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Introduction
In the etiology of mental disorders, biological methylation processes play a key role. The main source and effective donor of methyl groups in the central and peripheral nervous system is ademethionine (heptral “) – an active sulfur-containing metabolite of methionine, a natural antioxidant and antidepressant that is formed in the liver in an amount of up to 8 g / day and is present in all tissues and body fluids, and most of all – in places of education and consumption, i.e. in the liver and brain.
In this regard, two particularly important biochemical processes in the liver are the synthesis of methionine and S-adenosyl-L-methionine by methylation of homocysteine. The enzymes S-adenosyl-methionine-synthetase and methionine-adenosyl-transferase (MAT) are involved in the formation and functioning of ademetionine. The latter is encoded on two genes – MAT1A and MAT2A, catalyzing the formation of SAM, and only MAT2A expression is associated with faster cell proliferation.
The circular DNA of human SAM synthetase includes 3217 nucleotides encoding a protein of 395 amino acid residues with a molecular weight of 43 647 daltons. In the messenger RNA of the human genome, a single region is responsible for the coding of this protein, and the structural features of the liver-specific S-adenosylmethionine synthetase gene in humans and rats turned out to be quite similar.
The idea of ​​using SAM as an independent drug (MP) is based on qualitative and quantitative correlations of the severity of mental and somatic disease states in humans and animals with the doses and content of SAM in normal or pathologically altered target tissues of the body.
The purpose of this information and analytical review is more pragmatic and consists in generalizing and comparing the observed clinical efficacy and safety of Heptral with existing drugs prescribed for the same indications. The most important and recognized of these indications are exogenous and endogenous depression, alcohol withdrawal, liver disease and arthralgia.
Sources of information
1. Medical and biological data of the Internet (Medline, Pubmed, etc.).
2. Thematic abstract journals of VINITI RAS.
3. Systematic reviews of the Cochran library (Oxford, UK) for 1984-2000.

Heptral – an antidepressant The
relative harmlessness of Heptral made it possible to assess its effect on the vital signs of healthy people. In particular, the heart rate and the concentration of adrenaline in the plasma of healthy subjects moderately decreased against the background of daily administration of 400 mg of heptral for a week as well as under the influence of MAO inhibitors, but the plasma MHPG level did not depend on the intake of heptral. An increase in the level of adrenaline when changing the position of the body from horizontal to vertical was easily stopped by taking Heptral, which indirectly confirms that it has antidepressant properties.
A statistical generalization (meta-analysis) of the results of 19 comparative clinical trials involving 498 depressed patients of varying severity made it possible to establish a reliable, 38-60%, increase in the antidepressant activity of heptral over placebo activity and the coincidence of its intensity with the antidepressant effects of standard tri- and heterocyclic drugs – imipramine, desipramine, amitriptyline and others with almost complete absence of their inherent side effects.
In standard clinical trials, Heptral was statistically significantly superior in efficacy to placebo and tricyclic antidepressants in recurrent endogenous and neurotic depression resistant to amitriptyline, differing from them in the ability to interrupt relapses and in the absence of side effects.
Almost all researchers note a more rapid development and stabilization of the antidepressant action of heptral (weeks 1 and 2, respectively) compared to standard drugs, especially with parenteral administration. In particular, in an open multicenter clinical study of 195 depressed patients, remission occurred after 7-15 days of parenteral administration of heptral at 400 mg / day, and when combined with tricyclic antidepressants, the effects were much faster and more pronounced than when combined with placebo. It should be noted that with an exacerbation of depressive symptoms, the level of ademetionine in the blood and tissues decreases, which requires an increase in dosages.

