Method for the treatment of duchenne muscular dystrophy/becker

 

(57) Abstract:

The method relates to medicine, namely, neurology, and is intended for the treatment of Duchenne muscular dystrophy/Becker. To do this, assign instenon Forte 1/2 tablets 2 times a day for 30 days, actoprotector bemythyl at a dose of 0.005 g/kg per day for 30 days. Spend amplipulse neostigmine methylsulfate on the forearms and lower limbs in the course of 15 treatments. In the future within 45-60 days appoint a bemythyl 1/2 of a daily dose. The method allows to increase the movement capabilities of the patient, duration of remissi, to slow the progression of the disease, to avoid side effects and to reduce the treatment time in the hospital.

The invention relates to medicine, specifically to the field of neurology, and can be used for the treatment of hereditary progressive pseudohypertrophy of Duchenne muscular dystrophy/Becker - diseases, pathogenesis of which can be revealed by multiple molecular and structural changes. They represented a violation of the structure and function of muscle proteins, and metabolism in the connective tissue disorder of microcirculation in the muscles, muscle hypoxia, changes in the trophic influence of motoneurons, resoureces.

Currently miodistrofiya Duchenne and miodistrofiya Becker-Kiner, previously described as various forms, in connection with the active introduction of molecular-genetic methods, one of which is a DNA probe analysis used to determine the variability vnutrennih polymorphic restriction sites (Dunnen J. T. D. et a1., 1989; Chamberlain, J. S. et al., 1988; 1990; Beggs A. N. et al., 1989; 1990; S. Abbs et al., 1991), has changed and approaches to clinical interpretation of the diagnosis.

One of the most important advances in molecular genetics has been the identification of the gene DMD/B - DMD (Duchenne muscular dystrophy) methods of positional cloning (Koenig M, 1987) and the product of the gene is dystrophin and its isoforms (Hoffman E. P. et al., 1988).

The detection of violations in a gene called dystrophin 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). From half to two thirds of patients have deletions, typically of several kilobase geneticheskogo DNA (Takeshima Y., Matsuo M, 1997). More than 60% of cases in the gene DMD/B in patients with boys found extensive deletions, exciting from one to several neighboring exons, usually concentrated in two "hot" areas in region 5' - what in the distal (Koenig M et al., 1989; Dunnen J. T. D. et a1., 1989; Liechti-Gallati, S. et al., 1989; Oudet, C. et al., 1992). Localization of hot spots of recombination is very similar to the distribution of the breakpoints of the deletions in patients with DMD/B. These results suggest the participation of the same molecular mechanism underlying the formation of deletions and high frequency of recombination in the gene DMD.

Deletions in the DMD-gene in the affected area of the same exons can be detected as in the case of clinical variant of Duchenne muscular dystrophy, and in the case of a clinical variant of the condition of Becker. This phenomenon corresponds to the hypothesis of translational shift "reading frames", when synthesized non-functional protein (Monaco A. P., Bertelson, C. J., Lieshti-Gallati S. et al. , 1986). If shift "reading frames" does not occur, is detected clinically more benign variant of the disease type of the condition of Becker or Mabry, if the shift occurs "reading frames", you will develop a more severe variant of the disease by type of Duchenne muscular dystrophy.

Thus, in-depth molecular analysis of Duchenne muscular dystrophy/Becker indicates significant heterogeneity associated with different mutations in the gene. Uch has a single DMD gene, and clinical variants of the disease sometimes long cannot be differentiated unambiguously applies the designation of the disease "miodistrofiya Duchenne/Becker".

In various works attention is paid to the correction of the energy deficit in skeletal muscle. Closest to the proposed method is a method of treatment of patients with myodystrophy coenzyme Q (ubiquinone). Ubiquinone has activity in two parts of the electron transport system of mitochondria: succineidae and NADP-oxidase. Installed deficiency of coenzyme Q in the muscles of patients with myodystrophy reduces ATP synthesis and promotes the formation of an energy deficit (Danowski T. S., 1971; Sovik O., 1971). However, the use of coenzyme Q in the treatment of patients with myodystrophy the resulting increase in muscle strength and motor activity was short-lived, was not observed suspension ministrations process, there was no remission in the course of the disease. Coenzyme Q had no effect in violation of Central hemodynamics, enhancing hypoxia in the muscle, which is particularly important for patients myodystrophy Duchenne/Becker in connection with the presence of lesions of the heart muscle - development cardiomyopath the isms through the activation functions of the structures of the hypothalamic-limbic-reticular complex in connection with the development of these patients polyglandular endocrine insufficiency in the accompanying encephalopathy (Leningrad region Badalyan with co, 1976).

