Meldonium, as a potential neuroprotective agent, promotes neuronal survival by protecting mitochondria in cerebral ischemia-reperfusion injury.

BACKGROUND: Stroke is a globally dangerous disease capable of causing irreversible neuronal damage with limited therapeutic options. Meldonium, an inhibitor of carnitine-dependent metabolism, is considered an anti-ischemic drug. However, the mechanisms through which meldonium improves ischemic injury and its potential to protect neurons remain largely unknown. METHODS: A rat model with middle cerebral artery occlusion (MCAO) was used to investigate meldonium's neuroprotective efficacy in vivo. Infarct volume, neurological deficit score, histopathology, neuronal apoptosis, motor function, morphological alteration and antioxidant capacity were explored via 2,3,5-Triphenyltetrazolium chloride staining, Longa scoring method, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay, rotarod test, transmission electron microscopy and Oxidative stress index related kit. A primary rat hippocampal neuron model subjected to oxygen-glucose deprivation reperfusion was used to study meldonium's protective ability in vitro. Neuronal viability, mitochondrial membrane potential, mitochondrial morphology, respiratory function, ATP production, and its potential mechanism were assayed by MTT cell proliferation and cytotoxicity assay kit, cell-permeant MitoTracker® probes, mitochondrial stress, real-time ATP rate and western blotting. RESULTS: Meldonium markedly reduced the infarct size, improved neurological function and motor ability, and inhibited neuronal apoptosis in vivo. Meldonium enhanced the morphology, antioxidant capacity, and ATP production of mitochondria and inhibited the opening of the mitochondrial permeability transition pore in the cerebral cortex and hippocampus during cerebral ischemia-reperfusion injury (CIRI) in rats. Additionally, meldonium improved the damaged fusion process and respiratory function of neuronal mitochondria in vitro. Further investigation revealed that meldonium activated the Akt/GSK-3ß signaling pathway to inhibit mitochondria-dependent neuronal apoptosis. CONCLUSION: Our study demonstrated that meldonium shows a neuroprotective function during CIRI by preserving the mitochondrial function, thus prevented neurons from apoptosis.

Meldonium Supplementation in Professional Athletes: Career Destroyer or Lifesaver?

Meldonium is a substance with known anti-anginal effects demonstrated by numerous studies and human clinical trials; however, it does not possess marketing authorization within the European Union, only in ex-Soviet republics. Since 2016, meldonium has been included by the World Anti-doping Agency (WADA) on the S4 list of metabolic modulators. In performance athletes, meldonium is now considered a doping agent due to its capacity to decrease lactate production during and after exercise, its capability to enhance the storage and utilization of glycogen, and its protective action against oxidative stress. Together, these attributes can significantly improve aerobic endurance, cardiac function, and capacity as well as shorten recovery times (allowing higher intensity training), thereby enhancing performance. The purpose of this review is to highlight the most important mechanisms underlying the protective effect of meldonium against mitochondrial dysfunction (MD), which is responsible for oxidative stress, inflammation, and the cardiac changes known as "athletic heart syndrome." Meldonium acts as an inhibitor of γ-butyrobetaine hydroxylase (BBOX), preventing the de novo synthesis of carnitine and its absorption at the intestinal level via the organic cation/carnitine transporter 2 (OCTN2) and directing the oxidation of fatty acids to the peroxisomes. The decrease in mitochondrial ß-oxidation of fatty acids leads to a reduction in lipid peroxidation products that cause oxidative stress and prevent the formation of acyl/acetyl-carnitines involved in numerous pathological disorders. Given the recent findings of the potentially detrimental effects of prolonged high-intensity exercise on cardiovascular health and coronary atherosclerosis, there may be legitimate arguments for the justification of the use of substances like meldonium as protective supplements for athletes.

Novel energy optimizer, meldonium, rapidly restores acute hypobaric hypoxia-induced brain injury by targeting phosphoglycerate kinase 1.

