RU2450822C1 - Using heptapeptide for treating parkinson's disease and method of treating such disease - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine, and concerns using heptapeptide Thr-Lys-Pro-Arg-Pro-Gly-Pro (Selinc).

EFFECT: intranasal application of the preparation in the concentration of 0,15 % in dose four to six drops in each nostril every 4-5 hours for 2-3 weeks allows higher clinical effectiveness in Parkinson's disease ensured by correction of neuropsycological disorders.

3 cl, 4 ex

Description

The invention relates to medicine, in particular to a method for the treatment of Parkinson's disease.

Parkinson's disease is a chronic progressive disease of the brain, which is based on the defeat of special pigmented midbrain cells that synthesize the substance dopamine, which is the main mediator of the central nervous system (CNS) that regulates motor functions. This disease was first described by James Parkinson in 1817 under the name "trembling paralysis." The core of the clinical picture of Parkinson's disease is the classical triad of symptoms - akinesia (hypokinesia), muscle rigidity and resting tremor. The disease can begin with each of these symptoms, and later others join it. In some cases, two or three main symptoms are noted in the opening. The fourth most important symptom of Parkinson's disease - postural instability - usually joins at a later stage of the disease. Subsequently, an in-depth interdisciplinary study of Parkinson's disease demonstrated the indispensable involvement of such structures as the basal parts of the frontal lobes (with the development of bradyphrenia, bradylalia, psychomotor retardation), the parietal and temporal lobes (with the development of apraxia, agnosia), and basal ganglia (with the appearance of dynamically progressive cognitive decline).

Mental disorders at an early stage of Parkinson's disease are quite rare, but tend to increase as the disease progresses. The profile of these changes is characteristic and reflects deviations when performing tests for memory, attention, psychomotor, visuospatial, regulatory functions, as well as emotional and personality disorders.

The use of symptomatic replacement therapy with L-DOPA, the biological precursor of dopamine, in medical practice makes it possible to compensate for the lack of dopamine in the brain, thereby improving the motor (primarily), mental and some other capabilities of the patient. Widely used are also drugs that directly affect dopamine receptors (dopamine receptor agonists), as well as drugs that affect the metabolism of dopamine and some other brain mediators. However, these drugs have a relatively short, limited effect (the so-called compensatory therapy) and affect mainly the motor sphere of the patient, without affecting, at the same time, the course of the disease. Unresolved is also the question of preventing further death of dopamine neurons of the midbrain (neuroprotection).

Closest to the invention is a method for the treatment of Parkinson's disease (PD), including the use of nootropic drugs that enhance the effect of compensating (basic) therapy of the disease, for example, nootropil-piracetam (Mashkovsky M.D. Medicines., M., 1993, v. 1 , p. 117). The disadvantage of this method is the long duration of treatment (up to 6 months), the slow onset and limited clinical effect, the need to prescribe high doses, and with prolonged use of drugs - reducing their effect on the patient. In addition, the neuroprotective effect of nootropic drugs has not been proven.

The technical result achieved by the implementation of the claimed invention is to increase the effectiveness of treatment by correcting neuropsychological disorders, as well as by reducing the severity of tremor (both resting tremor and postural tremor) inherent in this disease and, as a result, improving the quality of life of patients, suffering from Parkinson's disease.

To achieve the desired result, it is proposed to use the well-known heptapeptide of the general formula Thr-Lys-Pro-Arg-Pro-Gly-Pro for the treatment of Parkinson's disease (PD), while the claimed method for treating PD includes nasal administration of a heptapeptide-based drug of the general formula Thr -Lys-Pro-Arg-Pro-Gly-Pro.

A preferred, but not mandatory, implementation of the method involves the use of the drug "Selank nasal drops 0.15%" with a dose of four to six drops in each nostril with an interval of 4-5 hours for 2-3 weeks. At each dose, the drug is instilled 2-3 drops in each nostril in two doses with an interval of 15 minutes.

