A modern view on the possibilities of using alpha-lipoic acid

A modern view on the possibilities of using alpha-lipoic acid

Alpha lipoic acid (ALA) is a powerful antioxidant, which makes it possible to use it for the treatment and prevention of a wide range of diseases. The ability of ALA to influence inflammation, apoptosis, blood flow, endothelial dysfunction, activation of neurotransmitters, and metabolic processes determines its widespread use in various fields of medicine.

One of the promising areas for the use of alpha-lipoic acid is neurogenic erectile dysfunction against the background of obesity and metabolic syndrome. Several alpha-lipoic acid preparations are used in Russia, but the greatest practical experience has been accumulated with the drug Espa-lipon, which was one of the first to appear on the Russian market and has proven itself in terms of effectiveness.

Table 1. Differentiated approach to the treatment of metabolic disorders with lipid accumulation in hepatocytes

Clinical pharmacokinetics

Alpha lipoic acid is a disulfide derivative of octanoic acid [1]. ALA is a natural coenzyme of the mitochondria of a multienzyme complex that catalyzes the oxidative decarboxylation of alpha-keto acids such as pyruvate and alpha-ketoglutarate. ALA is a powerful antioxidant, which determines the possibility of its therapeutic use. The structural formula and properties of ALA were discovered in 1951, its first clinical trials were conducted in the same year, and the use of alpha-lipoic acid in humans began in 1970. Early research on the use of ALA was carried out against the backdrop of insufficient understanding of the mechanisms of its action and concerned mainly with lipid and carbohydrate metabolism.

Alpha lipoic acid is both fat- and water-soluble, so it can penetrate into any tissue of the body, providing an antioxidant effect not only outside, but also inside the cell. It also activates the activity of other antioxidants - vitamins A, C, glutathione and coenzyme Q10. ALA has unique properties that make it possible to use it for the treatment and prevention of a wide range of diseases, primarily of the peripheral nervous system and brain, since nervous tissue is extremely sensitive to the toxic effects of free radicals. Traditionally, ALA is used in the treatment of diabetic polyneuropathy. However, the toxic effect of free radicals, including the development of neuropathy and one of its early manifestations - neurogenic erectile dysfunction, is observed in a number of other conditions, such as diabetes mellitus (DM), obesity, aging, long-term use of medications (toxic neuropathy ), metabolic syndrome, metabolic liver diseases.

Pathogenetic use of alpha lipoic acid

The effect of ALA has been well studied in healthy volunteers and diabetic patients. The pharmacokinetic characteristics of ALA when administered intravenously do not differ in healthy people and patients with diabetes; a linear relationship was found between the concentration of ALA in plasma and the dose of the drug administered intravenously in the range from 200 to 1200 mg [2]. When taking tablets in healthy people, the linear dependence of the concentration of ALA in plasma on the dose of the drug was within the range of 50–600 mg. With any method of administration, after 24 hours there is no ALA left in the plasma, since it enters the liver, heart, and kidneys, where it accumulates, followed by excretion [1].

A study of the bioavailability of ALA in healthy subjects when taking tablets on an empty stomach or immediately after breakfast showed that food significantly reduced plasma ALA concentrations. In this regard, it is recommended to take ALA tablets immediately after sleep, 30–45 minutes before meals. ALA undergoes beta-oxidative degradation and is excreted in the urine as metabolites [2]. Numerous experimental studies have demonstrated that ALA is a powerful antioxidant due to its participation in the resynthesis of vitamin E and the ability of ALA to bind free radicals. It has also been suggested that ALA is an antioxidant that protects the sulfhydryl groups of the glucose transporter system, which in turn leads to increased insulin-dependent glucose utilization [1].

Oxidative stress and edema due to plasma extravasation, which develop after traumatic injury to brain tissue, are known to play an important role in the secondary mechanisms of brain dysfunction. The literature considers the possibility of using antioxidant therapy, including ALA, in these cases. In an experiment after traumatic brain injury, ALA reduced the severity of oxidative stress, swelling of brain tissue, and histopathological changes [3]. A number of antioxidants, including ALA, reduce the activation of apoptosis caused by ethanol. A clinical open study of 56 patients with alcoholic polyneuropathy revealed a decrease in positive and negative neuropathic symptoms when taking ALA at a dose of 300 mg daily, and ALA was more effective than thiamine.