BACKGROUND: Acute hypobaric hypoxia-induced brain injury has been a challenge in the health management of mountaineers; therefore, new neuroprotective agents are urgently required. Meldonium, a well-known cardioprotective drug, has been reported to have neuroprotective effects. However, the relevant mechanisms have not been elucidated. We hypothesized that meldonium may play a potentially novel role in hypobaric hypoxia cerebral injury. METHODS: We initially evaluated the neuroprotection efficacy of meldonium against acute hypoxia in mice and primary hippocampal neurons. The potential molecular targets of meldonium were screened using drug-target binding Huprot™ microarray chip and mass spectrometry analyses after which they were validated with surface plasmon resonance (SPR), molecular docking, and pull-down assay. The functional effects of such binding were explored through gene knockdown and overexpression. RESULTS: The study clearly shows that pretreatment with meldonium rapidly attenuates neuronal pathological damage, cerebral blood flow changes, and mitochondrial damage and its cascade response to oxidative stress injury, thereby improving survival rates in mice brain and primary hippocampal neurons, revealing the remarkable pharmacological efficacy of meldonium in acute high-altitude brain injury. On the one hand, we confirmed that meldonium directly interacts with phosphoglycerate kinase 1 (PGK1) to promote its activity, which improved glycolysis and pyruvate metabolism to promote ATP production. On the other hand, meldonium also ameliorates mitochondrial damage by PGK1 translocating to mitochondria under acute hypoxia to regulate the activity of TNF receptor-associated protein 1 (TRAP1) molecular chaperones. CONCLUSION: These results further explain the mechanism of meldonium as an energy optimizer and provide a strategy for preventing acute hypobaric hypoxia brain injury at high altitudes.

Meldonium Inhibits Cell Motility and Wound-Healing in Trabecular Meshwork Cells and Scleral Fibroblasts: Possible Applications in Glaucoma.

Meldonium (MID) is a synthetic drug designed to decrease the availability of L-carnitine-a main player in mitochondrial energy generation-thus modulating the cell pathways of energy metabolism. Its clinical effects are mostly evident in blood vessels during ischemic events, when the hyperproduction of endogenous carnitine enhances cell metabolic activities, leading to increased oxidative stress and apoptosis. MID has shown vaso-protective effects in model systems of endothelial dysfunction induced by high glucose or by hypertension. By stimulating the endothelial nitric oxide synthetase (eNOS) via PI3 and Akt kinase, it has shown beneficial effects on the microcirculation and blood perfusion. Elevated intraocular pressure (IOP) and endothelial dysfunction are major risk factors for glaucoma development and progression, and IOP remains the main target for its pharmacological treatment. IOP is maintained through the filtration efficiency of the trabecular meshwork (TM), a porous tissue derived from the neuroectoderm. Therefore, given the effects of MID on blood vessels and endothelial cells, we investigated the effects of the topical instillation of MID eye drops on the IOP of normotensive rats and on the cell metabolism and motility of human TM cells in vitro. Results show a significant dose-dependent decrease in the IOP upon topic treatment and a decrease in TM cell motility in the wound-healing assay, correlating with an enhanced expression of vinculin localized in focal adhesion plaques. Motility inhibition was also evident on scleral fibroblasts in vitro. These results may encourage a further exploration of MID eye drops in glaucoma treatment.

Insights into the pharmacodynamics and pharmacokinetics of meldonium after exposure to acute high altitude.