The heptapeptide of the general formula Thr-Lys-Pro-Arg-Pro-Gly-Pro is a synthetic heptapeptide (threonyl-lysyl-prolyl-arginyl-prolyl-glycyl-proline) C ₁₇ H ₆₃ N ₁₁ O ₁₉ with a molecular weight of 869.96, and is also known as a "Selank", used, in particular, as an anxiolytic agent (see RF patent for invention No. 2155065). In experiments on experimental models of anxiety states caused by emotiogenic stressful agents or a situation, a Selank-based drug has an anxiolytic effect without any side effects characteristic of known anxiolytics. It was determined that the anxioselective effect of this drug is combined with an activating effect on the mnemonic and cognitive functions of the brain. It is shown that the improvement of learning and memory processes, along with the absence of undesirable side effects, is an advantage and an additional fundamental difference between the Selank peptide anxiolytic and the action of known tranquilizers. This drug activated learning and memory processes (fixation, consolidation, reproduction) in normal ("intact") animals and in the experimental pathology of these brain functions caused by the administration of Ca ⁺⁺ blockers, protein synthesis, norepinephrine and serotonin, prenatal hypoxia, etc.

In a clinical study of a drug based on "Selank" as an anxiolytic, it was found that in the spectrum of psychotropic activity it fundamentally differs from typical benzodiazepines in the absence of a sedative, hypnotic and muscle relaxant effect. The drug is well tolerated by patients; during the study, it did not reveal any side effects. The data obtained made it possible to testify to the high selectivity of the anxiolytic effect of the drug, which is clearly realized in the effectiveness of its therapeutic use with a different structure of anxiety disorders, revealing new possibilities for influencing the natural course of PD associated with the use of the Selank heptapetide drug.

The treatment by the proposed method was subjected to 40 patients (the tremulous form of Parkinson's disease - 20 patients, the akinetic-rigid form - 20 patients) in the early stages of PD with emotionally affective disorders and the initial manifestations of extrapyramidal parkinson's syndrome. The age of patients was more than 40 years, the duration of the disease - from the first manifestations to two years. An analysis of the etiological factors, the features of the onset of the disease, the age and gender composition of the patients of the two groups indicated showed their comparability, i.e. the possibility of a comparative study of the dynamics of clinical indicators.

Clinical monitoring of patients was carried out every seven days. To assess the condition of patients used a standard set of scales used in international practice for the study of parkinsonism:

Hyun and Yar scale. In the group of 20 people examined, five showed the presence of a second degree of Parkinson's disease, six - 1.5 tbsp. severity, in nine patients - 1 tbsp. the severity of Parkinson's disease. In all patients, the disease is presented in a tremulous form;

Unified Parkinsons Disease Rating Scale (UPDRS) for a more accurate assessment of motor activity and the effect of treatment;

Beck scale - determination of the severity of depressive symptoms;

Hamilton Depression Scale;

Spielberger scale - determination of the level of situational and personal anxiety;

a series of tests to evaluate the function of the frontal lobes of the brain (Frontal Assessment Battery);

minimum scale for assessing the mental state of MMSE (Mini-Mental State Examination);

Cognitive Failures Questionnaire

restoration of the locus of control - an assessment in patients of the level of motivation for recovery;

BP quality of life rating system - (39 Parkinson's Disease Quality of Life - 39 Scoring System).

As a result of using the Selank-based drug in patients with PD, there was a positive dynamics, a distinct decrease in the severity of the tremor inherent in this disease, as well as a decrease in fatigue and an increase in working capacity.

The clinical effect was observed at different times after the start of treatment - in some patients within five days, in others - by the end of the second week of using the drug, followed by persistent positive dynamics in relation to depressive symptoms, reactive and personal anxiety; a less persistent positive effect was recorded in the study of intellectual-mnestic functions. Statistical analysis established an increase in the rate of positive clinical dynamics for the claimed method of treatment by the 5th and 21st days of observation, as well as the persistence of the positive effect for at least three weeks after the end of therapy with the drug based on Selank.

It should also be noted that the proposed method for the treatment of PD, including nasal administration of the drug, has a number of additional advantages: the absence of toxicity and side effects, the possibility of using a convenient dosage form (nasal drop), the absence of unnatural amino acids in the composition of the drug, leading to adverse effects .

The following examples clearly illustrate the good practice of using the drug based on the Selank heptapeptide, for which the drug Selank nasal drops 0.15% (colorless transparent solution with a light specific odor and taste for intranasal administration in 3 glass dropper bottles) was used ml), in the treatment of PD.

