Ademetionine in the treatment of chronic liver diseases with cholestasis


Chemical properties

Ademetionine – S-adenosylmethionine , a coenzyme that takes part in the reactions of transfer of methyl groups throughout the body. This substance was first described in the 50s of the 20th century by the Italian scientist Cantoni. According to Wikipedia, the product has a molecular weight = 399.5 grams per mole. Normally, the enzyme is formed by adenosyltransferase from ATP and methionine in liver tissue.

In the structure of the methionine , a methyl group is attached to the sulfur atom, and in the composition of S-adenosylmethionine it actively participates in chemical interaction reactions. During the course of more than 40 metabolic reactions, a transfer occurs from the CH3 to proteins, nucleic acids , fats and other substrates.

This chemical compound is most often used in the form of white powder When administered parenterally, the drug has greater bioavailability compared to the tablet form. After taking the tablets, only 5% of the active substance is absorbed. For oral administration disulfate , tosylate , butadeine sulfonate , monosital disulfate , etc. are used.

Ademetionine and protection against oxidative stress

S-adenosylmethionine protects cells from a number of toxic agents that contribute to the development of oxidative stress.

One of the mechanisms of the protective effect of SAM may be its participation in the regulation of methionine metabolism through the synthesis of glutathione, which is necessary to ensure the energy potential of the cell. In Fig. Figure 3 shows a diagram of the formation of glutathione through the transsulfuration of homocysteine ​​formed from S-adenosylmethionine with the participation of methionine adenosyltransferase (MAT), methionine synthases, citation-β-synthases and their cofactors - vitamins B6 and B12, as well as folates.


High concentrations of methionine are known to be toxic to the body. S-adenosylmethionine is synthesized from methionine and ATP in a reaction catalyzed by MAT. A large number of methyltransferases with complex regulatory mechanisms have been identified in cells. The complexity of methionine metabolism in liver cells is increased by the presence of an additional enzyme, glycine-N-methyltransferase, involved in the formation of SAM. The results of modeling the regulation of methionine [6] led to the conclusion that by switching the metabolism of methionine to its utilization, the liver and kidneys can stabilize the concentration of this substance in the blood when it is in excess. Apparently, such a switch in methionine metabolism can occur not only with an increase in methionine concentration, but also with oxidative stress, to counteract which the cell increases the concentration of glutathione.

Glutathione, a sulfur-containing endogenous peptide, is one of the main intracellular components of the system for protecting hepatocytes from free radicals, as well as endogenous and exogenous toxic agents. The synthesis and metabolism of glutathione depend on the transsulfuration of ademetionine through cysteine. Lack of glutathione in the liver during liver diseases leads to inactivation of ademetionine synthesates, which in turn disrupts the transsulfuration process, i.e., the process is regulated by positive feedback [7].

Under conditions of oxidative stress, increased production of free radicals leads to tissue damage, creating conditions that precede inflammation. Both oxidative stress and inflammation contribute to the development of diseases such as Alzheimer's disease, atherosclerosis and osteoarthritis. Therefore, many dietary supplements developed in recent years are designed to prevent diseases caused by these factors. In the US, SAM is commonly used as a dietary supplement. When added to food, it has a cytoprotective and antioxidant effect, since it is an intermediate in the metabolism of sulfur-containing amino acids and is involved in the biosynthesis of numerous bioactive compounds, such as hormones and neurotransmitters [8]. SAM inhibits ethanol oxidation, aerobic Fe2+ oxidation and O2 uptake [9].

A study of the effect of SAM on the expression of antioxidant stress proteins heme oxygenase-1 and ferritin in endothelial cells showed that induction of the oxygenase/ferritin system leads to tissue protection from inflammatory factors. Ademetionine increases mRNA and oxygenase levels in endothelial cells. Induction of oxygenase gene expression is associated with an increase in ferritin levels and is regulated at the transcriptional level through an increase in promoter activity. Activation of oxygenase by SAM is associated with a decrease in NADPH-mediated release of reactive oxygen species. Thus, the HO-1/ferritin system may be another target of the antioxidant action of ademetionine [10].