Objective: Meldonium, a well-known cardioprotective drug, has been reported to be protective against pulmonary injury at high altitudes; however, the pharmacodynamics of meldonium in other vital organs under acute high-altitude injury are less investigated and the related pharmacokinetics have not been fully elucidated. Methods and Results: The present study examined the basic pharmacodynamics and pharmacokinetics (PK) in rat exposure to acute high-altitude hypoxia after intragastrical and intravenous pre-administration of meldonium. The results indicate that meldonium can improve acute hypoxia-induced pathological damage in brain and lung tissues, and restore blood biochemistry and routine blood index of heart, liver and kidney tissues under a simulated acute high-altitude environment. Furthermore, compared to the normoxia group, rats exposed to simulated high-altitude hypoxia and premedicated with intragastrical meldonium showed linear kinetics in the dose range of 25-100 mg/kg, with a significantly increase in the area under curve (AUC) and reduced clearance rate. No significant differences in these meldonium of PK parameters were observed with intravenous administration. Additionally, meldonium was involved in the regulation of succinic acid and 3-hydroxypropionic acid. Conclusion: These results will contribute to our understanding of the preclinical PK properties of meldonium and its acute high-altitude protective effects.

[Prospects of use of research results for drugs with anitihypoxic and antioxidative properties in neuroprotective treatment strategies (Opinion of the Council of Experts dated 26 March 2022)]. / Perspektiva ispol'zovaniya rezul'tatov issledovaniya preparatov s anitigipoksantnymi i antioksidantnymi svoistvami v neiroprotektivnoi strategii lecheniya (Zaklyuchenie soveta ekspertov ot 26 marta 2022 g.).

Cerebrovascular diseases are one of the main causes of death and permanent disability. Effective and timely neuroprotective therapy can reduce the burden of cerebrovascular disease. The possibilities of neuroprotection as a method of prevention and medical rehabilitation of acute and chronic cerebrovascular diseases are addressed.

Meldonium Ameliorates Hypoxia-Induced Lung Injury and Oxidative Stress by Regulating Platelet-Type Phosphofructokinase-Mediated Glycolysis.

Hypoxic environments at high altitudes influence the long-term non-altitude health of residents, by inducing changes in metabolism and the mitochondria, severe lung injury, and endangering life. This study was aimed to determine whether meldonium can ameliorate hypoxia-induced lung injury and investigate its possible molecular mechanisms. We used Swiss mice and exposed type Ⅱ alveolar epithelial cell to hypobaric hypoxic conditions to induce lung injury and found that meldonium has significant preventive effect, which was associated with the regulation of glycolysis. We found using human proteome microarrays assay, molecular docking, immunofluorescence and pull-down assay that the target protein of meldonium is a platelet-type phosphofructokinase (PFKP), which is a rate-limiting enzyme of glycolysis. Also, meldonium promotes the transfer of nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus, which mitigates oxidative stress and mitochondrial damage under hypoxic condition. Mechanistically, meldonium ameliorates lung injury by targeting PFKP to regulate glycolysis, which promotes Nrf2 translocation from the cytoplasm to the nucleus to alleviate oxidative stress and mitochondrial damage under hypoxic condition. Our study provides a novel potential prevention and treatment strategy against hypoxia-induced lung injury.

Meldonium residues in milk: A possible scenario for inadvertent doping in sports?

Lately, the veterinary drug Emidonol® has been discussed as a possible scenario for inadvertent doping in sports. Emidonol® is approved for use in livestock breeding, exhibiting antihypoxic and weak sedative effects. The veterinary drug rapidly dissociates into meldonium, a substance prohibited in sports, and is excreted largely in its unchanged form into urine. To investigate if residues of meldonium in edible produce may result in adverse analytical findings in sports drug testing, a pilot study was conducted with three volunteers consuming a single dose of 100 ml meldonium-spiked milk at a concentration of 500 ng/ml (Study 1), and multiple doses of 100 ml of meldonium-spiked milk (500 ng/ml) on five consecutive days (Study 2). In the single dose study, urinary meldonium concentrations peaked between 2 and 6 h post-administration with maximum values of 7.5 ng/ml, whereas maximum meldonium concentrations of 18.6 ng/ml were determined after multiple doses 4 h post-administration. All samples were analyzed using an established and validated protocol based on HILIC-HRMS/MS.

