RU2173144C2 - Method of treatment of patients with duchenne's-becker's myodystrophy disease - Google Patents

Abstract

FIELD: medicine, neurology. SUBSTANCE: method involves prescription of instenon-forte in the dose 1/2 of dragee, 2 times per a day for 30 days, actoprotector bemithyl in the dose 0.005 g/kg per a day for 30 days. Also, amplipulse-phoresis with proserine is carried out on antebrachii and shank limbs, 15 procedures for a course. In further, bemithyl is prescribed in the dose 1/2 of daily one for 45-60 days. Method provides to increase motional ability of patient, prolonged remission, to delay disease progression, to exclude adverse effects and to decrease time treatment in hospital. EFFECT: enhanced effectiveness of treatment. 4 ex

Description

 The invention relates to medicine, specifically to the field of neurology, and can be used to treat hereditary progressive pseudo-hypertrophic muscular dystrophy of Duchenne / Becker - a disease in the pathogenesis of which multiple molecular and structural changes can be detected. They are represented by a violation of the structure and function of muscle proteins and metabolism in the connective tissue, a violation of microcirculation in the muscles, muscle hypoxia, a change in the trophic effect of motor neurons, which results in the formation of an energy deficit that contributes to the development of the myodystrophic process.

 Currently, Duchenne myodystrophy and Becker-Keener myodystrophy, previously described as various forms, due to the active introduction of molecular genetic research methods into practice, one of which is DNA probe analysis used to determine the variability of intragenic polymorphic restriction sites (Dunnen JTD et a1., 1989; Chamberlain JS et al, 1988; 1990; Beggs AN et al., 1989; 1990; Abbs S. et al., 1991), the approaches to the clinical interpretation of the diagnosis have changed.

 One of the most important achievements of molecular genetics was the identification of the DMD / B gene - DMD (Duchenne muscular dystrophy) by positional cloning (Koenig M., 1987) and the production of the dystrophin gene and its isoforms (Hoffman E.R. et al., 1988).

 Detection of dystrophin abnormalities in DMD / B is possible in approximately 65-70% of patients using blot hybridization (Southern) or polymerase chain reaction (van Essen A.J. et al., 1997). Between half and two thirds of patients have deletions, usually several kilobases of genomic DNA (Takeshima Y., Matsuo M., 1997). In more than 60% of cases in the DMD / B gene in sick boys, extensive deletions are detected that capture from one to several neighboring exons, usually concentrated in two “hot” regions - in the region of the 5'-end of the gene (exons 6-19) and 3'-end (exons 40-53), with 30% of deletions localized in the proximal part of the gene and 70% in the distal (Koenig M. et al., 1989; Dunnen JTD et a1., 1989; Liechti-Gallati S. et al., 1989; Oudet C. et al., 1992). The localization of recombination hotspots is very similar to the distribution of deletion breakpoints in patients with DMD / B. These results suggest the participation of the same molecular mechanism underlying the formation of deletions and an increased frequency of recombination in the DMD gene.

 Deletions in the DMD gene in the area of damage to the same exons can be detected both in the case of the clinical variant of Duchenne myodystrophy and in the case of the clinical variant of Becker myodystrophy. This phenomenon corresponds to the translation frame reading hypothesis when a non-functional protein is synthesized (Monaco A.P., Bertelson C. J., Lieshti-Gallati S. et al., 1986). If the shift of the reading frame does not occur, then a more benign variant of the course of the disease according to the type of Becker or Mabry myodystrophy is clinically revealed; if the shift of the reading frame occurs, then a more severe variant of the course of the disease according to the type of Duchenne myodystrophy develops.

 Thus, an in-depth molecular genetic analysis of Duchenne / Becker myodystrophy indicates its significant heterogeneity associated with various mutations in the gene. Considering that in the literature there is no separate designation of the Duchenne myodystrophy gene and the Becker myodystrophy gene, but there is a single DMD gene, and the clinical variants of the course of the disease can sometimes be unambiguously differentiated for a long time - the designation of the disease is Duchenne / Becker myodystrophy.