In Russia there are several preparations of alpha-lipoic acid, but the greatest practical experience has been accumulated with the drug Espa-lipon, which was one of the first to appear on the Russian market (1995) and has proven itself to be a highly effective remedy. Thanks to optimal dosages, the availability of oral and infusion forms of release, German quality and affordable price, Espa-lipon can be used as widely as possible in modern medicine.

Clinical Applications of Alpha Lipoic Acid

ALA can be used in many diseases, including pathologies of the central nervous system associated with oxidative stress and inflammatory changes. ALA inhibits the migration of T cells into the structures of the central nervous system. It has been shown that ALA can suppress the activity of cells that determine the immune response by inhibiting interleukins in them and stimulating cAMP. Fibroblasts from patients with Alzheimer's disease revealed pronounced oxidative stress associated with mitochondrial dysfunction. In the treatment of Alzheimer's disease, ALA is considered as one of the methods of neuroprotection. The neuroprotective capabilities of ALA are realized by improving mitochondrial function. It has been shown that ALA increases the production of acetylcholine in the brain by activating choline acetyltransferase and increasing the production of acetyl-coenzyme A, reduces cerebral oxidative stress and the synthesis of inducible nitric oxide synthase, which is the basis of its neuroprotective effect and makes it possible to use it in neurodegenerative processes. In two open-label clinical trials, 600 mg ALA was given to patients with Alzheimer's disease for 12 to 48 months and noted a slowing of disease progression in mild dementia (ADAScog

1. reduce the level of lipid peroxidation;
2. bind and inactivate toxic substrates in the hepatocyte as a result of increasing the synthesis of detoxifying substances;
3. block the activity of mesenchymal-inflammatory reactions;
4. slow down the progression of fibrosis [5].

Great importance is attached to basic therapy, including:

• cessation of the action of etiological factors;
• complete exclusion of alcohol;
• a diet rich in proteins (1 g of protein per 1 kg of body weight) and water-soluble vitamins, but low in fats;
• normalization of blood glucose, lipids, and uric acid levels in the presence of corresponding disorders.

As a rule, in case of fatty hepatosis with a known etiology, the absence of complications and normal biochemical test results, basic therapy turns out to be sufficient and adequate, and regression of fatty degeneration is observed after 3–6 months. In some cases, with the alcoholic etiology of the process, parenteral administration of water-soluble vitamins (B1, B6, B2, PP, B12, C) in standard therapeutic doses for 10–14 days is required in addition to basic therapy [6]. The main indications for drug therapy are: the development of steatohepatitis and fatty hepatosis of unknown etiology or the inability to stop the action of etiological and additional risk factors for its development [3, 7]. The choice of a specific drug or their combinations in the treatment of metabolic liver damage is influenced by many factors: the etiology and leading pathogenetic links of the process, the degree of activity, the presence of systemic and concomitant diseases, the cost of drugs and, importantly, the knowledge and experience of the doctor (Table 1). The widespread use of alpha-lipoic acid preparations (for example, Espa-lipon) for liver diseases causes the following effects of ALA [1, 5]:

• the ability to reduce the level of lipid peroxidation (binds free radicals and free tissue iron);
• participation in the oxidation of fatty acids and acetate (prevents the development of fatty liver steatosis);
• decarboxylation of beta-keto acids (energy supply to the cell and prevention of the development of ketoacidosis);
• increased transmembrane transport of glucose into the cell (accumulation of glycogen in the cell, increase in its energy balance);
• suppression of nitric oxide synthesis by hepatocytes (prevention and relief of rheological disorders and vascular disorders).

Alpha-lipoic acid preparations are recommended for use in alcoholic and non-alcoholic steatohepatitis, and in fatty steatosis to prevent progression and development of complications. Treatment can be carried out as monotherapy and in combination with other antioxidants and hepatoprotectors.

Currently, there are isolated publications on the effectiveness of treatment of patients with liver diseases associated with the hepatitis C virus, a combination of Espa-lipon 300 mg 2 times a day, silymarin 300 mg 3 times a day and selenomethionine 200 mcg 2 times a day, taken for year [8]. Additionally, a complex of vitamins B, C, E and microelements were prescribed. By the end of the one-year course of treatment, all patients achieved an improvement in clinical and biochemical parameters without eliminating the hepatitis C virus. This study showed that if it is impossible to carry out adequate antiviral therapy (the presence of side effects and contraindications, the ineffectiveness of previous therapy), the use of hepatoprotectors significantly improves the quality of life patient data. Thus, given the wide range of actions to restore almost all types of metabolism in the hepatocyte, alpha-lipoic acid preparations (for example, Espa-lipon) should find widespread use in the treatment of metabolic liver diseases of alcoholic and non-alcoholic origin.

