Heptral®
Ademetionine belongs to the group of hepatoprotectors and also has antidepressant activity.
It has choleretic and cholekinetic effects, has detoxification, regenerating, antioxidant, antifibrosing and neuroprotective properties.
Replenishes the deficiency of S-adenosyl-L-methionine (ademetionine) and stimulates its production in the body; it is found in all environments of the body. The highest concentration of ademetionine was observed in the liver and brain. Plays a key role in the metabolic processes of the body, takes part in important biochemical reactions: transmethylation, transsulfurization, transamination. In transmethylation reactions, ademetionine donates a methyl group for the synthesis of cell membrane phospholipids, neurotransmitters, nucleic acids, proteins, hormones, etc. In transsulfuration reactions, ademetionine is a precursor of cysteine, taurine, glutathione (providing a redox mechanism of cellular detoxification), coenzyme A (included in biochemical reactions of the tricarboxylic acid cycle and replenishes the energy potential of the cell). Increases the content of glutamine in the liver, cysteine and taurine in plasma; reduces the content of methionine in serum, normalizing metabolic reactions in the liver. After decarboxylation, it participates in aminopropylation reactions as a precursor of polyamines - putrescine (stimulator of cell regeneration and hepatocyte proliferation), spermidine and spermine, which are part of the ribosome structure, which reduces the risk of fibrosis. Has a choleretic effect. Ademetionine normalizes the synthesis of endogenous phosphatidylcholine in hepatocytes, which increases membrane fluidity and polarization. This improves the function of bile acid transport systems associated with hepatocyte membranes and promotes the passage of bile acids into the biliary tract.
Effective for intralobular cholestasis (impaired synthesis and flow of bile). Ademetionine reduces the toxicity of bile acids in hepatocytes by conjugating and sulfating them. Conjugation with taurine increases the solubility of bile acids and their removal from the hepatocyte. The process of sulfation of bile acids facilitates their elimination by the kidneys, facilitates their passage through the hepatocyte membrane and excretion in the bile. In addition, sulfated bile acids themselves additionally protect liver cell membranes from the toxic effects of non-sulfated bile acids (present in high concentrations in hepatocytes during intrahepatic cholestasis).
In patients with diffuse liver diseases (cirrhosis, hepatitis) with intrahepatic cholestasis syndrome, ademetionine reduces the severity of skin itching and changes in biochemical parameters, incl. concentration of direct bilirubin, activity of alkaline phosphatase, aminotransferases, etc.
The choleretic and hepatoprotective effect lasts up to 3 months after cessation of treatment.
It has been shown to be effective against hepatopathy caused by various hepatotoxic drugs.
Antidepressant activity appears gradually, starting from the end of the first week of treatment, and stabilizes within 2 weeks of treatment.
Heptral lyophilic solution d/iv and intramuscular injection 400 mg No. 5 + solution
Directions for use and doses
Intravenously and intramuscularly.
Before use, the lyophilisate for intramuscular and intravenous administration should be dissolved using the supplied solvent. The remainder of the drug must be disposed of. The appropriate dose of the drug for intravenous administration should then be dissolved in 250 ml of saline or 5% glucose solution and administered slowly over 1-2 hours. The drug must not be mixed with alkaline solutions and solutions containing calcium ions.
If the lyophilisate has a color other than almost white to white with a yellowish tint (due to a crack in the bottle or exposure to heat), the use of Heptral® is not recommended.
Initial therapy:
The recommended dose is 5-12 mg/kg/day intravenously or intramuscularly.
Depression
From 400 mg/day to 800 mg/day (1-2 bottles per day) for 15-20 days.
Intrahepatic cholestasis
From 400 mg/day to 800 mg/day (1-2 bottles per day) for 2 weeks.
If maintenance therapy is necessary, it is recommended to continue taking Heptral® in tablet form at a dose of 800-1600 mg/day for 2-4 weeks.
Therapy with Heptral® can be started with intravenous or intramuscular administration, followed by the use of Heptral® in tablet form, or immediately with the use of Heptral® in tablet form.
Elderly patients
Clinical experience with the use of the drug Heptral® did not reveal any differences in its effectiveness in elderly patients and younger patients. However, given the high likelihood of existing liver, kidney or cardiac dysfunction, other concomitant pathology or concomitant therapy with other drugs, the dose of Heptral® in elderly patients should be selected with caution, starting the use of the drug from the lower limit of the dose range.
