Meldonium - educational materials

Meldonium, also known by the trade name Mildronate, is a synthetic compound that was first developed in Latvia during the Soviet era [1]. It was originally created at the Institute of Organic Synthesis in Riga (Latvian SSR) by Professor Ivars Kalviņš and introduced as a pharmaceutical product in the 1980s by the Latvian pharmaceutical company Grindex. It was initially used in veterinary medicine to increase animal growth, and was later repurposed for use in humans to treat a range of cardiovascular and metabolic diseases.

The development of meldonium was driven by research efforts in the Soviet Union to improve energy use and endurance, both in animals and humans. During the late Soviet period and after the collapse of the USSR, meldonium gained popularity as a cardioprotective drug in various Eastern European countries. It was used to treat conditions such as angina pectoris, heart failure and in rehabilitation after heart surgery. Although well known in Eastern Europe and post-Soviet countries, meldonium only gained significant international attention around 2016, when the World Anti-Doping Agency (WADA) banned its use in professional sports due to evidence that it can enhance athletic performance. This led to increased global awareness of the compound and its properties.

Chemical composition and properties: The chemical name of meldonium is 3-(2,2,2-trimethylhydrazine) propionate dihydrate. Structurally, it is a small organic molecule containing a hydrazine group. This unique structure allows meldonium to affect the metabolism of carnitine, a nutrient involved in the transport of fatty acids to the mitochondria for energy production.

Available formulations: Meldonium is usually sold as capsules, solutions for injection and other oral forms. In medical facilities where it is approved, a doctor's prescription is generally required.

Meldonium as a cardioprotective agent

Meldonium, originally developed to help the body in low-oxygen conditions, is being widely studied as a heart-protective drug. It helps the heart work better after severe heart attacks, reduces levels of harmful substances associated with heart disease and improves quality of life in extremely hot or cold weather conditions. For example, Mikhin et al (2014) studied 140 patients (average age about 55) with a severe type of heart attack known as a Q-wave myocardial infarction [2]. Patients received meldonium at a dose of 1 g/day intravenously for 2 weeks and then orally for up to 1.5 months. Compared to those receiving standard therapy alone, patients receiving meldonium recovered their cardiac filling capacity faster. This was evident by lower levels of NT-proBNP, a marker of cardiac stress in the blood. The group taking meldonium also had fewer dangerous heart rhythm problems soon after arterial decongestion treatment. In addition, they showed fewer signs of oxidative stress, which can damage the heart. These results suggest that starting meldonium treatment early in a heart attack can reduce the risk of fatal heart rhythm problems and improve a patient's overall outcome.

In another study, Dambrova et al (2013) focused on the effects of meldonium on trimethylamine N-oxide (TMAO), a substance associated with artery clogging or atherosclerosis [3]. Eight healthy volunteers took meldonium (500 mg twice a day) after eating a diet rich in TMA. With meldonium, their blood TMAO levels were significantly lower, and more TMAO left the body with the urine. By reducing TMAO levels, meldonium may prevent arterial damage and lower the risk of heart disease.

Meldonium has also shown benefits in harsh weather conditions. In hot summer conditions, Smirnova et al (2014) administered meldonium (500 mg/day) to people with heart problems [4]. Compared to those who did not take meldonium, these patients had more stable blood pressure and heart rate, as well as higher sodium levels. They also felt better overall, as evidenced by better quality of life scores. Importantly, meldonium helped control harmful oxidative stress associated with heat. Similarly, during the cold winter, Smirnova et al (2014) studied CVD patients taking meldonium (1000 mg/day) along with their regular treatment [5]. These patients maintained stable blood sugar and cholesterol levels, while these levels worsened in those not taking meldonium. Meldonium users also reported feeling better during the coldest months, suggesting that meldonium helps the body adapt to harsh weather conditions and stay healthy.

Meldonium can improve heart function, reduce chest pain, stabilize heart rhythm and enhance the body's stress response during recovery from a heart attack. In a study, Statsenko et al (2014) examined 60 patients aged 45-75 who were recovering from a heart attack [6]. About three to four weeks after the heart attack, these patients had symptoms of chronic heart failure. Half of them received meldonium 1000 mg/day intravenously for 10-14 days along with their usual therapy, while the other half received only standard treatment. Compared with the standard group, those receiving meldonium reported fewer angina attacks (chest pain), relied less frequently on nitroglycerin and experienced fewer arrhythmias. They also showed improvements in heart rate variability (HRV), a sign that their cardiac control system was more stable. Their quality of life improved more than in the group without meldonium. Thus, short-term use of meldonium helped these patients recover faster and feel better after their heart attack.