One of the promising areas for the use of alpha-lipoic acid, which we widely use in our work, is neurogenic erectile dysfunction (ED) against the background of obesity and metabolic syndrome. Diagnosis of neurogenic ED, which can be considered a clear clinical manifestation of the negative effect of oxidative stress, leading to a decrease in the secretion of nitric oxide (the main neurotransmitter) by cavernous nerves, is quite simple (Kalinchenko-Rozhivanov method). Determination of penile neuropathy is carried out using the Tiotherm device, which has two different ends - metal (cold) and plastic (warm). Patients with neuropathy cannot distinguish the difference between a cold end and a warm end.

According to epidemiological studies, the incidence of diabetic neuropathy (DN) in diabetes varies from 5 to 100% depending on the examination methods used. Differences in incidence are due to the use of different criteria for diagnosing DN [9]. According to the prevailing point of view, the earliest and most common form of DN is diabetic peripheral polyneuropathy (DPN). 7.5% of patients with newly diagnosed type 2 diabetes already have clinical and laboratory manifestations of DPN [9]. However, according to our numerous studies, the earliest and most common form of DN in men with diabetes is erectile dysfunction, which significantly worsens the quality of life not only of the man, but also of the married couple, and is also the cause of the development of depression, which negatively affects the ability to achieve carbohydrate compensation. exchange.

We studied the clinical and epidemiological characteristics of neurogenic forms of sexual dysfunction in men with diabetes [10]. A continuous one-time study included 611 patients with diabetes (representative sample) living in various regions of the Russian Federation. All patients were surveyed using the International Index of Erectile Function 5 (IIEF-5) questionnaire and Aging Male Symptoms according to Heinemann. The degree of compensation of carbohydrate metabolism was assessed by the level of glycated hemoglobin (HbA1c) (the norm is up to 6.4%). Screening for diabetic polyneuropathy was carried out by studying vibration, temperature and tactile sensitivity of the lower extremities (NDS scale according to Young and TSS scale). To identify neuropathy of the genital organs, vibration, tactile and temperature sensitivity of the penis was assessed using the Kalinchenko-Rozhivanov method. To study the hemodynamics of the penis, Doppler ultrasound was performed using a Minimax Doppler Fono device from Minimax with a 10 MHz sensor. Statistica software package (StatSoft Inc., USA, version 6.0) was used for statistical data processing.

An increase in the prevalence of ED in older age groups has been revealed. With age, both men and women experience a decrease in the secretion of sex hormones - important endogenous antioxidants, which aggravates the manifestations of oxidative stress, and in a number of patients without diabetes is the leading cause of its occurrence. In addition, we found that the neurogenic form of ED in patients with type 1 and type 2 diabetes occurred before the first clinical manifestations of distal diabetic neuropathy in no less than 37.4 and 51.9% of cases, respectively. This feature makes it possible to use the neurogenic form of ED as an early clinical prognostic sign of the development of distal diabetic neuropathy. It should be noted once again that diabetes mellitus is not the only cause of the development of neurogenic erectile dysfunction. When determining the sensitivity of the penis became routine practice, we began to identify a sufficient prevalence of ED in men without diabetes. We were able to identify several reasons for the development of neurogenic ED, on the basis of which we propose the following classification of neurogenic ED:

1. Diabetic neurogenic ED.
2. Traumatic neurogenic ED (often observed after operations on the pelvic organs and penis).
3. Toxic neurogenic ED (develops against the background of alcohol intake, long-term use of medications, uremia, liver damage, vitamin deficiency; neuropathy developed against the background of infections, systemic diseases, allergic diseases).
4. Age-related neurogenic ED (develops against the background of decreased testosterone secretion).

Timely use of ALA for neurogenic erectile dysfunction in the setting of obesity is a prevention of the development of vascular erectile dysfunction, which is quite difficult to treat and precedes more serious vascular disasters such as stroke and coronary heart disease. Oxidative stress, hypercholesterolemia, endothelial activation and monocyte adhesion are the links in the formation of atherosclerotic lesions of the vascular wall.