Testing Meldonium: Assessing Soviet pragmatic alternatives to the randomized controlled trial.

BACKGROUND/AIMS: Current research largely tends to ignore the drug-testing model that was developed in the "Second World" as an explicit alternative to the randomized controlled trial. This system can be described as "socialist pharmapolitics," accounting for the specific features of state socialism that influenced the development and testing of experimental drugs. The clinical trials model employed in the "Second World" was heavily influenced by the Soviet Union, which was by far the most influential player in the socialist bloc during the Cold War. Based on extensive archival research, this article presents an empirical case of a late Soviet clinical trial as a pragmatic alternative to the randomized controlled trial model. It accounts for the divergences between the official model prescribed by the Soviet authorities and the messy realities of healthcare practice. It further outlines different factors that ultimately shaped how clinical trials were organized in Soviet institutions "on the ground." Accordingly, this article presents a "real-life" history of "socialist pharmapolitics" and outlines the problems that this system faced in practice. METHODS: Archival research was conducted at the Russian State Archive of Scientific and Technical Documentation in Moscow. Archival files include scientific, technical, and registration documentation such as biochemical, pharmacological, and clinical descriptions of the experimental drug Meldonium, letters between various hospitals, research institutes and the Soviet regulatory body, as well as 26 reports of completed clinical trials. Manual content analysis was used for the interpretation of results. RESULTS: This article presents an empirical case of a late Soviet clinical trial as a pragmatic alternative to the randomized controlled trial model. It demonstrates some key differences from the randomized controlled trial model. This article also highlights some of the discrepancies between the model that was officially prescribed by the Soviet authorities and the realities of experimental drug testing in the Soviet Union in the late 1980s and early 1990s. In particular, it notes some elements of randomization, double-blinding, and the use of placebo that were present in Meldonium trials despite being formally denounced by Soviet bioethics. CONCLUSION: The Soviet model for testing experimental drugs differed from the Western one substantially in a number of respects. This difference was not only proclaimed officially by the Soviet authorities, but was for the most part enforced in clinical trials in practice. At the same time, our research demonstrates that there were important differences between the official model and the clinical realities on the ground.

[The effect of L-carnitine depletion induced by long-term therapy of mice with meldonium on brain mitochondrial balance]. / Vliianie istoshcheniia L-karnitina pri dlitel'noi terapii mel'doniem na mitokhondrial'nyi balans v mozge myshei.

Meldonium is a metabolic drug used for treatment of coronary heart disease. The effect of the drug lies in its ability to inhibit synthesis and transport of L-carnitine. At the same time, a long-term deficiency of L-carnitine can theoretically negatively affect the activity of the transcription factor Nrf2, which is extremely important for maintaining mitochondrial balance in cells. We have shown that meldonium therapy for 3 months at a dose of 100 mg/kg in mice causes a decrease in the expression of the Nrf2 gene in the brain. A decrease in the Nrf2 level causes suppression of mitochondrial biogenesis, which is manifested in a decrease in the level of mtDNA and the level of Cox1 expression. However, no negative effect of meldonium on the bioenergetics parameters of mitochondria was found, as evidenced by the maintenance of a stable mitochondrial potential and the level of production of reactive oxygen species. Jne mohth after the end of the meldonium therapy, expression of the genes responsible for mitochondrial biogenesis and mitophagy (p62, Pink1, Tfam) was observed and the expression level of genes responsible for mitochondrial fusion returned to control values. These changes may be associated with the normalization of the level of L-carnitine in brain cells.

Hyperpolarized magnetic resonance shows that the anti-ischemic drug meldonium leads to increased flux through pyruvate dehydrogenase in vivo resulting in improved post-ischemic function in the diabetic heart.