In a clinical trial, Statsenko et al (2014) retested meldonium at a dose of 1,000 mg/day intravenously for 10-14 days in patients with heart failure who were in the early stages after myocardial infarction [7]. Compared with those on standard treatment, meldonium-treated patients had fewer episodes of chest pain, fewer irregular heartbeats and fewer signs of cardiac strain. Their heart structure and function looked better on tests, and their HRV values improved. These results confirm the potential of meldonium to help patients recover in the first weeks after a heart attack.

Meldonium also helps patients with diabetes. Belikova et al (2019) looked at patients with non-cardiac atherosclerosis (heart attack scarring) and type 2 diabetes [8]. These patients took meldonium and taurine together for 12 weeks. Compared to the group that did not take meldonium, they had better HRV results. Improved HRV means that the heart adapts better and remains more stable under stress. By reducing harmful oxidative stress and improving heart rate control, meldonium combined with taurine may promote better heart health in patients with diabetes.

Similarly, Nechaeva and Zheltikova (2015) studied 67 patients shortly after a heart attack [9]. For 12 weeks, one group received standard treatment for ischemic heart disease, while the other group took meldonium along with standard care. The group taking meldonium had fewer episodes of angina, fewer abnormal heart rhythms and lower blood pressure. They also felt better and reported less anxiety. These improvements suggest that meldonium helps restore the heart's energy balance and reduces harmful byproducts that can form after a heart attack.

Mildronium offers similar efficacy to standard medications in the treatment of stroke, and can help improve heart function, reduce cardiac workload and promote healthy blood vessels and circulation. In a study by Zhu et al (2013), they compared mildronate with cinepazide in a study of 227 patients with acute ischemic stroke [10]. Both groups also received aspirin. After two weeks and again after three months, there were no significant differences between the two therapies. Patients receiving mildronate recovered at a similar rate and had no more serious side effects than patients receiving cinepazide. This suggests that mildronate is as safe and effective as standard stroke treatment.

Liepinsh et al (2011) looked at healthy volunteers who took mildronate (500 mg twice a day) for four weeks [11]. They found that mildronate lowered levels of a substance called l-carnitine in the blood, while increasing levels of another substance, γ-butyrobetaine. It also led to greater urinary excretion of these substances. Changing these levels may help people with certain metabolic diseases and heart disease. Although further research is needed, mildronate's effects on these substances could potentially promote better heart health and energy use in the body.

Meldonium can also help patients after a heart attack, especially those with diabetes. Statsenko et al (2007) studied patients who were 3-4 weeks post-MI and had both chronic heart failure (CHF) and type 2 diabetes [12]. Those who took mildronate (1 g/day) along with standard therapy showed better cardiac pumping ability, better exercise tolerance and better renal function than those who received only standard therapy. They also had healthier cholesterol levels and blood sugar control. Overall, these patients felt better and more stable during their recovery.

In addition, mildronate appears to help older patients with coronary heart disease (CHD). Shabalin et al (2006) studied its effects in elderly patients with CHD and heart failure [13]. Those taking mildronate (500 mg/day) for 12 weeks showed less harmful oxidation of LDL ("bad" cholesterol) and an increase in nitric oxide, a substance that helps relax blood vessels. These changes may support better circulation and protect the heart over the long term. Moreover, Nevzorov and Markevich (2013) studied patients with both sudden (acute) and long-term (chronic) blood flow problems in the brain. The patients were given a single dose of 1000 mg of meldonium intravenously [14]. After treatment, they showed significant improvement. These results suggest that meldonium can help patients cope with cerebral ischemia in both emergency and regular care, making it a potentially effective therapeutic option.

In another study, Statsenko et al (2008) looked at patients with type 2 diabetes and nerve damage (sensorimotor neuropathy) [15]. Half received standard treatment plus alpha-lipoic acid and meldonium (1 g/day) for three months, while the others did not receive meldonium. Those taking meldonium did better overall. They had better nerve tests, better tissue oxygenation and less oxidative stress. This means that meldonium can protect nerves and reduce the damage caused by unstable molecules called free radicals. Moreover, Tanashyan et al (2020) tested meldonium (1000 mg/day) in patients with chronic cerebral blood flow problems caused by high blood pressure and arterial disease [16]. Compared to those on standard treatment, patients taking meldonium thought more clearly and quickly. They also felt calmer, had fewer anxiety symptoms and their quality of life improved. Meldonium also helped blood vessels work better, lowering some harmful markers. This suggests that meldonium may help improve mental function, mood and blood vessel health in people with ongoing cerebral circulation problems.

