Heptor

Heptor belongs to the group of hepatoprotectors with antidepressant activity. It has choleretic and cholekinetic effects. It has detoxifying, regenerating, antioxidant, antifibrosing and neuroprotective effects.

Replenishes ademetionine deficiency and stimulates its production in the body, primarily in the liver and brain. Participates in biological transmethylation reactions (methyl group donor) - the S-adenosyl-L-methionine molecule (ademetionine) donates a methyl group in methylation reactions of phospholipids of cell membranes, proteins, hormones, neurotransmitters, etc.; transsulfation - a precursor of cysteine, taurine, glutathione (provides a redox mechanism of cellular detoxification), coenzyme A. Increases the content of glutamine in the liver, cysteine and taurine in the plasma; reduces the content of methionine in the blood serum, normalizing metabolic reactions in the liver. After decarboxylation, it participates in aminopropylation processes as a precursor of polyamines - putrescine (stimulator of cell regeneration and hepatocyte proliferation), spermidine and spermine, which are part of the ribosome structure. It has a choleretic effect due to increased mobility and polarization of hepatocyte membranes due to stimulation and synthesis of phosphatidylcholine in them. This improves the function of bile acid transport systems associated with hepatocyte membranes and promotes the passage of bile acids into the biliary system. Effective for intralobular cholestasis (impaired synthesis and flow of bile). Promotes detoxification of bile acids, increases the content of conjugated and sulfated bile acids in hepatocytes. Conjugation with taurine increases the solubility of bile acids and their removal from hepatocytes. The process of sulfation of bile acids promotes their elimination by the kidneys, facilitates their passage through the hepatocyte membrane and excretion with bile. In addition, sulfated bile acids protect liver cell membranes from the toxic effects of non-sulfated bile acids, which are present in high concentrations in hepatocytes during intrahepatic cholestasis. In patients with diffuse liver diseases (cirrhosis, hepatitis) with intrahepatic cholestasis syndrome, it reduces the severity of skin itching and changes in biochemical parameters, incl. concentrations of direct and total bilirubin, activity of alkaline phosphatase, g-glutamyl transpeptidase, aminotransferases. The choleretic and hepatoprotective effect lasts up to 3 months after cessation of treatment. Shown to be effective in hepatopathy caused by hepatotoxic drugs. Prescribing ademetionine to patients with opioid addiction accompanied by liver damage leads to regression of clinical manifestations of withdrawal, improvement of the functional state of the liver and microsomal oxidation processes. Antidepressant activity appears gradually, starting from the end of 1 week of treatment and stabilizes within 2 weeks of treatment. Effective for recurrent endogenous and neurotic depressions resistant to amitriptyline. Has the ability to interrupt relapses of depression. Prescription for osteoarthritis reduces the severity of pain, increases the synthesis of proteoglycans and leads to partial regeneration of cartilage tissue.

Heptor, 20 pcs., 400 mg, enteric-coated tablets

"Heptor" in the treatment of alcoholic liver disease.

Alcohol is one of the most common causes of acute and chronic diffuse liver diseases.
An increase in alcohol consumption statistically significantly leads to an increase in mortality and a decrease in life expectancy and is one of the five most common causes of death in men in Russia and the USA. This is especially evident when analyzing mortality from liver cirrhosis, since the most vulnerable organ when exposed to alcohol is the liver. In recent years, many European countries, including Russia, have seen an increase in alcohol consumption. Russia ranks one of the first in the world in terms of the amount of alcohol consumed per year (14.6 l/year per resident of the Russian Federation), with 40-45% of the population (mostly men) drinking alcohol regularly.

Most researchers believe that drinking 40-80 g of pure ethanol per day for 10-12 years leads to a high risk of developing alcoholic liver disease (ALD). In women, the dangerous dose of ethanol is less than in men, and is 20 g per day. In addition, women are more sensitive to the toxic effects of ethanol than men; they more often develop cirrhosis of the liver against the background of alcoholic hepatitis. It has been proven that daily consumption of small doses of ethanol is more dangerous than periodic consumption of high doses, when the liver has a chance to regenerate.

The structure of ALD includes hepatic steatosis, acute and chronic alcoholic hepatitis, and cirrhosis of the liver, which can occur either alone or in combination with each other.

