RU2625754C1 - Combined drug of anxiolithic, stress-protector, nootropic and antioxidant action - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention is a combined drug of anxiolytic, stress-protective, nootropic and antioxidant action containing tryptophan, characterised by additional content of tiotriazoline at a quantitative ratio: tryptophan ranging from 1 to 7 wt parts per 1 wt part of thiotriazoline.

EFFECT: agent has a higher anxiolytic and antioxidant activity compared to the known agents and has additional nootropic and stress-protective action.

3 cl, 5 tbl, 2 ex

Description

The invention relates to pharmacy and medicine, and can be used in the pharmaceutical industry in the manufacture of medicines with a combined composition of active ingredients that are used to treat and prevent diseases of the central nervous system, accompanied by such conditions of the body as anxiety, anxiety, fear, emotional stress, based on stress. Also, the action of the proposed tool will be aimed at eliminating psychosomatic disorders in case of neurosis, neurosis-like conditions, withdrawal symptoms, alcoholism, and drug addiction.

A decrease in duration, as well as a deterioration in the quality of life, is directly related to an increase in the number of patients with central nervous system diseases whose ethnogenesis is stress [10]. In this regard, the development of measures for pharmacological correction of emotional stress is one of the urgent tasks of modern medicine. It is known [1, 2, 10, 11] that one of the links in the pathogenesis of emotional stress is the overproduction of reactive oxygen species (ROS) by the bioenergetic and neurochemical systems of the brain. Excess ROS in conditions of antioxidant deficiency leads to oxidative modification of lipids, nucleic acids and proteins. Oxidative modification of protein fragments of receptors, ion channels, synaptic structures of a neuron leads to impaired generation, formation, conduction of a nerve impulse, disrupts synaptic transmission and, as a result, leads to a deterioration in the cognitive-mnemonic functions of the brain [1, 2, 13]. It is also known that, under the influence of ROS, the expression of redox-sensitive genes is activated in the cell, some of which are necessary to protect cells from the toxic effects of oxidative stress, while others, with an excess of ROS, initiate apoptosis [1, 15]. In connection with the above, a promising direction of pharmacocorrection of stress and its consequences is the use of antioxidants, nootropics, anxiolytics [2, 3]. Structural analogues of neurotransmitters, such as noofen, glycine, GABA, and tryptophan, have found widespread use in clinical practice as stress protectors and anxiolytics [2].

Recently, there has also been a tendency to create combined drugs with a nootropic effect that can restore impaired mental and mental functions, reduce neurological deficits, and also protect the brain and increase the body's resistance to extreme influences.

However, the modern arsenal of anxiolytic, nootropic, stress-protective, antioxidant agents does not always meet all the requirements of clinicians. Most often, such drugs are prescribed in the form of separate dosage forms, which leads to polypharmacy, reduces the compliance of patients. Sometimes drugs are not effective enough. All this necessitates the creation of new combined highly effective and low-toxic drugs that would combine the positive effects of active active substances or even enhance their therapeutic effect.

Known combination drug Thiocetam, which in its composition contains thiotriazolin and piracetam (0.05 g of thiotriazolin and 0.2 g of piracetam). The drug has a pronounced antioxidant, anti-ischemic, nootropic and cerebroprotective effect [2, 6, 8, 9]. However, Thiocetam does not have anxiolytic properties and it does not have enough pronounced stress-protective activity.

Noofen is also known (the active substance is phenibut, (γ-amino-β-phenylbutyric acid) for oral use (Compendium - drugs online http://compendium.com.ua/info/262/olajnfarm/noofen-sup-sup -500-mg-i-poroshok-i-), which has antihypoxic, antiamnestic and anxiolytic (tranquilizing) effects.Noofen stimulates learning processes, improves memory, increases physical and mental activity.Noofen also has tranquilizing features: eliminates psychoemotional stress, anxiety , fear, emotions onal lability, irritability, improves sleep; prolongs and enhances the effect of sleeping pills, drugs, antipsychotics and anticonvulsants. Under the influence of Noofen, higher nervous activity indicators (attention, memory, speed and accuracy of sensory-motor reactions) improve. The drug lengthens the latent period and reduces the duration and the severity of nystagmus, has an antiepileptic effect. Does not affect choline and adrenoreceptors. Noofen significantly reduces the manifestations of asthenia and vasovegetative symptoms, including headache, a feeling of heaviness in the head. In patients with asthenia and in emotionally labile patients, from the first days of treatment with the drug, their health improves, interest and initiative increase, motivation for active work without a sedative effect or arousal. It has been established that when taking Noofen during traumatic brain injury, the number of mitochondria in the cells of perifocal tissues increases and bioenergetic processes in the brain improve. In the presence of disturbances in the activity of the heart and stomach, it normalizes the processes of lipid peroxidation.