The antioxidant benefits of meldonium were also noted by Suslin et al (2003) [17]. They studied patients with minor strokes and blood flow problems who took mildronate (500 mg/day) or L-carnitine. Both reduced harmful oxidation of fats in the blood, and L-carnitine also helped control blood sugar levels and improved thinking and memory. These findings support meldonium's role in protecting the brain and blood vessels from damage. Ol'binskaia and Golokolenova (1990) also found that meldonium helped reduce certain types of abnormal heartbeats in people with heart disease [18]. When administered intravenously, it also increased cardiac strength, and patients tolerated it well with no reported side effects.

Meldonium appears to promote cardiac healing after a heart attack, improve blood flow, reduce chest pain and reduce the risk of complications. It may be useful alone or in combination with other drugs. Studies suggest that meldonium, alone or in combination with other drugs, may speed recovery from a heart attack and help manage chest pain and heart failure symptoms. In a clinical trial, Teplyakov et al (2003) studied 47 patients with heart damage after a heart attack [19]. One group had mild heart failure and took meldonium alone (0.75-1 g/day). Another group had more severe heart failure and took meldonium together with atenolol (25-50 mg/day) for three weeks. In both groups, meldonium helped reduce the heart's oxygen demand and relieved chest pain. In the group with severe heart failure, the combination of meldonium with atenolol provided even greater protection without harming blood flow. Only a few patients (4.2%) experienced minor side effects. This shows that meldonium, alone or with atenolol, can safely promote heart health in people who have undergone a heart attack.

Another study by Savchuk et al. (1991) looked at the effects of meldonium on blood flow to the heart [20]. In animals, meldonium opened the blood vessels of the heart, improving blood flow and protecting the heart under low oxygen conditions. Similar results were observed in people with chest pain (angina), where meldonium promoted better blood flow through the coronary arteries, helping to reduce cardiac stress. In addition, Svanidze et al (2006) combined meldonium with two other therapies (high-dose glucose-insulin-potassium solution and preductal MR) in 20 patients who had just undergone a heart attack [21]. Compared to the 20 patients who received standard therapy, patients undergoing this "metabolic triad" had fewer abnormal heart rhythms and healed faster, as evidenced by more rapid normalization of ECG changes. This suggests that adding meldonium to the treatment plan may help the heart heal more effectively after a heart attack.

Studies also suggest that meldonium can relieve chest pain, increase physical endurance and support people with more advanced heart failure when used along with standard therapies. Dudko et al (1989) studied 50 patients with activity-induced angina [22]. They compared mildronate alone with placebo and used exercise tests on stationary bicycles to measure patients' progress. Those taking mildronate experienced fewer angina attacks and were able to exercise for longer before experiencing symptoms. This means that mildronate may help reduce chest pain and increase physical performance in people whose angina is exacerbated by exercise.

Another study by Chumburidze et al (2005) looked at patients with severe chronic heart failure (CHF), classified as NYHA class III-IV [23]. These patients were already taking standard treatment, such as diuretics, ACE inhibitors, beta-blockers and digoxin. After adding mildronate, the patients showed marked improvement. They were able to walk farther during the 6-minute test, their heart function improved on ultrasound, and they moved into a better heart failure class, meaning they felt less constrained by their symptoms. This suggests that adding mildronate may help the heart work more efficiently, giving patients with severe heart failure a better quality of life.

Human studies on meldonium indicate that it may play a significant role as a cardioprotective agent. Studies have shown that meldonium helps improve heart function after severe heart attacks, increases exercise capacity, stabilizes heart rhythm and reduces chest pain. It aids recovery by promoting better energy utilization in the heart, lowering harmful metabolic byproducts and protecting the heart under harsh conditions such as extreme temperatures and low-oxygen environments. Meldonium also shows potential benefits in patients with diabetes, heart failure and other cardiovascular risk factors. Although further research is needed to fully understand its mechanisms and establish standard treatment protocols, existing evidence suggests that meldonium may be a safe and effective addition to therapy to improve heart health and patient outcomes.