In mammalian cells, two genes (MAT1A and MAT2A) encode two homologous MAT catalytic subunits, while a third gene, MAT2β, encodes a β subunit that regulates the MAT2A-encoded isoenzyme. The liver normally expresses MAT1A, whereas extrahepatic tissues express MAT2A. In hepatocellular carcinoma (HCC) cells, MAT2A and MAT2β are induced, which facilitates the growth of cancer cells. Patients with cirrhosis of various origins, including alcoholic cirrhosis, have reduced levels of liver MAT activity and SAM biogenesis. Using a Mat1a knockout mouse model characterized by increased sensitivity to oxidative stress and spontaneous development of HCC, it was shown that the susceptibility to HCC may be partly explained by a deficiency of SAM. Ademetionine inhibits the mitogenic effect of growth factors, in particular hepatocyte growth factor, and after partial hepatectomy, a fall in SAM levels is necessary for liver regeneration, but it should be temporary, since a persistent deficiency of SAM can lead to the appearance of a proliferative phenotype and the development of HCC. SAM controls not only liver cell growth, but also apoptosis. Interestingly, in normal hepatocytes SAM is an anti-apoptotic factor, and in liver cancer cells it is pro-apoptotic. In proliferating cells, SAM selectively induces Bcl-xs, an alternatively spliced ​​isoform of Bcl-xL that promotes apoptosis. Results obtained in recent years indicate that SAM is not only a donor of methyl groups, but also a key regulator of hepatocyte growth, death and differentiation [11]. There is growing evidence that SAM modulates the growth of both normal and proliferating hepatocytes, but its mechanism of action is different in the two settings. SAM can serve as both an antiapoptotic (in normal hepatocytes) and proapoptotic (in liver cancer cells) agent. These unique properties of SAM make it a potentially attractive agent for chemotherapy and treatment of HCC.

Pharmacodynamics and pharmacokinetics

Synthetic Ademetionine compensates for the deficiency of coenzyme in the body, stimulating its production in the tissues of the brain and liver. The substance donates the CH3 in methylation of cell membranes, hormones , neurotransmitters and cellular proteins. The chemical compound is a precursor to taurine , CoA , cysteine , glutathione and other thiol compounds , spermine , putrescine a , spermidine .

The substance has an anticholestatic effect. Medicines based on this component eliminate cholestasis and stimulate the restoration of normal bile flow. This occurs due to its ability to increase the mobility and degree of polarization of hepatocyte , stimulating the synthesis of phosphatidylcholine .

Ademetionine also accelerates the detoxification processes of fatty acids and increases the level of conjugated and sulfated fatty acids. Hepatocytes are more easily excreted with bile from the kidneys. Sulfated fatty acids can protect liver cells from the toxic effects of non-sulfated fatty acids.

The antidepressant effect of the drug occurs during the first week of treatment and stabilizes over the next 14 days. The substance is quite effective for neurotic and recurrent endogenous depression , as a prophylactic agent.

For cirrhosis or hepatitis of the liver , with intracranial cholestasis the medicine relieves skin itching, normalizes biochemical blood parameters ( bilirubin , aminotransferases , alkaline phosphatase , etc.). In half of the patients, asthenic syndrome or its intensity decreases significantly. The effect of treatment lasts for 3 months. The drug is also quite effective in case of increased load on the liver due to medication use in opioid addicts.

The substance has demonstrated sufficient effectiveness in the treatment of osteoarthritis with pronounced pain. proteoglycans is stimulated and cartilage tissue is restored.

