RU2045958C1 - Nootropic drug and pharmaceutical nootropic composition - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: this method prescribes using heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro as nootropic drug. Novel nootropic composition includes about 0.95 to 1.05 g/l heptapeptide as active compound and 0.95 to 1.05 g/l of Nipagin as conservant, water being remainder. EFFECT: higher effectiveness when administered nasally in small doses (droplets) and greater simplicity. 2 cl

Description

 The invention relates to medicine, namely to the development and use of a new nootropic agent. It can be used to treat intellectual and mnestic disorders in a neurological clinic for vascular brain lesions, asthenoneurotic conditions of various genesis, including after exposure to ionizing radiation, for chronic progressive diseases of the nervous system, for the treatment and rehabilitation of patients who have undergone neurosurgical operations and a brain injury, in anesthesiology for the prevention and treatment of post-narcotic mnestic disorders, as well as to increase the adaptive recreational opportunities of a healthy person in extreme conditions (for example, operators in the most critical periods of work, in emergency situations, athletes).

 The relevance of the development of the drug is determined by the general tendency to an aging population, an increase in the prevalence of ischemic disorders of cerebral circulation and vascular dementia in most economically developed countries of the world and the extreme insufficiency of effective nootropic drugs in modern medicine.

 The practical possibility of development is due not only to the ability of nootropics to correct neurological deficits in vascular, infectious, hereditary and other diseases of the nervous system, but also to increase the general activity, labor and social adaptation of patients, reducing economic losses from their temporary disability, disability. The urgency of the problem is also associated with the ability of nootropics to expand the boundaries of the physiological adaptation of a healthy person engaged in the most complex, responsible and intense types of work, increase the body's resistance to extreme situations, and increase the creative activity of a person in old and old age.

Known drug piracetam (nootropil) is the main representative of the groups of nootropic drugs, the highest effectiveness of which is confirmed in a number of clinical and experimental studies [1]
However, the clinical effect of this drug is manifested only in relatively high doses; in the treatment of chronic conditions, the therapeutic effect is observed, as a rule, only after 2-3 weeks from the start of treatment, which can also be long in time (up to 6 months); with the use of piracetam in some patients there are dyspeptic phenomena, exacerbation of coronary insufficiency; the drug is contraindicated in acute renal failure.

 Known peptide preparation ebiratide with nootropic activity. (G. Weimer, et al. Neurochemical effect of the synthetic ACTH (4-9) analog Hoe 427 (Ebiratid) in rat brain Peptides, 9 (5), 1081-1087 (1988) (2).

 The disadvantages of this tool include: the rapid loss of biological activity due to enzymatic degradation (duration of action 1 h); narrow dose range (1-10 mcg / kg, higher doses are not effective); the presence of unnatural amino acids in the structure of this product, as well as aliphatic diamine, which can lead to adverse consequences.

Known heptapeptide of the General formula
Met Glu His Phe Pro Gly Pro as a memory stimulant of prolonged action (USSR Patent N 939440, class C 07 C 103/52, 1981).

 However, the possibility of using it as a medicinal nootropic agent is not described.

 Known medicinal composition of a nootropic agent in the form of a 22% or 33% solution of piracetam in distilled water.

 However, the concentration of the active component in this composition is high, it is used as a solution inside or for injection, and in high doses, it requires long-term use and is contraindicated in acute renal failure.

 The technical result achieved during the implementation of the invention is the discovery of a wide range of therapeutic effects of the known memory stimulant, the identification of the possibility of its use in low doses as a nootropic agent, obtaining a convenient dosage form without undesirable side effects and with good tolerance.

This is achieved by the fact that the known heptapeptide of the general formula:
Met Glu His Phe Pro Gly Pro is used as a nootropic agent.

In the medicinal composition of a nootropic agent containing the active substance and distilled water, the heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro and the additional preservative nipagin are contained as the active substance in the following ratio of components, g / l:
Heptapeptide Met-Glu-His-
Phe-Pro-Gly-Pro 0.95 1.05
Nipagin 0.95 1.05
Distilled water Else.

