluctophoresis series in 160 patients aged 35-75 years with chronic periodontal disease are discussed in the paper. It was shown that fluctophoresis may improve both clinical and rheographic values, as well and laser Doppler flowmetry rates because of improved microcirculation. Mildronat fluctophoresis influences myogenic regulation while nivaline acts as neurogenic vessel tone regulator. Acovegine fluctophoresis is effective in cases with neither myogenic nor neurogenic regulation disorder.

[Cytoprotectors and their application in sports medicine].

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.