 Various works focus on the correction of skeletal muscle energy deficiency. Closest to the proposed method is a method of treating patients with myodystrophy coenzyme Q (ubiquinone). Ubiquinone has activity in two links of the electron transport system of mitochondria: succin oxidase and NADP oxidase. The established deficiency of coenzyme Q in the muscles of patients with myodystrophy reduces ATP synthesis and contributes to the formation of energy deficiency (Danowski T.S., 1971; Sovik O., 1971). However, when using coenzyme Q in the treatment of patients with myodystrophy, the resulting increase in muscle strength and motor activity was short-term, there was no suspension of the myodystrophic process, and there were no remissions during the course of the disease. Coenzyme Q did not affect the violation of central hemodynamics, which contributes to increased hypoxia in the muscles, which is especially important for patients with Duchenne / Becker myodystrophy due to the presence of damage to the heart muscle - the development of cardiomyopathy. The negative side of this treatment method was the lack of influence on neurotrophic mechanisms through activation of the function of the structures of the hypothalamic-limbic-reticular complex due to the development of polyglandular endocrine insufficiency in these patients as a result of concomitant encephalopathy (L.O. Badalyan et al., 1976).

 The aim of our invention is to achieve an increase in motor capabilities, an increase in the duration of remissions, slowing the progression of the disease in patients with Duchenne / Becker myodystrophy. In connection with the above-mentioned drawbacks of coenzyme Q therapy, we have proposed a new method for treating Duchenne / Becker myodystrophy using instenon, the clinical effectiveness of which is determined by a wide spectrum of action, cumulative effect, bemitil actoprotector, which stimulates redox processes that occur with the release of energy, and amplipulsphoresis on the muscles of the limbs, contributing to the conduct of nerve impulses in the area of the neuromuscular junction. This goal is achieved by the fact that instenon-forte (manufacturer Huffslund Nycomed Pharma AG, Linz), known as a pharmacopoeial drug approved for use, is a combination of three components: hexobendin and ethamivan, which affect the metabolism of the central nervous system and muscles; etophylline, which has an effect on myocardial metabolism, is prescribed per os in a dose of 1/2 tablets 2 times a day for 30 days. At the same time, an actoprotector bemitil is prescribed, which enhances the synthesis of mitochondrial enzymes in the muscles and stimulates redox processes, as well as a pharmacopeia drug, a derivative of 2-ethylthiobenzimidazone hydrobromide monohydrate at the rate of 0.005 g / kg per day, 3 times a day for 30 days, then at a maintenance dose ( 1/2 daily dose) within 45 days, and in severe cases of the disease within 60 days. In order to restore the conduction of nerve impulses in the area of the neuromuscular junction, 10 days after the start of the course of drug therapy, a course of prosperin amplipulphoresis was performed. A medicinal substance (proserin) is introduced from the forearms and legs. Rectified operation mode, 1st and 2nd type of operation (1st type of operation - “constant modulation” current (PM) is formed as a result of modulations of the carrier frequency current with a low frequency in the range from 10 to 150 Hz. 2nd type of operation is “send-pause current” ( PP) is a series of modulated oscillations with a frequency set in the range from 10 to 150 Hz, alternating with a pause of 7 minutes PM, then PP 3 minutes, 3 minutes break and another 3 minutes of exposure to current. 15 treatments are performed daily.

 Instenon contains three components: ethamivan, hexobendin, etofillin.

 Ethamivan has a pronounced positive effect on the adaptive capabilities of the hypothalamic-limbic-reticular complex, which are depressed in conditions of impaired homeostasis. Activation of the reticular formation of the trunk - the main trigger for maintaining the adequate functioning of neural complexes of the cortex and subcortical-stem structures, ensuring the patient's exit from the state of posthypoxic encephalopathy.

 Hexobendin increases the utilization of glucose and oxygen due to the activation of anaerobic glycolysis and pentose cycles, stimulates anaerobic oxidation, providing an energy substrate for the synthesis and metabolism of mediators.

 Etofillin - activates myocardial metabolism, increasing cardiac output.

 Due to the structural similarity with purine bases (adenine and guanine), the activoprotector bemitil activates the synthesis of mitochondrial enzymes, increasing the energy potential of muscle tissue (Bobkov Yu.G., Vinogradov V.M., Katkov V.F. et al. Pharmacological correction of fatigue. -M .: Medicine, 1984).

 Proserin, administered by amplipulse phoresis, an anticholinesterase agent of predominantly peripheral action, has a postsynaptic sensitizing and presynaptic facilitating effect, which is manifested by an improvement in neuromuscular transmission.

 This combined use of instenon, an actoprotector of bemitil followed by proserin amplipulse phoresis is pathogenetically justified, since, on the one hand, due to activation of redox processes, the energy deficit of muscle tissue is corrected during Duchenne / Becker myodystrophy, which decreases as a result of the effect on neurotrophic processes due to exposure on the hypothalamic-limbic-reticular complex and reduction of muscle hypoxia as a result of correction of central hemodynamics. An increase in the energy potential of a muscle cell promotes the synthesis of proteins and enzymes, which leads to a decrease in the permeability of muscle cell membranes, promotes muscle reinnervation, a slowing of the myodystrophic process and the formation of remission (V.S. Lobzin, L.A. Saykova, A.G. Shiman. Nervous muscular diseases, 1998).

