RU2548775C1 - Method of treating nonalcoholic fatty liver disease with use of pentoxifylline ampli-pulse phoresis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: conducting No. 5 dietary therapy and doing therapeutic exercises are prescribed. That is combined with taking low-mineralised carbonated sodium calcium chloride hydrogen carbonate sulphate mineral water "Essentuki Novaya" at 3.5 ml per 1 kg of patient's body weight 30-40 minutes before meals; 2% pentoxiphyline full-length ampli-pulse-phoresis procedures are performed daily with an anode placed on a projection of liver, whereas a cathode is placed symmetrically on back in the III and II operation modes (6 minutes each), at modulation frequency 150 Hz, modulation depth 75%; the therapeutic course includes 10 procedures.

EFFECT: method enables reducing the length of treatment and increasing the clinical effectiveness.

5 tbl, 2 ex

Description

The invention relates to medicine, in particular to gastroenterology, for the treatment of physical factors of patients with non-alcoholic fatty liver disease and can be used in specialized medical institutions, rehabilitation departments and centers, sanatoriums of a gastroenterological profile.

Non-alcoholic fatty liver disease (NAFLD) is one of the most important medical and social problems, as it leads to a deterioration in the quality of life and often to disability and increased mortality in this category of patients. So, if liver steatosis in most cases proceeds benignly and asymptomatically, non-alcoholic steatohepatitis is characterized by damage to hepatocytes, inflammation and development of connective tissue, which can lead to the formation of cirrhosis, liver cell failure and hepatocellular carcinoma (Mehdiyev S.N. Non-alcoholic fatty disease liver: clinic, diagnosis, treatment / S.N. Mehdiyev, V. B. Grinevich, Yu.A. Kravchuk, A. V. Brashenkova // Attending physician. - 2008. - No. 2. - P.29-32) . In addition, primary NAFLD is closely associated with abdominal obesity and metabolic syndrome, which significantly increases the cardiovascular risk and affects the incidence, prognosis and life expectancy of patients (K. Komshilova, Non-alcoholic fatty liver disease in obesity / K.A. Komshilova, E. A. Troshina, S. A. Butrova // Obesity and Metabolism. - 2011. - No. 3. - P.3-11). Timely treatment of the disease and the exclusion of risk factors can contribute to the reverse development of the pathological process. Therefore, the search for new treatments for NAFLD is highly relevant.

The key to the treatment and prevention of NAFLD is lifestyle modification aimed at reducing body weight and including diet and physical activity (Minushkin O.N. Non-alcoholic liver steatosis, diagnosis, treatment approaches / O.N. Minushkin // Attending physician. - 2012. - No. 2. - P.45-49; Pimanov S.I. American recommendations for the diagnosis and treatment of non-alcoholic fatty liver disease: something is becoming clearer / S.I. Pimanov // Application Consilium Medicum. Gastroenterology. - 2012. - No. 2. - S.92-96).

A known method of treatment of NAFLD, which is the closest in technical essence to the proposed invention, including therapeutic nutrition for diet No. 5 and physiotherapy exercises (Podymova S.D. Evolution of ideas about non-alcoholic fatty liver disease. // Experimental and clinical gastroenterology. - 2009. - No. 4. - S.4-12). This treatment method is a prototype for the present invention and consists in the appointment of therapeutic nutrition for diet No. 5 with a protein content of up to 100-120 g / day, a limited number of animal fats enriched with lipotopic factors (cottage cheese, buckwheat, wheat, oatmeal), vitamins and trace elements, as well as physiotherapy exercises in the form of adequate physical exertion for at least 40-60 minutes a day. Dietary nutrition and dosed physical activity helps to reduce body weight, improve the functional state of the hepatobiliary system and reduce the severity of insulin resistance - the leading etiopathogenetic factor of NAFLD. It should be noted that the effectiveness of these measures depends entirely on the compliance of patients and the duration of treatment. Unfortunately, only diet therapy and physiotherapy exercises do not always achieve the desired result. In addition, treatment of NAFLD should be comprehensive and aimed at different pathogenetic links (correction of metabolic disorders, reduction of oxidative stress and endotoxin-mediated release of cytokines, etc.). Also, this method does not provide for direct anti-inflammatory, hepatoprotective effects on the liver.