Meldonium for endurance and exercise performance

Meldonium (mildronate) shows great potential for improving endurance, exercise capacity and overall fitness in people with various heart conditions. When added to standard treatments, it appears to help patients exercise longer, experience fewer symptoms and improve their quality of life. In a clinical trial, Liamina et al (2014) studied 35 patients with heart disease who underwent a procedure called percutaneous coronary intervention (PCI) [24]. All patients participated in 10 sessions of controlled physical training at an intensity of about 80% for two weeks. One group also received meldonium (1000 mg/day). Compared to those who trained without meldonium, the meldonium group exercised significantly longer and showed improvements in oxygen consumption and heart test results. They also had healthier blood markers related to cardiac stress. In short, meldonium helped these patients get more out of their workout sessions, increasing the duration and strength with which they could push themselves.

In another study, Gureev et al (2021) looked at mice performing intense swimming sessions [25]. This strenuous exercise caused oxidative stress, damaging the energy-producing parts of the heart. When the mice were given meldonium, their hearts were better protected, even under heavy physical stress. By promoting energy balance and reducing harmful effects, meldonium helped maintain their exercise capacity and protected their hearts from stress-related damage. In addition, Dzerve et al (2011) tested different doses of meldonium in more than 500 patients with stable angina, a type of chest pain that occurs during exercise [26]. After 12 weeks, those taking a total of 1,000 mg of meldonium per day (divided into two 500-mg doses) showed the greatest improvement in the duration of exercise before experiencing chest pain. Lower doses did not help as much, and higher doses were not as effective either. The right dose of meldonium allowed these patients to exercise longer and harder with less discomfort.

In addition, Grigoryan et al (2019) studied 147 patients with ischemic heart disease (IHD) and dangerous heart rhythms [27]. Half of them took meldonium along with their usual medications for two months. These patients not only experienced fewer episodes of chest pain and abnormal heartbeats, but also improved their ability to exercise. Meldonium helped the heart work more efficiently, allowing patients to be more active and endure exercise with less discomfort. In another study, Nechaeva et al (2014) looked at patients with connective tissue dysplasia [28]. After taking mildronate intravenously for 10 days and then orally for four months, these patients showed better cardiac function and were able to cope with physical activity more easily. They reported feeling stronger, less fatigued and enjoying better overall well-being. No serious side effects were reported, suggesting that mildronate can safely support improved exercise performance in this group.

Moreover, Kalvinsh et al (2006) focused on older patients with chronic heart failure, a condition that often limits activity due to fatigue and shortness of breath [29]. Those who added mildronate (750 mg/day) to their regular treatment for one month had fewer angina attacks, felt more comfortable with daily tasks and performed better on walking tests. This shows that even in older people with serious heart disease, mildronate can increase their ability to be active and improve daily endurance. Also, Lyamina et al (2016) studied patients recovering from a partial revascularization procedure known as PCI. All participants engaged in a structured exercise rehabilitation program that included sessions on a treadmill of increasing intensity [30]. One group also received meldonium (1,000 mg/day intravenously), while the other did not, and the third group did not adhere to the exercise program. After 2.5 months, those who combined meldonium with exercise training achieved the greatest improvement. They increased their exercise duration by almost 44% and increased their MET (metabolic equivalent) level by more than 42%. In comparison, patients who exercised without meldonium improved less, and those who did not exercise improved very slightly. This shows the potential of meldonium to enhance the benefits of exercise rehabilitation, making it a cost-effective addition to post-PCI care.

In another study, Baulin et al (2015) tested different drug combinations on rats performing a forced swim test [31]. This test measures how long the animals can swim before fatigue, reflecting their physical endurance. The researchers found that a combination of asparcam, mildronate (meldonium) and metaprote produced the best results, allowing the rats to swim longer without any harmful side effects. This suggests that meldonium may be part of a safe and effective formula for increasing physical performance.

These studies consistently show that meldonium improves exercise tolerance, endurance and overall physical performance - both in patients with heart disease after cardiac surgery and in animal models subjected to strenuous exercise. When combined with standard therapies and exercise programs, meldonium appears to help individuals exercise longer, experience fewer symptoms and improve quality of life, often without significant side effects. Optimal dosing, especially around 1,000 mg/day, appears to be the key to achieving the best results. Although further research is needed to fully understand its mechanisms and confirm its benefits in broader populations, meldonium is a promising addition to strategies aimed at increasing exercise capacity and promoting rehabilitation after cardiac interventions.

