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GASTROENTEROLOGY

INVENTION
Patent of the Russian Federation RU2286785

METHOD FOR TREATMENT OF ALCOHOL ILLNESS OF THE LIVER

METHOD FOR TREATMENT OF ALCOHOL ILLNESS OF THE LIVER

The name of the inventor: Starodub Evgeniy Mikhailovich (UA); Samogalskaya Elena Evgenievna (UA); Mazur Ivan Antonovich (UA); Avramenko Nikolay Alexandrovich (UA)
Name of the patent holder: Limited Liability Company "Pharmatron" Scientific and Production Association (Pharmatron) (UA), Ternopil State Medical Academy named after I. I. Gorbachevsky (UA)
Address for correspondence: 69096, Zaporozhye, ul. Chervona Kinnota, 23, Patent Office of the NGO "Farmatron", N.F. Androsov
Date of commencement of the patent: 2004.05.06

The invention relates to medicine, in particular to gastroenterology, and concerns the treatment of alcoholic liver diseases, including the complex administration of thiamine bromide, cyanocobalamin, thiotriazoline, legalona and pancreatin. To do this every other day, intramuscularly inject 1.0 ml of a 5% solution of thiamine bromide and 0.05% cyanobalamine solution. The course of treatment is one month. In the course of the first ten days, intramuscular injection of a 2.5% solution of thiotriazoline is administered 2 ml twice a day, and over the next twenty days 100 mg of thiotriazoline are administered three times daily in the form of tablets. In addition, during the whole month, legalona is administered two tablets three times a day and pancreatin at a dose of 0.25 mg three times a day. The course of treatment is repeated after 6 and 12 months. Due to the mutual effect of the drugs at their specific dosages, the sequence and duration of administration, the method provides a significant improvement in clinical and laboratory parameters and rehabilitation of patients for 6-12 months.

DESCRIPTION OF THE INVENTION

The invention relates to the field of medicine, in particular to methods of treating liver diseases, and can be used in the treatment of alcoholic liver diseases (ABP).

It is known to use in the treatment of chronic hepatitis of the liver an antioxidant, hepatoprotective drug "Silibor" in tablets (Ukrainian patent No. 4362, class A 61 K 31/41). The use of "Silibor" for the treatment of liver diseases, in particular chronic hepatitis, gives positive results, but not in sufficient measure, since it has a narrow spectrum of pharmacological activity and is ineffective in the treatment of alcoholic liver diseases (ABP).

In the above-mentioned patent data are given on the effectiveness of the use of "Silibor" and the suppository "Tiotriazolin" in the treatment of chronic hepatitis.

As can be seen from the results presented in the patent description, the use of suppositories of thiotriazoline for the treatment of chronic hepatitis is much more effective than the use of silibor.

Tiotriazolin is the medical name for morpholines of 3-methyl-1,2,4-triazolin-5-thioacetate protected by the Ukrainian patent No. 1988, cl. CO 7 D 413/12 is an antioxidant, hepatoprotective, cardioprotective, anti-inflammatory, immunomodulating, anti-ischemic, membrane-stabilizing agent.

But the use of only thiotriazoline in the treatment of alcoholic liver diseases does not provide a complete and stable cure.

A known method of treatment of ABP, which includes complex therapy with the use of antioxidant, hepatoprotective agents, for example silibor or legalon, preparations that contain B vitamins, for example thiamine bromide and cyanocobalamin, as well as symptomatic therapy with the use of diuretics in the presence of edematous ascites syndrome. The course of treatment is one month (Babak O.Ya. Modern gastroenterology, 2002, No. 1, pp.33-35).

The disadvantage of the known method is the low effectiveness of treatment and the reduction of its results over time.

According to these indicators, the patient's condition returns to the input parameters or worsens 12 months after the start of treatment.

The invention is based on the task of developing a method for treating ABP, which provides the maximum effectiveness of treatment and the preservation of its results over time.

