RU2211703C2 - Antistress and nootropic preparation of antiviral and immunostimulating action - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: the present innovation deals with pharmacological compositions indicated for prophylaxis and treatment of stress and viral diseases and those associated with decreased immunity. The suggested composition of peptide delta of sleep, (DSIP)-reaferon, at the ratio of components in composition being 1•10³-10⁴ IU/1 mg DSIP-reaferon, provides antiviral action upon the body along with antistress effect and increases immunity, as well. As for DSIP-reaferon composition and those upon its basis at additional supplementation of glycine, carnosine, melatonin have the opportunity to increase body immunity, activate cerebral processes, favors prophylaxis and treatment of psychoemotional disorders and viral diseases. The suggested innovation enables to achieve synergistic effect of components applied to prevent the development of viral diseases at the background of stress and increase body immunity. EFFECT: higher efficiency of prophylaxis and therapy. 3 cl, 11 tbl

Description

 An antistress and nootropic agent with antiviral and immunostimulating effects relates to medicine, namely to pharmacological compositions intended for the prevention and treatment of stress and developing against its background viral diseases and diseases associated with a decrease in immunity, for the regulation of the integral activity of the brain.

 Stress is a disease of a civilized society. As science and technology develops, a person is increasingly affected by external influences for which he is not prepared by natural evolution (electromagnetic waves, huge speeds of movement, etc.). Man-caused stresses on the nervous system, negative emotions associated with basic fears (fear of death, fear of job loss, insecurity in the future, etc.), an increase in the burden associated with the work performed, a decrease in the social significance and material standard of living of our society - All this provokes a person's stress response to very minor stimuli. In addition to these social factors, factors affect a person: weather conditions, magnetic storms, radiation background, air and water pollution, various infectious diseases.

 Beginning with the works of G. Selye [1], who was the first to create the doctrine of “adaptation disease,” the biochemical and physiological processes that occur in the human body under the influence of extreme and pathological stimuli leading to a stress reaction, are studied. to non-specific changes.

 Currently, the clinic distinguishes between three stages of the adaptation syndrome under stress: anxiety stage (the initial forces of the body are mobilized); stage of resistance; stage of exhaustion (the syndrome becomes pathogenic).

 Stress-induced disorders of the protective functions of the body are diverse, and the possible consequences are very serious. For example, with deep stress, the activity of natural killer cells, which are the first echelon of the fight against the development of tumors, sharply decreases [2]. Against the background of stress, non-lethal viral diseases become fatal, as shown in experiments with the introduction of the influenza virus, which against the background of stress penetrates the blood-brain barrier [3].

 Deep brain structures control the activity of organs and cells of the immune system. Signals from the c.n.s. to the immune system are transmitted through nerve conductors, open synapse, neurotransmitters, as well as hormonal and through neuropeptides. Under the influence of neuropeptides in organs and cells, changes in their metabolic and functional activity occur. With disorders of neuroendocrine regulation, dysfunctions of the immune system occur. With the development of immunodeficiency, various forms of pathology arise. Stress plays a crucial role (especially long and deep) in weakening the immunological potentials of the body, because there is a decrease in the proliferative and antibody-forming ability of cells of the immune system.

 Cells of the immune system, which have different receptor sensitivity to hormones, react differently to small and significant, in particular, long-term hormone fluctuations, i.e. main target cells in different phases of stress may be unequal [4].

 The study of the relationship between stress, immunity, and regulatory peptides made it obvious that a number of peptides are included in stress-induced reactions of the body [5]. Some of them, for example, opioid ones, play a limiting role, i.e. are natural stress-protective factors.

 Among drugs with anti-stress, stress-protective, nootropic and anti-drug effects, sleep delta peptide (DSIP) is known in medical practice, i.e., a nonapeptide with the amino acid sequence Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu, where Trp is tryptophan, Ala is alanine, Gly is glycine, Asp is aspartic acid, Ser is serine, Glu is glutamic acid [6].

 DSIP normalizes or limits biochemical changes in the body caused by stress. DSIP has neuroprotective activity, but is not an immunomodulator.