However, the spectrum of nootropic action of Noofen is very narrow - the drug exhibits only an antiamnestic effect (affecting short-term memory), without affecting long-term memory, level of judgment, cortical control (http://gomelpsyhosp.by/?p=1080). Noofen has a number of side effects, which limits its use in clinical practice, especially pediatric and gerontological. The drug can be addictive, has withdrawal syndrome (http://otravleniya.net/ximicheskie-otravleniya/fenibut-privykanie.html). There is evidence that Noofen with prolonged use may have a negative effect on the liver.

Tryptophan is known (http://www.likar.info/lekarstva/Triptofan/), which is a precursor to the neurotransmitter serotonin. Tryptophan helps to improve mood, relieve anxiety, hyperactivity, obsessive states and chronic fatigue syndrome, eliminates feelings of fear and tension, and contributes to good sleep and normal sleep.

However, tryptophan does not have a pronounced independent nootropic, stress-protective and antioxidant effect.

Of undoubted interest is the search for ways to enhance the protective properties of tryptophan by combining with substances that can improve the energy supply of the brain, exhibit antioxidant effects and inhibit oxidative stress, and thereby restore the sensitivity of neuron receptors. These substances include thiotriazolin. Thiotriazolin is able to enhance the anxiolytic effect of tryptophan by regulating Red / Oxi-dependent mechanisms for increasing affinity for serotonin receptors. Tryptophan, in turn, can enhance the antioxidant effect of thiotriazoline. So, tryptophan, by converting it to melatonin in the body, can form a kind of tandem with thiotriazoline to utilize such ominous oxygen radicals as hydroxyl radical and peroxynitrite. Tryptophan together with thiotriazolin can affect the memory mechanisms both short-term - by suppressing amnesia caused by an excess of free radicals, and long-term - due to the joint effect on ATP-dependent mechanisms of the synthesis of memory proteins.

A similar combined effect of tryptophan and thiotriazolin, aimed at regulating Red / Oxi - dependent mechanisms of the affinity of serotonin receptors, restoring the function of this system (reducing anxiety, fear, sleep disturbance, anxiety), as well as enhancing the antioxidant and energetic effects (memory processes), can use in the prevention and treatment of diseases whose important pathogenesis is stress, and these are diseases of the central nervous and cardiovascular system.

The basis of the invention is the task of developing a combined drug that will have a higher anxiolytic and antioxidant activity compared to known means, and will additionally have a nootropic and stress-protective effect.

The problem is solved in that in the combined drug anxiolytic, stress-protective, nootropic and antioxidant effects containing tryptophan, the new is that it additionally contains thiotriazoline.

Also new is the fact that the combined drug of anxiolytic, stress-protective, nootropic and antioxidant action contains tryptophan and thiotriazoline in the following ratio: tryptophan - in the range from 1 to 7 mass fractions, thiotriazoline - 1 mass fraction.

Also new is the fact that the combined drug of anxiolytic, stress-protective, nootropic and antioxidant action takes the form of tablets, capsules, injection and infusion solutions.

Based on the studied mechanisms of action of both components of the proposed combination agent containing tryptophan and thiotriazoline, and suggesting the possibility that the proposed combination agent may have a more effective anxiolytic and antioxidant effect, an experimental study was conducted in this direction.

When conducting experimental studies that confirmed the hypothesis, an additional non-obvious property of the combination of tryptophan with thiotriazoline was discovered - its nootropic and stress-protective effect, as well as an increase in the anxiolytic and antioxidant effect.