Alcoholic liver damage is characterized by an “erased” course of the disease; patients seek medical help when ascites, jaundice and other symptoms of the disease appear.

Judgment about the alcoholic nature of the disease is based on a number of diagnostic signs:

1. An indication of alcohol abuse or the presence of signs of chronic alcohol abuse.

2. Rapid improvement in clinical signs of the disease during abstinence.

3. Significant hepatomegaly.

4. Prevailing increase in the level of AST and γ-GT in the blood serum.

Treatment of patients with ALP should be individual and comprehensive, taking into account the severity of the condition and the potential risk of complications. Since the course of treatment for ALD is long and expensive, it is necessary to search for effective and affordable hepatoprotectors.

On the basis of the gastroenterology department of the Voronezh Regional Clinical Hospital No. 1 (chief physician - Doctor of Medical Sciences, Professor, Honored Doctor of the Russian Federation V.N. Ektov), an open clinical study was conducted on the effectiveness and safety of the drug "Heptor" (S-adenosine-L-methionine) , , Russia.

"Heptor" is a preparation of ademetionine, which is a natural substance endogenously synthesized from methionine and adenosine. Ademetionine is involved in three vital biochemical reactions: transmethylation, transsulfuration and aminopropylation, and thus plays a critical role in a complex of metabolic processes. During the formation of ALD, the first target of the action of ethanol and its toxic metabolites is the cell membranes of hepatocytes. Membranes, in addition to performing a structural function, participate in the processes of molecular transport, cell division and differentiation, and stimulate the activity of various enzyme systems. Ademetionine, being a methyl group donor, takes part in the synthesis of phosphatylcholine, the main structural component of the cell membrane. In addition, ademetionine has an antioxidant, detoxifying effect, accelerates the regeneration of liver tissue, slows down the development of fibrosis, and also has an anti-neurotoxic effect. In addition, ademetionine plays a key role in the metabolism of nucleic acids and polyamines and is a precursor of glutathione. These processes almost always suffer in liver diseases and require the administration of exogenous ademetionine. Clinical studies have shown an increase in the survival rate of patients with compensated and subcompensated alcoholic cirrhosis (Child-Pugh classes A and B) with the use of ademetionine: the two-year survival rate was 90% compared with patients receiving placebo [1]. Somewhat later, in a study by JM Mato et al. (1999) demonstrated that the use of ademetionine at a dose of 1200 mg per day in patients with compensated and subcompensated liver cirrhosis leads to a reduction in mortality and the need for liver transplantation from 29 to 12% compared with the placebo group [2]. More recent work indicates that exogenously administered ademetionine is directly involved in the processes of growth, regeneration and death of hepatocytes [3].

Thus, the choice of the drug was due to the presence of a sufficient number of clinical studies confirming the effectiveness of ademetionine in the treatment of alcoholic liver disease, on the one hand, and the affordable price of Heptor on the Russian drug market.

The study included 40 patients with Child-Pugh class A liver cirrhosis (LC), who were undergoing inpatient or outpatient treatment in the gastroenterological departments of the State Regional Clinical Hospital No. 1, in a medical facility in Voronezh.

Criteria for inclusion in the study:

men and women aged 30 to 65 years;
history data - consumption of dangerous doses of ethanol (>40 g of pure ethanol for men and >20 g of pure ethanol for women);
duration of consumption of ethanol-containing drinks 8-10 years;
patients' consent to participate in the study.

Patients were not included in the study:

with the presence of liver cirrhosis of another etiology, the presence of liver cirrhosis of Child-Pugh classes B and C.
the presence of severe concomitant pathology (cardiovascular, lung diseases, malignant tumors);
incapable of abstinence during the clinical trial;

Materials and methods of research.

The study group consisted of 32 men (80%) and 8 women (20%); average age 47.3+ - 2 years, who, as a result of a comprehensive examination, were diagnosed with liver cirrhosis (class A according to the Child-Pugh diagnostic criteria).