 The aim of this invention is the creation of a pharmaceutical composition having both antistress and nootropic effects, and immunostimulating and antiviral effects to prevent the development of stressful viral diseases and increase immunity. The problem was solved by creating a composition based on the DSIP peptide and analogue of alpha-2-interferon - the recombinant drug "reaferon".

 The essence of this invention is that the composition consists of substances not previously used together, but possessing in this combination a synergistic effect. At the cellular level, alpha-2-interferon (an immunomodulator) and a DSIP peptide (protecting neurons from destruction and maintaining them in a stable state) act simultaneously on the central nervous system.

 The composition used a synthetic DSIP peptide synthesis scheme (4 + 5); such a peptide is an optically pure compound without admixture of isomeric products of α _ → β transpeptidation [7], [8].

 Reaferon - recombinant alpha-2-interferon is produced by a bacterial strain of pseudomonad, the genetic apparatus of which contains the gene for human leukocyte alpha-2-interferon [9].

 Alpha-2-interferon is a leukocyte or genetically engineered origin (reaferon), known as a modulator of cellular immunity. The immunomodulatory effect of alpha-2-interferon is based on the ability to stimulate the activity of macrophages and NK (natural killer cells that are involved in the body's immune response). The antiviral effect of alpha-2-interferon is also based on the effect of this substance on the cell membrane by combining with cell receptors and changes in their properties: resistance and resistance of cell membranes to exogenous irritants - viruses.

Reaferon, acting on the RNA of the virus, thereby prevents its reproduction [10]. The activity of this immunoregulator of polypeptide nature with intranasal administration is manifested in a concentration of 1 • 10 ⁶ -1 • 10 ⁵ IU / ml. The choice of genetic engineering alpha-2-interferon is associated with its production (without blood products) and the absence of side effects (dyspeptic phenomena).

 The data on the properties of reaferon, indicated above, relate to the body, which is in a normal state. Under stress, many processes in the cells proceed differently. So, for example, with an emotional load on the body, rearrangement of cell metabolism occurs, up to intense shifts in DNA synthesis in bone marrow cells [11].

 An intracellular mechanism is observed for changes in protein production by cells of the immune system under stress, which causes changes in the functional capabilities of the cell. Neuropeptides are involved in the regulation of the function of the immune system, including the implementation of stress-induced disturbances in its functioning. The direct participation of neuropeptides in the interaction between the nervous and immune systems has been experimentally proven [12].

 The physiological activity of peptides allows them to influence the functions of other systems, including the immune [13]. It is proposed to use the nonapeptide DSIP in combination with reaferon, as a means of reducing the excess production of free radicals in mitochondria, as well as an immunomodulator that acts on the cell, thereby increasing the stability of the cell membrane and weakening the pathogenic effects of viruses and other stress factors on the cell and body as a whole.

The claimed composition, DSIP reaferon, provides a synergistic effect, which reduces the optimal dose of ingredients. This DSIP reaferon complex is administered intranasally: by instillation into the nasal cavity, which ensures delivery of the composition to the central nervous system through the lymphatic drainage system of the nasolabial triangle. Composition DSIP-reaferon with an ingredient ratio of 1 mg: (1 • 10 ³ -1 • 10 ⁴ ) ME have an effective effect on the body. This has been proven by laboratory and clinical trials (see table 1).

 Due to the fact that at present there is a tendency to switch to genetically engineered products (they are cheaper, not related to donated blood), the alpha-2-interferon leukocyte in the composition is replaced and genetic engineering, i.e. reaferon, recombinant human alpha is used -2-interferon synthesized by the producer strain.

The composition DSIP-reaferon with a ratio of ingredients of 1 mg: (1 • 10 ³ -1 • 10 ⁴ ) ME gave positive results in tests on volunteers.

The composition DSIP reaferon was prepared in 2 ways:
1. By mixing lyophilized DSIP peptide powders and reaferon.

 2. By mixing two solutions of the components, followed by their freeze drying in one bottle.

The results of biological tests were not dependent on the procedure for preparing the composition. When dissolved in water, the composition does not give opalescence, the solution is clear, the activities of the components making up the composition are stable: for reaferon 1 • 10 ³ -1 • 10 ⁴ ME per 1 mg DSIP.

