What are placebo drugs Mildronate? Molecular biologist: “Mildronate is not a dummy, for heart patients it can be a way to get back to normal, but not a doping
There is active discussion on social networks about the drug that caused Russian athletes to suffer from doping. “If mildronate increases endurance, then maybe it’s worth taking it when you exercise?” fitness fans ask. “What if this medicine is dangerous for everyone, since it is banned for athletes?” others worry. For a comment, we turned to Doctor of Medical Sciences, Professor, Head of the Department of Myocardial Diseases and Heart Failure at the Institute of Clinical Cardiology. A.L. Myasnikov Russia Cardiology Research and Production Complex Sergei Tereshchenko.
- Sergey Nikolaevich, in what cases is mildronate prescribed and how widely is it used now?
This drug is used for cardiovascular diseases to nourish the myocardium (heart muscle - author). It is also used in neurology, in particular for cerebrovascular accidents. In Russia, mildronate is often prescribed to heart patients - we have a “love” for drugs to nourish the heart muscle.
- How justified is this?
The idea itself is good, but, as far as I know, there are no large-scale clinical studies that would 100% confirm the effectiveness of mildronate and other drugs for improving metabolism in myocardial cells.
The international scientific database Pubmed has data confirming that mildronate is ultimately capable of increasing endurance.
Perhaps these were various small studies, pilots, experimental and the like. I repeat, I am not aware of classical clinical trials on a large number of people with several phases that would unequivocally confirm the serious effect of mildronate.
That is, it is possible that such an effect still exists, but it has not been proven in the classical way, in full?
Yes. By the way, this is also the reason - due to the lack of full-fledged clinical trials, mildronate cannot enter the international pharmaceutical market and is not used in other countries.
- Does it have analogues?
Probably not. There is preductal (the active ingredient trimetazidine), which has a similar task - to improve metabolism, that is, metabolism in the cells of the heart muscle. But the mechanism of action of this medicine is completely different. By the way, Preductal was included in the list of doping drugs even earlier than Mildronate.
If a healthy person starts taking such medications for prevention, during active sports, for example, what will happen?
Nothing good. Why treat a healthy person, interfere with the normal functioning of the heart and disrupt it from the outside? I strongly advise against taking Mildronate for healthy people.
Patients are also worried: if this medicine is prohibited for athletes, then perhaps it is dangerous for others, including heart patients?
Before registration, drugs must be tested for safety. Therefore, those who take mildronate for medical reasons should not worry about harm.
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Molecular biologist: “Mildronate is not a dummy, for heart patients it can be a way to get back to normal, but not a doping”
At the request of KP, scientist Garik Mkrtchyan studied serious international research on the sensational drug and responded to
Over the past few days, five Russian athletes have been caught doping because of the drug mildronate (aka meldonium). The loudest was the recognition of Maria Sharapova. At one time, the medicine could be used by athletes, but at the beginning of 2015, after a publication by German scientists, Mildonium was moved to the list of prohibited substances. We asked an expert to comment on the research on this drug.
AND AT THIS TIME
The State Duma is convening for an emergency meeting because of Sharapova
In one day, several of our athletes were blacklisted
The doping scandal continues to gain momentum. Seven Russian athletes from different sports have already been involved in its orbit.
The loudest self-exposure was made by tennis player Maria Sharapova, who could lose tens of millions of dollars and even end her career.
BY THE WAY
Meldonium, invented in Latvia, was made “bad” by German scientists
"KP" talks about how a widely used drug became prohibited for athletes
Over the past couple of days, meldonium has become one of the most famous drugs in Russia. Since January 1, 2016, it has officially been on the list of substances that are prohibited for use by the World Anti-Doping Agency. This drug is widely used in Eastern European countries and was first developed by the Latvian professor Ivars Kalvins, who, after a loud scandal, hastened to declare that meldonium does not help improve results, but only preserves the health of athletes
For quotation: Samorodskaya I.V. Meldonium: review of research results // RMJ. Medical Review. 2013. No. 36. S. 1818
Metabolic drugs (adenosine triphosphates (ATP), cocarboxylase, nandrolone, inosine and a number of others) were widely used in the last century in the USSR to treat a number of diseases. These drugs were recommended for use in educational medical literature and were prescribed by practicing doctors. There was great demand for them. With the development of evidence-based medicine methods and the formation of recommendations for patient management by professional communities of doctors, interest in these drugs has weakened, but has not disappeared completely.