In order to make a diagnosis and evaluate the effectiveness and safety of the drug, the following were carried out:

questionnaire (PAS questionnaire) to identify chronic alcohol intoxication;
assessment of changes in biochemical parameters of blood serum; activity of transaminases, alkaline phosphatase, GGTP, bilirubin, total protein and protein fractions, prothrombin, lipid spectrum indicators: cholesterol, triglycerides;
ultrasound examination (determining the size of the liver and spleen, the diameter of the intrahepatic bile ducts, common bile duct, portal vein);
Doppler ultrasound (determining the speed and direction of blood flow);
esophagogastroduodenoscopy (determining the presence of varicose veins of the esophagus);
determination of markers of viral hepatitis.

All patients in the study group were prescribed ademetionine (Heptor) orally at a dose of 800 mg/day.

The effectiveness of treatment was determined by the following parameters:

improvement of the subjective well-being of patients;
relief of the main clinical manifestations of liver cirrhosis;
significant improvement in laboratory parameters: cytolysis syndrome, cholestasis syndrome;
positive dynamics of the liver according to ultrasound.

The assessment of the safety of treatment was carried out on the basis of subjective tolerability of the Heptor drug by patients and data from laboratory research methods (CBC, FAM, blood parameters).

Clinical symptoms and laboratory data (CBC, TAM, ALT, AST, ALP, GGTP, total protein, bilirubin) were assessed at the beginning of treatment, on the 14th and 28th days of therapy; the level of albumin, PTI, cholesterol, triglycerides - at the beginning and on the 28th day of treatment with Heptor.

It should be noted that 31 patients (77.5%) showed signs of chronic pancreatitis with impaired exocrine function; in 9 (22.5%) endoscopic examination revealed erosive gastritis not associated with H. pylori. For the treatment of concomitant diseases, patients were respectively prescribed enzyme preparations without bile acids (Creon 25 thousand units per meal), proton pump inhibitors at a dose of 40 mg/day. When conducting psychometric tests, encephalopathy 0-1 was revealed in all patients, and therefore the patients were prescribed lactulose (Duphalac) in a dose of 20-30 ml (the dose was selected individually).

Results.

According to the results of the questionnaire (PAS), 28 patients (70%) gave positive answers to 18 questions and 12 patients (30%) gave positive answers to 15 questions, which suggested a high probability of systematic alcohol consumption, which contributed to the formation of ALD and cirrhosis in patients .

Figure 1. Results of analysis of PAS questionnaires (patients with alcoholic liver disease at the stage of cirrhosis, Child-Pugh class A)

The clinical picture of cirrhosis was dominated by astheno-vegetative and dyspeptic syndromes (Table 1).

Table 1

Dynamics of astheno-vegetative and dyspeptic syndromes in patients with alcoholic liver disease at the stage of Child-Pugh class A cirrhosis during treatment with the drug "Heptor"

Sign	Number of patients with symptoms		Number of patients without symptoms
	Before treatment (n=40)		After 2 weeks (n=40)		After 4 weeks (n=40)
	n	%	n	%	N	%
Weakness	40	100	15	37,5	38	90
Decreased performance	40	100	18	45	34	85
Fast fatiguability	40	100	12	30	35	87,5
Feeling of heaviness in the right hypochondrium	40	100	18	45	38	95
Belching	40	100	17	72,5	37	92,5
Nausea	40	100	16	40	40	100
Flatulence	40	100	13	32,5	37	92,5

During the initial examination, weakness, decreased performance, fatigue, a feeling of heaviness in the right hypochondrium, belching, nausea, and flatulence were detected in all patients included in the study.

After 2 weeks from the start of treatment, the following dynamics of indicators of astheno-vegetative and dyspeptic syndromes were revealed: weakness was relieved in 15 patients (37.5%), decreased performance - in 18 (45%), fatigue - in 12 (30%) , a feeling of heaviness in the right hypochondrium - in 18 (45%), belching - in 17 (72.5%), nausea - in 16 (40%), flatulence - in 13 (32.5%). When studying patients at the end of a 4-week course of treatment, it turned out that the clinical manifestations of astheno-vegetative syndrome were relieved on average in 87.5% of patients: weakness was relieved in 36 patients (90%), decreased performance in 34 (85%), fatigue - in 35 (87.5%). Clinical manifestations of dyspeptic syndrome were relieved on average in 95% of patients: a feeling of heaviness in the right hypochondrium - in 38 (95%), belching - in 37 (92.5%), nausea - in all studied patients, flatulence - in 37 (92, 5%).

