RU2208443C2 - Method for treating multiple sclerosis - Google Patents

Abstract

FIELD: medicine, neurology. SUBSTANCE: the present innovation deals with treating patients with demyelinizing diseases, multiple sclerosis, in particular. It includes introduction of proteolytic inhibitor and water-soluble antioxidant into different surface inguinal lymph nodes at single doses being by an order lower against average therapeutic ones at the rate of 0.4 ml/min daily for 20 d. EFFECT: improved results of therapy. 6 cl, 2 ex, 2 tbl

Description

 The invention relates to medicine and can be used in the treatment of demyelinating diseases, namely multiple sclerosis. A method for the treatment of demyelinating diseases in combination with antioxidants. Proteolysis inhibitors and antioxidants are administered endolymphatically. This technique blocks the system of proteolytic enzymes and prevents the decomposition of the main myelin protein, inhibits lipid peroxidation and the formation of autoantibodies to the main myelin protein, promotes the production of virus-induced α-interferon, reduces the stationary period of treatment by 23% and reduces the financial cost of the necessary drugs drugs.

 The invention relates to medicine and can be used in the treatment of demyelinating diseases, in particular multiple sclerosis.

 A method for endolymphatic administration of proteolysis inhibitors and antioxidants is known in the treatment of diabetic lower limb angiopathy. For the treatment of multiple sclerosis, the method is proposed for the first time.

 There are numerous treatment regimens for multiple sclerosis - from oral administration of corticosteroids and adrenocorticotropic hormone (ACTH), intramuscular and intravenous administration of solymedrol (EI Gusev, TL Demina, AN Boyko. Multiple sclerosis. Moscow, 1997, p. 2880) before treating multiple sclerosis with exposure to the central nervous system by electromagnetic fields (Sandyk R. Treatment with electromagnetic fields reversaes the long-ferm clinical clinical coursae of a patient with chronic progressive multiple sclerosis. Int. J. Neuroscl, 1997, Aug. 90 ( 3-4), c. 177-185).

 Closest to our proposed method is a method of treating multiple sclerosis, including intravenous administration of proteolysis inhibitors and antioxidants (O.A. Khondkarian et al., 1987 p. 237; E.I. Gusev et al., 1997, p. 295-296 )

 The prototype of the proposed method does not take into account the ability of the blood-brain barrier not to pass drugs into the substance of the central nervous system, thereby creating an obstacle to achieve a positive effect of therapeutic measures.

 The purpose of the invention is the improvement of treatment results by ensuring the delivery of drugs to the affected tissues through the BBB.

 The novelty of the treatment of multiple sclerosis lies in the endolymphatic method of introducing a combination of proteolysis inhibitors and antioxidants in a specific mode and at certain doses. At the same time, an optimal pathway for direct endolymphatic administration was developed, namely, intranodular, characterized by certain technical methods.

 The method of endolymphatic administration is as follows.

 In the position of the patient on the back in the dressing room, the surgical field is processed in the projection of the inguinal lymph nodes. On the inner surface of the thigh, the inguinal lymph node is palpated and fixed. A hypodermic needle is used to puncture the lymph node. Injected into the lymph node are proteolysis inhibitors (contracal - 10 thousand Atre, or trasilol - 100 thousand KIV, or gordox - 50 thousand KIV) and antioxidants (emoxipin - 1% solution - 5.0 ml, or mexidol - 2 ml, Actovegin - 80 mg or 5% solution of ascorbic acid in a single dose.– 5 ml). Moreover, the introduction of drugs is carried out in different lymph nodes. The sequence of drug administration does not matter. The rate of administration is 0.4 ml / min. Endolymphatic therapy is performed daily for 20 days, in single doses an order of magnitude less than the average therapeutic.

 With a remitting variant of the course of the disease, patients were hospitalized for treatment no later than 3-5 days after the onset of exacerbation of the disease.