When the relationship between free fatty acids (FA) and the risk of mortality from cardiovascular pathology of atherosclerotic origin was identified, research began on partial fatty acid oxidation (pFOX) inhibitors. Theoretically, metabolic agents that increase the efficiency of oxygen use, switch metabolism to more economical pathways, and protect tissues from the effects of oxidative stress during reperfusion, should have an anti-ischemic effect due to their effect on metabolic processes in the myocardium. In 1961, the first drug appeared - trimetazidine, which inhibits the rate of FA oxidation inside mitochondria. In the mid-1970s. At the Institute of Organic Synthesis (Latvia), trimethylhydrazinium propionate was synthesized, which limits the transport of FAs through membranes. In 1976, the drug received its first license - the “Certificate of Authors” of the USSR. Since 1984, the drug meldonium has been approved for use in medicine. One of the meldonium preparations is Cardionate®.
It has been shown that meldonium is able to slow down the rate of β-oxidation of FAs in mitochondria and limit the transport of FAs through cell membranes, which is important in conditions of excessive accumulation of FAs; reduces oxygen consumption in the body as a whole, ensures ischemic preconditioning processes by reducing the rate of transmembrane transport of FAs, acyl-CoA and acylcarnitine into cells, reducing oxygen consumption, slowing β-oxidation of FAs and increasing the rate of biosynthesis of γ-butyrobetaine; induces NO biosynthesis in the endothelium of blood vessels, reducing the resistance of peripheral blood vessels and platelet aggregation, increasing the elasticity of erythrocyte membranes; allows you to minimize metabolic acidosis that develops as a result of activation of anaerobic glycolysis and accumulation of lactic acid. That is why a number of Russian specialists believe that the use of drugs blocks the partial oxidation of free fatty acids - pFOX inhibitors and directly affects the metabolism of ischemic myocardium, which makes it possible to reduce metabolic disorders that underlie the destabilization of coronary heart disease (CHD).
According to the manufacturer's annotation, meldonium is used as part of complex therapy for coronary artery disease (angina pectoris, myocardial infarction (MI)), chronic heart failure, dishormonal cardiomyopathy; acute and chronic cerebrovascular accidents (stroke and cerebrovascular insufficiency); with reduced performance, physical overstrain (including athletes), in the postoperative period to speed up rehabilitation; with withdrawal syndrome in chronic alcoholism (in combination with specific therapy for alcoholism).
The purpose of this review is to examine the published results of clinical studies evaluating the recommendations mentioned in the abstract.
A.V. Kuznetsova, A.T. Teplyakov studied the effect of 4-week therapy with Cardionat® on the anti-ischemic effectiveness of antianginal therapy, quality of life and physical tolerance in 30 patients with coronary artery disease in combination with arterial hypertension (AH) associated with type 2 diabetes mellitus. The addition of the drug Cardionat® to standard antianginal therapy led to a significant decrease in the number of anginal attacks - by 55.6%, while the daily requirement for nitroglycerin significantly decreased by 55.1%. Patients also showed a decrease in the functional class (FC) of angina pectoris. According to bicycle ergometry data, a significant increase in physical tolerance was revealed - by 28.7%, while the 6-minute walking distance increased by 13.2%, and the quality of life improved by 27.8%. The drug Cardionat® was well tolerated; only 2 (6.6%) patients experienced palpitations while taking it, which went away on their own and did not require discontinuation of the drug.