 It was found that the heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro, known as an animal memory stimulant, has a wide spectrum of action, but does not have undesirable side effects, is active in low doses, and is convenient to use due to the use of drug form in the form of drops in the nose. The dosage form is named "Semax".

 The drawing shows the results of changes in the behavioral activity of white rats in an open field test under the influence of the known and new nootropics.

 PRI me R 1. The effect of the heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro on the behavioral effects in the experiment.

 a). In experiments on white rats (males) weighing 200 g, we studied the level of orientational research activity of animals by double landing in the "open field". The "open field" was an arena with a diameter of 80 cm, divided into sectors. During the experiment, the rat was planted in the center of the arena, motor activity (by the number of segments traveled), vertical activity (the number of lifts on the hind legs), the number of muzzle touches (washing) and the number of bowel movements were visually assessed.

 The magnitude of the horizontal and vertical locomotor activity is mainly an indicator of an indicative reaction. A sharp decrease in locomotor activity can also serve as an indicator of fear, since most rats with a fright are characterized by a reaction of stasis. In addition, with fear, the number of bowel movements increases. The number of washings can serve as a criterion for assessing the emotionality of animals. Using the method of "open field" you can also evaluate the degree of memorization by animals of the experimental situation. To do this, rats were placed in the arena twice: for the first time for two minutes and the second time after seven days, also for two minutes. The higher the magnitude of motor activity during the second stay of rats in the arena, which reflects the magnitude of the tentative research reaction, the therefore, the worse the rat remembered the situation of the experiment during his first stay in the "open field". The mileage, the number of exits to the center, the number of racks, washings and bowel movements for 2 min of rats in the field under stress-free conditions were recorded. In the experimental and control groups there were 12 animals.

 Saline was injected intraperitoneally to the control animals 15 minutes prior to the first landing, and the experimental heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro at a dose of 0.015 mg / kg.

 The results of the experiments are presented in the table.

 From the data of the table it follows that in the control animals after 7 days, the orientation-research reaction remains the same, they again quite actively examine the experimental arena. Experienced rats treated with heptapeptide examine the arena only in the first 30-45 seconds after being in it, then their motor activity decreases sharply. The horizontal component of motor activity is reduced by 31% (p <0.05). Thus, the introduction of a heptapeptide at a dose of 0.015 mg / kg significantly affects the indicators of orientational research activities of animals, improving their response to the experimental situation.

 b) The effect of the heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro on the correction of pharmacologically induced disturbances in animal behavior.

 In experiments on white rats (males) weighing 200 g, the effect of the heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro on the behavior of animals after changing the functional state of the catecholaminergic systems of the brain by the administration of haloperidol (0.05 mg / kg 15 min before test), apomorphine (1 mg / kg in 3 min), phenamine (1 mg / kg in 30 min). Then, half of the test groups were injected with the heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro (0.015 mg / kg 5 minutes before the test).

 The level of orientation and research activity was evaluated by the method of double landing in the "open field". Rats were placed in the arena of the "open field" for two minutes twice, a second time 7 days after the first experiment. The results are presented in the drawing.

 It was shown that haloperidol and apomorphine itself inhibit the orienting and research activity of experimental animals in an open field during the first landing (a decrease in the horizontal and vertical components of activity by 30-50%). Additional heptapeptide administration did not significantly affect these effects. At the second landing it was revealed that in animals treated with haloperidol and apomorphine, there is no normal extinction of the indicative reaction. Against this background, the heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro has a normalizing effect, reducing the amount of motor activity.

 Phenamine at the first landing stimulates research and development activities, as well as grooming (stereotype). The heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro clearly counteracts these effects. When re-placed in an open field, the animals of this group did not differ from the control.

 Thus, the heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro positively and reliably affects the orientational research activity of animals, correcting pharmacologically induced disturbances in their behavior, i.e. optimizes brain functions, providing better adaptation of the body to the environment.