 The results of treatment of 56 patients with multiple sclerosis aged 18 to 50 years were analyzed. The average age was 34.5 ± 5.3 years. There were 38 women and 18 men. In all patients, neurological deficits were assessed using the Kurtzke (FS) scale and the Kurtzke Extended Disability Scale (DSS) (1983). Reliability of multiple sclerosis was evaluated according to the criteria of C. Poser (1983). In all cases, the diagnosis is confirmed by magnetic resonance imaging of the brain, and, if necessary, the spinal cord.

 We studied immunological parameters (the number of T-helpers and T-suppressors, immunoregulatory index, the level of virus-induced α-interferon, the number of autoantibodies to the main myelin protein). Immunological studies were performed on 7, 14, 21 days and after 6 months. Evaluation of antioxidant protection was carried out according to indicators of catalase activity (M.A. Korolyuk et al., 1988) and blood red blood cell peroxidase and lacrimal fluid peroxidase (T. Popova, L. Neikovskaya, 1971) in patients with multiple sclerosis before and after treatment.

 A decrease in the Kurtzke score (DSS) by one point or more was regarded as a beneficial effect, while an increase of one or more points was considered an adverse effect. The dynamics of indicators on FS scales without changes in DSS was considered as an insignificant effect (M.V. Pashchenkov et al., 1997).

 In 43 patients, the ball had a cerebrospinal form of the disease, in 7 - cerebral and in 6 - spinal. All patients were in the stage of exacerbation of the disease.

 2 groups of patients were formed - the main and control. The groups were comparable by sex, age, duration and course of the disease, predominant localization of foci of demyelination. All patients underwent clinical examination during the course of treatment (1, 7, 14, and 21 days) and at its end (after 6 months).

 The main group consisted of 29 patients. Of these, cerebrospinal form of the disease was in 22 patients, cerebral in 3 and spinal in 4 patients. The remitting form of the course of the disease was in 18 people, the second progressive course in 11 patients. In the treatment of the main group of patients, endolymphatic administration of proteolysis inhibitors (contracal - 10 thousand Atre, or Gordox - 50 thousand KIV, or trasilol - 100 thousand KIV, or epsilon-aminocaproic acid 5% solution - 10 ml) and antioxidants (emoxipin) was used - 5.0 ml of a 1% solution, or Mexidol - 2 ml, Actovegin - 80 mg or 5% ascorbic acid solution at a single dose - 5 ml) daily for 20 days. Symptomatic therapy included intramuscular administration of vitamins (pyridoxine chloride - 1.0, thiamine bromide - 1.0, nicotinic acid 1% solution - 2.0 ml), intravenous administration of drugs (ascorbic acid 5% solution - 5.0 ml , cerebrolysin - 5.0 ml intravenously, essence 5.0% intravenously). Hormonal drugs were not used.

 The control group included 27 patients. The average score on the FS score was 13.56 ± 1.09. The average score on the DSS scale was 3.98 ± 0.37. The cerebrospinal form of the disease was recorded in 21 patients, cerebral in 4 and spinal in 2 patients. A remitting form of the course of the disease was in 19 people, a secondary progression course was in 8. Patients of the control group, along with symptomatic therapy, received intramuscular injections of proteolysis inhibitors (10 thousand AtreE, or Gordox - 50 thousand KIV, or trasilol - 100 thousand each. KIV, or epsilon-aminocaproic acid 5% solution - 10 ml) and antioxidants (emoxipin 1% solution - 5 ml, or mexidol - 2 ml, or actovegin - 80 mg, or 5% ascorbic acid solution in a single dose - 5 ml ) within 20 days. Symptomatic therapy included intramuscular administration of vitamins (pyridoxine chloride - 1.0, thiamine bromide - 1.0, nicotinic acid 1% solution - 2.0 ml), intravenous administration of drugs (ascorbic acid 5% solution - 5.0 ml , cerebrolysin - 5.0 ml intravenously, essence 5.0% intravenously). Endolymphatic administration of drugs was not carried out.

 The conducted statistical studies using nonparametric statistics showed the reliability of the results.

 The results of a clinical examination of patients in both groups showed that after 6 months from the start of treatment, the Kurtzke index in the main group of patients was 3 points (a decrease of 1.97 points or 60.4%). On the control MRI, the previous volume of focal demyelination without signs of activity of the pathological process in them remained.