M.E. Statsenko et al. A number of studies have been conducted to evaluate the wide variety of effects of meldonium. In one of them, the authors examined 60 patients aged 45-65 years with chronic heart failure (CHF) FC II-III according to the classification of the Society of Heart Failure Specialists (2002) in the early post-infarction period (3-4 weeks from the onset of MI). All patients had clinical and laboratory manifestations of metabolic syndrome (MS). Patients received basic therapy for CHF (enalapril, bisoprolol, acetylsalicylic acid, simvastatin), and, if necessary, diuretics and nitrates. They were randomized into 2 groups: patients in the main group (30 people) were prescribed Cardionat® in a dose of 1.0 g/day orally in addition to basic therapy for CHF; in the control group (30 people), only basic therapy for CHF was used. At the end of the 12-week course of therapy, the left ventricular (LV) myocardial mass index did not change significantly in both groups. Therapy with the inclusion of the drug Cardionat® contributed to the improvement of the autonomic regulation of cardiac activity by reducing sympathetic and increasing parasympathetic activity, and was accompanied by an increase in exercise tolerance. According to the results of the step walking test, in group 1, the distance traveled increased significantly (by 15.5% compared to 9.7% in the control group); There was a decrease in the severity of heart failure in the main group by 31.4% versus 15.7% in the basic therapy group (p<0,01). В 1-й группе через 12 нед. лечения число больных с ХСН II ФК увеличилось на 25,1% при одновременном снижении числа больных с ХСН III ФК на 28,7%. В контрольной группе доля больных с ХСН II ФК увеличилась только на 13,4%, а число больных с ХСН III ФК уменьшилось на 13,4%. По данным Миннесотского опросника, проявления сердечной недостаточности достоверно уменьшились в 1-й группе на 14,8% и на 4,4% - во 2-й (р<0,05). В конце исследования отмечено достоверное урежение частоты приступов стенокардии в неделю в 1-й группе на 31,9% и на 17,4% - во 2-й.
M.N. Mikhailova et al. The observational study included 30 patients with coronary artery disease who received standard therapy (β-blockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), acetylsalicylic acid, diuretics). Against this background, the drug Cardionat® was added to the treatment at a dose of 1000 mg/day. Against the background of complex treatment, in 59% of cases there was an improvement in general well-being, and in some cases, cessation of anginal pain. Average number of angina attacks per day by the end of the 4th week. decreased from 19.5 (0.7 per person) to 11 (0.4 per person), which amounted to 43.5%. Improved quality of life according to the Minnesota Questionnaire was noted by 30% of patients. Exercise tolerance at the beginning of treatment averaged 280 m, at the end of therapy - 288 m. The authors noted that the clinical effect of the drug appeared on days 5-7. treatment and reached a maximum by the end of the 3rd week.
S.K. Kononov et al. On the basis of the City Arrhythmology Center of Kirov, a study was carried out to evaluate the effect of meldonium therapy on the maintenance of sinus rhythm in patients with atrial fibrillation (AF) and MS. The study included 30 patients with persistent AF and MS. After successful electrical cardioversion, all patients were prescribed amiodarone as antiarrhythmic therapy (average maintenance dose - 180.1±15.5 mg). All patients received complex therapy for MS, including antihypertensive, lipid-lowering drugs, and metformin. Two groups were formed: 15 patients with AF and MS who did not receive meldonium, and 15 patients with AF and MS who were prescribed meldonium (capsules 500 mg 2 times a day). In accordance with the manufacturer's recommendations, the drug was taken by patients for 3 months. At baseline, both groups of patients were comparable in terms of laboratory and clinical characteristics.
After 6 months Observations among patients receiving meldonium, the sinus rhythm retention time was 161±43.3, in the control group - 109±75.5 (p=0.03). The proportion of patients who maintained sinus rhythm at the end of the observation period in the meldonium group was 80% versus 50% in the control group. The authors attribute the results to the fact that meldonium, capable of improving energy processes in cells, probably increased the effectiveness of complex therapy; a more pronounced effect on key parts of MS was observed, which led to improved clinical, laboratory, structural parameters and ultimately increased the effectiveness antiarrhythmic therapy for AF.
I.G. Gordeev et al. 149 patients with stable angina pectoris II-III FC aged from 41 to 75 years who underwent coronary bypass surgery under artificial circulation or percutaneous coronary intervention were studied. In patients of group 1 (n=79 people), meldonium was added to the drug therapy used for the treatment of coronary artery disease in the preoperative period at a dosage of 750 mg/day for 3 days, then 750 mg/day 2 times/week . Group 2 - control (n=70 people), in which patients did not receive metabolic drugs. The inclusion of meldonium in traditional drug therapy led to a decrease in the index of impaired local segmental contractility of the LV (LVLS) by 15% on the 3rd day after revascularization, while in the comparison group that did not receive meldonium, the value of LVLS decreased by only 3.5 %. Before performing balloon angioplasty, as a result of the preoperative use of meldonium, the INLS decreased by 14%, in the comparison group - by 2.5%. After performing balloon angioplasty, the ILS decreased by 19.5% from the initial level, and in the comparison group - by 12%. The inclusion of meldonium in the preoperative preparation allowed an increase in LVEF by 12% after angioplasty; no changes were recorded in the comparison group in the first days after surgery.