 The composition was tested on volunteers during the flu epidemic.

 Several stressful stimuli are influenced - these are social stressors, natural and climatic, as well as the influence of personal characteristics of the body (character type, health).

Clinical trials were conducted in an epidemiologically unfavorable period of the year for influenza and other viral respiratory diseases: in the winter. The group of volunteers was in an extremely stressful situation - it was intensive work for 8-10 hours a day, work in a densely populated area. All observed were divided into three groups of 5 people:
1 group that received the intranasal composition DSIP-reaferon for 20 days at 2-4 mg once a day;
2 group, which received by instillation only reaferon at 1 • 10 ³ -1 • 10 ⁴ IU two to four times a day for 20 days;
Group 3 - the control, which received a placebo, instilled 2-4 mg of distilled water once a day for 20 days.

The test results showed:
Over the entire period of the trial, 1 group of volunteers did not get any colds, in addition, after the first three days of taking DSIP reaferon, there was a slight increase in the psychoemotional state, mood improved, volunteers noted improved sleep, a feeling of a “rested person”, performance was improved, and memory improvement.

 During the tests, during the course of 20 days, the 2nd group of volunteers also did not get colds, but they didn’t notice any other positive changes, they still had a lower emotional state, low working capacity, high fatigue, psychological stress was observed, which was accompanied by an inadequate reaction of the volunteers .

 The 3rd group of volunteers, the control, gave the following results: out of five people, 4 fell ill with respiratory diseases 7-10 days after the start of the experiment, and therefore left the observation area (see Table 2).

 The drug DSIP-reaferon was used in a group of people often and for a long time suffering from acute respiratory diseases. An analysis of the immune system in such patients indicates a significant shift in the number of immunosuppressants, which leads to increased sensitivity to respiratory viruses.

 The group of patients was 18 people: 50% of men aged 25 to 42 years, the last diagnosis of acute respiratory viral infections less than 1 month ago; 50% of women aged 28 to 55 years, the last visit to a doctor is also less than 1 month ago.

 The course of treatment ranged from 10 to 15 days, the daily dose of DSIP reaferon was from 2 to 6 mg. Patients noted an improvement in overall well-being, a surge of new strength in both men and women showed an improvement in psychoemotional state, improved sleep, laboratory studies of nasal swabs determined a decrease in the titer of the secreted virus (87%). This composition did not cause any adverse reactions. Observation of these patients for 2 months after taking DSIP reaferon showed that none of the test group went to the doctor (see Table 3).

The above example shows that taking 2 mg of DSIP reaferon, with a content of reaferon 1 • 10 ³ , for 10 days, increases the body's resistance to acute respiratory diseases, mobilizes the nervous and immune systems, which indicates the synergistic effect of the two components taken: DSIP and reaferon.

The use of one reaferon (pure) for the prevention of acute respiratory viral infections in similar observations on patients gave a positive effect with daily intake of reaferon in doses of 8 • 10 ⁴ for 10 days, with side effects: decreased appetite, nausea, dizziness.

 When using DSIP-reaferon, the concentration of reaferon was reduced by almost 10 times, the drug did not cause any side effects.

Clinical trials confirm the activity of the DSIP-reaferon complex. The claimed tool contains a synergistic effect of the ingredients: DSIP nopeptide and reaferon, in a ratio of 1 mg: (1 • 10 ³ -10 ⁴ ). Moreover, this tool has antistress and antiviral effects, when used in a dose of 2-6 mg for 10 days.

 It is known that the duration of immunodeficiency in a viral infection is largely determined by both the properties of the virus itself and the type of patient response. It is suggested, for example, that the herpes simplex virus (HHV-7) is associated with chronic fatigue syndrome. Herpes-virus nature has chicken pox, herpes Zoster (shingles), infectious mononucleosis, cytomegalovirus infections, hepatitis. In a weakened body, a herpetic infection can manifest itself as a co-infection with bacterial pneumonia and other diseases. Herpes viruses in the face of immunodeficiency can occur in a wide variety of forms of the disease. From the statistics of recent years, it is known that 80% of children by the age of 6 are infected with herpes virus (infection occurs by airborne droplets).