The aim of our invention is the achievement of increasing mobility, increase the length of remission, slowing of disease progression in patients with myodystrophy Duchenne/Becker. In connection with the above-mentioned disadvantages of therapy with coenzyme Q we have proposed a new method for the treatment of Duchenne muscular dystrophy/Becker with the use of the drug instenon, the clinical effectiveness of which is determined by a wide range of actions, cumulative effect, Ecoprotection the bemythyl stimulating redox processes with the release of energy, and amplipulse neostigmine methylsulfate on the muscles of the limbs, contributing to nerve impulses in the field of neuromuscular junction. This goal is achieved by the fact that instenon Forte (manufacturer Hafslund Nycomed Pharma AG, Linz), known as the officinal drug permitted for use, which is a combination of three components: hexobendine and etamivan affecting the metabolism of the Central nervous system and muscles; etofylline, affect the metabolism of the myocardium, administered per os at a dose of 1/2 tablets 2 times a day for 30 days. is stimuliruyushie redox processes, also Pharmacopeia drug derived 2-ethylthiophenethylamine hydrobromide monohydrate based 0.005 g/kg per day 3 times per day for 30 days, then a maintenance dose (1/2 of the daily dose) within 45 days, and if severe disease within 60 days. The purpose of recovery of nerve impulses in the field of neuromuscular junction after 10 days from the beginning of a course of drug therapy conducted course amplipulse neostigmine methylsulfate. Drugs (neostigmine) is introduced with forearms and shins. Mode straightened, 1 and 2 rod (1 genus of work - current constant modulation (PM) is formed as a result of the modulation current of the carrier frequency to low frequency in the range from 10 to 150 Hz. 2 the nature of work - the current "make - break" (PP) is a series of modulated oscillations set in the range from 10 to 150 Hz frequency, alternating with a delay of 7 minutes PM, then PM 3 minutes, 3 minutes break, and another 3 minutes of exposure to shock. Treatment 15 procedures carried out daily.

Instenon contains three components: etamivan, geksobendin, etofillin.

Etamivan has a strong positive impact on the adaptive capacity of the hypothalamic-limbic-Reti main trigger of maintaining an adequate functioning of the neural complexes of the cortex and subcortical-stem structures, providing the patient from a state of post-hypoxic encephalopathy.

Geksobendin increases utilization of glucose and oxygen due to the activation of anaerobic glycolysis and pentony cycles, stimulates anaerobic oxidation of supplying energy substrate for the synthesis and metabolism of neurotransmitters.

Etofillin - activates the metabolism of the myocardium, increasing cardiac output.

Actoprotector bemythyl due to the structural similarity to purine bases (adenine and guanine) activates the synthesis of mitochondrial enzymes, increasing the energy potential of the muscle tissue (Bobkov Y. G., Vinogradov, C. M. , skating Rinks C. F. and other Pharmacological correction of fatigue. -M.: Medicine,1984).

Neostigmine entered using amplipulse, anticholinesterase agent predominantly peripheral action that has the postsynaptic sensitizing and facilitate presynaptic effect, which is manifested by the enhancement of neuromuscular transmission.

This method is the combined use of the drug instenon, ectoprocta the bemythyl with subsequent amplipulse neostigmine methylsulfate pathogenetically justified, since on the one hand due to the Akti is distrofia Duchenne/Becker, which is reduced in its effects on neurotrophic processes due to the impact on the hypothalamic-limbic-reticular complex and reduce hypoxia muscles in the correction of Central hemodynamics. Increase the energy potential of muscle cells promotes activation of the synthesis of proteins and enzymes, resulting in decreased permeability of the membranes of muscle cells, promotes muscle reinnervation is detected, the deceleration ministrations process and the formation of remission (C. C. Lobzin, L. And Sykova, A., Siman. Neuromuscular diseases, 1998).