Other potential effects of meldonium

Meldonium is also being investigated in various research models for other health and performance benefits beyond its traditional use in supporting cardiac function [32]. Studies ranging from high-altitude conditions and stroke scenarios to neurodegenerative diseases and cognitive impairment suggest that meldonium can help protect cells, improve metabolism and enhance overall brain, lung and reproductive system function. It supports better energy production under low-oxygen conditions, protects neurons from damage, improves memory and learning, or increases semen quality and testosterone levels in livestock.

Protection against hypoxia-induced lung damage

In a study simulating lung injury at high altitude, Swiss mice and lung cells were placed in low-oxygen conditions [33]. Meldonium helped keep the lungs healthy by controlling how cells use energy and reducing harmful oxidative stress. It did this by affecting a key enzyme called PFKP and activating Nrf2, a protein that boosts the body's natural defenses. In effect, this protected the cells' energy factories (mitochondria) and suggested a new way to prevent or reduce lung damage caused by a low-oxygen environment.

Neuroprotection in cerebral ischemia and reperfusion

In a study on a stroke model, rats were subjected to a procedure to block the main artery to the brain, and nerve cells were deprived of oxygen and nutrients in the laboratory [34]. Meldonium treatment led to a reduction in areas of brain damage, better movement and improved overall brain health. It kept nerve cells alive by preserving the shape and function of their energy factories (mitochondria), enhancing natural antioxidant defenses and ensuring continuous energy (ATP) production. In addition, meldonium helped repair damaged mitochondrial processes and triggered signals (via the Akt/GSK-3β pathway) that protected nerve cells from death.

Meldonium in Huntington's disease

Researchers studied the effects of meldonium on cellular energy use in laboratory and animal models of Huntington's disease (HD) [35]. By improving how cells use energy, meldonium reduced harmful protein clumps, increased PGC-1α (a key energy regulator) activity, and increased the production of healthy mitochondria. In a fly model with HD-like symptoms, meldonium improved movement and helped the flies live longer. These results suggest that meldonium may protect brain cells in HD by promoting optimal energy use.

Meldonium for acute brain injury caused by hypobaric hypoxia

In a study simulating low-oxygen conditions occurring at high altitudes, pretreatment with meldonium protected mouse brains and nerve cells from damage [36]. It did so by promoting energy production, reducing oxidative stress and maintaining cerebral blood flow. Meldonium worked by interacting with an energy-related protein (PGK1), which in turn helped improve the function of mitochondria, the cell's power plants. These protective effects make meldonium a promising way to help brains cope with sudden, severe drops in oxygen levels.

Mildronate improves cognitive function and reduces amyloid pathology

In a mouse model of Alzheimer's disease, daily mildronate injections improved memory and learning ability [37]. Mice treated with mildronate had fewer harmful amyloid deposits in the brain and showed signs that their brain's immune cells were more active. Mildronate also reduced the activity of acetylcholinesterase, an enzyme that affects communication between nerve cells. Although it did not change some markers of synaptic health, the overall improvement suggests that mildronate may help slow or reduce the harmful effects of Alzheimer's disease.

Mildronate improves functional recovery

In a rat model of stroke, researchers tested mildronate administered after temporary blockage of the main cerebral artery [38]. Although mildronate did not reduce the area of brain damage, rats receiving daily doses (100 or 200 mg/kg) for 14 days showed better motor function and balance than untreated rats. Its effect was to change the way the brain used certain nutrients, lowering l-carnitine levels and raising GBB levels. This suggests that mildronate may help improve physical abilities after a stroke, even if it does not directly reduce the damaged area in the brain.

Comparison of the neuroprotective effects of mildronate and L-carnitine

Researchers have investigated how mildronate and l-carnitine can protect the brain in mice with age-related memory problems or mental deterioration caused by inflammation [39]. L-carnitine helped improve memory in mice with inflammation and protected their brain cells by activating the natural defense system (Nrf2). However, mildronate worked best in older mice, in which memory loss was harder to reverse. It reduced harmful stress in the brain and improved energy balance without relying on Nrf2. Together, these results show that l-carnitine may be better for short-term inflammation-related problems, while mildronate may help with more persistent, age-related cognitive decline.