 The group showed a decrease in the Kurtzke index by 0.5-1 points (a decrease was 87.4-74.9%) for 3-6 months in 55.6% of patients. 2 patients after 4-6 months were forced to arrange 1 group, which was not observed in the main group of patients. On repeated MRIs, the appearance of new foci of demyelination periventricularly and in the cerebellum with an increase in atrophic processes in the type of internal hydrocephalus and expansion of the convexital space of the skull was noted.

 The results of immunological studies are presented in table 1.

 An analysis of the studied immunological data showed that endolymphatic therapy promotes the growth of virus-induced α-interferon compared to the initial state on the 7th day 2 times, on the 14th day - 4 times, on the 21st day from the beginning of endolymphatic therapy the titer of the studied value becomes equal to normal indicator and after 6 months remains at the same level (320).

 The dynamics of mitogen-induced γ-interferon throughout the entire observation period did not undergo any significant changes. Only after 6 months in the main group, a certain increase in the titer of the studied interferon was noted - up to 16, which is 50% of the generally accepted normal values.

 A study of the dynamics of antibodies to the myelin basic protein showed that in the main group of patients who received endolymphatic administration of proteolysis inhibitors and antioxidants in complex therapy, a certain increase in the level of antibodies was noted at first compared to the level before treatment (by 358 μg / ml), which was also observed in the control group of patients (258 μg / ml). Subsequently, the dynamics of the decrease in antibodies to the myelin basic protein in the main and control groups differed sharply. On days 14, 21 and 6 months in the main group, the level was 44.3%, 17.7% and 44.3%, respectively, in relation to the level of antibodies to the myelin basic protein before treatment. In the control group of patients at the indicated time, the concentration of antibodies to the main myelin protein was 146.8%, 120.5% and 85.8% of the initial value, respectively.

 Thus, in the main group of patients, the level of antibodies to the main myelin protein after 6 months was 41.6% lower than it was recorded before the start of endolymphatic therapy.

 A study of the dynamics of CD 4+ and CD 8+ cells revealed an important role not only in the concentrations of these cells, but in their ratio - the immunoregulatory index (IRI), which reflects the activity of the helper and suppressor units of T-cell immunity.

 After 6 months from the start of treatment, IRI in the main group was 1.6 (in the control group - 2.1), both due to a decrease in CD 4+ and due to an increase in CD 8+. In the main group, the CD 4+ level by the end of the observation was 82.1% of the initial value, while in the control group it was 85.7%. The level of CD 8+ in the main group increased by 147.4%, and in the control group - by 121.1%.

 The activity of the antioxidant defense enzyme system was evaluated in healthy individuals, as well as in patients with multiple sclerosis before treatment and 3 months after the end of therapy. The results are presented in table 2.

 As can be seen from table 2, all the studied parameters in patients with multiple sclerosis were significantly changed. During treatment, in the main group of patients who underwent endolymphatic administration of proteolysis inhibitors and antioxidants, normalization of the studied parameters occurred to a greater extent than in the control group. Thus, the erythrocyte catalase level in the main group increased by 140.6% and was almost equal to that of healthy individuals. At the same time, the catalase activity of red blood cells in patients of the control group amounted to 109.6% of the initial value. The erythrocyte peroxidase of patients with multiple sclerosis at the time of exacerbation of the disease amounted to 626.4% of the value of healthy individuals. After treatment using endolymphatic administration of proteolysis inhibitors and antioxidants, its level decreased by 104.3% of the value of healthy individuals, while in the control group, peroxidase activity amounted to 440.9% of the values obtained in healthy individuals. Saliva peroxidase activity was compared with the norm and before treatment was 70.3% of the normal value. After a course of endolymphatic therapy in the main group, it increased by up to 96.0% of the normal indicator, and in the control group it was only 76.9% of the indicator in the group of healthy individuals.