A group of researchers in the double-blind, placebo-controlled, randomized study MILSS (MILdronate and Stable Angina) studied the effect of meldonium on exercise tolerance. The study included 512 patients with stable angina. The patients were divided into 4 groups: 3 groups received standard therapy plus meldonium, group 4 received standard therapy plus placebo. In the group with a dose of meldonium 100 and 300 mg, the increase in the duration of the load was 2.12±108.45 and 11.48±62.03 s, respectively, in the placebo group - 7.10±81.78 s. There were no statistical differences between the groups. Among patients receiving meldonium at a dose of 1000 mg/day, a statistically significant increase in the duration of physical activity was recorded by 35.18 ± 53.29 s (p = 0.002).
Considering the promise of neuroprotection with the help of antioxidants in the treatment of cerebral circulatory disorders, a study of the clinical effectiveness of meldonium in patients with lacunar strokes was conducted at the Research Institute of Neurology of the Russian Academy of Medical Sciences, assessing its effect on the dynamics of neurological deficit, the state of lipid peroxidation processes and cerebral hemoperfusion. The study, which was carried out using an open method, included 45 patients aged 44 to 80 years with lacunar strokes in the acute period. Meldonium was administered intravenously by drip at a daily dose of 500 mg of the drug in 250 ml of physiological solution once in the morning for 21 days. If necessary, antihypertensive and cardiac drugs were prescribed. Therapy with nootropic, psychotropic drugs, antiplatelet agents and anticoagulants was excluded. The positive clinical effect of meldonium according to subjective assessment (well-being, severity of cephalgic, asthenic syndromes) was recorded in 76% of observations. In 17 observations, a decrease in the degree of hemiparesis was noted.
Assessment of the degree of reduction in the severity of neurological deficit according to the National Institutes of Health scale revealed complete restoration of neurological functions in 12 patients with an initial neurological deficit with a score of 10-11 points; significant improvement - in 3 patients (neurological deficit decreased by 6 points compared to that before the start of therapy); slight improvement - in 2 patients (neurological deficit decreased by 3 points compared to baseline). In 2 patients, during the course of treatment, side effects were recorded in the form of an increase in blood pressure within 15% of the initial level and an increase in the severity of noise in the head.
As a result of meldonium therapy, the overall dynamics of mental activity improved, which was expressed in the form of a shortening of the time to memorize 10 words. A study of intellectual activity revealed a statistically significant shortening in the time of performing serial counting “100-7” in patients treated with meldonium. In addition, there was a tendency to reduce the number of errors made. The improvement in short-term memory (reproduction of number series in forward order) after treatment with meldonium was not statistically significant. The improvement in working memory (reproduction of number series in reverse order), where the role of attention processes increases significantly, turned out to be statistically significant. When studying auditory-verbal memory by memorizing 10 words after 5 repetitions and attention by searching for numbers using Schulte tables, no significant dynamics of indicators were noted. The authors believe that antioxidant therapy with meldonium has a certain positive effect on the course of mental processes in patients with lacunar stroke.
G.P. Khasenova et al. The effectiveness of the drug meldonium in the complex treatment of patients with dyscirculatory encephalopathy stage II of atherosclerotic genesis was studied. The study included 50 patients who were divided into 2 groups: 25 patients received standard treatment and 25 patients were additionally prescribed meldonium (in the hospital, 5 ml per 100 ml of sodium chloride solution intravenously 1 time per day for 10 days and outpatient 500 mg 2 times a day for 2 months). To confirm the diagnosis, all patients underwent magnetic resonance or computed tomography of the brain before treatment.
Patients taking meldonium had no complaints of heaviness in the head, and there was a significant regression of neurological symptoms and syndromes compared to the results of a clinical neurological examination conducted in the control group after treatment. Dizziness in the control group decreased only in 7 (28±8.98%) patients, in the group taking meldonium - in 15 (60±9.8%); recovery of sensory disorders in the control group was observed in 4 (16±7.33%) patients, in the main group - in 9 (36±9.6%); oculomotor disorders in the control group regressed in 2 (8±5.43%) patients, in the main group - in 3 (12±6.5%); imbalance was better regressed in the main group - in 4 (16±7.33%) patients, in the control group - only in 2 (8±5.43%); autonomic disorders regressed in the control group in 5 (20±8%) patients, in the main group in a significantly larger number of patients - 11 (44±9.93%); pseudobulbar syndrome regressed in 1 (4±3.91%) patient in the control group, in the main group - in 2 (8±5.43%); hearing improved in 1 (4±3.91%) patient of each group; sleep was restored in the main group in 80% (20) of patients, as opposed to the control group, where sleep improved in only 44% (11); Emotional-volitional disorders that required correction with sedatives regressed in the main group in 23 (92±5.43%) patients, in the control group - only in 11 (44±9.93%).