The experiment proved that the administration of ALA reduced the size of atherosclerotic plaques in the abdominal aorta, which was accompanied by a decrease in the content of fatty and inflammatory cells in the aortic wall. ALA improved the vascular response to angiotensin II, acetylcholine and insulin, and reduced oxidative stress. The use of ALA reduces free radical damage to myocytes due to oxidative stress during myocardial ischemia. In the experiment, the administration of ALA led to a significant decrease in apoptosis, a decrease in lipid peroxidation, and an increase in the activity of glutathione in the mitochondria of cardiomyocytes, which prevented the development of irreversible disorders of cardiac function. In the ISLAND study, taking ALA tablets at a dose of 300 mg as monotherapy in patients with metabolic syndrome for 4 weeks led to an increase in endothelium-dependent vasodilation of the brachial artery, which was accompanied by a decrease in plasma interleukin-6 and plasminogen activator-1. Thus, the effect of ALA on endothelial dysfunction, realized through its effect on anti-inflammatory and antithrombotic mechanisms, has been shown [11].

Pilot studies have shown that ALA reduces apoptosis associated with oxidative stress but stimulates apoptosis in various cancer cells. An experiment on cell culture showed that ALA dose-dependently inhibits the proliferation of human breast cancer cells and activates the process of apoptosis in them. Similar results were obtained for lung cancer cells, with ALA activating apoptosis in cancer cells through both caspase-independent and caspase-dependent pathways. Doctors from New Mexico (USA) described the case of a patient with pancreatic cancer with liver metastases, whose condition improved after ALA infusions in combination with low-dose naltrexone. The patient was alive and well 78 months after initial presentation. Cisplatin, a widely used anticancer drug, increases lipid peroxidation and decreases the activity of antioxidant enzymes in renal tissue. Treatment with cisplatin can cause acute kidney damage, and irreversible filtration impairment may occur. The experiment showed that ALA reduces the symptoms of acute kidney injury by reducing the expression of inflammatory adhesion molecules and apoptosis processes. Chemotherapy with cisplatin and paclitaxel can cause damage to peripheral nerves due to dysfunction of the mitochondrial apparatus of cells. The experiment showed that ALA can prevent the development of polyneuropathy by reducing oxidative stress and protecting mitochondria from damage when using these drugs [12].

Conclusion

Thus, an analysis of experimental and clinical studies indicates the universality of the antioxidant effect of ALA in the vascular bed and cytoplasm of the cellular structures of various organs. The ability to use alpha-lipoic acid to influence inflammation, apoptosis, blood flow, endothelial dysfunction, activation of neurotransmitters, and metabolic processes allows us to consider its preparations as a potential drug in various fields of medicine. We believe that in all patients with neurogenic erectile dysfunction, the use of alpha-lipoic acid should be a course regimen, and discontinuation of the drug is possible only after complete restoration of sexual function and elimination of the causes of oxidative stress (elimination of obesity, metabolic syndrome, toxic factors).

Thioctic acid: antioxidant therapy for neurological diseases

The use of thioctic acid in medical practice is largely associated with the development of ideas about “oxidative stress” and lipid peroxidation as a fairly universal pathogenetic mechanism of cell and tissue damage [24]. The antioxidant effect of thioctic acid is due to the presence of two thiol groups in the molecule (hence the prefix “thio”), as well as the ability to bind free radicals and free tissue iron (preventing its participation in lipid peroxidation) [10]. Thioctic acid not only has independent antioxidant potential, but also provides powerful support for the work of other antioxidant units in the body [23]. In this regard, its protective effect is closely related to homeostasis in the glutathione and ubiquinone system [8]. The production of reactive oxygen species increases significantly with inflammation, immunological disorders, hypoxia, hyperoxia, exposure to drugs, radiation, and antioxidant deficiency.

Thioctic acid is one of the most powerful antioxidants used in the treatment of diabetic neuropathy [2, 25]. Thioctic acid is a coenzyme of key enzymes in the Krebs cycle, which explains its effectiveness. An additional advantage in the mechanism of action of thioctic acid is its clearly documented effect of glucose utilization [15]. The high efficiency and pathogenetic effect of thioctic acid have been proven by numerous experimental and clinical studies. The adequate and rational use of thioctic acid preparations is based on the results of numerous studies (ALADIN I, ALADIN II, ALADIN III, ORPIL, NATHAN, DECAN, SYDNEY), which tested the dose, frequency of administration and course duration (Table 1).