The solution of this problem provides a method of treatment of ABP due to the fact that the patient is complexly administered thiamine bromide, cyanocobalamin, tiotriazoline, legal and pancreatin for a month, while a 5% solution of thiamine bromide and 0.05% cyanocobalamin solution is injected intramuscularly with 1.0 ml , Alternating every other day, and the intramuscular injection of a 2.5% solution of thiotriazoline 2.0 ml twice daily for the first 10 days, and 100 mg of thiotriazoline three times a day in the form of tablets in the following 20 days, in addition to During the whole month, two tablets are administered legally twice a day three times a day and pancreatin is given at a dose of 0.25 mg three times a day, the course of treatment is repeated after 6 and 12 months.

CLINICAL EFFECT OF THE USE OF THE INVENTION

The use of the ABP treatment method according to the invention contributes to a certain reduction in the expressiveness of all clinical syndromes in comparison with conventional therapy and the preservation of treatment results over time.

The essence of the invention is explained by the following description and the results of clinical studies.

38 patients with ABP were examined, the mean age was 43.4 ± 3.7 years, and the study group was dominated by patients of working age 73.53%. Among the patients were 34 men and 4 women.

In 8 patients, chronic alcoholic hepatitis (HAP) was diagnosed with minimal activity of the process, in 22 - alcoholic cirrhosis of the liver in the subcompensation stage (ADC), in 8 - alcoholic cirrhosis of the liver in the stage of decompensation (ADPC).

Variation of the diagnosis was made according to the clinical-anamnestic (presence of abdominal pain, dyspeptic, icteric, edematous and ascites and asteno-vegetative syndrome, alcohol abuse) and laboratory-instrumental (biotechnical examination with the definition of catalase, liver damage markers, virological examination for Markers of hepatitis B and C, ultrasound (ultrasound), in some cases, liver biopsy) data.

The state of lipid peroxidation (LPO) of antioxidant protection (AOP) was assessed by the concentration in the blood of malonic dialdehyde (MDA), superoxide dismutase (SOD), catalase (CT) before and after treatment.

Patients ABP were divided into two groups, representative of age, sex, duration and severity of the course of the disease.

The first group (18 persons) received a treatment complex, which included silibor or legally in tablets, vitamins of group B - solutions of thiamine bromide and cyanocobalamin, diuretic therapy in the presence of edematous ascites syndrome.

The second group (20 persons) received tiotriazoline, except for the indicated therapy, for the first 10 days a 2.5% solution of the drug was injected in / m 2.0 ml twice a day for the next 20 days - tablets of 100 mg three times a day. These therapeutic complexes were administered again at 6 and 12 months from the start of treatment. Accordingly, the effectiveness of treatment was assessed after each course.

RESULTS AND ITS DISCUSSION

At the initial examination, the main complaints of the patients were unpleasant sensations or pain in the right hypochondrium, nausea, bloating, general weakness. With objective examination, hepatomegaly was detected in 100% of patients, splenomegaly - in 21%, ascites - in 20%. The severity of clinical symptoms in the examined patients was assessed in points (from 1 to 3) (Table 1)

Evaluation of laboratory indicators revealed the presence of hyperbilirubinemia in 32 (84.2%), hypoproteinemia in 11 (28.9%), increased transaminases in 34 (89.4%) and alkaline phosphatase in 21 (55%) patients. At the same time, the level of these indicators was not significantly different in patients with HAT, ACPs, and ADPD.

The study of the status of the indicators of POL-AOZ showed a statistically significant increase in the level of MDA to 4.93 ± 0.39 μmol / l (p <0.001), a decrease in catalase activity to 16.16 ± 2.89%, SOD to 39.43 ± 2, 43 conventional units. (P <0.05). In ADPD patients, the level of MDA and SOD significantly differed from those in patients with CAG and ADCs, which confirmed more pronounced changes in the liver parenchyma with decompensated cirrhosis.

At ultrasound examination in all patients hepatomegaly of different degree of severity with signs of fibrosis was revealed, in 52,94% - splenomegaly. Expansion of the portal vein was noted in 52.3% of patients.