 Herpes viruses integrate into the genetic apparatus of the host cell and remain in it in an inactive form for life. Under certain conditions of the host organism, the virus multiplies intensively in the cell, new virions damage the cell and enter the lymphatic vessels, and then into the blood, where they are found on the blood cells: red blood cells, platelets, lymphocytes. In this case, the functional activity of these elements is disrupted, which ultimately leads to immunosuppression. With a normal immune response, the virus is eliminated from most organs and tissues of the body with the exception of paravertebral sensory ganglia, where it remains in a latent state throughout the life of the host. The activation of the virus occurs with insufficient activity of macrophages, T-helper lymphocytes (CD-4), cytotoxic lymphocytes, as well as with a decrease in the body's production of immunity mediators, including interferon.

 In the active phase, herniasvirus infection manifests itself in the form of respiratory diseases of undecrypted etiology, aphthous stomatitis in children, various lesions of the nervous system, skin, mucous membranes, conjunctiva and cornea of the eyes, genitals. Reaferon (in vitro) is known to be particularly active against RNA viruses (vesicular stomatitis virus, enterovirus EV-7). DNA-containing viruses (smallpox vaccine, BOB) and herpes simplex (HBV-1) are more resistant to it.

The use of the DSIP - reaferon complex in doses of 1 mg: (1 • 10 ³ -10 ⁴ ) IU was used to prevent respiratory viral infections. Based on the immunomodulatory effect of reaferon, which manifests itself in the stabilization of the functional ability of T-lymphocytes, reaferon was included in the composition to block the production of the virus at one or another level. This drug gives a more inhibitory than stopping effect in the treatment of viral infections.

 Testing the composition DSIP-reaferon as a therapeutic agent was carried out on volunteers suffering from herpes infection, confirmed by recurrent Herpes simplex. The period of exacerbation proceeded with a vivid clinical picture of Herpes nosales, Herpes labialis: painful rashes on the lips (5 people), on the nasolabial folds (3 people), on the wings of the nose (4 people), with catarrhal phenomena (12 people) .), headache (12 people), low-grade fever (10 people). From the history of patients it was obvious that they get sick more often in the cold season (9 people), with strong nervous loads (7 people), and there are also unfavorable working conditions (chemical laboratory) (4 people). All patients (12 people) were prescribed DSIP-reaferon intranasally 2-6 mg per day for 7 days. A control group of patients (12) received conventional treatment.

 The clinical picture of patients taking the drug - the DSIP-reaferon complex has clearly changed: the healing process of the rashes accelerated to 5 days, while the temperature returned to normal, within 1-2 days (10 people); the psychoemotional state of patients improved, pain decreased in the first - second days of taking the drug. Recovery was observed on day 9-10 of the disease.

 In the control group that did not receive the composition, the development of the disease was accompanied by rashes, fusion of the vesicles, an increase in their area of damage, the general condition was characterized by moderate severity (5 people). Recovery was observed on day 15-17 of the disease.

 The composition was applied to children (7-8 years old) with aphthous stomatitis (3 people). The drug DSIP-reaferon was administered intranasally at 2-4 mg per day for 7 days. At the same time, there was a decrease in temperature to normal by the end of the first day, a decrease in pain by 2 days, the absence of new rashes, and the general condition improved. Epithelization of the mucous membranes ended by the 5th day of the disease (see table. 4).

The use of reaferon in small concentrations of 1 • 10 ³ -1 • 10 ⁴ ME in combination with the anti-stress nonapeptide DSIP helps the body overcome the stressful situation caused by an acute infectious process and pain in the affected area. The DSIP-reaferon complex can be used at different stages of the disease (at the very beginning of the disease; in complex therapy during the rehabilitation of patients; for the prevention of viral infections).

 The synergistic effect of the components of DSIP reaferon provides a therapeutic effect, and allows you to reduce the dose of these components, compared with if they were assigned separately.

 It is known from the literature [14] that the introduction of glycine, acting with a synergistic effect with respect to DSIP, in the ratio of components 1: (1-100), allows one of the mechanisms of the implementation of the pathogenic effect of stress on the body - excess production of free radicals in mitochondria - and thus reduce the pathogenic effect of free radicals on cells and tissues.