A multicenter, randomized, double-blind study (SYDNEY II) assessed the effectiveness of thioctic acid in the treatment of patients with diabetic polyneuropathy (DPN) [1, 3]. The study was conducted from 2004 to 2006, it involved 87 patients with diabetes mellitus (DM) of type 1 and 2, who were undergoing inpatient (National Healthcare Institution Central Clinical Hospital No. 1 of JSC Russian Railways) and outpatient treatment (Department endocrinology of the State Educational Institution of Additional Professional Education of the Russian Medical Academy of Postgraduate Education (Roszdrav). The SYDNEY study concluded that intravenous alpha lipoic acid for 3 weeks. causes a significant reduction in neuropathic symptoms and neurological objective symptoms that are painful for patients. Considering the dose-dependent effect of side effects, the optimal dosage is 600 mg of thioctic acid. The authors concluded: as a result of a comprehensive clinical and neurophysiological study of patients with type 1 and type 2 diabetes, it was noted that the earliest EMG indicator of sensory nerve damage in diabetes is a decrease in the action potential. Pain reduction occurred from the 2nd week. taking thioctic acid at a dose of 1800 mg/day, from the 4th week. reception - at a dose of 1200 mg and only by the 5th week. - while taking 600 mg of thioctic acid [3]. In patients with DPN (n=24) participating in the study, using thioctic acid at a dose of 1800 mg/day for 3 weeks. neuropathic symptoms and neurological deficits decreased; the incidence of side effects was comparable to the placebo group [29].

In medical practice, a number of thioctic acid preparations are used for therapeutic purposes, which are represented by its three main salts: ethylenediamine, trometamol and megluminic [12]. One of the drugs whose active substance is thioctic (alpha-lipoic) acid is Thiogamma® (pharmaceutical (Germany)). Thiogamma® is a meglumine salt of alpha-lipoic acid, polyethylene glycol is used as a solubilizer, their advantages are to suppress the formation of free radicals, improve the energy metabolism of neurons, and restore impaired endoneurial blood flow. The drug is available in the form of tablets containing 600 mg of the drug, a solution for intravenous infusion in bottles containing 600 mg of the drug in the form of meglumine salt, and ampoules. Meglumine (N-methyl-D-glucamine) is known to be used as a stabilizer in many pharmaceutical products [12]. Meglumine is also used to reduce the toxicity of gadolinium in magnetic resonance contrast media. It is used as the antimonate meglumine to treat leishmaniasis. It was demonstrated that in the experiment, mice accepted a dose of up to 1 g/kg when administered intraperitoneally without side effects. There is only one report of the development of an anaphylactic reaction in a patient with osteoid osteoma after the use of gadoteric and gadopentetic acid during an MRI study. No descriptions of other negative effects of meglumine could be found. Thus, we can conclude that of all the stabilizers used for the manufacture of dosage forms of thioctic acid, meglumine is the least toxic.

Instructions for use of the drug Thiogamma® were approved on 04/15/1999 by the State Pharmacological Committee of the Ministry of Health of Russia, re-registration on 05/24/2010 (for tablet forms), 02/29/2012 (for injection forms) [19]. The drug is prescribed 1 r./day 300–600 mg, taken without chewing, with a small amount of liquid. According to the ALADIN I study [28], the effect of alpha-lipoic acid on positive neuropathic symptoms at doses of 600 and 1200 mg is practically the same. In a clinical study of 3 weeks of intravenous alpha-lipoic acid, side effects (headache, nausea, vomiting) were more common with 1200 mg (32.6%) than with 600 mg (19.8%) with placebo. (20.7%) [28]. It was concluded that a dosage of 600 mg of alpha-lipoic acid is optimal both from the point of view of clinical effectiveness and taking into account the possibility of developing side effects.