Heptral with withdrawal symptoms
The experience of testing and using heptral for alcohol withdrawal and opium addiction is apparently quite limited, since there are no English-language publications on this topic in available Internet databases. The following are the main results of two domestic clinical trials of Heptral, conducted in the Department of Clinical Psychopharmacology of the Research Institute of Narcology of the Ministry of Health of the Russian Federation (Director of the Research Institute, Corresponding Member of the Russian Academy of Medical Sciences, Prof. N. N. Ivanets) and at the Central Research Institute of Gastroenterology and the 17th Narcological Hospital in Moscow .
1. Heptral for alcohol withdrawal
Stopping the habitual consumption of alcohol is fraught with fatal complications. Clinically, alcohol withdrawal is manifested by tremors, hallucinations, seizures and delirium, infectious and somatic diseases and injuries. Symptoms appear after a few hours and gradually disappear within 2-3 days. Alcoholic delirium usually develops in 5-10% of cases after 3-4 days and also includes trembling, agitation, confusion, loss of orientation and a sharp increase in autonomic activity – fever, tachycardia and profuse sweating; lethality is about 5%. Convulsive seizures are quite rare, occur 12-48 hours after alcohol withdrawal and are usually generalized; their number is small and they are stopped by conventional drugs.
The aim of the study was to study the hepatotropic effect and effectiveness of Heptral in the treatment of depressive disorders and pathological craving for alcohol (with alcohol withdrawal syndrome) in an open-label study.
Examined 20 alcoholic men 30-60 years old with a disease duration of 6-25 years, 12 of them – with hereditary burden. All patients were diagnosed with stage II alcoholism: with a predominance of the pseudo-bore form – in 14, a constant form against a background of high tolerance – in 6 patients.
All of them had diagnostic criteria for stage II alcoholism: primary pathological craving for alcohol, a pronounced symptom of “loss of control”, maximum alcohol tolerance, fully formed alcohol withdrawal syndrome (AAS) – morning intoxication, altered patterns of intoxication combined with amnesia during the period of intoxication, aggravation premorbid character traits, adverse social and somatic consequences of the disease.
AAS was accompanied by the usual somatovegetative and psychopathological disorders. The severity of AAS was regarded as mild in 6 and moderate in 14 patients, with a Hamilton score of at least 14 points, which was a criterion for inclusion in the study along with a pathological attraction to alcohol and liver pathology. All patients had an enlarged liver, 17 were diagnosed with alcoholic fatty hepatosis, and 3 had chronic alcoholic hepatitis.
Heptral was prescribed in 2 parenteral bottles (800 mg) for 2 weeks. and then 1 tablet (200 mg) 4 times a day for the next 2 weeks. Along with Heptral, vitamins of groups B and C were prescribed and, if necessary, antihypertensive drugs (magnesium sulfate) and benzodiazepines (only at night) in the first 2 days.
Results. The therapeutic effect was noted on days 2-4 of treatment. Fear and anxiety disappeared, irritability decreased, asthenia decreased and physical condition improved, blood pressure returned to normal, appetite appeared, tremor and hyperhidrosis disappeared. By the end of the week, mood was leveled, sleep was restored, depressive symptoms decreased by 60-70%, and after 4 weeks depressive disorders were completely stopped. Craving for alcohol decreased on average by the 10th day. On the scale of general impression, the results were assessed as significant improvement within the framework of depression and as moderate – in relation to craving for alcohol and hepatotropic action (a trend towards positive dynamics of liver function and a decrease in its size). The drug was well tolerated and there were no side effects, complications or addiction to it.
In the instructions for the use of heptral, it is recommended to prescribe it for intrahepatic cholestasis induced by liver lesions of various origins, cirrhotic and precirrhotic conditions, encephalopathies of secondary genesis, depressive syndromes (including secondary) and with withdrawal syndrome.
Heptral is contraindicated in case of individual hypersensitivity to it, in the first two trimesters of pregnancy and lactation. In cirrhotic and precirrotic conditions associated with hyperazotemia, heptral oral administration should be carried out under medical supervision and nitrogen level control. Heptral is not recommended for children without strict indications. No interactions of heptral with other drugs were observed and no clinical cases of overdose were noted.
2. Heptral for opiate withdrawal
Under the observation were 20 male patients 17-38 years old with a diagnosis of “opium addiction of the 2nd degree, withdrawal symptoms” and with a disease duration of 1-22 years; in 50% of cases, the course of drug addiction was aggravated by taking diphenhydramine (1-2 tablets per drug injection). Treatment consisted of administering Heptral intravenously, 800 or 1600 mg / day in the first 14 days and 1600 mg / day in tablets for the next 14 days. We observed an improvement in the functional state of the liver and stimulation of microsomal oxidation processes, expressed in increased clearance and accelerated elimination of the marker preparation of antipyrine. The reverse development of clinical manifestations of abstinence and a distinct antidepressant effect was also noted.

Heptral is a hepatoprotector
Most of the etiological factors of intrahepatic cholestasis inhibit the activity of S-adenosylmethyl synthetase and reduce the production of S-ademethionine, which is accompanied by a violation of biochemical processes in hepatocytes – transmethylation and trans sulfidation. As a result, they decrease: the content of phospholipids, the activity of Na + K + -ATPase and other carrier proteins, membrane fluidity, capture and excretion of bile components, cellular reserves of thiols and sulfates (glutathione, taurine, etc.), which have a pronounced antioxidant effect and are the main substances in detoxification of endogenous and exogenous xenobiotics. Deficiency of these products leads to cytolysis of hepatocytes in cholestasis of any genesis.
The clinical manifestations of cholestasis are quite the same, these are:
1. excessive intake of bile elements in the blood;
2. a decrease in the amount or absence of bile in the intestine;
3. The effect of bile components on liver cells and tubules.
Regurgitation of bile into the blood induces pruritus, jaundice, xanthomas, xanthelasmas, darkening of urine, and systemic lesions:
acute renal failure;
the development of ulcers, erosions and bleeding in the stomach;
increased risk of endotoxemia and septic complications.