Example 1. Patient T., 67 years old. Diagnosis: Parkinson's disease, rigid-trembling form, 1.5 severity according to Hen and Yar. Complaints of poor sleep, emotional lability with a predominance of a decreased mood background, decreased memory for current events, decreased ability to concentrate, shaking peace of mind in the right hand, stiffness, “poverty” of facial expressions, moderate impaired gait, muscle pain.

Anamnesis. Sick for 1.5 years. At the beginning of the disease, a feeling of awkwardness appeared in the right hand, stiffness, slow movement in the right hand, it became difficult to coordinate movements. Later, staggering when walking joined, memory for current events decreased, there was a trembling of peace in his right hand. The disease slowly steadily progressed, the severity of the above symptoms increased. Notes a decrease in mood for several years.

Objectively: rest trembling in the hands, more on the right, increased muscle tone by plastic type in the limbs, more in the right hand, hypomimia. Violation of the smoothness of the performance of arbitrary movements in the limbs, posturally stable.

A course of treatment with the drug “Selank nasal drops 0.15%” was carried out, 6 drops in each nostril with an interval of 4-5 hours for 21 days against the background of basic therapy. At each dose, the drug was instilled 3 drops in each nostril in two doses at intervals of 15 minutes. On the 4-5th day from the start of treatment, the patient noted improvement in well-being. Objectively, a decrease in tremor, an improvement in activity in everyday life. By the end of the 2nd week of using the drug, there is a positive trend in relation to previously identified moderate depressive symptoms, reactive and personal anxiety, cognitive impairment, moderate frontal dysfunction. It is noteworthy that an increase in the positive effect with the continued use of the drug “Selank nasal drops 0.15%”, however, after the end of therapy the most persistent positive dynamics were observed in relation to depressive symptoms, anxiety and frontal dysfunction.

Example 2. Patient T., 68 years old. Diagnosis: Parkinson's disease, dermal-rigid form. Complaints of trembling hands at rest, more on the right, fatigue, slow and stiffness in the muscles of the arms and legs, more on the right, decreased performance, poor sleep, periodic headaches, slow switching from one type of activity to another, reduced background mood, sometimes - tearfulness.

Anamnesis. She became ill 2 years ago, when the above complaints gradually began to develop, mood worsened, sleep was disturbed, trembling appeared in the right extremities, after 1.5 years the symptoms of the disease appeared on the contralateral side. Gradually, the condition worsened, self-service difficulties appeared; increased severity of tremor, oligobradikinesia. In neurological status: hypomimia; hypersalivation, acherokinesis. Hand shake at rest, more on the right. Oligo and bradykinesia, more on the right. Muscle tone is changed according to the extrapyramidal type: plasticity is noted, the phenomenon of the “gear wheel” in the muscles of the hands and forearms. The gait is slow, awkward, while walking it drags the right leg.

A course of treatment with the drug "Selank nasal drops 0.15%" was carried out, in the form of drops in the nose, 6 drops in each nostril with an interval of 4-5 hours, for 21 days. At each dose, the drug was instilled 3 drops in each nostril in two doses at intervals of 15 minutes. After completing the course of treatment, the patient became more active, her mood increased, and tearfulness disappeared. When testing neurological status using the UPDRS scale, a decrease in the severity of tremor was revealed. Complications and side effects during the treatment period were not observed. After the end of therapy, persistence of the effect was noted relative to emotionally-affective disorders, anxiety, and cognitive decline. The positive dynamics in terms of manifestations of frontal dysfunction turned out to be less stable, and 3 weeks after the end of taking Selanka nasal drops 0.15%, the level of performance of the battery of frontal tests returned to the original one.

Example 3. Patient K., 46 years old. Diagnosis: Parkinson's disease, akinetic-rigid form, 1.5 degrees according to Hen and Yar. Complaints of rapid fatigability, slowness and stiffness in the muscles of the arm (left), legs, more on the left, decreased performance, poor sleep. Pain in the muscles of the hands, shoulder girdle, legs, back, significantly increasing at the beginning and at the end of the action of DOPA drugs. Gradual decrease in sensitivity to basic anti-Parkinsonian therapy.