Example 1. Patient D.,age 7, history N1527 diagnosed with Progressive muscular dystrophy of the Duchenne/Becker", was admitted with complaints of gait disturbance type "duck", the deformation of the feet with high arch and install on your fingers, fatigue when walking and climbing stairs, weakness in the hands, attention span. From the anamnesis it is known that the third child in the family, the eldest brother 11 years also has myodystrophy Duchenne/Becker, and at the time of admission was a wheelchair. Both children revealed a deletion in the field 8-19 exons, the older the child, the disease is diagnosed in 8 years, the first signs of 1.5 years in the form of muscle weakness in the Oia with 2 years the diagnosis was first installed in 3.5 years. Admission was restricted volume of active movements when lifting from the provisions of sitting, "squatting", lying down, with difficulty climbing stairs, is myopathy. Expressed diffuse wasting of muscles of the shoulder girdle, proximal arms, a "winged scapula", scoliosis, pseudohypertrophy calf muscles, decreased tendon reflexes on the hands; the absence of knee and Achilles reflexes on the feet. The decrease in muscle strength up to 3-4 points. EMG data indicate the defeat of the motor neuron at the axonal level. In the study of blood has increased CPK, LDH, ALT, AST, bilirubin. The patient received treatment with coenzyme Q according to standard techniques. On the background of the treatment slightly increased volume of active movements, in blood enzyme activity is unchanged after treatment in the future continued to decline. At 1 month after treatment, the positive dynamics was neutralized.

Example 2 . Patient Century,10 years, history N876, the diagnosis of Progressive muscular dystrophy of the Duchenne/Becker", was admitted with complaints of gait disturbance type "duck", talipes with the set is the lake of Duchenne muscular dystrophy/Becker exhibited in 1 year, as the case of the family (sick cousin sibs and uncle on mother's side), in the study of CPK blood was noted increased to 6000 units (normal up to 200 units), also increased CPK blood was noted in the female sibs to 650 units and the mother of the proband to 440 units Deletion in the family have been identified in connection with the crossover. The disease is severe, with early disability. Admission: common diffuse hypotrophy shoulder girdle and muscles of the hips, reasonable pseudohypertrophy calf muscles, decreased tendon reflexes of the upper extremities, absence of knee and Achilles reflexes. Expressed psychoorganic syndrome. EMG data indicate the defeat of the motor neuron at the axonal level. Were treated with coenzyme Q by standard methods in 1 month, noted moderate positive dynamics in the form of a moderate increase muscle strength, increase range of motion. Changes in blood CPK, LDH were observed. Received positive dynamics was neutralized during the month.

Example 3. Patient C., age 7, history N4607, the diagnosis of Progressive muscular dystrophy of the Duchenne/Becker", was admitted with complaints of gait disturbance type "with the right hand, attention span. From the anamnesis it is known that the first signs of disease are noted in 4.5 years, when examination revealed increased transaminase - treated in DGIB N 3 and further during the year had been diagnosed with Hepatitis, Busselton form. The diagnosis of Duchenne muscular dystrophy/Becker exhibited at the age of 5.5 years. According to the DNA probe diagnostics revealed a deletion in the region of exon 44.

Admission was restricted volume of active movements when lifting from the provisions of sitting, squatting, lying is myopathy. Expressed wasting of muscles of the shoulder girdle, pectoral muscles, proximal arms, shoulder blades, a "winged", scoliosis. Calf muscles gipertrofirovannyy, sealed. The reduction of force in front of the muscle groups up to 3 points to the right and up to 4 points left. Absent knee and Achilles tendon reflexes. EMG data indicate the defeat of the motor neuron at the axonal level. In the study of blood - increased CPK, LDH, ALT, ACT. The patient received instenon Forte 1/2 tablets 2 times a day in combination with Ecoprotection the bemythyl 1/2 pill 3 times a day for 30 days, on the 10th day from the start of drug therapy have ampliroll is her. On the background of the treatment increased volume of active movements, muscle strength increased to 4 points on the right and a score of 4.5 on the left, to a lesser extent uses myopathy techniques, according to the biochemical analysis of blood, decrease in ALT, AST, bilirubin, a moderate increase of the enzymatic activity of CPK, LDH. After the third course of treatment appeared knee tendon reflexes. The progression of the disease is not marked.