Example 1. The main group. Patient O., 42 years old, was admitted to the clinic of surgical diseases and new endosurgical technologies of the Moscow University of Medicine and Dentistry on April 5, 1999 with a diagnosis of multiple sclerosis, a cerebrospinal form of remitting course. According to the patient, he fell ill more than two years ago when he first noticed a visual disorder. Later there were paresthesias on the left legs, mild pelvic disorders, decreased potency. He was treated at the place of residence (Moscow region) and in clinics in Moscow, where hormonal and symptomatic therapy was mainly carried out with a short-term improvement in well-being (by 3-5 months). In January 1999, when examining the brain of magnetic resonance imaging, the following was established. The obtained T ₂ - weighted images reveal many small foci of increased MR signal (up to 4 mm in diameter) located in the cerebral hemispheres, in the legs of the brain, in the inner capsule on both sides, in the corpus callosum, in the semi-oval centers on both sides, near the posterior horns of the left lateral ventricle, around the anterior horns of both ventricles. The lateral and third ventricles of the brain are moderately dilated, their shape is not changed. Sellar region without features. The tonsils of the cerebellum are located above the Chamberlain line. Given the predominant lesion of white matter, a demyelinating disease (multiple sclerosis) was diagnosed. The Kurtzke index was 5 points. When studying the immunological status, the content of antibodies to the myelin basic protein reached 722 μg / ml. The titer of virus-induced α-interferon was 16. The level of CD 4+ was reduced by 29.9%, with a normal rate of CD 8+, the immunoregulatory index was below the norm by 0.14 and amounted to 1.06 (normal indicator - 1.2 -2.0). The activity of erythrocyte catalase was 142.3 mmol / min per 1 g of Нb, erythrocyte peroxidase activity was 789.7 mmol / min per 1 g of Нb, tear peroxidase was 268.4 mmol / min per ml. Against the background of ongoing therapy using endolymphatic administration of proteolysis inhibitors and antioxidants, the patient noted increased sexual potency, normalization of the functions of the pelvic organs and urination, increase in muscle strength and distance traveled. A decrease in the Kurtzke index by 2 points (by 40%) was recorded, the activity of erythrocyte catalase reached 136.1% of the initial value, which is 96.2% of the average normal value. The amount of red blood cell peroxidase after treatment was 18.5% of the original, which amounted to 117.2% of the average normal value. The level of tear peroxidase after treatment is fixed at 127.5% of the original, which is 91.4% of the average normal. The formation of antibodies to the myelin basic protein decreased to 320 μg / ml, which is 44.3% of the initial level. The titer of the virus induced α-antibodies to the main myelin protein increased after 7 days to 16 and after 20 days to 128, the CD 8+ level increased by 121.2% and amounted to 40%, and the CD 4+ level decreased by 3% (32% ), which changed the immuno-regulatory index mainly due to an increase in the number of CD 8+.

 6 months after completion of inpatient treatment, the patient was examined the state of the immune system. It was found that the level of antibodies to the main myelin protein was 330 μg / ml, the titer of virus-induced production of α-interferon 320, the titer of mitogen-induced production of γ-interferon increased to 16 (4 times). A decrease in the number of CD 4+ (up to 32%) and an increase in CD 8+ (up to 43%) were noted. On the control MRI, there were no new foci of demyelination.

 Clinical and laboratory research data correlated with positive changes in the patient’s well-being both at home and in the workplace, where he entered to work after improving his well-being. The patient dispenses with outside help; his gait improved, his vision, sexual potency recovered, his intestines and pelvic organs returned to normal.

 Example 2. The control group. Patient S., 33 years old, was admitted to the clinic of surgical diseases and new endosurgical technologies of the Moscow University of Medicine and Dentistry on April 12, 1999 with a diagnosis of multiple sclerosis cerebrospinal form - remitting course. According to the patient, the first signs of the disease were noticed in June 1995, which was manifested in shakiness of the gait, loss of visual fields in the morning, false urge to urinate, decreased sexual potency, and spelling. He was treated at the place of residence (Kostroma region) and in clinics in Moscow, where hormonal and symptomatic therapy was carried out without subjective improvement in well-being. The Kurtzke index was 4.5 points.