As a result of treatment of patients with discirculatory encephalopathy of atherosclerotic origin in the control group, the level of cholesterol and triglycerides did not decrease; in the main group there was a decrease in cholesterol levels by 23.36% (-1.75 mmol/l), triglycerides by 11.75% (-0.37 mmol/l). Before treatment, the main group was dominated by patients with moderate diffuse changes in the bioelectrical activity of the brain (60±9.8%). After completing the course of treatment with meldonium, a decrease in the number of patients with pronounced diffuse changes and an increase in the number of patients with mild diffuse changes in the bioelectrical activity of the brain were noted (8±5.4 and 40±9.8%, respectively). The authors believe that the therapy led to a significant improvement in the condition of patients in whose complex treatment meldonium was used.
V.V. Ponomarev et al. in 2012, a randomized study was conducted at the clinical hospital in Minsk (Belarus), which included 60 patients with chronic cerebrovascular insufficiency, diagnosed in accordance with the classification of cerebrovascular diseases. Patients (25 people) with a long course of the disease (over 10 years) predominated. The criterion for inclusion of patients in the study was the presence of neurological and neuropsychological disorders corresponding to stages I-II of dyscirculatory encephalopathy, which were confirmed by instrumental and laboratory data. Exclusion criteria: age 85 years or older; decompensation of concomitant somatic diseases; the presence of persistent neurological deficit; severe cognitive impairment of vascular or other origin; the presence of individual intolerance to the drug. All patients of the main group received meldonium 1000 mg (2 ampoules) intravenously daily for 8-10 days, then 500 mg orally 2 times a day (morning and evening) for 30 days. The treatment complex also included antihypertensive and hypoglycemic drugs (according to indications), antiplatelet agents (acetylsalicylic acid). Vasoactive agents, other antihypoxants, or nootropics were excluded.
The effectiveness of complex therapy including injectable and capsulated forms of meldonium was assessed on the basis of the general clinical impression of the doctor (dynamics of the MMSE test, the “10 words” test and the Munstenberg technique) and the patient during the final visit. The authors drew attention to the fact that in the overwhelming majority of cases, the opinions of the doctor and the patient regarding the results of treatment coincided, and their “good” assessment prevailed. During meldonium therapy, the most pronounced positive dynamics were revealed when assessing neuropsychological indicators, such as short-term memory and attention. Reliable positive neuropsychological changes are achieved only by the 30-40th day of therapy, which should be taken into account when choosing the duration of treatment. The authors noted good tolerability of the drug and, therefore, high adherence of patients to the prescribed treatment.
A. Savchenko and N. Zakharova analyzed the results of treatment of 21 patients (14 men and 7 women) aged 56.1±0.7 years 1-3.5 years after moderate and severe contusions of the convexital parts of the brain and 22 patients ( 13 men and 9 women) at the age of 58.3±0.7 years, 1.5-3.5 years after acute ischemic cerebrovascular accident in the system of the middle cerebral arteries. The study did not include persons with decompensated conditions according to the criteria of consciousness, blood circulation, motor functions, or with paroxysmal manifestations. Patients took meldonium 0.5 g orally 2 times a day for 6 weeks; Patients stopped taking antiplatelet (dipyridamole, acetylsalicylic acid) and antihypertensive (atenolol, enalapril) drugs within 2-6 months. before starting to take meldonium. Meldonium had a positive effect on a number of quality of life indicators: mobility, ability to self-care, and household activity. Increase in blood flow rate after 6 weeks. treatment with meldonium occurred in 8 patients of the 1st group and in 10 patients of the 2nd group, although no significant changes were noted (41.2±5.5 and 43.4±5.9 cm/s, respectively). The peripheral resistance index in the same patients decreased from 0.88±0.06 and 0.82±0.05 to 0.64±0.05 and 67.3±0.06, respectively (p<0,05) и достигал уровня показателей здоровых лиц (0,66±0,06), что свидетельствовало о снижении тонуса резистивных сосудов мозга и улучшении микроциркуляции в церебральной зоне поражения.