The diabetic heart has a decreased ability to metabolize glucose. The anti-ischemic drug meldonium may provide a route to counteract this by reducing l-carnitine levels, resulting in improved cardiac glucose utilization. Therefore, the aim of this study was to use the novel technique of hyperpolarized magnetic resonance to investigate the in vivo effects of treatment with meldonium on cardiac metabolism and function in control and diabetic rats. Thirty-six male Wistar rats were injected either with vehicle, or with streptozotocin (55 mg/kg) to induce a model of type 1 diabetes. Daily treatment with either saline or meldonium (100 mg/kg/day) was undertaken for three weeks. in vivo cardiac function and metabolism were assessed with CINE MRI and hyperpolarized magnetic resonance respectively. Isolated perfused hearts were challenged with low-flow ischemia/reperfusion to assess the impact of meldonium on post-ischemic recovery. Meldonium had no significant effect on blood glucose concentrations or on baseline cardiac function. However, hyperpolarized magnetic resonance revealed that meldonium treatment elevated pyruvate dehydrogenase flux by 3.1-fold and 1.2-fold in diabetic and control animals, respectively, suggesting an increase in cardiac glucose oxidation. Hyperpolarized magnetic resonance further demonstrated that meldonium reduced the normalized acetylcarnitine signal by 2.1-fold in both diabetic and control animals. The increase in pyruvate dehydrogenase flux in vivo was accompanied by an improvement in post-ischemic function ex vivo, as meldonium elevated the rate pressure product by 1.3-fold and 1.5-fold in the control and diabetic animals, respectively. In conclusion, meldonium improves in vivo pyruvate dehydrogenase flux in the diabetic heart, contributing to improved cardiac recovery after ischemia.

Screening method of mildronate and over 300 doping agents by reversed-phase liquid chromatography-high resolution mass spectrometry.

Considering the huge amount of substances associated with athletic performance improvement, current doping control analysis requires a comprehensive screening method, which leads to the detection of prohibited substances of different physico-chemical properties. This comprehensiveness associated with instrumental approaches based on high resolution mass spectrometry has allowed the development of extremely sensitive and selective detection methods. Furthermore, it is desirable the method to be simple, fast and straightforward. Mildronate is a highly polar quaternary amine, classified as metabolic modulator by the World Anti-Doping Agency (WADA). The inclusion of mildronate in the screening strategy is a challenge considering its singular physicochemical properties, compared to numerous doping agents of low and medium polarity. For this purpose, a method combining solid-phase extraction (SPE) and dilute-and-shoot approach has been developed and validated, allowing the detection of mildronate and other 332 prohibited substances. In the sample preparation protocol, the enzymatic deconjugation step and SPE conditions were stressed to enable the recovery of mildronate without jeopardizing the detection of other doping agents. The C18/18% SPE cartridge without any type of ionic interaction, associated with the dilute-and-shoot approach proved to be effective for all monitored substances. The instrumental method employed was based on liquid chromatography using a reversed-phase column in a 12-minute gradient coupled to a high-resolution mass spectrometry in full scan with positive and negative switching and fragmentation in the positive mode, for the most critical detection compounds. The performance of the method was evaluated regarding selectivity, precision, recovery, carry-over, limit of detection and stability, following the recommendations of WADA.

Protective Effects of Meldonium in Experimental Models of Cardiovascular Complications with a Potential Application in COVID-19.

Right ventricular (RV) and left ventricular (LV) dysfunction is common in a significant number of hospitalized coronavirus disease 2019 (COVID-19) patients. This study was conducted to assess whether the improved mitochondrial bioenergetics by cardiometabolic drug meldonium can attenuate the development of ventricular dysfunction in experimental RV and LV dysfunction models, which resemble ventricular dysfunction in COVID-19 patients. Effects of meldonium were assessed in rats with pulmonary hypertension-induced RV failure and in mice with inflammation-induced LV dysfunction. Rats with RV failure showed decreased RV fractional area change (RVFAC) and hypertrophy. Treatment with meldonium attenuated the development of RV hypertrophy and increased RVFAC by 50%. Mice with inflammation-induced LV dysfunction had decreased LV ejection fraction (LVEF) by 30%. Treatment with meldonium prevented the decrease in LVEF. A decrease in the mitochondrial fatty acid oxidation with a concomitant increase in pyruvate metabolism was noted in the cardiac fibers of the rats and mice with RV and LV failure, respectively. Meldonium treatment in both models restored mitochondrial bioenergetics. The results show that meldonium treatment prevents the development of RV and LV systolic dysfunction by enhancing mitochondrial function in experimental models of ventricular dysfunction that resembles cardiovascular complications in COVID-19 patients.