 PRI me R 2. The drug Semax nootropic drug for clinical use. The nootropic effect of Semax was studied in 303 people in 5 medical institutions: the Research Institute of Neurology of the Russian Academy of Medical Sciences, the Center for Vegetative Pathology of the Ministry of Health of the Russian Federation, and the Moscow Medical Academy. I.M.Sechenov, Military Medical Academy. S.M. Kirov, Institute of the Human Brain of the Russian Academy of Sciences.

 The purpose of the study was to evaluate the effectiveness of the influence of Semax on intellectual-mnestic disorders, the dynamics of mental processes in patients with various types of brain disorders and a group of healthy people in the camera profession.

 Based on the clinical trials of Semax, the following conclusions were made.

 The drug can be used for intranasal clinical use as a nootropic agent in a hospital and clinic for the treatment of intellectual-mnestic disorders, asthenic disorders in neurological patients with cerebrovascular pathology and chronic diseases of the nervous system.

 Semax can be recommended as a nootropic agent for wide clinical use in the treatment and rehabilitation of patients undergoing neurosurgery and craniocerebral trauma. It reliably improves short-term and delayed memory, visual memory, mental pace after calypsol anesthesia, which allows us to recommend its use in surgery and anesthesiology in the early postoperative period for the prevention and treatment of post-narcotic mnestic disorders.

 In a psychiatric clinic, it is advisable to use semax as a nootropic drug at a dose of up to 5000 mcg per day for the treatment and rehabilitation of patients with astheno-neurotic symptoms and organic brain damage after exposure to ionizing radiation.

 The drug does not affect the efficiency of the cardiorespiratory system, does not eliminate the dysfunction of the autonomic nervous system, and therefore, Semax monotherapy in patients with severe astheno-neurotic syndrome with hypochondriac manifestations and severe autonomic dystonia with autonomic crises is ineffective. Perhaps the use of Semax in the treatment of astheno-neurotic conditions and autonomic dystonia (without autonomic crises).

 Semax enhances targeted motivation, selective attention, and the reserve capabilities of the body’s functional systems during mental and physical overloads, which allows it to be recommended as a nootropic remedy for the correction of neuropsychic fatigue and to increase adaptive and adaptive capabilities for people in the operator’s professions during the most critical periods of work and during emergency situations.

 PRI me R 1. Patient K. 42 years old, a soldier. He was examined and treated in the psychosomatic department of the psychiatry clinic of VMedA them. S.M. Kirova from 04/12/93 to 05/26/93, regarding the prolonged astheno-neurotic state of mixed genesis (somatogenic and radiation) with persistent clinical manifestations. From the anamnesis: born in the family as a second child. Heredity is not psychopathologically burdened. Grew and developed without features, did not lag behind peers in development. I went to school from the age of 7, studied well, and after graduating from 10 classes I entered the military school. Studying was easy, he successfully completed his studies, got married and until the end of 1986 served in various positions, always characterized positively. In 1986-1987, he participated in the aftermath of the Chernobyl accident. During this period, I felt a slight sore throat, slight fatigue, weakness, increased sweating, and slight dizziness. For the first time after Chernobyl, health deterioration began to be noted a year and a half later, when the phenomena of increased fatigue, weakness after insignificant physical exertion began to increase, the process of falling asleep was disturbed, headaches appeared, and blood pressure rises began to be noted. Initially, he was treated on an outpatient basis, took hypotensive drugs, sleeping pills, but did not notice the effect of the treatment. The phenomena of weakness and increased exhaustion gradually increased, became irritable at work, and conflicts with his wife and children became more frequent. Over the past year and a half, there has been a persistent decrease in potency, hair loss, weight loss of 12 kg, constant headaches, memory impairment for current events, disturbances in the process of falling asleep and sleep depth, early awakening, unstable mood, stomach pain after eating, heaviness in the right hypochondrium. Examined at the clinic VPT VMmed them. S.M. Kirova, due to the predominance of astheno-neurotic symptoms in the clinical picture of the disease, was transferred to the psychosomatic department of the psychiatry clinic.