Effect of ademetionine on cell homeostasis

To date, the connection between methylation processes and the modulation of the content of endogenous substances leading to mental disorders has been demonstrated; in particular, a connection has been established between folate deficiency, the cycle of which is associated with SAM metabolic pathways, and the formation of clinical depression. The main result of this relationship is the synthesis of methyl groups in the folate cycle, which are utilized by SAM as a donor of these groups. There is a homeostasis mechanism (Fig. 4) that allows the generation of SAM upon homocysteine ​​remethylation.

Another relevant aspect of studying the activity of ademetionine may be the connection of its cycle with the metabolism of homocysteine ​​(Fig. 3). Homocysteine ​​is a natural sulfur-containing amino acid not found in proteins, which is a product of methionine metabolism and a predictor of many pathological changes in the human body (cardiovascular, mental diseases, intrauterine development disorders) [12]. Two homocysteine ​​pathways (remethylation to methionine, requiring folate and B12, and conversion to cystathionine, requiring pyrodoxal phosphate) are coordinated by SAM, which acts as an allosteric inhibitor of methylenetetrahydrofolate reductase and as an activator of cystathione-β-synthase. Taking into account the role of ademetionine in the methylation cycle and its association with homocysteine ​​metabolism, it can be assumed that SAM can influence the total homocysteine ​​content in the blood. In addition, SAM is a potential activator of the enzyme cystathione synthetase, which promotes the removal of homocysteine. The effect of SAM on homocysteine ​​metabolism is currently being studied, since specialized clinical studies must evaluate the effects of SAM use in hyperhomocysthenia [13]. In the presence of hyperhomocysthenia, oral administration of ademetionine may alter the course of the disease by promoting the removal of excess homocysteine. Some authors believe that increased protein methylation caused by the addition of SAM leads to the formation of dimethylarginine, a potential inhibitor of nitric oxide synthetase, which plays an important role in endothelial dysfunction in hyperhomocysthenia [14]. Further study of the regulation of the homocysteine ​​cycle by ademetionine, the concentration of which can be used to judge the formation of pathological changes in the body, will make it possible to predict the effectiveness of therapy and optimize its regimen [15].

From an analysis of the regulatory role of ademetionine in metabolic processes occurring in liver hepatocytes and other cells of the body, we can conclude that it is an extremely necessary compound for life support. This implies the high pharmacological potential of ademetionine and drugs created on its basis. If liver damage results in a lack of endogenous ademetionine, administration of exogenous ademetionine helps prevent the accumulation of toxic metabolites in hepatocytes and maintain the permeability and fluidity of cell membranes, which is necessary for the activity of membrane-bound enzymes.

Indications for use

The drug is prescribed:

  • for fatty liver ;
  • patients with chronic hepatitis and toxic damage to liver tissue of various origins (from alcohol, viruses, drugs);
  • for chronic acalculous cholecystitis ;
  • patients with liver cirrhosis ;
  • with cholangitis or encephalopathy , including those caused by liver failure;
  • pregnant women with intracranial cholestasis ;
  • for the treatment of withdrawal syndrome as part of complex therapy;
  • for depression in combination with other drugs to prevent depressive episodes.

Antidepressant effect of ademetionine

Disturbances in SAM-dependent methylation processes can cause metabolic and structural changes that have serious functional consequences for the central nervous system. Ademetionine, on the one hand, is directly involved in the synthesis of catecholamines (for example, adrenaline), on the other hand, it affects the methylation of membrane phospholipids, which regulate membrane fluidity and the functioning of receptors. The important anti-neurotoxic role of ademetionine in the central nervous system is carried out through cysteine, a precursor of two antitoxic agents: taurine and glutathione.

The antidepressant effectiveness of ademetionine has been known for two decades, and it has been found that its action is very different from that of known antidepressant drugs, such as norepinephrine and serotonin reuptake inhibitors or monooxygenase inhibitors. Ademetionine is classified as an atypical antidepressant, and its neuropharmacological effect is usually associated with stimulation of the formation of neurotransmitters.