Evaluation of the results of treatment for clinical symptoms showed a positive dynamics in patients of both groups, but more pronounced in patients of the second group. The comparative characteristics of the main clinical symptoms are given in Table 2.

These data indicate that complex therapy using tiotriazoline contributed to a significant decrease in the expressiveness of all clinical symptoms compared with traditional therapy, maintaining the stability of patients for 12 months. In 16 (80.0%) patients of the second group, work capacity was fully restored, which indicates a significant improvement in the quality of life.

The results of laboratory studies and revealed a significant decrease in the basic biochemical parameters in patients of both groups after 1 month, but subsequent observations recorded the stability of the parameters in the second group and their increase in 1 year in the patients of the first group.

The presented data testify to the improvement of the functional capabilities of the hepatic tissue, i.e., the high hepatoprotective properties of thiotriazoline, which are observed according to the results obtained both with XAG and with ADC.

The study of the system of indicators of the POL-AOZ system after treatment revealed a tendency towards normalization of MDA level in patients of the first group, the level of CT and SOD did not change (Table 4). Simultaneously, the patients of the second group had a significant positive dynamics of the parameters of the LPO-AOZ: in 1 month in patients with CAG and ADCs, in 6 months in all patients of the group, in 12 months in patients of the 2 groups normalization of the level of MDA and CT was noted.

Thus, tiotriazolin exhibits high antioxidant, hepatoprotective, membrane-stabilizing properties in ABP, thereby improving the condition of patients with ABP, stabilizing the functional processes of the liver.

In addition to conducting clinical studies on the effectiveness of the use of known complex therapy in the treatment of ABP and the proposed treatment, two equivalent age and status of patients with ABP were treated.

For example, we give the history of disease.

1. Patient A., born in 1955. Diagnosis: alcoholic liver cirrhosis, active phase, minimal activity, decompensation stage. Hepatic-cell failure, portal hypertension II, hepatic-renal failure.

Entered the gastroenterological clinic (Ternopil City Hospital No. 2) on 20.11.2001 with complaints of pronounced general weakness, abdominal enlargement, bloating, poor appetite and sleep. The patient over the years abused alcohol. 1,5 years ago the diagnosis of cirrhosis of the liver was established, it was treated permanently (plant hepatoprotectors, diuretic, detoxification, symptomatic therapy). The patient's condition progressively worsened, he constantly took 20-40 mg of furosemide in combination with veroshpiron without the proper effect, was recognized as an invalid of the 2nd group.

At objective research: the general condition of average gravity; The sclera is sub-bacterial, the skin is pale, and the abdomen is considerably enlarged in size. Pulse 72 beats per 1 minute, blood pressure - 115/75 mmHg. Heart tones are weakened, activity is rhythmic, lungs have hard breathing. The abdomen is enlarged in size, because of the free fluid, the organs of the abdominal cavity could not be palpated. Edema on the legs absent. Daily diuresis without diuretics 400 ml.

The main clinical symptoms in points: abdominal pain - 2 points, dyspeptic - 2.5 points, edematous-ascitic - 3 points, astheno-vegetative - 3 points.

The general analysis of the blood: hemoglobin - 90 g / l, erythrocytes - 3,1 · 10 12 / l, leukocytes - 3,9 · 10 9 / l, sedimentation rate of erythrocytes (ESR) - 36 mm / h; Biochemical blood test: bilirubin 47.1 μmol / l, alanine aminotransferase (ALT) 1.20 μmol / hl, aspartate aminotransferase (ACT) 1.83 μmol / l. Parameters of lipid peroxidation system - antioxidant protection: malonic dialdehyde (MDA) - 5,113 μmol / l, superoxide dismutase (SOD) - 30,18 standard units, catalase - 12,16%. When ultrasound examination of the abdominal cavity revealed ascites, the liver was reduced in size, dense, tuberous, spleen 150 × 80 mm, portal vein diameter - 14 mm.