 Upon admission and subsequently without signs of productive psychotic symptoms. Contact is available, describes in detail the history of life and disease. The speech is quiet, vocabulary corresponds to the education and intelligence. On the face, an expression of sadness, firmly fixed on his condition, is concerned about the increase in symptoms and the lack of effect of the treatment. Emotionally labile, on the face “a game of vasomotors”, easily responds with a decrease in mood on topics related to the prospects of their state of health. Memory for current events is reduced, constantly refers to the notebook. Sluggish, asthenized, depleted, unproductive. She associates her disease with exposure to ionizing radiation during the liquidation of the consequences of the Chernobyl accident. During the examination, a reduced ability to remember, an increase in the time to solve arithmetic problems, a low amount of attention, a high level of neurotization, profile elevations on the depression and hypochondria scale, and a low level of social adaptation were revealed. The EEG study indicated a slight predominance of slow-wave activity in the frontal leads. Against the background of complex therapy and taking Semax at a dose of 5000 mcg per day for 7 days, the patient showed a clear dynamics of the state: he became more active, lethargy disappeared, mental and physical fatigue decreased, mood, attention, memory, mental performance improved, but headaches remained pain that decreased after transcranial electroanalgesia. Further, the EEG indicated an increase in the A-rhythm in the occipital leads, a decrease in the severity of the D and T rhythms in the frontal leads. The use of the drug Semax was not accompanied by any side effects.

 PRI me R 2. Patient P. 44 g, was in the Research Institute of Neurology RAMS on treatment since 02.04. June 10, 1992. Diagnosis: cervical osteochondrosis, vertebrobasilar insufficiency with stem crises of the hyper- and hypotonic type. Blood flow insufficiency in both vertebral arteries, mixed-type vegetovascular dystonia with sympathoadrenal crises, asthenoneurotic syndrome in a patient from a family burdened by Huntington’s chorea gene. Complaints upon receipt of periodic headaches, dizziness, sometimes staggering when walking, sometimes blurred coordination in the hands, depressed mood, impaired attention, memory.

 Anamnesis of the disease: considers herself sick for about 3 years, when headaches appeared, sometimes speech difficulties (it is difficult to choose words), dizziness recurring, lately fussiness, impaired coordination in hands, sometimes staggering when walking. In addition, she became emotionally labile, mood, attention, memory decreased, sleep disturbed. Family history: Huntington's chorea was sick by his father, his aunt on the mother's side, two sisters.

Objective examination data: blood pressure 100/60 mm Hg pulse of 48 beats per minute. Horizontal nystagmus with extreme leads of the eyeballs. Slight smoothness of the right nasolabial fold. Irregular twitching in the distal arms and legs, tendon reflexes are enlivened, D = S. There are no pathological reflexes. In the Romberg position, a slight staggering to the sides. Coordination tests are not always accurate. Bright spilled persistent dermographism. Hyperhidrosis. Emotionally labile, a tendency to depressive reactions. Psychiatrist consultation: astheno-depressive syndrome of complex origin with obsessive inclusions. EEG: alpha activity is represented in the form of single waves, moderate diffuse changes in the EEG type of rhythm desynchronization with signs of dysfunction of the mid-stem structures. X-ray of the cervical spine: osteochondrosis C ₅ -C ₇ vertebrae. Chest x-ray without pathology. Doppler ultrasound of the vessels of the head: circulatory deficiency in both internal carotid arteries, asymmetry of blood flow in both vertebral arteries (left 46 m / s, right 10-12 m / s) with discirculation in both vertebral arteries.

 Treatment: semax series 1.08.90 14 days. The patient started treatment on the background of depression due to severe nephew disease. The patient cries, does not sleep well at night. At the end of treatment, an improvement was noted: the mood became smoother, sleep returned to normal, headache disappeared, became active, hyperkinesis also decreased slightly. According to the psychologist’s conclusion, after conducting a course of treatment with Semax, a significant improvement in auditory-speech memory and an increase in concentration were noted.