Kidney failure
There are limited clinical data on the use of Heptral® in patients with renal failure; therefore, caution is recommended when using Heptral® in such patients.
Liver failure
The pharmacokinetic parameters of ademetionine are similar in healthy volunteers and in patients with chronic liver diseases.
Children
The use of Heptral® in children is contraindicated (efficacy and safety have not been established).
Heptral in the treatment of chronic liver diseases with cholestasis
The liver is a central organ of chemical homeostasis, where a single metabolic and energy pool is created for the metabolism of fats and carbohydrates; in addition, the liver is involved in the synthesis of certain enzymes, vitamins, and is directly involved in water, mineral and pigment metabolism; The detoxifying function of the liver is extremely important.
Table. Treatment results (dynamics of main clinical and laboratory syndromes)
The range of pathological conditions of the liver is very large, and most of these changes can be accompanied by a violation of any of the listed liver functions or many with one or another predominance.
Bile formation is one of the most important functions of the liver. Any disturbances in the synthesis, secretion or flow of bile, leading to biochemical, pathophysiological, pathoanatomical changes, accompanied by certain clinical manifestations, are designated by the term “cholestasis”, which is classified into 2 groups: intrahepatic and extrahepatic. Extrahepatic cholestasis is caused by a mechanical obstruction in the ductal system, and intrahepatic cholestasis is caused by impaired hepatocyte function or impaired bile flow in the intercellular space. In turn, intrahepatic cholestasis is classified into two subgroups: hepatotubular (intralobular) and ductal (interlobular). The different types of cholestasis overlap to a large extent. The accumulation of bile acids inside liver cells can ultimately lead to their death, i.e. a vicious circle arises in which intrahepatic cholestasis caused by various types of liver damage in turn exacerbates these disorders (1).
Heptral (ademetionine) – S – adenosyl – L – meteonine – an amino acid that is synthesized in the body and is involved in enzymatic transamination and transsulfurization, synthesis and activation of hormones, neurotransmitters, nucleic acids, phospholipids. By donating a methyl group during remethylation and transsulfurization, ademetionine promotes the formation of glutathione, the main cellular antioxidant that neutralizes the effects of a number of exo- and endotoxins.
In medical practice, it is used in two forms: injection, consisting of 1 bottle with lyophilized ademetionine salt and 1 ampoule of solvent, which makes the injected medium neutral (pH 7.5 ± 1). The oral form of Heptral is white tablets in an enteric coating, insoluble in the acidic environment of the stomach. Ademetionine is a universal compound involved in three important metabolic reactions: transmethylation, transsulfuration and aminopropylation (polyamine synthesis), where it serves either as a group donor or an enzyme modulator. The active role of ademetionine in these reactions is due to the presence of a positive charge on the sulfur atom, due to which sulfur-carbon bonds are broken.
Regardless of the pathogenesis of intrahepatic cholestasis, ademetionine plays an important role in both the development and prevention of intrahepatic cholestasis. Ademetionine is a methyl group donor, participating in transmethylation reactions (this is the biosynthesis of phospholipids, which are the main building blocks of the cell membrane). The amount of phospholipids determines the “fluidity” of the cell membrane. It has been shown that the “fluidity” of the cell membrane is the most important factor influencing membrane-associated enzymatic processes. The structure and composition of hepatocyte membranes is a key element in the regulation of the most important metabolic pathways involved in bile production (Chawla et al, 1990).
A decrease in the “fluidity” of the membrane leads to a decrease in the activity of the Na/K – ATPase pump and disruption of sodium-dependent syntransport systems (which are directly related to the transport of bile acids). Ademetionine is able to prevent such changes.
The second positive aspect of the influence of ademetionine is its participation in maintaining a sufficient level of glutathione, a sulfur-containing peptide related to the protection of liver cells from toxic damage by free radicals. Finally, by participating in sulfation reactions, ademetionine plays an important role in the detoxification of a number of metabolites, such as toxic bile acids, converting them into sulfates, which do not have a damaging effect on the cell. The previous two effects are directly related to protecting the liver from the toxic effect of ethanol, which is realized through acetaldehyde. These effects are prevented by ademetionine by maintaining mitochondrial glutathione transport.