Treatment is prescribed: complete refusal of alcohol intake, legalon according to 2 tablets. 3 times a day, a 5% solution of thiamine bromide in 1 ml of IM once every day, 0.05% cyanocobalamin solution, 1 ml of IM once every day, 0.25 pancreatin three times a day, veroshpiron - 200 mg / day , Furosemide - 80 mg per day, tiotriazoline first 10 days 2.5% solution of 2.0 ml IM twice a day, the next 20 days - a tablet of 100 mg three times a day.

After 4 weeks from the beginning of treatment, improvement of the state (appetite, sleep, working capacity) was noted, the abdomen decreased substantially, daily diuresis - up to 1000 ml (without diuretics). The patient was discharged home with recommendations for taking diuretics: furosemide 20 mg every other day, veroshpiron 100 mg per day, hypothiazide 50 mg once every 5 days. After 1 month, the dose of furosemide is reduced to 20 mg once every 3 days. During 6 months from the beginning of treatment the patient's condition remained relatively satisfactory, the ascites phenomena are stable.

On May 21, 2002, a repeated course of the above therapy was prescribed. After the treatment, the laboratory tests revealed an improvement in the general parameters: hemoglobin - 99 g / l, erythrocytes - 3,5 · 10 12 / l, leukocytes - 4,8 · 10 9 / l, ESR - 15 mm / h and biochemical blood tests: Bilirubin 21.3 μmol / l, ALT 0.59 μmol / hl, ACT 0.77 μmol / hl, MDA 4,455 μmol / l, SOD 33,18 μl / l, catalase - 14.08%. When ultrasound examination of the abdominal cavity revealed a decrease in the phenomena of ascites. On November 12, 2002, a third course of therapy was appointed, at the end of which, with objective examination, the patient's condition was assessed as satisfactory, sclera and skin pale pink, pulse 72 in 1min, blood pressure 120/75 mmHg. Heart tones are weakened, activity is rhythmic, in the lungs vesicular breathing. The abdomen is of normal size, free fluid palpation is not determined. Daily diuresis without diuretics 1000 ml. The main clinical symptoms in points: abdominal pain - 0 points, dyspepsia - 0.5 points, edematous-ascitic - 1 point, asthenic-vegetative - 1 point.

Significant improvement in laboratory parameters was noted in comparison with the state at the beginning of the study: hemoglobin - 112 g / l, erythrocytes - 3.8 · 10 12 / l, leukocytes - 5.4 · 10 9 / l, ESR - 13 mm / h; Bilirubin 19.8 μmol / l, ALT 0.51 μmol / hl, ACT 0.62 μmol / hl, MDA 4,024 μmol / l, SOD 49.33 standard units, catalase - 16.54%. With an ultrasound examination of the abdominal cavity, a small amount of free liquid was detected.

2. Patient B., born in 1956. Diagnosis: alcoholic liver cirrhosis, active phase, minimal activity, decompensation stage. Hepatic cell insufficiency. He entered the gastroenterological clinic (Ternopil City Hospital No. 2) on 21.03.2001 with complaints of pronounced general weakness, enlarged abdomen, pain in the right upper quadrant, poor appetite and sleep. Over the years he abused alcohol. 1,5 years ago, a diagnosis was made: cirrhosis of the liver, was treated as an outpatient (plant hepatoprotectors, diuretics, detoxification and symptomatic therapy). The patient's condition progressively worsened, was recognized as a disabled group II.

At an objective research: the general condition of average gravity of a sclera and a skin subicteric. Pulse 64 beats per minute, blood pressure - 110/70 mm Hg. Heart tones are weakened, activity is rhythmic, lungs have hard breathing. The abdomen is considerably enlarged in size due to free fluid, the organs of the abdominal cavity could not be palpated. Edema on the legs absent. Daily diuresis without diuretics 500 ml.

The main clinical symptoms in points: abdominal pain - 2 points, dyspeptic - 2.5 points, edematous-ascitic - 3 points, astheno-vegetative - 3 points.