 Against the background of the use of the drug Semax side effects or complications were not observed.

 PRI me R 3. Patient W. 52 g was in the Research Institute of Neurology RAMS from 08.06.92 to 06.21.02 with a diagnosis of initial manifestations of insufficient blood supply to the brain. Upon receipt of a complaint of fatigue, decreased household memory, distraction, decreased performance, sleep disturbance. During a neuropsychological examination, a decrease in the concentration of attention, associative, situational memory, a decrease in the reaction rate to the presented sound, light stimuli was noted. After a 2-week course of treatment with Semax, a positive dynamics of the patient's condition was noted. Well-being improved, became more active, collected, sleep improved. An objective psychophysical examination showed an improvement in all types of memory, an increase in reaction speed and concentration of attention.

 Thus, experimental studies and course treatment of patients with Semax with a positive therapeutic effect make it possible to offer it as a nootropic drug in a wide medical practice.

 Semax is non-toxic, convenient for use in clinical practice due to its good tolerance, the absence of side effects, a convenient dosage form (nasal drops).

 Comparison of semax with the best nootropic (piracetamnotropyl) and foreign peptide analogue (ebiratide) revealed its significant advantages.

 Comparison of the activity of Semax and Piracetam showed that the effective dose of Semax (0.015-0.050 mg / kg) is significantly (6000 times) lower than for piracetam (100-300 mg / kg).

 The advantage of Semax also lies in the fact that it consists of natural amino acids found in the body and is rapidly metabolized. Due to the peculiarities of the natural metabolism of the natural amino acids that make up Semax, toxic products cannot form during its breakdown, which also distinguishes it from piracetam, which is excreted by the kidneys without metabolizing, and is contraindicated in acute renal failure. Semax is not toxic: if for piracetam the minimum lethal dose is about 10 g / kg, i.e., 100 times higher than the effective, then for Semax it was not possible to detect significant disturbances in the condition of animals and there were no fatal outcomes with an increase in the effective dose by 200 times ( up to 10 mg / kg).

 Comparison of semax with the peptide analogue of ebiratide showed that semax is devoid of the inherent disadvantages of ebiratide. Semax is characterized by unidirectional action in a wide range of doses without side effects; 24 or more times prolongation of the action time in comparison with the known neuropeptides; the absence of unnatural D-amino acids and aliphatic diamine in its composition, which can lead to adverse consequences.

 The results of clinical trials are obtained using a composition containing 0.95-1.05 heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro, 0.95-1.05 nipagin, the rest is distilled water.

 The optimality of the indicated concentration of heptapeptide and nipagin in the composition and the inappropriateness of going beyond these limits are shown. 7 known stabilizers were tested and the optimality of nipagin was shown.

 It was found that a single dose of the new composition in terms of the heptapeptide Met-Glu-Gis-Phe-Pro-Gly-Pro is 3-30 μg / kg (200-2000 μg / person weighing 70 kg); daily dose: 7-70 mcg / kg (500-5000 mcg / person). The drug is recommended to be taken within 3-5 days, 2-3 times a day with an interval of 4-5 hours. The course of treatment is 3-5 days daily. If necessary, the course of treatment can be extended up to 14 days.

 The drug is injected with a pipette in volumes not exceeding 2-3 drops in each nostril (at the rate of 1 drop of 50 μg of the active substance).

Claims (2)

1. The use of a heptapeptide of the formula
Met Glu His Phe Pro Gly Pro
as a nootropic agent. 2. A pharmaceutical composition of nootropic action containing the active substance and distilled water, characterized in that the active substance contains a heptapeptide of the formula
Met Glu His Phe Pro Gly Pro
and additionally preservative nipagin in the following ratio of components, g / l:
Heptapeptide of the Formula 0.95 1.06
Nipagin 0.95 1.05
Distilled Water Else

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