Clinical studies of the effectiveness of Heptral in patients suffering from liver diseases with intrahepatic cholestasis began in the 90s of the last century. Thus, Frezza et al (1990) treated 220 patients with biopsy-proven liver pathology (intrahepatic cholestasis) with ademetionine. A necessary condition for treatment was at least a twofold increase in total and conjugated bilirubin and alkaline phosphatase in the blood serum. Patients received either 1600 mg of the drug orally or placebo. The duration of treatment was 15 days. At the same time, the effectiveness of Heptral was proven both in relation to clinical manifestations and laboratory indicators of cholestasis (compared to placebo). In 1992, Manzillo et al. 420 patients were treated in 2 stages (first - 800 mg per day intravenously for 2 weeks, then 1600 mg per day or placebo for 8 weeks). They confirmed an even greater effect with increasing duration of treatment (it amounted to 68%). Thus, it has been shown that in patients with chronic liver diseases, longer treatment is associated with further improvement in liver biochemical parameters. Subsequently, the effectiveness of ademetionine was confirmed in women with intrahepatic cholestasis during pregnancy (Frezza M., Terpin, 1992), in patients with depression (Rozenbaum, 1990), in patients with chronic pancreatitis - in order to inhibit the activity of free radicals (Bilton et al, 1994); in acute pancreatitis (Braganza et al, 1995) - to reduce oxidative stress. Other possibilities for using Heptral are also being considered (prevention of liver damage during parenteral nutrition, during hypoxic conditions, during liver transplantation operations). Evaluation of the effectiveness of Heptral in different groups of patients (alcohol damage, viral, in the stage of liver cirrhosis, in the dystrophic stage with hepatic cell failure). Various doses of the drug, different routes of administration, and different durations of treatment were considered (500 mg, 800 mg, 1600 mg). All studies were compared with placebo and the effect of Heptral was 60% or higher, oral administration enhanced the effect of parenteral administration (treatment duration ranged from 2 weeks to a month or more (Lieber CS, 1999; Di Perri T. et al, 1999; Mato JM , 1999).Tolerability of Heptral was assessed by all researchers as good. Side effects in the form of short-term insomnia, nausea, sweating, mild phlebitis in a double-blind study were noted in a very small number of patients and did not differ from the placebo group.
Considering the above, we also assessed the effectiveness of Heptral in 60 patients with chronic liver diseases and cholestasis syndrome based on our clinical experience.
Characteristics of patients:
- primary biliary cirrhosis – 8 patients;
- alcoholic hepatitis – 22 patients;
- chronic hepatitis C – 20 patients;
- chronic hepatitis B – 4 patients;
- chronic viral hepatitis in the stage of liver cirrhosis – 4 patients;
- primary sclerosing cholangitis – 2 patients.
There were 38 men, 22 women; age – from 30 to 65 years (average age 43.4 ± 1.7 years); the average duration of the disease was 5.7 ± 3 years (minimum – 3 years, maximum – 12 years). Patients with alcoholic liver damage for a long time (from 15 to 17 years) drank alcohol with a frequency of 2 to 7 times a week; The daily dose of alcohol in terms of ethanol ranged from 60 to 200 ml. The criteria for inclusion in this group were: diffuse nature of liver damage, “alcoholic” history, systemic nature of the damage, absence of markers of hepatitis B and C viruses.
Research methods:
- clinical assessment (jaundice, pruritus, asthenic syndrome, hepatomegaly, splenomegaly, ascites);
- biochemical monitoring (AlAT, AST, bilirubin, cholesterol, γ GTP, alkaline phosphatase, protein and protein fractions, creatinine - initially and at the end of the course of treatment);
- ultrasonic monitoring and assessment of densitometric parameters, liver and spleen sizes, splenic vein diameter, measurement of the “attenuation column” with disabling automatic signal amplification in depth;
- markers of hepatitis B and C viruses (anti-HCV; HbsAg; HbeAg; HBcAg; HCV - RNA; HBV - DNA);
- routine laboratory tests (general blood test, urine test);
- patients with liver cirrhosis underwent endoscopy to assess the degree of varicose veins of the esophagus and “coronary” veins of the stomach.
Treatment
Heptral was prescribed at a dose of 800 mg intravenously, slowly for 14 days, followed by switching to oral administration at a dose of 1600 mg per day (divided into 2 doses) for 14 days.
In 10 patients with insufficient effect of therapy (persisting cholestasis and skin itching), the doctor individually decided to continue treatment with Heptral at a daily dose of 3200 mg (1600 mg x 2 doses) for 2 weeks. This decision was made by the physician if there were serious reasons to believe that the possible benefit of increasing the dose outweighs the risk.
Clinical experience with the use of a dose of 3200 mg allowed us to evaluate the therapeutic effect, dose tolerability, feasibility and possibilities of using a high dose.