The rationale for the development of the proposed method was the following data. It is known that drinking mineral waters of the Essentuki type, on the one hand, have a beneficial effect on liver function (normalization of metabolic processes in hepatocytes, improved fat metabolism, anti-inflammatory, choleretic, membrane-stabilizing effect); on the other hand, mineral waters, due to activation of the enteroinsular axis, increased tissue sensitivity to insulin, etc., contribute to a decrease in clinical, metabolic, and hormonal disorders in diabetes mellitus and abdominal obesity, the leading factors in the etiopathogenesis of NAFLD (Botvineva L.A. Prophylactic and therapeutic effect of spa factors in patients with diabetes mellitus / L.A. Botvineva, G.M. Krashenitsa, N.D. Polushina, D.I. Topuria, A.V. Mogila, N.A. Samsonova, E.G. Kesidi // Manual for doctors .-- Pyatigorsk, 2003. - 19 p .; Botvineva L.A. Effect drinking water mineral water in the treatment of patients with metabolic syndrome / L.A. Botvineva, N.A. Samsonova, L.N. Melnikova // Materials of the anniversary scientific-practical conference dedicated to the 150th anniversary of the Russian balneological society. - Pyatigorsk. - 2013 - S.357-358; Polushina ND Change in tissue sensitivity to insulin under the influence of drinking mineral waters (clinical and experimental studies) / ND Polushina, L.A. Botvineva, V.K. Frolkov // Issues of balneology, physiotherapy and physiotherapy. - 1998. - No. 6. - S.21-24).

Of course, these therapeutic effects of drinking mineral waters are important in the treatment of NAFLD. In addition, we offer a direct effect on the liver with the help of pentoxifylline amplipulsophoresis, a method that potentiates the therapeutic effect of sinusoidal modulated currents (amplipulse therapy) and the pentoxifylline drug. Amplipulse therapy has anti-inflammatory, analgesic, choleretic effect, activates blood circulation, metabolic processes, improves the functional state of the liver (Ushakov A.A. Modern physiotherapy in clinical practice / A.A. Ushakov - M .: Medicine, 2002. - 364 p. BC General physiotherapy / BC Ulashchik, I.V. Lukomsky - Minsk, 2003. - 512 p .; Filimonov PM; Sinusoidal modulated currents (SMT) in the treatment of biliary sludge in a clinic / PM Filimonov, D.Yu. Korotkova, I.O. Buslavskaya, TR Filimonova // Questions of balneology, izioterapii and medical physical training -. 2011. - №6 -. S.21-23). And the well-known vasodilator - pentoxifylline not only improves microcirculation and rheological properties of blood, but also, as recent studies have shown, has an antioxidant effect and has pronounced immunomodulating activity (inhibits the production of a number of cytokines, including tumor necrosis factor, interleukins-1, -2 , -6, etc., which play an important role in the development of inflammation in various diseases, including non-alcoholic steatohepatitis) (Ushkalova EA, Pentoxifylline in alcoholic and non-alcoholic lesions x liver / E.A. Ushkalova // Farmateka. - 2006. - No. 9. - P.4-8). The antifibrotic effect of pentoxifylline is also described (Windmeier C. Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis / C. Windmeier, A. Gressner // Gen. Pharmacol. - 1997. - 29 (2). - P.181- 196).

Thus, the method we developed not only potentiates the effect of several therapeutic factors, but also involves the impact on various pathogenetic links of NAFLD.

The technical result of the proposed method is to improve clinical, biochemical, immunological, hemodynamic indicators, the state of peroxide homeostasis and a decrease in insulin resistance in patients with non-alcoholic fatty liver disease due to the complex effect on various pathogenesis factors and the direct anti-inflammatory, hepatoprotective effect on the liver, which leads to a reduction in the duration and increase the effectiveness of treatment of this category of patients.

The specified technical result is achieved by the fact that in the complex of treatment of non-alcoholic fatty liver disease, therapeutic nutrition is used according to diet No. 5, physiotherapy exercises, ingestion of low-mineralized carbon dioxide chloride-hydrocarbonate-sulfate-sodium-calcium mineral water "Essentuki-Novaya" and daily amplipulphoresis 2 % solution of pentoxifylline in the rectified mode, with the location of the anode on the projection of the liver, the cathode symmetrically on the back, with III and II types of work - 6 minutes each, with a modulation frequency of 150 n, the modulation depth of 75%, a course of 10 treatments.