 Example 1. Patient D., 7 years old, case history N1527, diagnosis “Duchenne / Becker progressive muscular dystrophy,” was admitted with complaints of impaired gait type “duck”, deformity of the feet with a high arch and installation on the fingers, fatigue when walking and climbing stairs, weakness in hands, distracted attention. From the anamnesis it is known that the third child in the family, the elder brother of 11 years old, also suffers from Duchenne / Becker myodystrophy and at the time of admission was a wheelchair invalid. Both children showed a deletion in the region of 8-19 exons, in the oldest child, the disease was diagnosed at 8 years old, the first signs from 1.5 years of age in the form of muscle weakness in the legs, quickly tired when walking, impaired gait, could not run, jump; the youngest child has the same manifestations from 2 years old, the diagnosis was first established at 3.5 years. On admission, there was a restriction in the volume of active movements when lifting from a sitting position, “squatting”, lying down, with difficulty climbing stairs, using myopathic techniques. Diffuse hypotrophy of the muscles of the shoulder girdle, proximal parts of the arms, "pterygoid scapula", scoliosis, pseudohypertrophy of the calf muscles, decrease in tendon reflexes on the hands are expressed lack of knee and Achilles reflexes on the legs. Decrease in muscle strength to 3-4 points. EMG data indicate damage to the motor neuron at the axonal level. In the study of blood, there is an increase in CPK, LDH, ALT, ACT, bilirubin. The patient received treatment with coenzyme Q according to generally accepted methods. Against the background of the treatment, the volume of active movements increased slightly, according to blood tests, the enzymatic activity without dynamics after the course of treatment continued to decrease in the future. 1 month after the treatment, the positive dynamics were leveled.

 Example 2 Patient V., 10 years old, case history N876, diagnosis Duchenne / Becker progressive muscular dystrophy, was admitted with complaints of gait impairment of the duck type, deformity of the feet with installation on fingers, limited movement - within the apartment, weakness in the hands . From the anamnesis, it is known that the diagnosis of Duchenne / Becker myodystrophy was set at 1 year, since the case is family-related (the cousin siblings and uncle on the mother's side are ill), an increase of up to 6,000 units was noted in the study of blood CPK. (the norm is up to 200 units), also an increase in blood CPK was observed in the female sibling to 650 units. and the mother has proband up to 440 units. Deletion in the family was not identified due to crossing over. The course of the disease is severe, with early disability. On admission: widespread diffuse hypotrophy of the upper shoulder girdle and thigh muscles, moderate pseudohypertrophy of the calf muscles, decreased tendon reflexes from the upper extremities, lack of knee and Achilles reflexes. Expressed psycho-organic syndrome. EMG data indicate damage to the motor neuron at the axonal level. Coenzyme Q was treated according to generally accepted methods for 1 month, moderate positive dynamics was observed in the form of a moderate increase in muscle strength, an increase in range of motion. Changes in blood tests for CPK, LDH were not observed. The resulting positive dynamics leveled within a month.

 Example 3. Patient C., 7 years old, medical history N4607, diagnosed with Duchenne / Becker progressive muscular dystrophy, was admitted with complaints of impaired gait by the type of “duck”, the installation of the foot on the fingers, fatigue when walking and holding items mainly right hand, distracted attention. From the anamnesis it is known that the first signs of the disease were noted at 4.5 years old, when an examination revealed an increase in blood transaminase - was treated in Children's hospital No 3 and subsequently during the year was observed with a diagnosis of Hepatitis, anicteric form. Duchenne / Becker myodystrophy was diagnosed at 5.5 years of age. According to DNA probe diagnostics, a deletion was detected in the region of exon 44.