Example 4. Patient M.,age 9, was admitted to the hospital with complaints of gait disturbance, fatigue when walking, frequent falls, weakness in the hands, disinhibition, attention span, echolalia. From the anamnesis it is known that the disease is first detected in 8 years, in a genetic sent in connection with psychopathic personality changes, initially drew attention gait disturbance, diffuse wasting of muscles of the shoulder girdle and proximal arms, pseudohypertrophy calf muscles. When DNA probe diagnostics deletion is not detected, probably, there is a point mutation. In neurological status: severe malnutrition supraspinatus, infraspinatus, deltoid, trapezoidal, and the muscles of the thighs. Moderate hypertrophy of the calf muscles. Tendon regola type psychoorganic syndrome. EMG data indicate the defeat of the motor neuron at the axonal level. ECG: sinus tachycardia, turn left ventricular anterior shift of the transition zone to the right, deep teeth Q in V5-V6. According to Echocardiography convincing structural changes it is not revealed. On EEG - General diffuse changes in the bioelectrical activity of the brain. In the blood increased CPK, LDH, ALT, ACT. The patient received treatment instenon 1/2 tablets 2 times a day for 30 days in combination with Ecoprotection the bemythyl 0,125 g 3 times a day and amplipulse neostigmine methylsulfate with 10 days of drug therapy N15 on the forearms and shins. At discharge, decreased fatigue, increased strength in the muscles of the limbs. Further received outpatient maintenance dose bemythyl 0,125 1 g once daily for 60 days. After the second course of treatment appeared to increase levels of CPK, LDH; after the third course of treatment appeared knee tendon reflexes.

The proposed method of treatment used on 36 patients myodystrophy Duchenne/Becker. The treatment results in significant improvement in 83,3% of patients, moderate improvement in 17.7% of patients. Deterioration in patients in this way was not observed. Average about the th method of treatment can significantly increase the volume of active movements in the limbs, muscle strength, slows the progression of the pathological process, improves the General condition of patients.

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

All patients (36 patients) was observed persistent therapeutic effect, positive dynamics of biochemical and electromyographic parameters.

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

Thus, the proposed method for the treatment of Duchenne muscular dystrophy/Becker gives effect, as evidenced by the dynamics of the clinical picture, laboratory studies, characterizing the level of metabolic and energetic processes in the muscles, these electrophysiological studies.

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

The essential difference between the proposed method is that the use instenon in combination with Ecoprotection the bemythyl and amplipulse neostigmine methylsulfate in straight mode on the forearms and shins, due to the ECCA.

Application of the method is most effective in the initial stages of the disease, as well as in benign disease with a deletion in the field 42-50 exons.

The proposed method of treatment does not cause side effects, no contraindications, simple, and available to use in any neurological ward and outpatient settings.

A method of treating myodystrophy Duchenne/Becker by drug therapy, characterized in that the prescribed medication interoperate 1/2 tablets 2 times in laziness within 30 days, actoprotector bemythyl at a dose of 0.005 g/kg per day for 30 days and spend amplipulse neostigmine methylsulfate on the forearms and lower limbs in the course of 15 treatments in the future within 45 - 60 days to appoint a bemythyl 1/2 of a daily dose.

 

Same patents:

The invention relates to medical devices, more specifically to a device for the combined effect of laser radiation and electrophoresis, which are used in the treatment of various forms of diseases, periodontal disease, periodontitis and other inflammatory and degenerative diseases of periodontal tissues
The invention relates to medicine, dermatology

The invention relates to means for stabilizing the state of biological objects, in particular to maintain the tone, removing various pathogens and allergic effects, adaptation to drugs, for the prevention and treatment of viral and bacteriological diseases, for the potentiation of drugs, as well as to enhance the effect of bioinformatics exposure, recovery, energy capacity, reduce congestion information from impact

The invention relates to medicine, namely to iontophoretically delivery to a patient suffering from a migraine, the compounds of formula (I)

The invention relates to clinical immunology and can be used for the treatment of chronic sinusitis

The invention relates to a gastroenterologist and is intended for the treatment of chronic pancreatitis

The invention relates to physical therapy and is intended for treatment of dumping syndrome in patients undergoing surgery for ulcer

The invention relates to physical therapy and dermatology

The invention relates to neurosurgery and is intended for treatment of traumatic brain injury

The invention relates to dermatology, and can be used in the treatment of alopecia areata

The invention relates to medicine, namely to substances that cause the induction of microsomal liver enzymes

The invention relates to novel condensed polycyclic heterocyclic compounds of the formula I and the way they are received
The invention relates to medicine, namely to Oncology and neurosurgery
The invention relates to medicine, in particular to cancer, and can be used in radiation therapy of malignant tumors

The invention relates to medicine, derivatives and analogs of adenosine, which have activity as agonists of adenosine and are suitable as cardioprotective, anti-ischemic and protivoepilepticheskih funds, to pharmaceutical compositions containing such compounds

The invention relates to crystalline forms of 6(R) or 6(S)-tetrahydrofolate acid, method for their production and pharmaceutical compositions

Antiherpetic agent // 2164138
The invention relates to medicine
The invention relates to medicine, namely to rheumatology, and can be used for the treatment of rheumatoid arthritis
The invention relates to medicine, in particular to Pediatrics (pediatric Allergology)
Up!