[Chronic cerebrovascular diseases and neuroprotection: the clinical efficacy of meldonium (Mildronat)]. / Khronicheskie formy narushenii mozgovogo krovoobrashcheniya i neiroprotektsiya: klinicheskaya effektivnost' primeneniya mel'doniya (Mildronat).

OBJECTIVE: To evaluate the efficacy of meldonium (mildronat) in patients with chronic cerebral vascular disease (CVD). MATERIAL AND METHODS: An open comparative study of the clinical efficacy of meldonium (mildronat) in patients with chronic CVD caused by arterial hypertension and atherosclerosis was conducted. The main group included 30 (60%) patients who were prescribed meldonium (mildronat) at a dose of 1000 mg per day in addition to routine basic therapy. The control group was consisted of 20 (40%) patients who received routine basic therapy only. The duration of the study was 60 days. To evaluate the clinical efficacy of the meldonium (mildronat), the main subjective clinical symptoms, neurological, psychoemotional and cognitive status, quality of life were assessed when patients were included in the study (before treatment), on the 11th and 60th days from the start of treatment. To assess the meldonium (mildronat) effect on the endothelium vascular wall, asymmetric dimethylarginine (ADMA), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and endothelin-1 were determined in the blood when patients were included in the study, on the 11th and 60th days from the start of treatment. RESULTS: Meldonium (mildronat) has a positive therapeutic effect on the main clinical symptoms and cognitive functions which appears in increasing the quickness of mental activity, improving short-term and operative memory, increasing the resistance of mental processes and memory traces to interfering influences, and improving cognitive evoked potentials P300 results. Meldonium (mildronat) therapy leads to the decrease in the level of state and trait anxiety. The quality of life of patients treated with meldonium (mildronat) increases due to the physical and mental components. The effect of meldonium (mildronat) on the decrease in endothelin-1 and PAI-1 levels, which indicates the antitrombogenic effect of the drug, has been identified. CONCLUSION: Nootropic, anxiolytic and antitrombogenic effects of meldonium (mildronat) in patients with chronic CVD are demonstrated that makes it possible to recommend this drug for widespread use by specialists in clinical practice.

The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity.

A mismatch between ß-oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3-(2,2,2-trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington's disease (HD). Here, new THP-derived carnitine-lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster.

Meldonium determination in milk and meat through UHPLC-HRMS.

A simple and sensitive procedure for the quantification of meldonium in milk and meat by UHPLC-HRMS is presented. Some products were investigated to contain this substance due to using a veterinary drug called "Emidonol". According to the instruction for this drug, it can be used for injection (for cows) and as an additive in drinking water for chickens. Although meldonium is not a threat for human health, it is strictly prohibited in professional sports according to WADA Prohibited List. Sample preparation conditions were optimized for both matrices that allowed to eliminate matrix effects and achieve reproducible and accurate results. Protein precipitation with dilution were applied for milk samples, while chicken meat and liver were homogenized with quartz sand to achieve satisfactory meldonium recovery. The results of milk and meat samples analysis purchased at the farmers' fair are presented in this article. Meldonium concentration in raw milk was investigated to be up to 880 ng/mL. However, pasteurization can be used for partial cleanup from meldonium (up to 2 times). The same research was conducted for chicken meat and liver. Thermal treatment shows a good result for a meat cleanup. The proposed method was partially validated, limits of detection and quantification were established for each matrix.