At the same time, a deficiency of bile in the intestine is fraught with steatorrhea and malabsorption syndrome, a deficiency of fat-soluble vitamins, and impaired bone mineralization. An excess of bile components leads to necrosis of hepatocytes and tubules and to liver cell failure, and with prolonged cholestasis cirrhosis forms with the development of ascites, edema, and hepatic encephalopathy. Often cholestasis (for example, drug) is asymptomatic and its only manifestation is the results of biochemical liver tests.
The etiological effect on cholestasis is problematic, and most patients are prescribed pathogenetic and symptomatic treatment. Heptral is the drug of choice in most cases for the following mechanisms and causes of cholestasis:
Decreased fluidity (permeability) of the basolateral and / or canalicular membrane of hepatocytes during pregnancy, alcoholic and medicinal liver damage.
Inhibition of Na + K + -ATPase and other membrane carrier proteins in drug and / or bacterial liver damage.
Destruction of the cytoskeleton of hepatocytes, impaired vesicular transport in viral, alcoholic and drug hepatitis, cirrhosis, endotoxemia, sepsis, benign recurrent cholestasis.
Violation of the integrity of the tubules (membranes, microfilaments, cellular compounds) under the influence of drugs, oral contraceptives, bacterial infections, Beiler’s disease.

Clinical trials:
1. In an open clinical trial, heptral treatment of alcoholic liver diseases (34 people) for 14 days with an intravenous drip of 800 mg / day, and in the next 14 days, 400 mg / day 2 times inside (tablets) led to the disappearance of signs depression, improvement of biochemical and physical (liver density) indicators.
2. Treatment of 23 patients with chronic hepatitis C with interferon a2 was accompanied by the development of cholestatic and depressive syndromes. Signs of cholestasis were manifested in the first 3 months of treatment and especially clearly in patients with cirrhotic transformation of the liver. The inclusion of Heptral in the complex of therapy helped to timely stop depressive and cholestatic phenomena and to conduct a full course of antiviral therapy with interferon a2.
3. In the treatment of 8 patients with medicinal lesions of the liver, an improvement in the general condition and normalization of liver tests were observed.
4. Heptral was prescribed to 32 patients with chronic diffuse liver diseases and intrahepatic cholestasis, 16 of whom had primary biliary cirrhosis. During the first 16 days of phase I of treatment, Heptral was injected intravenously at 800 mg / day, and in the next 16 days – 1600 mg / day. Most patients showed a pronounced positive effect – the symptoms of asthenia, skin itching, jaundice, as well as a statistically significant normalization of biochemical parameters disappeared. In patients with primary biliary cirrhosis, there is a tendency to lower cholesterol and bilirubin in the blood. With repeated courses, heptral tolerance and a lack of resistance to its positive effect were noted.

Heptral – an analgesic
Osteoarthrosis is a degenerative joint disease characterized by progressive catabolic loss (“wear”) of articular cartilage due to an imbalance between the synthesis and degradation of cartilaginous proteoglycans, followed by bone growths along the edges of the articular surfaces. It mainly develops in the elderly, but can occur at any age, especially as a result of trauma, chronic inflammatory diseases, and congenital joint defects. Most often, the distal and proximal interphalangeal joints of the hands, the hip and knee joints, the cervical and lumbar spine are affected. Spondyloarthrosis sometimes leads to narrowing of the spinal canal (caudogenic intermittent claudication), pain in the legs and buttocks when standing or walking. It is accompanied by severe bone and muscle pain.
The goal of therapy is to relieve pain and prevent disability. The use of non-steroidal anti-inflammatory drugs (NSAIDs) can provide short-term pain relief, but with prolonged use, harmful side effects (eg, gastric bleeding) develop and cartilage loss increases. The empirical use of Heptral in osteoarthritis has led to analgesia comparable to NSAIDs with no side effects, as well as to stimulation of proteoglycan synthesis and partial regeneration of cartilage tissue.

Conclusion The
possibilities of heptral, alone and in combination with other drugs, in the treatment of depressive disorders are far from exhausted. As already noted, in the available Internet databases there are no English-language publications on the treatment of heptral withdrawal symptoms, and in a random sample of 18 domestic articles, only non-steroidal anti-inflammatory drugs were used in the treatment of arthralgia. There is a further study of the effectiveness of Heptral in the treatment of affective disorders, inhibition of prolactin secretion, etc. Pharmacokinetics has not been studied at all, although the relationship of the antidepressant efficacy of ademetionine with its concentration in blood and tissues appears explicitly or implicitly in many studies, which suggests the possibility of searching for optimal treatment regimens among existing … So far, it has been possible to find out that its transport through the villi of preparations of the human placenta proceeded rather slowly, like passive diffusion of L-glucose, and was accompanied by non-enzymatic conversion to a metabolite of an unknown structure. The transport of melatonin and its antipyrine marker drug proceeded most rapidly, while vitamin E diffused 10 times slower than L-glucose and ademethionine, but its non-racemic free forms were much faster. Measurable concentrations of ademetionine after parenteral administration were found in CSF in patients with senile dementia, which gives hope for new possibilities in the treatment of this and other neurodegenerative diseases with heptral.