In August 1998, an MRI scan was performed. A series of axial, sagittal, and frontal T ₁ and T ₂ - weighted MRI tomograms of the brain visualize multiple foci of a hypersignal in T ₂ - images located in periventricular zones, mainly oval, up to 11-18 mm in size, perpendicular to the lateral ventricles . Single hypersignal foci are seen in the brain stem (level of the legs of the brain) and the right hemisphere of the cerebellum. Single foci, located subcortical, are displayed on T ₁ - weighted programs, in the form of a hypo-signal - "old" foci. Diffuse expansion of the lateral ventricles, intracerebral tanks. A moderate increase in the subarachnoid space in the projection of the frontal and parietal lobes. The displacement of the median structures of the brain is not recorded. The area of the Turkish saddle, the pituitary gland, the optic chiasm of the optic nerves and parasellar structures are without pathological features. The sphenoid sinus is airy.

 An examination at the Department of Surgical Diseases and New Endosurgical Technologies revealed the following. The content of antibodies to the myelin basic protein was 560 μg / ml. The titer of virus-induced α-interferon was 32. The level of CD 4+ was reduced by 117.4% (54%) of the normal value, CD 8+ was below the norm by 50% (17%). The immunoregulatory index was 3.18 (1.18 higher than normal). The activity of erythrocyte catalase was 157.6 mmol / min per 1 g of Нb, erythrocyte peroxidase activity was 704.3 mmol / min per 1 g of Нb, tear peroxidase was 281.4 mmol / min per ml. As a result of the complex therapy using hormone therapy, at the end of the inpatient course of treatment, a slight increase in muscle strength was noted, imperative urination remained, the state of sexual potency was unchanged. A decrease in the Kurtzke index by 0.75 points (by 16.7%) was recorded, the activity of erythrocyte catalase was 103.6% of the initial value and is 84.1% of the average value of the normal indicator. The amount of red blood cell peroxidase after treatment was 721.4 μmol / min per 1 g of Нb (102.4% of the initial value), which amounted to 80.7% of the average normal value. The level of tear peroxidase after treatment was 298.8 μmol / min per ml (106.2% of the initial value), which is 81.6% of the average normal. Reducing the formation of antibodies to the myelin basic protein to 460 μg / ml, which is 82.1% of the initial level. The titer of virus-induced α-antibodies to the myelin basic protein did not change after 7 days, after 20 days it increased to 64, the level of CD 8+ increased by 105.9% (18%), the level of CD 4+ decreased to 94.4% ( 52%) of the initial value, which changed the immuno-regulatory index to 2.9. This indicator was higher than the upper limit of the norm by 0.9.

 6 months after completion of inpatient treatment, the patient was examined the state of the immune system. It was found that the level of antibodies to the main myelin protein was 720 μg / ml, titer of virus-induced production of α-interferon 64, titer of mitogen-induced production of γ-interferon 2 (unchanged). The amount of CD 4+ was 50%, CD 8+ - 19%. On the control MRI revealed new foci of demyelination in the cerebellum.

 Clinical and laboratory research data correlated with the positive state of the patient, who complained of double vision, shakiness when walking, great difficulty climbing stairs, pelvic dysfunction, and a significant decrease in potency. Got a disability of group II.

Claims (7)

 1. A method of treating multiple sclerosis by symptomatic treatment, including the introduction of proteolysis inhibitors and water-soluble antioxidants, characterized in that the proteolysis inhibitor and water-soluble antioxidant are administered to different superficial inguinal lymph nodes at a rate of 0.4 ml / min daily for 20 days.  2. The method according to claim 1, characterized in that as an inhibitor of proteolysis using contrical in a single dose of 10 thousand Atre.  3. The method according to claim 1, characterized in that as a proteolysis inhibitor, gordox is used in a single dose of 50 thousand KIV.  4. The method according to claim 1, characterized in that a 5% solution of epsilon-aminocaproic acid in a single dose of 10 ml is used as a proteolysis inhibitor.  5. The method according to claim 1, characterized in that as an antioxidant use a 1% solution of emoxipin in a single dose of 5 ml.  6. The method according to claim 1, characterized in that a 2% solution of Mexidol in a single dose of 2 ml is used as an antioxidant.  7. The method according to claim 1, characterized in that as an antioxidant use a 5% solution of ascorbic acid in an amount of 5 ml.

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