Anamnesis. She became ill 2 years ago, when the above complaints gradually began to develop, mood worsened, sleep was disturbed, trembling appeared in the left extremities, after 0.5 years the symptoms of the disease appeared on the contralateral side. For more than 4 years, takes up to 1000 mg of DOPA per day or more. Gradually, the condition worsened, self-care was difficult; oligo-bradykinesia was increasing.

In neurological status: hypomimia, the right nasolabial fold is smoothed. Muscle tone is changed in plastic type in the pronators and arch supports of the limbs, mainly on the left. Constant trembling of rest in the hands, worse on the left, intensifying. Tendon reflexes are lively, symmetrical. When walking, "drags" the left leg. Oligo, brady and hypokinesia. Coordinator tests are satisfactory; when performing a finger test, a shallow intentional tremor is performed. There is a decreased mood background, moderate cognitive impairment, and changes when performing “frontal tests”.

A course of treatment with the drug "Selank nasal drops 0.15%" was carried out, in the form of drops in the nose, 4 drops in each nostril with an interval of 4-5 hours, for 21 days. At each dose, the drug was instilled in 2 drops in each nostril in two doses with an interval of 15 minutes. After completing the course of treatment, the patient became more active, improved sleep, improved mood. A significant decrease in pain in the muscles of the shoulder girdle and back was also noted. The patient noted an increase in sensitivity to DOPA therapy. Complications and side effects during the treatment period were not observed.

Example 4. Patient S., 66 years old. Diagnosis: Parkinson's disease, dermal-rigid form. Complaints of trembling hands at rest, more on the right, quick fatigability, slowness and stiffness in the muscles of the arms and legs, more on the right, decreased performance, poor sleep, periodic headaches, decreased memory, and attention. Pain in the muscles of the legs, especially in the right. Gradual decrease in sensitivity to basic anti-Parkinsonian therapy.

Anamnesis. He became ill 1 year ago, when the above complaints gradually began to develop, mood worsened, sleep was disturbed, trembling appeared in the right extremities. Marks an increase in the symptoms of the disease over the past month, appeared from the contralateral side.

In neurological status: hypomimia, chin rest tremor, hand rest tremor, more on the right. The tone is slightly changed in plastic type in the pronator-arch supports of the hands and forearms. Tendon reflexes from the arms and legs are slightly reduced. When carrying out coordinating tests - slight mimicking, intention on the right. When walking, propulsions appear intermittently. At the peak of the dose, dyskinesia occurs (15-20 minutes) in the form of pathological rotation of the right foot, which is also accompanied by pain.

A course of treatment with the drug "Selank nasal drops 0.15%" was carried out, in the form of drops in the nose, 6 drops in each nostril with an interval of 4-5 hours, for 21 days. At each dose, the drug was instilled 3 drops in each nostril in two doses at intervals of 15 minutes. After completing the course of treatment, the patient became more active, his sleep improved, and the propulsions completely stopped. The patient noted an increase in sensitivity to DOPA therapy. When testing the patient after the end of taking Selank, there was a persistent positive dynamics in relation to emotional-affective disorders, anxiety, moderate "frontal" dysfunction. Complications and side effects during the treatment period were not observed.

Summing up, the clinical trials showed that the use of the drug based on the hepatapeptide "Selank" in the treatment of PD has a positive effect on the severity and pace of recovery processes, contributes to the correction of extrapyramidal motor disorders and normalization of sensitivity to basic antiparkinsonian therapy. The above properties of the drug allow you to use it as a means of choice in the correction of traditional basic anti-Parkinsonian therapy and neurological disorders in patients with PD.

Claims (3)

1. The use of a heptapeptide of the general formula Thr-Lys-Pro-Arg-Pro-Gly-Pro as an agent for the treatment of Parkinson's disease. 2. A method of treating Parkinson's disease, comprising nasal administration of a heptapeptide drug of the general formula Thr-Lys-Pro-Arg-Pro-Gly-Pro. 3. The method according to claim 2, in which the drug "Selank nasal drops 0.15%" is used with a dose of four to six drops in each nostril with an interval of 4-5 hours for 2-3 weeks.