Applying this effect in the proposed composition with reaferon, by introducing glycine, the amount of DSIP (expensive in synthesis) was reduced tenfold. The therapeutic and prophylactic effect of the composition: DSIP: Glу: reaferon, where 1 mg DSIP: Gly contains (1 • 10 ³ -1 • 10 ⁴ ) ME reaferon, and the weight ratio of DSIP: Gly 1: (20-40) - remains during testing unchanged compared with the drug: DSIP: reaferon. Glycine-DSIP reduces the pathogenic effects of free radicals on cells and tissues, while exhibiting an antioxidant property.

 Studies have been conducted on the effect of the DSIP-reaferon-glycine complex on transient hypoxic load in patients with chronic fatigue syndrome suffering from multiple sclerosis during the flu epidemic. 26 patients (19 women and 7 men) with a progressive-remitting course of cerebrospinal form of multiple sclerosis at the age of 17 to 39 years, disease duration from 3 to 10 years were examined.

 When assessing the initial state of patients, signs of sympathetic-adrenal tension were observed, which was clinically consistent with asthenoneurotic syndrome and autonomic dystonia. When using patients suffering from multiple sclerosis, DSIP-reaferon-glycine, an increase in the body's resistance to hypoxia was observed. Fixing the positive hemodynamic characteristics of blood parameters, performed Stange tests, the duration of the threshold apnea - all this indirectly confirmed the effectiveness of this composition as an antioxidant, antistress, immunostimulating complex (see Table 5).

 Thus, the proposed complex of nonapeptide DSIP-reaferon-glycine has a complementary and mutually reinforcing effect on the essential pathogenetic mechanisms of damage to brain function in various kinds of stressful situations. The introduction of glycine allowed an order of magnitude reduction in the amount of expensive DSIP in the composition, which is technologically cost-effective.

 The top row in the group is before, the bottom is after the test.

 The fact that the proposed tool has an anti-stress, nootropic and immunostimulating effect was observed when it was used by patients with chronic tick-borne encephalitis (Lyme disease).

 We examined 30 people (12 men and 18 women) in the late stages of Lyme disease with primary damage to the nervous system. The complex therapy was introduced complex DSIP-reaferon-glycine, 2-6 mg for 10 days. The effectiveness of this therapy was confirmed by indicators of neurological status and clinical studies.

 The authors' idea was confirmed that DSIP nonapeptide doses can be reduced by a factor of tens in this complex without reducing the therapeutic effect (see Table 6).

 Patients complained of intellectual-mnestic and emotional disorders in the form of forgetfulness, slow thinking, impaired ability to use existing knowledge, headaches, increased irritability, sleep disturbance, dizziness, unsteady gait.

 As a result of the therapy, 86.6% of patients achieved various degrees of clinical improvement. The most pronounced effect, manifested by an almost complete leveling of both subjective and objective symptoms, was observed in 15 patients (50%).

 A significant reduction in the number of complaints, including those most significant for patients (headache, memory impairment, sleep disturbance), while maintaining mild focal symptoms in the form of areflexia, hypesthesia in locally limited areas, a complete restoration of muscle strength and muscle tone was observed in 11 people ( 36.6%). No positive changes were observed in 4 patients (13.4%) (see table 7).

The complex (nonapeptide DSIP-reaferon-glycine) included the dipeptide carnosine. It allows you to improve the quality of the proposed drug, since the constituent components have a complementary and mutually reinforcing effect on significant pathogenetic mechanisms of damage to the function of brain tissue [15]. The ratio of components in the complex: 1 • 10 ³ -10 ⁴ ME reaferon and 1 g of the composition DSIP-glycine: carnosine in the ratio 1: (20-40) :( 3-30).

 DSIP-reaferon-glycine-carnosine - the complex was administered by instillation into the nasal cavity, which ensures the drug enters the central nervous system, through the lymphatic drainage system of the nasolabial triangle that closes the olfactory brain, which ensures the fastest and most efficient delivery of components to the brain tissue.

 The effect of compounds with antistress (DSIP), with antiviral and immunomodulating (reaferon), and two components with antioxidant properties (glycine and carnosine), different in their mechanism of action (direct and indirect) - provides a powerful therapeutic and preventive effect of the components.