Mildronate improves learning, memory and neuronal plasticity

In studies using rats trained in tasks that tested learning and memory, mildronate improved their performance, making it easier for them to remember and learn new information [40]. When the researchers took a closer look, they found that mildronate stimulates the growth of new nerve cells in the brain's memory center (hippocampus) and upregulates important proteins related to learning and communication between brain cells. By increasing markers such as GAP-43 (associated with nerve growth) and regulating key neurotransmitter systems, mildronate helped support the brain's ability to adapt and create new memories. These findings suggest that mildronate may be useful in treating memory problems, including those seen in conditions such as dementia.

Mildronate protects against memory impairment and neuronal dysregulation

Rats exposed to stressful conditions or treated with haloperidol showed memory problems and changes in brain proteins related to learning and normal nerve cell function [41]. Treatment with mildronate prevented these problems. Under stress, it helped maintain normal levels of critical proteins such as BDNF, which promotes nerve growth and survival, and restored memory performance. For haloperidol-induced memory problems, mildronate restored normal levels of BDNF and AChE, protecting the brain's communication systems. By normalizing these brain signals, mildronate helped the rats think and remember better, suggesting that it may help protect the brain from certain drugs or stressful situations that damage memory.

Meldonium for sexual health

In a study evaluating the effects of meldonium on male reproductive health, researchers gave boars 2.0 grams of meldonium daily for 90 days [42]. Compared to untreated boars, those receiving meldonium showed better sexual behavior, as evidenced by a shorter reaction time before ejaculation. In addition, their sperm showed better progressive motility, suggesting better semen quality. Further studies showed positive changes in the testes. Treated boars had thicker spermatogenic epithelium - indicating healthier sperm-producing tissue - and an increase in the number of Leydig cells, which produce testosterone. Correspondingly, blood tests confirmed higher testosterone levels in boars treated with meldonium. Importantly, meldonium had no negative effect on general blood chemistry markers such as creatinine, bilirubin, cholesterol, glucose, AST and ALT, suggesting that it was well tolerated over the long term. These results indicate that prolonged use of meldonium can improve sexual performance, semen quality and testosterone levels in boars without harming their overall biochemical health. Further studies may help determine whether meldonium can serve as a useful agent for improving semen quality in livestock.

From improving brain health and memory to supporting high-altitude lung function and even improving reproductive performance, meldonium shows broad potential. While additional research is needed to fully understand its mechanisms and confirm its long-term safety and efficacy, these findings underscore meldonium's ability to affect key biological processes and offer new opportunities to improve health and performance in both humans and animals.

Pharmacokinetic, safety and tolerability profiles of meldonium

Meldonium (mildronate) has shown generally favorable pharmacokinetic, safety and tolerability profiles in both healthy volunteers and patient populations in multiple studies [43, 44]. Pharmacokinetic (PK) assessments in healthy subjects have provided insight into its absorption, distribution, metabolism and excretion, while clinical studies in patients have shown its good safety margin when used as adjunctive therapy for various cardiovascular and metabolic conditions. Both oral and intravenous forms show good tolerability in healthy subjects, and studies with patients indicate similar safety profiles under real-world therapeutic conditions.

Pharmacokinetics

Studies in healthy volunteers suggest that the pharmacokinetics of meldonium may be dose-dependent and exhibit nonlinear properties at certain doses. Zhang et al (2013) studied single oral doses of 250 to 1,500 mg of meldonium and noted a dose-dependent increase in both area under the curve (AUC) and peak plasma concentration (Cmax) [43]. However, the half-life (t1/2) and volume of distribution (Vd/f) appeared to vary with dose, indicating nonlinear kinetics at higher dosing levels. Repeated dosing (500 mg three times daily for 13 days) led to accumulation, reflecting the need for careful dose selection and monitoring during long-term therapy. Similarly, a study of intravenous mildronate (Zhao et al., 2016) showed linear pharmacokinetics in the 250-750 mg dose range, minimal accumulation with repeated dosing and primary renal excretion. No significant gender-related differences were observed [44].

Tolerance and security

In all studies, meldonium consistently showed a favorable safety profile. Healthy Chinese volunteers receiving oral doses of 250 to 1,500 mg (Zhang et al., 2013) experienced no serious adverse events, and the drug was generally well tolerated [43]. Intravenous doses of 250, 500 and 750 mg (Zhao et al., 2016) similarly showed good tolerability, with no significant changes in vital signs, laboratory results or electrocardiogram, and no serious adverse events [44].