The method is as follows: patients are prescribed a set of therapeutic and preventive measures, including a spa regime, therapeutic nutrition according to diet No. 5, physiotherapy exercises, internal intake of low-mineralized carbonic chloride-hydrocarbonate-sulfate-sodium-calcium mineral water "Essentuki-New", at the rate of 3.5 ml per 1 kg of patient’s body weight, 3 times a day 30-40 minutes before a meal; pentoxifylline amplipulse phoresis on a liver projection (Amplipulse-5 apparatus). At the same time, the first pad (from the anode) with an area of 300 cm ³ impregnated with a working solution (5 ml of 2% solution of pentoxifylline) is superimposed on the projection of the liver, symmetrically on the back - 2 pad (from the cathode); straightened mode, type of work III, II - 6 minutes each, modulation frequency 150 Hz, modulation depth 75%, daily, 10 procedures per course. The proposed therapeutic method contributes to the normalization of the functional state of the liver, lipid metabolism, peroxide homeostasis, hormonal and cytokine status of patients with NAFLD.

The proposed method is illustrated by the following examples.

1. Patient S. S. A., 39 years old, medical history No. 682. Diagnosis at admission: Non-alcoholic steatohepatitis with a mild degree of activity. Abdominal obesity 2 tbsp. Arterial hypertension 2 tbsp., Risk 2. Complaints upon admission: aching pains in the epigastrium and right hypochondrium, bitterness in the mouth, bloating, unstable stool, increased fatigue. There is no history of alcohol abuse and the use of hepatotoxic drugs. On examination - a patient of the correct physique, height 176 cm, weight 119 kg, waist circumference 120 cm, BMI 37.5 kg / m ² . On palpation of the abdomen, moderate pain in the right hypochondrium and epigastric region is noted; the lower edge of the liver +2 cm, sensitive to palpation. Blood test: hemoglobin - 142 g / l, white blood cell count - 7.3 · 10 ⁹ / l, ESR - 8 mm / h, prothrombin - 103%. Blood biochemical analysis: total bilirubin - 18.2 μmol / L, thymol sample - 7.5 units, ALT - 1.23 μmol / L, ACT - 0.61 μmol / L, gamma-glutamyl transpeptidase - 1956 nmol / s, alkaline phosphatase - 56.4 IU / l, total cholesterol - 7.08 mmol / l, triglycerides - 2.85 mmol / l, high density lipoproteins - 1.07 mmol / l, low density lipoproteins - 5.89 mmol / l lipoproteins of very low density 1.31 mmol / L, glucose 5.6 mmol / L, malondialdehyde 5.6 μmol / L, catalase 11.9 μkat / L. Serum cytokine levels: interleukin-6 - 4.6 pg / ml, interleukin-10 - 2.0 pg / ml, TNF-α - 5.0 pg / ml. Fasting insulin levels - 24.2 μIU / ml, HOMA-IR - 6.0. The analysis for markers of viral hepatitis is negative. According to ultrasound: hepatomegaly (thickness of the right lobe of the liver 14.6 cm by 16.9 cm), echoes of fatty hepatosis; according to dopplerography of the blood vessels of the liver, the peak systolic velocity of portal blood flow is 17.6 cm / s, the average speed is 14.3 cm / s.

A course of treatment was carried out - a gentle-training regimen of motor activity, diet nutrition No. 5, internal intake of mineral water from the "Essentuki-Novaya" spring, pentoxifylline amplipulphoresis to the liver region according to the method described above. When discharged from the clinic, disappearance of abdominal pain, dyspeptic manifestations, normalization of stool, and a decrease in general weakness were noted. On palpation of the abdomen, pain was not determined, the lower edge of the liver was +1 cm. Body weight decreased to 115.5 kg (3.5 kg), waist circumference was 117 cm, BMI - 36.2 kg / m ² . Blood test: hemoglobin - 144 g / l, white blood cell count - 6.9 · 10 ⁹ / l, ESR - 6 mm / hour, prothrombin - 105%. Blood biochemical analysis: total bilirubin - 14.1 μmol / L, thymol sample - 3.9 units, ALT - 0.66 μmol / L, ACT - 0.48 μmol / L, gamma-glutamyl transpeptidase - 1554 nmol / s, alkaline phosphatase - 35.8 IU / l, total cholesterol - 5.94 mmol / l, triglycerides - 1.90 mmol / l, high density lipoproteins - 1.35 mmol / l, low density lipoproteins - 4.27 mmol / l , very low density lipoproteins - 0.87 mmol / L, glucose - 5.3 mmol / L, malondialdehyde - 4.3 μmol / L, catalase - 18.6 μkat / L. Serum cytokine levels: interleukin-6 - 2.8 pg / ml, interleukin-10 - 3.2 pg / ml, TNF-α - 3.1 pg / ml. Fasting insulin levels - 18.5 μIU / ml, HOMA-IR - 4.4. According to dopplerography of the vessels of the liver, the peak systolic blood flow velocity is 19.8 cm / s, the average speed is 17.2 cm / s.