DSIP-reaferon-glycine-carnosine - (DSIP: Glu: carnosine) - in a weight ratio of 1 g per 1 • 10 ³ -10 ⁴ IU of reaferon was used for 7-10 days in doses of 2-6 mg per day by intranasal administration within 10 days, patients with a diagnosis of chronic Lyme disease, with a predominant lesion of the nervous system and a disease duration of 6 to 5 years (see table 8).

 The presence of a chronic neuroinfectious process in the body was accompanied by an energy deficit, which entails pathobiochemical reactions. The infectious process affected the neural structures. Among them, a significant role is played by the violation of redox processes that lead to subsequent disorganization of neuronal metabolism and neurotransmission.

 According to the results of clinical-heevrological and laboratory-instrumental observation, the maximum effect was obtained in the group of patients receiving the DSIP-reaferon-glycine-carnosine complex. There was a relief of intellectual-mnestic disorders in 87.5% of patients, restoration of the bioelectrical activity of the brain, a decrease in the level of sensitization of lymphocytes to brain-specific antigens (see Table 9).

 The combination of DSIP-reaferon-glycine-carnosine has an interferon-inducing effect, and also has an adaptive effect on the body, which allows for finer immunocorrective therapy and prevents the possible aggravation and progression of pathological processes in neuroborreliosis (Lyme disease), usually triggered by the influence of adverse factors of the current environment (see table 10).

 The peptide delta sleep, affecting the state of stress, in its action in c. n from. should overlap with the action of melatonin (produced by the pineal gland). Melatonin is known to be secreted in the absence of light [16].

 Under the influence of melatonin, the amount of GABA and serotonin in the midbrain and hypothalamus increases. GABA is a brake mediator in the c.n.s. It is known that a decrease in the activity of serotonergic components affects the pathogenesis of depressive states and disorders. Violation in patients associated with impaired sleep rhythm causes a depressive state.

 Melatonin has a normalizing effect on the processes of rhythmostasis, and stabilization of the body is universal; adaptogenic, chronotropic properties of melatonin are manifested [17].

 Violation of temporary adaptation is observed when changing time zones. Alcohol intake interferes with the production of melatonin in the body. The depressive state in people the day after taking a large portion of alcohol is partially associated with a sharp decrease in the body's melatonin, a vital neurotransmitter.

 Passion for computer games, a long stay at the lit screen of children leads to a violation of biorhythms, therefore, to a decrease in the synthesis of melatonin by the body.

 Adding melatonin to the composition: DSIP-reaferon-glycine-carnosine at a dose close to physiological allows you to have a composition suitable for preventing or eliminating the effects of psychoemotional disturbances caused by a lack of melatonin in the body.

 Medicinally released tablets of melatonin contain 3 mg of the drug, melatonin per os is traditionally used. The daily maximum dose is 6 mg. Melatonin penetrates well through the blood-brain barrier. In the composition, it is proposed to use melatonin up to 0.5 mg.

The drug is administered intranasally, so the action is effective. Composition DSIP: reaferon: glycine: carnosine: melatonin at a weight ratio of 1 mg of the composition (DSIP-glycine-carnosine-melatonin) 1 • 10 ³ -1 • 10 ⁴ ME reaferon, and in the proportion DSIP-glycine-carnosine-melatonin = 1 : (20-40) :( 3-30) :( 10:50).

 The composition DSIP-reaferon-glycine-carnosine-melatonin in the indicated proportions was used in the treatment of patients with viral hepatitis, icteric form, moderate. We evaluated the hepatotropic effect of the drug (according to the dynamics of the functional parameters of the Alt liver, total bilirubin) and the effect on the psychoemotional state of patients (according to Spielberg-Khanin tests) in order to reveal the dynamics of the composition.

 Volunteers (41 people) were selected with moderate and severe forms of HCV, HBV and mixed viral hepatitis; the groups included men and women aged 16 to 44 years. The drug was taken at 2-6 mg for 6 days, then the course was repeated after ten days for 6 days at 2-6 mg per day (see table. 11).