Considering the frequency and significance of asthenic and depressive disorders in cardiovascular diseases, V.V. Tsoma et al. assessed the effect of meldonium on the severity of asthenic syndrome (AS) in elderly patients with hypertension when used as part of combination therapy. We examined 180 patients (n=180; >65 years) with stage I-II hypertension and secondary somatogenic AS (according to the MFI-20 scale). Patients were randomized into 3 groups according to the drug dosage regimen: Group 1 - a course of meldonium (500 mg once in the morning for 3 months, followed by a break of 3 months; 2 courses); Group 2 - continuous use (500 mg once in the morning for 12 months); Group 3 - control (they took only antihypertensive drugs). AS was assessed using the MFI-20 scales at baseline and at week 52. treatment.
According to the study, in groups 1 and 2, manifestations of AS decreased. In group 1, the proportion of patients with general asthenia decreased by 70.5% (p<0,05), физической астенией - на 47,7% (р<0,05), пониженной активностью - на 33,3%, сниженной мотивацией - на 25%. Во 2-й группе отмечено уменьшение количества пациентов с общей астенией на 60% (р<0,05), физической астенией - на 39,7%, пониженной активностью - на 79,9% (р<0,05), сниженной мотивацией - на 12,2% и психической астенией - на 77,7% (р<0,05). В 3-й группе (контроль) данные показатели практически не изменились, а по шкале психической астении доля пациентов увеличилась на 45,4% (р<0,05). Авторы считают, что мельдоний в дозе 500 мг/сут непрерывно в течение 52 нед. в составе комплексной терапии АГ способен уменьшать проявления вторичного соматогенного АС.
Thus, the feasibility and effectiveness of metabolic therapy remain a matter of debate. Studies evaluating meldonium (including Cardionate) used different treatment regimens and different evaluation criteria, and the drug was evaluated in different categories of patients. The main areas of use of this drug are coronary artery disease and encephalopathy of various origins. All published research results indicate some positive effects. In many publications, the assessment of the effect is largely based on the patient’s subjective feelings, which are associated with health-related quality of life, and which have been given no less importance (than an increase in life expectancy) in recent decades.
It should be noted that even randomized studies do not always provide complete comparability of comparison groups. Thus, in the study by Yu.N. Sirenko et al. The compared groups differed statistically and clinically significantly at the stage of forming the study, therefore, even after applying statistical methods to correct the results obtained, it is unlikely that the issue of the superiority of thiotriazoline over meldonium can be finally resolved. For a comparative assessment, additional research is needed.
Meldonium in its mechanism of action is close to the more widely known drug trimetazidine, the anti-ischemic and antianginal effects of which have been proven in larger multicenter studies. Thus, in 2012, a meta-analysis of 17 randomized trials was published. According to these data, trimetazidine in patients with heart failure, to varying degrees, statistically significantly reduces the frequency of re-hospitalizations, FC of heart failure, increases exercise tolerance, and reduces LV diastolic volume. Similar data were obtained in another meta-analysis (218 studies, more than 19 thousand patients) assessing the effect of trimetazidine in patients with angina pectoris. In 2013, the results of an Italian study were published (more than 600 patients with heart failure, 362 received trimetazidine), which revealed a statistically significant reduction in long-term mortality among patients receiving trimetazidine. The drugs trimetazidine and meldonium have similar mechanisms of action.
Modern recommendations of professional communities for the management of patients with coronary artery disease are mainly focused on the use of β-blockers, ACE inhibitors, nitrates, calcium antagonists, statins, and antiplatelet agents. Not all groups of drugs have proven effectiveness in terms of increasing survival and reducing the incidence of life-threatening complications for all groups of patients. Even with regard to the most studied of them, there are constant discussions about the benefit/harm ratio. It is quite natural that unstudied or insufficiently studied drugs remain, so to speak, “on the sidelines” of events. And at the moment, when deciding to recommend metabolic drugs, practitioners must actually rely on their knowledge, experience, take into account the specific situation, the degree of confidence in the clinical studies conducted and the results presented in them. It is also worth noting that clinical recommendations are also often based on expert opinions due to the fact that today there are no convincing, evidence-based studies regarding the whole variety of different clinical situations.
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