Thus, as a result of the treatment, there was a positive dynamics of both subjective symptoms and objective indicators characterizing the functional state of the liver (normalization of ALT, ACT, gamma-glutamyl transpeptidase, alkaline phosphatase, decreased thymol test, improved liver blood flow), lipid metabolism ( decrease in total cholesterol, triglycerides, low density lipoproteins, weight loss, waist circumference and BMI), carbohydrate metabolism (decrease in insulin and HOMA -IR), cytokine status (decreased secretion of pro-inflammatory cytokines - interleukin-6, tumor necrosis factor TNF-α, and increased content of anti-inflammatory cytokine - interleukin-10), state of peroxide homeostasis (normalization of plasma levels of malondialdehyde and catalase). The result of the treatment is regarded as "improvement."

2. Patient S.V.I., 55 years old, medical history No. 378. Diagnosis at admission: Non-alcoholic fatty liver disease: liver steatosis. Postcholecystectomy syndrome (cholecystectomy in 1985 for cholelithiasis): biliary sphincter of Oddi dysfunction. Abdominal obesity 1 tbsp. Arterial hypertension 2 tbsp., Risk 2. Upon receipt, complained of periodic aching pain in the right hypochondrium, bitterness in the mouth, unstable stool with a tendency to diarrhea. According to the anamnesis, the patient denies the use of alcohol and the use of hepatotoxic drugs. On examination, a patient of the correct physique, height 160 cm, weight 88 kg, waist circumference 102 cm, body mass index (BMI) - 34 kg / m ² . On palpation of the abdomen, moderate pain in the right hypochondrium is noted; the liver protrudes from the edge of the costal arch by 1 cm, sensitive to palpation. Blood test: hemoglobin - 135 g / l, the number of leukocytes - 4.6 · 10 ⁹ / l, ESR - 8 mm / h, prothrombin - 95%. Biochemical analysis of blood: total bilirubin - 10.9 μmol / l, thymol sample - 8.1 units, ALT - 0.32 μmol / l, ACT - 0.22 μmol / l, gamma-glutamyl transpeptidase - 504 nmol / s l, alkaline phosphatase - 38.4 IU / l, total cholesterol - 7.23 mmol / l, triglycerides - 2.35 mmol / l, high density lipoproteins - 1.27 mmol / l, low density lipoproteins - 5.23 mmol / l, very low density lipoproteins - 1.08 mmol / l, glucose 5.7 mmol / l, malondialdehyde - 4.8 μmol / l, catalase - 12.6 μkat / l. Serum cytokine levels: interleukin-6 - 2.6 pg / ml, interleukin-10 - 1.8 pg / ml, TNF-α - 2.9 pg / ml. Fasting insulin levels - 23.4 μIU / ml, HOMA-IR - 5.9. The analysis for markers of viral hepatitis is negative. According to ultrasound: hepatomegaly (thickness of the right lobe of the liver 13.8 cm by 16.7 cm), echoes of fatty hepatosis; according to dopplerography of the blood vessels of the liver, the peak systolic velocity of portal blood flow is 20.3 cm / s, the average speed is 16.2 cm / s.

The treatment was carried out - sparingly-training mode of motor activity, diet nutrition No. 5, internal intake of mineral water from the "Essentuki-Novaya" spring, pentoxifylline amplipulphoresis to the liver region according to the method described above. When discharging from the clinic, the patient did not complain, during palpation of the abdomen, pain was not determined, the lower edge of the liver was at the level of the costal arch. Body weight decreased to 85 kg (per 3 kg), waist circumference was 100 cm, BMI - 33 kg / m ² . Blood test: hemoglobin - 140 g / l, white blood cell count - 4.7 · 10 ⁹ / l, ESR - 6 mm / hour, prothrombin - 101%. Blood biochemical analysis: total bilirubin - 8.9 μmol / L, thymol sample - 6.4 units, ALT - 0.32 μmol / L, ACT - 0.24 μmol / L, gamma-glutamyl transpeptidase - 476 nmol / s, alkaline phosphatase - 23.8 IU / l, total cholesterol - 6.06 mmol / l, triglycerides - 1.09 mmol / l, high density lipoproteins - 1.69 mmol / l, low density lipoproteins - 4.33 mmol / l very low density lipoproteins - 0.9 mmol / L, glucose - 5.4 mmol / L, malondialdehyde - 3.6 μmol / L, catalase - 18.9 μkat / L. Serum cytokine levels: interleukin-6 - 2.3 pg / ml, interleukin-10 - 4.0 pg / ml, TNF-α - 1.7 pg / ml. Fasting insulin levels - 16.2 μIU / ml, HOMA-IR - 3.9. According to dopplerography of the vessels of the liver, the peak systolic blood flow velocity is 31.1 cm / s, the average speed is 23.0 cm / s.