The clinical use of thioctic (alpha-lipoic) acid (in particular, Thiogamma®) is based on the many biochemical and physiological effects of this substance [6]. The main mechanisms of action of Thiogamma®, according to those set out in the Methodological Recommendations of V.V. Gorodetsky (2004) [8], can be presented as follows:

• influence on energy metabolism, glucose and lipid metabolism (participation in the oxidative decarboxylation of keto acids) with activation of the Krebs cycle; increased uptake and utilization of glucose by the cell and oxygen consumption; increase in basal metabolism; normalization of gluconeogenesis and ketogenesis; inhibition of cholesterol formation;
• cytoprotective effect: increased antioxidant activity (direct and indirect through the vitamin C/E, cystine/cysteine ​​and glutathione systems); stabilization of mitochondrial membranes;
• influence on the reactivity of the body: stimulation of the reticuloendothelial system; immunotropic effect; anti-inflammatory and analgesic activity (associated with antioxidant effects);
• neurotropic effects: stimulation of axon growth, positive effect on axonal transport, reduction of the harmful effects of free radicals on nerve cells, normalization of abnormal glucose supply to the nerve, prevention and reduction of nerve damage in experimental diabetes;
• hepatoprotective effect: accumulation of glycogen in the liver, inhibition of lipid accumulation in the liver (in some pathological conditions), increased activity of a number of enzymes, improvement of the functional activity of the liver;
• detoxification effect (FOS, lead, arsenic, mercury, sublimate, cyanides, phenothiazides, etc.).

The main indications for the use of the drug Thiogamma® in the treatment of diseases accompanied by neurological symptoms are focused on diabetic and alcoholic polyneuropathy [18]. Currently, thioctic (alpha-lipoic) acid, in particular Thiogamma®, is the most effective agent in the treatment of peripheral polyneuropathy, which has been confirmed by large-scale multicenter long-term studies, such as the ALADIN Study (Alpha-Lipoic Acid in Diabetic Neuropathy) [16]. However, the antioxidant activity of thioctic acid is used in many areas of medicine [10] (Table 2).

Thioctic (alpha-lipoic) acid is a powerful lipophilic antioxidant and is rightfully considered the “gold standard” for the pathogenetic treatment of diabetic polyneuropathy (DPN) [8]. A number of studies have shown that the use of alpha-lipoic acid at a dose of 600 mg/day intravenously or orally for 3 weeks. up to 6 months reduces to a clinically significant extent the main symptoms of DPN, including pain, paresthesia and numbness. It is known that the cause of a 50–70% decrease in the rate of insulin-dependent transmembrane glucose transport in diabetes is oxidative stress. The basis for treating DPN with thioctic (alpha-lipoic) acid drugs is the fact that in diabetes there is a deficiency of alpha-lipoic acid, and alpha-lipoic acid (which has a powerful antioxidant effect), in turn, increases the bioavailability of glucose in insulin-dependent and non-insulin-dependent tissues , increases the absorption of glucose by peripheral nerves to normal levels, and also promotes an increase in endoneurial glucose reserves, which has a beneficial effect on the restoration of energy metabolism of nerves. It is believed that the administration of thioctic acid is advisable for insulin-resistant forms of diabetes [10]. In this case, it is considered optimal to prescribe an intravenous drip of alpha-lipoic acid solution at the beginning of treatment for 3 weeks. (15 droppers) followed by taking 600 mg of the drug in tablet form (1 r./day 30–40 minutes before meals) for 1–2 months. [8].

The effectiveness of Thiogamma® in DPN has been convincingly demonstrated in many clinical studies. At the Sofia Medical University (Bulgaria), T. Tankova et al. (2000) conducted a randomized, open, placebo-controlled study [7–9] to evaluate the effectiveness of the drug Thiogamma® using a 2-stage prescription regimen: after a period of intravenous infusions, the drug was administered orally. A constant dose of 600 mg/day was used, intravenous administration was carried out for 10 days, oral administration for another 50 days. A pronounced clinical effect appears after the first 10 days of therapy. When compared with the control group, in patients receiving Thiogamma®, the intensity of spontaneous pain in the legs decreased by 40%, and vibration sensitivity, which was significantly reduced before treatment and determined in various areas of the foot, increased by 35%. By the end of the course of therapy, positive dynamics were noted in reducing the severity of pain according to VAS and increasing vibration sensitivity. Positive dynamics of indicators characterizing the severity of damage to the autonomic nervous system were also obtained: over 60 days of therapy, manifestations of autonomic neuropathy decreased by 40% and the drop in systolic blood pressure during an orthostatic test decreased by 2.5 times, which indicates an improvement in the function of the autonomic nervous system.