The general analysis of the blood: hemoglobin - 82 g / l, erythrocytes - 2.67 · 10 12 / l, leukocytes - 4.6 · 10 9 / l, ESR - 29 mm / h; Biochemical blood test: bilirubin - 52.4 μmol / l, ALT - 1.31 μmol / hl, ACT - 1.45 μmol / hl. The parameters of the lipid peroxidation system - antioxidant protection: MDA - 5.191 μmol / l, SOD - 29.78 units, catalase - 11.60%. When ultrasound examination of the abdominal cavity revealed ascites, the liver was slightly reduced in size, dense, tuberous, spleen 140 × 80 mm, portal vein diameter - 15 mm.

Treatment is prescribed: refusal of alcohol, legalon according to 2 tablets. 3 times a day, a 5% solution of thiamine bromide in 1 ml of IM once every day, 0.05% cyanocobalamin solution, 1 ml of IM once every day, 0.25 pancreatin three times a day, veroshpiron - 200 mg / day , Furosemide - 100 mg per day.

After 4 weeks from the start of treatment, there was a slight improvement in the state (appetite, sleep), the abdomen slightly decreased in volume, daily diuresis - up to 800 ml. The patient was discharged home with recommendations for taking diuretics: furosemide 40 mg every other day, veroshpiron 150 mg per day, hypothiazide 50 mg once every 5 days. For 6 months from the start of treatment, the dose of diuretics was not reduced, since the phenomena of ascites were preserved. After 6 months from the beginning of treatment, a repeated course of the above therapy is prescribed. After the treatment, laboratory examinations were performed which revealed a slight improvement in the general parameters: hemoglobin - 85 g / l, erythrocytes - 3.0 · 10 12 / l, leukocytes - 4.9 · 10 9 / l, ESR - 15 mm / h and biochemical Blood tests: bilirubin 43.7 μmol / l, ALT 0.89 μmol / hl, ACT 1.49 μmol / hl, MDA 4.423 μmol / l, SOD 34.09 units / unit. , Catalase - 14.07%. With ultrasound examination of the abdominal cavity organs, a slight decrease in the amount of free liquid was revealed. The third course of therapy was appointed on 30.03.2002. At the end of therapy with objective examination, the patient's condition was assessed as moderate-to-severe, sclera and skin sub-bacterial, pulse 68 beats per minute, blood pressure 105/70 mmHg. Heart tones are weakened, activity is rhythmic, lungs have hard breathing. The abdomen is enlarged. Daily diuresis without diuretics 500 ml.

The main clinical symptoms in points: abdominal pain - 1.5 points, dyspeptic - 2.0 points, edematous ascites - 2.5 points, asteno-vegetative - 2.5 points.

Compared with the state at the beginning of the study, laboratory indicators without significant changes: hemoglobin 88 g / l, erythrocytes - 2,8 · 10 12 / l, leukocytes - 4,4 · 10 9 / l, ESR - 25 mm / h; Biochemical blood test: bilirubin - 42.3 μmol / l, ALT - 0.97 μmol / hl, ACT - 1.38 μmol / hl, MDA - 5.636 μmol / l, SOD - 32.13 usl.ed ., Catalase 13.12%. With ultrasound, it was found that the abdominal organs as a result of treatment did not significantly improve.

CLAIM

A method for treating alcoholic liver diseases comprising complex administration of thiamine bromide, cyanobalamine, thiotriazoline, legalon and pancreatin for a month, alternating every other day with intramuscular injection of 5% thiamine bromide solution and 0.05% cyanobalamine solution, which are used at a dose of 1.0 ml , With intramuscular injection of a 2.5% solution of thiotriazoline 2 ml twice a day for the first 10 days, and 100 mg of thiotriazoline three times a day in the form of tablets in the following twenty days, in addition to the whole month Enter legally two tablets three times a day and pancreatin at a dose of 0.25 mg three times a day, the course of treatment is repeated after 6 and 12 months.

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Date of publication 06.01.2007gg