 On admission, there was a restriction in the volume of active movements when lifting from a sitting position, squatting, lying down, using myopathic techniques. Hypotrophy of the muscles of the shoulder girdle, pectoral muscles, proximal arms, scapula "pterygoid", scoliosis is expressed. The calf muscles are hypertrophied, densified. Reduced strength in the front muscle groups to 3 points on the right and up to 4 points on the left. There are no knee and Achilles tendon reflexes. EMG data indicate damage to the motor neuron at the axonal level. In the study of blood tests - an increase in CPK, LDH, ALT, ACT. The patient received instenon-fort in 1/2 tablets 2 times a day in combination with an actoprotector Bemitil in 1/2 tablets 3 times a day for 30 days, on the 10th day from the start of drug therapy, proserin amplipulphoresis was performed on the forearm and lower leg N15. In the future, Bemitil was prescribed in 1/2 tablets for 45 days. Against the background of the treatment, the volume of active movements increased, muscle strength increased to 4 points on the right and 4.5 points on the left, uses myopathic methods to a lesser extent, according to biochemical analysis of blood, a decrease in ALT, ACT, bilirubin, a moderate increase in the enzymatic activity of CPK, LDH. After the third course of treatment, tendon knee reflexes appeared. Disease progression is not observed.

 Example 4. Patient M., 9 years old, was admitted to the hospital with complaints of impaired gait, fatigue when walking, frequent falls, weakness in the hands, disinhibition, distracted attention, echolalia. From the anamnesis it is known that the disease was first detected at the age of 8, it was sent to the medical genetic center in connection with psychopathic personality changes, initially impaired gait, diffuse hypotrophy of the muscles of the shoulder girdle and proximal parts of the hands, pseudohypertrophy of the calf muscles. With DNA probe diagnostics, no deletion was detected; a point mutation is likely to occur. In neurological status: severe hypotrophy of supraspinatus, infraspinatus, deltoid, trapezius, as well as thigh muscles. Moderate hypertrophy of the calf muscles. Tendon reflexes are low, knee and Achilles tendon reflexes are absent. Symptoms of lesions of the frontal lobes by the type of psycho-organic syndrome are expressed. EMG data indicate damage to the motor neuron at the axonal level. ECG - sinus tachycardia, left ventricular anterior rotation with shift of the transition zone to the right, deep Q waves in V5-V6. According to echocardiography, no convincing structural changes were detected. On the EEG - common diffuse changes in the bioelectric activity of the brain. In the analysis of blood, increased CPK, LDH, ALT, ACT. The patient received treatment with instenon in 1/2 tablets 2 times a day for 30 days in combination with an actoprotector bemitil 0.125 g 3 times a day and prolcer amplipulphoresis from day 10 of drug therapy N15 on the forearm and lower legs. By the time of discharge, fatigue decreased, strength in the muscles of the limbs increased. Subsequently, he received an outpatient maintenance dose of bemitil of 0.125 g once a day for 60 days. After the second course of treatment, there was an increase in the level of KFK, LDH; after the third course of treatment, knee tendon reflexes appeared.

 The proposed method of treatment is applied to 36 patients with Duchenne / Becker myodystrophy. As a result of treatment, a significant improvement was noted in 83.3% of patients, moderate improvement in 17.7% of patients. Deterioration in the treatment of patients with this method was not noted. The average duration of patients in the hospital was 25 days.

 Clinical observations showed that this method of treatment can significantly increase the amount of active movements in the limbs, muscle strength, the progression of the pathological process slows down, and the general condition of patients improves.

 In parallel with the assessment of clinical symptoms, a biochemical and electrophysiological study was performed before and after treatment (1 and 6 months after treatment).

 All patients (36 people) showed a persistent therapeutic effect, positive dynamics of biochemical and electromyographic indicators.

 Side effects in the treatment of patients with Duchenne / Becker myodystrophy by the proposed method was not observed.

 Thus, the proposed method for the treatment of Duchenne / Becker myodystrophy gives an effect confirmed by the dynamics of the clinical picture, laboratory studies characterizing the level of metabolic and energy processes in the muscles, data of electrophysiological studies.

 Follow-up observations showed that the duration of remission is from 4 to 6 months.

 A significant difference of the proposed method lies in the fact that they use instenon in combination with actemoprotector bemitil and amplipulphoresis of proserin in the rectified mode on the region of the forearms and lower legs, as a result of which the total effect is more pronounced, leading to stabilization of the myodystrophic process.

 The application of the method is most effective in the initial stages of the disease, as well as in the benign course of the disease with a deletion in the region of 42-50 exons.

 The proposed method of treatment does not cause side effects, has no contraindications, is simple to perform, is available for use in any neurological department and on an outpatient basis.

Claims (1)

 A method for the treatment of Duchenne / Becker myodystrophy by drug therapy, characterized in that they are prescribed instenonfort drugs 1/2 tablets 2 times a day for 30 days, bemitil actoprotector at a dose of 0.005 g / kg per day for 30 days and prozerin amplipulphoresis on the forearms and lower legs of the limbs for a course of 15 procedures, then for 45-60 days, bemitil is prescribed 1/2 of the daily dose.