As part of another monocenter, randomized, double-blind, placebo-controlled study, 120 patients with type 1 and type 2 diabetes were examined, of which 60 received placebo and 60 received alpha-lipoic acid (at a dose of 600 mg in 225 ml of saline at a time of intravenous drip administration 30–40 min) [1]. We studied the effect of this drug on the clinical manifestations of DPN, electromyographic (EMG) indicators, indicators of quantitative sensory and autonomic testing in 60 patients with type 1 and type 2 diabetes. The duration of the study was 4 weeks. Positive neuropathic symptoms were chosen as the main criterion for the clinical effectiveness of the study drug due to the fact that they primarily disrupt the patient’s quality of life. An improvement in the distal latency indicator in an EMG study indicates that the main unpleasant sensations (pain, burning, numbness, paresthesia), which worsen the patient’s quality of life, decreased during alpha-lipic acid therapy due to improved peripheral nerve function. Thus, the drug has been shown to be highly effective in relation to most of the studied indicators of the condition of peripheral nerves. It was concluded that thiocotic (alpha-lipoic) acid preparations can be successfully used in the treatment of symptomatic DPN.

In a study by I. I. Matveeva et al. [13], conducted in the “Diabetic Foot” office of the Izhevsk Endocrinology Center, examined 126 patients with newly diagnosed type 2 diabetes (screening), who were prescribed the drug thioctic acid intravenously for 10 days at a dose of 600 mg, subsequently in tablets of 600 mg. mg daily for 8–10 weeks. Based on the results of the study, it was concluded that the drug thioctic acid is highly effective in the treatment of distal DPN, clinical symptoms and the condition of peripheral nerves improve, oxidative stress and insulin resistance decrease.

In another study [14], 50 patients with diabetic and hypothyroid distal symmetric sensorimotor polyneuropathy were prescribed the drug Thiogamma®, first at a dose of 600 mg (equivalent to 1167.70 meglumine salt of alpha-lipoic acid) intravenously, drip for 10 days, 1 injection per day , the injection rate was no more than 50 mg/min. It is also important to note that a distinctive feature of the drug Thiogamma® is the release form, which allows the drug to be administered intravenously, by drip, without requiring prior dilution. Then, for 30 days, patients took Thiogamma® 600 mg in the morning and on an empty stomach. During the study, the author came to the conclusion that among all forms of DPN, the greatest effect of using the drug Thiogamma® was noted in the treatment of acute sensory polyneuropathy and radiculoplexopathy; in the treatment of progressive sensorimotor polyneuropathy, the use of Thiogamma® also showed a statistically significant therapeutic result. In relation to hypothyroid polyneuropathy, Thiogamma® showed high efficiency, in particular for reducing and eliminating pain, however, the positive dynamics during treatment with Thiogamma® clearly correlated with adequate replacement therapy with thyroid hormones.

In a study by E. Yu. Komelyagina et al. (2006) [11] presented the results of a comparison of the effectiveness of two options for treating DPN with thioctic acid drugs: option 1 - oral administration of 1800 mg/day (600 mg 3 times/day) for 4 weeks. (n=15) and 2nd option - oral administration of 600 mg/day for 3 months. (n=15). The study showed that in both modes of use, the drug thioctic acid provides a significant reduction in the severity of neuropathic complaints in patients with diabetes with a satisfactory level of compensation for carbohydrate metabolism. Based on the results of the study, the authors came to the conclusion: “... the choice of treatment regimen for DPN using thioctic acid drugs is individual and depends on the specific situation: in case of severe pain symptoms, a shorter course with a high dosage of the drug (1800 mg/day for 4 weeks. ), with unexpressed symptoms - a longer course with a lower daily dosage (600 mg/day for 3 months)...".

The range of use of drugs containing thioctic acid, both as monotherapy and as part of complex therapy, is constantly expanding. In a comparative open randomized study [5], conducted at the Department of Occupational Diseases of the St. Petersburg State Medical Academy named after. I. I. Mechnikov, evaluated the effectiveness of the drug, the active substance of which is thioctic acid, in the complex treatment of manifestations of vibration disease (syndrome of vegetative-sensory polyneuropathy of the extremities, angiodystonic syndrome). Use at a dosage of 600 mg daily as part of complex therapy for 21 days significantly reduces the frequency of subjective complaints of patients, leads to a persistent reduction in relapses of pain in the extremities, a decrease in the frequency of attacks of vasospasms, enhancing the effect of therapy in general. Thus, the effectiveness of this drug has been shown in relation to vascular tone, blood filling and venous outflow, which, according to the authors, causes the development of anti-inflammatory, anti-edematous, analgesic effects and contributes to the normalization of homeostasis.