During therapy with Heptor, the manifestations of asthenovegetative and dyspeptic syndromes observed in patients with ALD at the stage of liver cirrhosis (class A according to the Child-Pugh criteria) significantly decreased.

Dynamics of laboratory data

The results of a general blood and urine test did not differ from normal values both before and after the course of treatment.

When examining patients with cirrhosis before the start of treatment, all patients revealed: an increase in the level of ALT (on average up to 3.5 N), AST (on average up to 2.2 N), an increase in bilirubin (on average up to 2.1 N) (Table 2).

table 2

Dynamics of biochemical parameters in patients during treatment with the drug "Heptor"

	Research days
	Day 0	Day 14	Day 28
AlAt	3.5 N	2.9N	1.5N
AsAt	2.2 N	1.5N	N
GGTP	4.3N	3.7N	1.9N
alkaline phosphate	2.5N	1.8 N	N
Bilirubin	2.1N	1.7N	N (89%)
Albumen	46,0±1,6	—	49,0±1,8
PTI, %	78,0±6,5	—	81,0±8,1

The dynamics of biochemical parameters were assessed on days 14 and 28; indicators of protein-synthetic liver function - on the 28th day of treatment.

Cytolysis rates decreased in all patients already on the 14th day of treatment and practically returned to normal by the 28th day of therapy. By the 14th day, ALT decreased on average to 2.9 N (by 17%), by the 28th day - to 1.5 N (by 53%); AST in all patients decreased compared to baseline to 1.5 N (32%) by the 14th day and by the 28th day did not exceed normal values. Positive dynamics of changes in bilirubin concentration were also noted: by the 14th day, the bilirubin level decreased to 1.7 N (by 19%), by the 28th day it was within normal limits in 89%, in 11% of patients, bilirubin was increased to 1 ,2 N. Thus, within 28 days of treatment of patients with cirrhosis, regression of the cytolytic syndrome occurred in the majority of patients.

Before the start of therapy, the patients included in the study showed an increase in the level of cholestasis markers: ALP (on average up to 2.5 N) and GGTP (on average up to 4.3 N). During treatment with Heptor, positive dynamics were noted:

a decrease in the level of alkaline phosphatase by the 14th day of the study to 1.8 N (by 28%), by the 28th day - to normal levels;
a decrease in the level of GGTP by the 14th day of the study to 3.7 N (by 14%), by the 28th day - to 1.9 N (by 56%);

As can be seen from the data presented in Table 2, by the 28th day of the study in the study group of patients, an increase in albumin level by 6.5% and PTI level to normal values was detected.

The initial cholesterol level in the study group of patients was on average 1.7 N, the triglyceride level was 1.5 N. As a result of the treatment, the cholesterol level decreased to normal levels by the 28th day in 83% of patients, the triglyceride level by the 28th day reached normal levels in all patients.

conclusions

In a study of the effectiveness and safety of the use of the drug Heptor in patients with alcoholic liver disease at the stage of cirrhosis (Child-Pugh class A), it was found that the use of the drug Heptor for 28 days leads to:

reducing the severity of symptoms of asthenovegetative and dyspeptic syndromes,
improvement of protein-synthetic function of the liver,
reducing the severity of lipid metabolism disorders,
positive dynamics of biochemical parameters (ALP, GGTP, AlAt, AsAt, bilirubin),
subjective improvement in the well-being of patients.

The course of treatment revealed that the drug was well tolerated by patients.

Thus, the study showed the effectiveness and safety of the use of the drug "Heptor" in patients with alcoholic liver disease at the stage of Child-Pugh class A cirrhosis.

IN AND. Mordasova

Voronezh Regional Clinical Hospital No. 1

Literature:
1. Mato JM, Camara J, Ortiz P et al. S-adenosylmethionine in the treatment of alcoholic cirrhosis: results from a multicentric placebo-controlled, randomized double-blind clinical trial. Hepatology 1997; 26:251A.
2. Mato JM, Camara J, Fernandez de Paz J et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. Hepatology 1999; 30: 1081-1089.
3. Mato JM, Shelly C.Lu Role of S-Adenosyl-L-Methionine in liver health and injury. Hepatology 2007; 45: 1306-1312.