The results of several randomized clinical trials involving 498 patients with depression of varying severity showed a significant (38–60%) excess of the antidepressant activity of Heptral® over the activity of placebo, while its effectiveness was equivalent to the effect of standard tri- and heterocyclic antidepressants - imipramine, desipramine, amitriptyline and others with almost complete absence of their inherent side effects [26–27].

Data obtained from studying the psychotropic activity of Heptral® in the treatment of protracted and resistant to traditional thymoanaleptic depressive disorders, as well as assessing its tolerability and safety, allowed the authors to conclude that this drug can be used in the treatment of a wide range of non-psychotic depressions, in particular asthenic [ 28]. Moreover, while in the treatment of depressive attacks and episodes of recurrent depressive disorder no particular advantages of Heptral® over traditionally used antidepressants were noted, in relation to somatized dysthymia this drug showed effectiveness, allowing it to be considered a drug preferable for use in medical practice. It has a set of properties that influence both the depressive effect and somatopsychic disorders.

The use of ademetionine has a positive regulatory effect on the balance of neurotransmitters. In addition, the effectiveness of ademetionine is high in the treatment of depressive disorders and pathological craving for alcohol (with alcohol withdrawal syndrome, accompanied by the usual somatovegetative and psychopathological disorders). When treated with Heptral® (2 bottles parenterally - 800 mg for 2 weeks, then 1 tablet - 200 mg 4 times a day for the next 2 weeks in combination with taking vitamins and, if necessary, antihypertensive drugs), the therapeutic effect was noted at 2–4 th days of treatment. By the end of the week, mood leveled out, sleep was restored, depressive symptoms decreased by 60–70%, blood pressure decreased, and after 4 weeks depressive disorders were completely relieved. The craving for alcohol decreased on average by the 10th day. The drug was well tolerated, there were no side effects or complications, and no addiction phenomenon was observed [20].

Side effects

During treatment with the drug, the following often develop:

  • nausea, pain in the gastrointestinal tract;
  • diarrhea , heartburn , indigestion .

Less commonly may occur:

  • dryness of the oral mucosa, esophagitis , increased gas formation , bleeding from the gastrointestinal tract, hepatic colic ;
  • sleep disturbance, confusion , headaches, paresthesia , dizziness;
  • pain and muscle cramps, arthralgia , genitourinary infections;
  • skin rashes, sweating , itching and dry skin;
  • reactions at the injection site, including skin necrosis ;
  • anaphylaxis , laryngeal edema , Quincke's edema ;
  • asthenia , swelling, chills , general weakness, hyperthermia , hot flashes.

In patients with bipolar depression, the medication may cause an affect reversal ( mania ).

Introduction

S-adenosyl-L-methionine (SAM) is an endogenous chemical compound found in all living organisms.
It is synthesized in liver cells from methionine and adenosine with the participation of the enzyme S-adenosylmethionine synthase (up to 8 g/day) and is found in all tissues of the human body. Due to its unique structure and physiological properties, ademetionine serves as a substrate for many biological reactions, being a donor of methyl groups, an activator of enzymes and a precursor of such important compounds for the body as cysteine, taurine, glutathione and coenzyme A. In terms of the variety of reactions, ademetionine is second only to ATP, participating in three the most important metabolic pathways – transmethylation, transsulfuration and aminopolypropylation [1]. Naturally, such a physiologically active endogenous cellular component is of not only scientific but also applied interest, since pharmacologically active and cell-safe drugs can be created on its basis. Since drugs containing ademetionine as an active ingredient have already shown their effectiveness in medicine (a convincing example is the use of Heptral®), the purpose of this review is to focus attention on the unique properties of ademetionine, which allow it to modulate cell metabolism, especially under stressful conditions (oxidative stress, development of proliferation and carcinogenesis), as well as interact with biomarkers that are predictors of pathological changes in the body, which ultimately can contribute to the development of new highly effective drugs.

Ademetionine is highly chemically active and therefore unstable. Its active role in biological reactions is due to the presence of a positive charge on the sulfur atom (Fig. 1), due to which sulfur-carbon bonds are broken.