Research by M. Senoglu et al. (2009) [27] showed the effectiveness of alpha-lipoic acid against such clinical symptoms as pain, paresthesia, hypoesthesia in patients with compressive radiculopathy due to discoradicular conflict. The results of this study correlate with a study in which M. Ranieri et al. (2009) [26] assessed the effectiveness of the additional use of a combination of alpha-lipoic and gamma-linolenic acid in a 6-week rehabilitation program for patients with discogenic radiculopathy when compared with a similar group of patients receiving only a rehabilitation program. A case of effective use of the drug thioctic acid (600 mg/day for 1 month) as part of complex therapy in a patient with stage III Lyme disease (neuroborreliosis, changes in the central nervous system, damage to the cranial nerve, peripheral polyneuropathy due to neuroborreliosis) is described [4].

Employees of the Clinic of Neurology and Neurosurgery of the Medical Faculty of the Russian State Medical University (now Russian National Research Medical University) E. I. Chukanova et al. (2001–2014) [20–22] a number of studies were conducted to evaluate the effectiveness of the use of thioctic acid in the treatment of patients with discirculatory encephalopathy (DE) and when prescribed in complex pathogenetic therapy of vascular cognitive impairment. Based on the example of a study of 49 patients with DE, it was shown [20] that when prescribing thioctic acid in a dosage regimen of 600 mg 2 times / day for 7 days, switching to 600 mg 1 time / day for 53 days orally in 30 min before meals allows you to achieve a positive effect by the 7th day of treatment (at a dose of 1200 mg/day); when the dose is reduced to 600 mg/day (from the 8th day of treatment), the positive effect of the drug on the dynamics of the neurological status is maintained and is most pronounced by 60th day. Positive dynamics were noted in the neurological and neuropsychological status of patients with DE. Based on the results of the study, it was concluded that thioctic acid is effective not only in the treatment of patients with DE with elevated glucose levels, but also in patients with cerebrovascular insufficiency without diabetes [20]. In a study of a group of 128 patients with DE [21], a pharmacoeconomic analysis of the effectiveness of treatment with thioctic acid was conducted in patients with different stages of chronic cerebral vascular insufficiency. The drug thioctic acid was prescribed orally at a daily dose of 600 mg 2 times/day for 7 days, switching to 600 mg 1 time/day for 23 days 30 minutes before meals. The study established: in patients with stage I DE. — regression of asthenic syndrome, vestibular ataxia, axial reflexes; in patients with stage II DE. — increasing the effectiveness of influencing the indicators of the “movement” scale, ataxia, pseudobulbar syndrome; in patients with stage III DE. — a positive effect on the indicators of the “movement” scale, ataxia (frontal and cerebellar), pseudobulbar syndrome, which persisted until the 12th month. observations, and also showed a statistically significant effect on the dynamics of the amyostatic syndrome score. The authors of the study concluded that treatment with thioctic acid in patients with DE leads to significant clinical improvement, reduces the risk of strokes during the course of the disease and reduces the percentage of disease progression in patients with stage I and II DE. A small percentage of side effects were noted. Thioctic acid is well tolerated by patients, including patients of older age groups. Thioctic acid therapy is preferable from an economic point of view compared to the cost of treatment of patients in the control group who received antihypertensive and antithrombotic therapy, which is associated with its high effectiveness in influencing the risk of TIA, stroke and progression of DE.

Conclusion

The data available today allow us to recommend that a doctor prescribe the drug Thiogamma® in the treatment of patients with neuropathy of somatogenic origin. The developed scheme of 2-stage administration of the drug Thiogamma® is successfully used with a high degree of efficiency: intravenous infusions of the finished solution of the drug Thiogamma® for 10 days (in bottles of 50 mg of solution for infusion of 12 mg/ml, which is equivalent to 600 mg of thioctic acid, with the time of intravenous drip administration for 30–40 minutes) followed by administration of the tablet form of the drug (600 mg/day) for 50 days. From the point of view of clinical effectiveness and taking into account the possibility of side effects, a dosage of thioctic (alpha-lipoic) acid of 600 mg/day is optimal. Individual approach to the dosage regimen: for severe pain symptoms - a shorter course with a high dosage of the drug (1800 mg/day for 4 weeks), for less severe symptoms - a longer course with a lower daily dosage (600 mg/day for 3 months).

It is important to note that a distinctive feature of the drug Thiogamma® is its release form, which allows the drug to be administered intravenously, by drip, without requiring prior dilution.

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