METABOLIC THERAPY IN THE COMPLEX TREATMENT OF CHRONIC PANCREATITIS WITH STABLE CORONARY ARTERY DISEASE.

OBJECTIVE: The aim: To study the effectiveness of using medicine meldonium in standard therapy to the correction of prooxidant-antioxidant and kallikrein-kinin disorders in patients with chronic pancreatitis andstable coronary artery disease. PATIENTS AND METHODS: Materials and methods: The study included 90 patients with chronic pancreatitis andstable coronary artery disease.They were divided into two groups: I group (45 patients) received standard treatment; II group (45 patients) along with basic therapy received medication meldonium (Vazonat) for 2 capsules (500 mg) once daily for two months. Indicators prooxidant-antioxidant system in blood plasma was determined by biochemical method, indicators of kallikrein-kinin system- by chromatographic method. RESULTS: Results: The better status of the prooxidant-antioxidant system and kallikrein-kinin system was observed in patients who received in addition to standard protocol treatment with meldonium. CONCLUSION: Conclusions: Adding to the complex therapy of patients with chronic pancreatitis and stable coronary artery disease of the medicine meldonium helps to improve the prooxidation-antioxidant status and disorders in the kallikrein-kinin system more significantly compared with standard basic therapy.

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.

Increased fatty acid oxidation and mitochondrial proliferation in liver are associated with increased plasma kynurenine metabolites and nicotinamide levels in normolipidemic and carnitine-depleted rats.

Dysregulation of the tryptophan (Trp)-NAD+ pathway has been related to several pathological conditions, and the metabolites in this pathway are known to influence mitochondrial respiration and redox status. The aim of this project was to investigate if stimulation of beta-oxidation and mitochondrial proliferation by the mitochondrial-targeted compound 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA) would influence metabolites of the Trp-Kyn-NAD+ pathway. We wished to investigate how carnitine depletion by meldonium-treatment influenced these metabolites. After dietary treatment of male Wistar rats with 1-triple TTA for three weeks, increased hepatic mitochondrial- and peroxisomal fatty acid oxidation resulted. The plasma content of total carnitines decreased compared to control animals, whereas hepatic genes involved in CoA biosynthesis were upregulated by 1-triple TTA treatment. The plasma Trp level and individual metabolites in the kynurenine pathway were increased by 1-triple TTA, associated with decreased hepatic gene expression of indoleamine2,3-dioxygenase. 1-triple TTA treatment increased conversion of Trp to nicotinamide (Nam) as the plasma content of quinolinic acid, Nam and N1-methylnicotinamide (mNam) increased, accompanied with suppression of hepatic gene expression of α-amino-α-carboxymuconate-ε-semialdehyde decarboxylase. A positive correlation between mitochondrial fatty acid oxidation and Trp-derivatives was found. Almost identical results were obtained by 1-triple TTA in the presence of meldonium, which alone exerted minor effects. Moreover, the plasma Kyn:Trp ratio (KTR) correlated negatively to mitochondrial function. Whether increased flux through the Trp-NAD+ pathway increased redox status and lowered inflammation locally and systemically should be considered.

News and views in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): The role of co-morbidity and novel treatments.

Though affecting many thousands of patients, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) should be considered an orphan disease, since the cause remains elusive and no treatment is available that can provide complete cure. There is reasonable insight into the pathogenesis of signs and symptoms, and treatments specifically directed to immunological, inflammatory and metabolic processes offer relief to an increasing number of patients. Particular attention is given to the importance of co-morbidity requiring appropriate therapy. Promising results are obtained by treatment with Metformin, or possibly Momordica charantia extract, which will correct insulin resistance, with Meldonium improving the transportation of glucose into the mitochondria, with sodium dichloroacetate activating pyruvate dehydrogenase, and with nutraceutical support reducing oxidative and inflammatory impairment.