The problem of instability of ademetionine was solved by adding the butane disulfonic acid anion (SD4) to the active substance and creating a safe and effective drug Heptral®, used in gastroenterology for the treatment of intrahepatic cholestasis and in psychiatry for the treatment of various types of depression. The chemical name of Heptral® is S-adenosyl-L-methionine-1,4 butane disulfonate. To increase the stability of the drug, it is possible to use other compounds, for example, salts or esters of paratoluenesulfonic acid, but butane disulfonates are considered more stable and intravenous forms based on them are less painful when administered. The injection form of Heptral® consists of one bottle of lyophilized ademetionine salt and one ampoule of solvent. The composition of the solvent buffer makes the environment of the mixed components almost neutral before injection (pH - 7.35–7.45). In intensive therapy, in the first 2–3 weeks of treatment, the drug is prescribed at 400–800 mg/day intravenously (very slowly) or intramuscularly, the powder is dissolved only in the special supplied solvent (L-lysine solution). The oral form of Heptral® is a white tablet in an enteric coating, insoluble in the acidic environment of the stomach.

Taking into account its antidepressant and hepatoprotective effects, Heptral can be recommended in the complex treatment of withdrawal syndrome. The drug normalizes the production and flow of bile acids from liver cells into the biliary tract, improves gastrointestinal motility. By restoring the content of the endogenous metabolically active substance ademetionine in liver cells, the drug increases the protective properties of cells to various damaging factors (alcohol, antibiotics, toxic substances).

Ademethionine, instructions for use (Method and dosage)

The drug is prescribed orally, intramuscularly or intravenously.

The tablets are not split or chewed; they are taken between meals, preferably before lunch. The recommended daily dosage is 0.8-1.6 grams. Treatment with tablets can be carried out for 2 months, depending on the indications and recommendations of the attending physician.

Instructions for Ademethionine, intravenous and intramuscular administration

The lyophilisate for injection is thoroughly dissolved in a pre-prepared solvent (most often a lysine solution is included ) . The injection is given slowly, during the acute period (the first 14-21 days of illness). It is recommended to administer 0.4-0.8 grams of the substance. After achieving a lasting result and transferring the patient from the hospital, it is better to switch to the tablet form of the medicine.

It is recommended that debilitated or elderly patients begin treatment with the minimum active and effective doses.

special instructions

Considering that the medicine has a certain tonic effect, it should not be taken before going to bed.

Therapy with the drug must be carried out under the supervision of a doctor. During the course of the drug, it is necessary to determine the level of creatinine and urea in the urine, and the level of nitrogen in the blood.

If the body has a deficiency of folic acid or vitamin B12 , then treatment may not be effective enough. It is recommended to take these drugs in parallel.

Because this medicine may cause dizziness, do not drive or perform potentially life-threatening activities during treatment.

Preparations containing (Ademetionine analogues)

Level 4 ATC code matches:
Carnitine chloride

Carnitine

Heptral

Karniten

Gepadif

Elkar

Heptor

Structural analogs of Ademethionine (synonyms): Heptor , Heptral , Heptor N.

Reviews

Some reviews about the use of this substance:

  • “... After passing the med. The commission advised my husband to treat his liver and prescribed infusions of this drug. The medicine is expensive, but effective; after the hospital, my husband took another course of pills. Now the tests are normal, the condition of the skin has improved, the white coating on the tongue has disappeared, there were no adverse reactions during treatment”;
  • “... I took the drug when problems with the liver began. Among the adverse reactions, I was constantly thirsty and had heartburn during treatment with pills. I am very pleased with the result, although the medicine turned out to be expensive”;
  • “... Several years ago I used it to treat gallstones. At the same time, the doctor prescribed medicinal herbs and vitamins. But, unfortunately, after only a week of taking the medicine, I began to feel heaviness in my lower back, my creatinine level increased, and I was forced to stop treatment.”
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