Studies on patient populations [43, 44] - ranging from those with ischemic heart disease to those undergoing cardiac rehabilitation after PCI - have also highlighted the mild safety profile of meldonium. While these studies focused primarily on efficacy, exercise tolerance and improvement in cardiac function, they consistently reported a low incidence of adverse events, reinforcing the drug's tolerability. No serious drug safety concerns, serious side effects or intolerance were documented, even in elderly patients or those with chronic diseases.

Meldonium dosage

The dosage of Meldonium (mildronate) varies depending on the condition being treated, the patient's overall health and the route of administration chosen. Although exact dosing regimens should always be determined by a qualified healthcare professional, several clinical studies and common practices can provide general guidelines:

• Cardiovascular diseases (e.g., ischemic heart disease, angina pectoris): Doses typically range from 500 mg to 1,000 mg per day, often divided into two doses taken orally. In some clinical trials, a dose of 1,000 mg per day has been shown to be more effective than lower doses in improving exercise tolerance and reducing angina symptoms. Mildronate is also used intravenously under certain conditions, usually at a similar total daily dose (about 500-1000 mg / day).
• Chronic heart failure or recovery from myocardial infarction:
  Studies have used a dose of 500-1000 mg daily, administered orally or intravenously, to support cardiac function, improve exercise capacity and facilitate recovery. Intravenous administration is usually given for a short initial period (e.g., 10-14 days), followed by oral dosing.
• Diabetic neuropathy and other metabolic diseases: Daily doses of about 1,000 mg have been used in combination with other therapies to improve nerve function, reduce oxidative stress and improve metabolic control.
• Improving performance in rehabilitation programs: For patients undergoing cardiac rehabilitation after procedures such as percutaneous coronary intervention (PCI), meldonium doses of 1,000 mg/day have been combined with structured exercise programs to extend exercise duration, increase oxygen uptake and support overall recovery.
• Adjusting the dose: Mildronate exhibits some dose-dependent pharmacokinetics. At higher doses, it may exhibit nonlinear behavior and accumulate over time. Therefore, dose adjustments may be necessary depending on response and tolerability, and doses above 1,000 mg/day are less commonly used in routine clinical practice because they have shown diminishing benefits in some studies.

The appropriate dose of meldonium must be optimized according to the individual patient's condition, treatment goals and physician's judgment. Patients should follow the recommendations and directions provided by their healthcare providers.

How long does meldonium last?

The time it takes for meldonium (mildronate) to show noticeable effects can vary depending on the condition being treated and the individual patient. In general, meldonium is not a drug that provides immediate relief; instead, it gradually improves cellular energy balance and cardiovascular function over time. Many clinical studies and patient reports suggest that benefits often become apparent within a few weeks of consistent use.

For example, in cardiac rehabilitation, patients receiving meldonium along with exercise therapy may begin to experience improved exercise tolerance, reduced fatigue or better heart rate response after about 2 to 4 weeks. In cases of stable angina or chronic heart failure, noticeable improvements in exercise capacity and quality of life may also become apparent in a similar time frame. It is important to remember that individual responses may vary. Some patients may experience subtle benefits more quickly, while others may need a bit more time before seeing significant changes.

Is it legal to buy meldonium?

The legality of meldonium purchase depends largely on the country and the intended use:

• Availability by country: In many Eastern European countries (e.g., Latvia, Lithuania and Russia) meldonium (known by the trade name Mildronate) is approved as a prescription drug for the treatment of certain heart diseases. In these regions, it can be legally purchased in pharmacies with a doctor's prescription.

Outside these areas, meldonium is not approved by major regulatory bodies such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). As a result, it is not legally available for sale as a prescription or over-the-counter drug in countries such as the United States, Canada and most of Western Europe.

• Application in sports: In athletic competition, meldonium is banned by the World Anti-Doping Agency (WADA). Athletes who purchase and use meldonium risk violating anti-doping regulations and may be suspended or otherwise penalized.

Disclaimer

This article was written for educational purposes and is intended to raise awareness of the substance being discussed. It is important to note that the substance discussed is a substance, not a specific product. The information contained in the text is based on available scientific research and is not intended to serve as medical advice or promote self-medication. The reader should consult any health and treatment decisions with a qualified health professional.

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