 Alt exceeded the norm by more than 2 times; total bilirubin exceeded the norm by more than 2.5 times. The psychoemotional state of patients was evaluated with a high level of anxiety, depression.

 A positive effect of the drug DSIP-reaferon-glycine-carnosine-melatonin on some psychophysiological parameters of patients, in particular, on the level of reactive anxiety and general well-being of patients with hepatitis, was revealed, while an adaptive effect was observed.

 Analyzing the results, it can be seen that in patients with viral hepatitis B and C, after 5 days of treatment, the effect of the drug appears, which indicates a prolonging effect. The drug improves the general well-being of patients, stabilizing their psycho-emotional sphere, facilitating the course of the disease.

List of references
1. G. Selye. Stress without distress. Moscow. Progress, 1982.

 2. The interaction of normal killer cells and tumor cells. Moscow. 1983, p. 70-79. Bulletin of the Academy of Medical Sciences of the USSR. 1985.8, p. 23-29.

 3. Neurohumoral regulation of immune homeostasis. Theses of the All-Union Symposium. Leningrad. 1986, p. 81.

 4. Stress and immune system. Ed. N.P. Plotnikoff et al. New York, London: Plenum Press. 1986, p. 431-432.

 5. Immunophysiology. / Ed. E.A. Root "Science", St. Petersburg, 1993, p. 579-692.

 6. A) Neuroscience Lett., 1979, v. 13, p. 165-172.

 B) Graf V., et al, Peptides, 1982, v. 3, p. 623-626.

 C) Dokl. Academy of Sciences, 1982, v. 267, p. 913-917.

 C) Experiencia, 1981, v. 37, p. 230-233.

 7. J. General chemistry. 1981, v. 51, p. 1964-1971.

 8. J. General chemistry. 1981, v. 51, p. 2153-2154.

 9. Reaferon. Collection of scientific papers. Ministry of Health. USSR. Research Institute of influenza. Leningrad. 1988, p. 7-14.

 10. A) J. "Advances in Physiol. Sciences", 1975, 6 (4), p. 65-77.

 B) Guide Vidal. Medicines in Russia. Ed. 5. Moscow. 1999. "AstraPharmService". E-121.

 11. E.A. Korneva. E.K. Shkhinek, "Hormones and immune systems", Leningrad, "Science", 1988, p. 151-192.

 12. E.A. Korneva. E.K. Shkhinek, "Hormones and immune systems", Leningrad, "Science", 1988, p. 140-141.

 13. J. "Pathological physiology and experimental therapy", 1984, 1, p. eleven.

 14. RF patent 2099078, BM 35, 12.20.97.

 15. RF patent 2084238, BM 20, 07.20.97.

 16. J. Am. Chem. Soc., 1951, v. 81 (11), 6084-6085.

17. a) Advances Pharmacol, 1968, v. 6 (part a), 141-151;
b) Vidal Handbook, B-383, E-143.

Claims (1)

1. A tool with antistress, nootropic, antiviral and immunostimulating effects and containing synergistically active ingredients: DSIP nonapeptide with the amino acid sequence Trp-Ala-Gly-Asp-Ala-Ser-Gly-Glu and gene-engineered alpha interferon (reaferon) in the ratio:
DSIP - 1 Mr
Reaferon - 1 • 10 ³ -1 • 10 ⁴ IU
2. The tool according to p. 1, characterized in that it further comprises glycine, in a mass ratio of 1 mg:
DSIP - 1
Glycine - 20 - 40
Reaferon - 1 • 10 ³ -1 • 10 ⁴ ME
3. The tool according to p. 1, characterized in that it further comprises glycine and carnosine dipeptide in a mass ratio of 1 mg:
DSIP - 1
Glycine - 20 - 40
Carnosine - 3 - 30
Reaferon - 1 • 10 ³ -1 • 10 ⁴ ME
4. The tool according to p. 1, characterized in that it further comprises glycine, dipeptide carnosine and melatonin in a mass ratio of 1 mg:
DSIP - 1
Glycine - 20 - 40
Carnosine - 3 - 30
Melatonin - 10 - 50
Reaferon - 1 • 10 ³ -1 • 10 ⁴ ME

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