Clinical manifestations of the disease depending on the nosological form and their dynamics under the influence of Heptral therapy are presented in the table.
The numerator represents the initial data, the denominator represents the effectiveness of therapy.
10 patients with persistent skin itching, jaundice, and asthenia continued treatment with Heptral at a daily dose of 3200 mg (1600 mg ´ 2 times a day) for another 2 weeks. At the same time, clinical syndromes were stopped and laboratory parameters continued to improve.
From the presented table it can be seen that the clinical effect of Heptral within 4 weeks of treatment was observed in the majority of patients (complete relief from 50 to 100%) in different groups of patients. More effective in patients with alcohol impairment (according to all clinical and laboratory indicators). Asthenic syndrome began to decrease by the 5-7th day of treatment, skin itching began to decrease by the end of the second week, and it is important to note that its dynamics were noticeable even while the laboratory cholestasis syndrome persisted. In most patients, positive changes in liver size were recorded (to a greater extent in cases of alcohol damage). Ascites was recorded in 6 patients (4 with liver cirrhosis and 2 with exacerbation of alcoholic hepatitis).
Resolution of ascites was achieved in all patients - in 4 patients with liver cirrhosis, it was necessary to introduce veroshpiron and diuretics into the treatment complex.
In 10 patients, no noticeable changes in laboratory signs of cholestasis were noted, and clinical syndromes only decreased in intensity. In this group of patients, the dose of Heptral was increased to 3200 mg/day for another 14 days (1600 mg ´ 2 times a day).
In almost all patients, this treatment was accompanied by further improvement or normalization of clinical manifestations and positive dynamics of laboratory parameters (especially bilirubin, which did not show positive dynamics at the initial doses).
There were no side effects in patients receiving Heptral at a dose of 3200 mg per day, and the drug was well tolerated.
General conclusion
- Heptral is an effective drug in the treatment of patients suffering from chronic inflammatory liver diseases with cholestasis.
- The effect depends on the dose used and duration of treatment.
- A dose of Heptral 3200 mg/day for 2 weeks of treatment, as our clinical experience has shown, may be an alternative to the recommended 4-week two-phase course.
- The drug is most effective for alcoholic liver damage.
Both forms of the drug were well tolerated; no side effects were observed.
How much do Heptral tablets and ampoules cost?
Price of Heptral in Ukraine
In Dnepropetrovsk, Kharkov, Odessa, Kiev and other large cities you can buy IV Heptral at a price of 670 to 755 UAH. The cost of 1 bottle of powder for preparing an injection solution is 210-215 UAH.
The price of Heptral in tablets 400 mg is from 756 to 1175 UAH.
Price of Heptral in Russian pharmacies
You can buy Heptral in Moscow, St. Petersburg, Ufa or Novosibirsk for an average of 1.5 thousand rubles (400 mg tablets, pack No. 20). The price of Heptral in ampoules is 1600-1900 rubles.
Cost of the drug in Belarus
You can buy Heptral injections for 675-925 thousand rubles, tablets - for 680-874 thousand rubles.
- Online pharmacies in RussiaRussia
- Online pharmacies in UkraineUkraine
- Online pharmacies in KazakhstanKazakhstan
ZdravCity
- Heptral intestinal tablets.
p.o 400 mg 20 pcs. EbbVi S.r.L. RUB 1,739 order - Heptral tablets p.p.o. enteric solution 500 mg 20 pcs. Abbott S.r.L./ Ebbwy S.r.L.
RUB 2,175 order
Pharmacy Dialogue
- Heptral tablets 400 mg No. 20Abbot
RUB 1,784 order
- Heptral bottle 400 mg No. 5 + Abbot solution
RUB 1813 order
- Heptral tablets 500 mg No. 20Abbot/Ebbvie
RUB 2,148 order
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Pharmacy24
- Heptral 500 mg No. 20 tablets Abbvi S.r.l., Italy
1218 UAH order - Heptral 500 mg N5 powder Famar Legle, France
1084 UAH order
PaniPharmacy
- Heptral tablets Heptral 500 mg enteric tablets No. 20 Italy, Abbvie
1236 UAH. order
- Heptral bottle Heptral powder lyophilized for injection 500 mg bottles with solvent in ampoules 5 ml No. 5 Greece, Famar
1107 UAH. order
- Heptral bottle Heptral powder lyophilized for the preparation of injection solution 400 mg with solvent ampoules 5 ml No. 5 France, Famar L'Aigle
1033 UAH. order
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