Thus, as a result of treatment, positive dynamics of the clinical manifestations of the disease, as well as laboratory and instrumental studies (functional liver tests, indicators of intrahepatic hemodynamics, lipid and carbohydrate metabolism, peroxide homeostasis, immunological parameters) were noted. The patient was discharged from the clinic with improvement.

The method was tested in the conditions of the Essentuki Clinic, a branch of the FSBI PGNIIK FMBA of Russia, in two groups of patients - the main (20 people) and control (20 people) who received treatment according to the method of the invention and prototype, respectively. The clinical characteristics of patients are presented in table 1.

According to the data in Table 1, the clinical groups were representative.

The dynamics of the clinical manifestations of the disease in the main and control groups is shown in Table 2.

The data presented in table 2 indicate that the positive dynamics of the main clinical manifestations of the disease was more pronounced in the main group compared with the control.

The results of dopplerography of the blood vessels of the liver, presented in table 3, indicate a significant improvement in hepatic hemodynamics as a result of treatment by the proposed method, compared with the control group, which is explained by the potentiation of the hemodynamic effects of sinusoidal modulated currents and the pentoxifylline angioprotector.

The dynamics of these laboratory studies are presented in table 4. The results obtained indicate an improvement in the functional state of the liver, lipid peroxidation, and lipid and carbohydrate metabolism. When comparing the results of treatment in both groups, a pronounced advantage of the treatment complex with the use of pentoxifylline amplipulphoresis is observed. In patients of the main group there was a significant improvement in indicators characterizing the cytolytic, cholestatic and mesenchymal inflammatory syndromes of liver pathology. In the control group, a favorable trend of these liver samples was observed, but no statistically significant changes were noted. Favorable changes in lipid metabolism were also more clearly observed in the main group.

The results of the study of peroxide homeostasis indicate a pronounced antioxidant effect of the treatment complex using pentoxifylline amplipulphoresis: the level of malondialdehyde in blood plasma significantly decreased (1.3 times), and the catalase level significantly increased (1.6 times). In the control, similar changes were less pronounced (p _1-2 <0.05).

An analysis of the dynamics of carbohydrate metabolism revealed a statistically significant decrease in insulin resistance in the main group (Table 4), which confirms the pronounced insulinotropic effect of drinking mineral waters of the Essentuki type.

The dynamics of serum cytokines are presented in table 5. The results of the study indicate that the proposed method has an immunomodulating effect in patients with NAFLD. As a result of treatment, there was a significant increase in the secretion of the anti-inflammatory cytokine - interleukin-10 and suppression of the production of tumor necrosis factor - TNF-α, which plays an important role in the development of inflammation and liver fibrosis.

The overall treatment effectiveness was 90% and 65% in the main and control groups, respectively (p _1-2 <0.05).

Thus, in order to increase the efficiency of treatment of patients suffering from non-alcoholic fatty liver disease, along with therapeutic nutrition according to diet No. 5 and physiotherapy exercises, it is additionally recommended to administer low-mineralized carbonic chloride-bicarbonate-sulphate-sodium-calcium mineral water and pentoxifylline amplipulphoresis to the area liver according to the developed technique. This leads to a decrease in the clinical manifestations of the disease, a significant improvement in the basic functions of the liver and the state of its hemodynamics, contributes to the normalization of lipid and carbohydrate metabolism, peroxide homeostasis, slows down the development of oxidative stress, reduces insulin resistance, and has a corrective effect on the secretion of cytokines, thereby inhibiting the progression of the pathological process. The proposed method of treatment can be used in a package of measures for the treatment and prevention of the progression of NAFLD.

Claims (1)

A method of treating patients with non-alcoholic fatty liver disease, including therapeutic nutrition according to diet No. 5, physiotherapy exercises, characterized in that they additionally take in the low-mineralized carbon dioxide chloride-hydrocarbonate-sulfate-sodium-calcium mineral water "Essentuki-Novaya" and carry out amplipulphoresis 2 daily % solution of pentoxifylline in the rectified mode, with the location of the anode on the projection of the liver, the cathode symmetrically on the back, with III and II types of work - 6 minutes each, with a modulation frequency of 150 Hz, with a modulation depth of 75%, per course of 10 procedures.