Various combinations of thiotriazolin with tryptophan - 1: 1 were studied; 1: 2; 1: 4; 1: 5; 1: 7, respectively, in the conditions of the test "hanging by the tail." The optimal combination of thiotriazoline with tryptophan - 1: 4 was revealed. Table 1 below provides data that confirms this.

The anxiolytic effect of the combined preparation with a different ratio of active components (thiotriazoline with tryptophan) was studied in 50 nonlinear white rats of both sexes weighing 170-230 g. A blitz test, the use of which is possible to determine the level of anxiety and ascertain the anxioprofile of drugs, is by hanging the animal by the tail. The method is based on the observation that animals, when suspended by the tail, will demonstrate an appropriate period of immobility, the duration of which can be used to judge the level of anxiety, fear and despair. Combinations of thiotriazolin with tryptophan were administered at a dose of 250 mg / kg intragastrically as an aqueous solution using a metal probe 60 minutes before testing. After the introduction of the studied combinations, the animal was pulled out of the cage and held by the tail near the body in a hanging position, head down. The time was recorded during which the animal would remain immobilized (that is, until the animal's muzzle reached the base of the tail) [10, 14].

As a result of the studies, it was found that the combination of thiotriazoline and tryptophan in the ratio of 1: 4, respectively, but the combination with the ratio of 1: 1, turned out to be the most active; 1: 2; 1: 5 and 1: 7 are also therapeutically effective.

As is known (Kukes V.G. Clinical Pharmacology, 4th edition, Moscow, “GEOTAR-Media”, 2008, pp. 164-169; Gilman A.G. Clinical Pharmacology according to Goodman and Gilman, Moscow, “Practice”, 2006, p. 57), the pharmacodynamic interaction of drugs can be directed both towards enhancing their pharmacological effects, and to weaken them. Therefore, although thiotriazoline and tryptophan each have a wide range of positive pharmacological effects, it is not obvious to a specialist that thiotriazoline or tryptophan can be used in combination with any other drugs.

Also, drugs may have physical incompatibility. It is due to the physical properties of the ingredients that make up the drug, and can be caused by insolubility, smoothing of the ingredients, and other processes.

The components of the proposed combined drug may also be chemically incompatible, due to their chemical interaction. This usually leads to a decrease or complete loss of therapeutic activity of the drug.

Medicinal substances can act antagonistically or mutually reinforce each other's side or toxic effects, and thus have pharmacological incompatibility. The pharmacological incompatibility of drugs in many cases precludes the possibility of their simultaneous use. Incompatible combinations of components make the fixed drug combination therapeutic inferior, and in some cases even life-threatening to the patient.

It is also not obvious that if you prescribe drugs with different active substances in different dosage forms in the treatment regimen and prescribe a drug that contains the same active substances combined in one dosage form, the effect will be the same.

Thus, the possibility of creating a specific combination drug can only confirm or refute an experimental study. In our case, this is a combination of tryptophan with thiotriazolin.

Talking about the positive result of the interaction of the above components of the combined drug can only be based on experimental studies. Without studying the results of such studies, the idea of a possible high therapeutic effect of the combined agent is only a theoretical premise.

This application presents the results of original studies of the proposed combination, which confirm the high anxiolytic, stress-protective, nootropic and antioxidant activity of the combined preparation containing thiotriazoline and tryptophan in its composition.

Example 1. Anti-anxiety (anxiolytic) action

The anxiolytic effect of drugs and their combinations was studied on 50 white non-linear rats of both sexes weighing 170-230 g. A blitz test was used to determine the level of anxiety and ascertain the anxioprofile of drugs (hanging the animal by the tail). The combined thiotriazoline with tryptophan (1: 4) was administered at a dose of 250 mg / kg, Noofen tablets at a dose of 250 mg / kg, tryptophan, which was administered at a dose of 250 mg / kg, was also studied as a reference drug in this series of studies. After drug administration (60 minutes before testing), the animal was pulled out of the cage and held by the tail near the body in a hanging position, head down. The time was recorded during which the animal would remain immobilized (that is, until the animal's muzzle reached the base of the tail) [10, 14].

As a result of the studies, it was found that with the introduction of the combined agent of thiotriazolin and tryptophan (1: 4), the animals were 48.7% longer (p <0.05) during the experiment, which can be regarded as a decrease in anxiety and fear (table 2).

Less pronounced changes in the duration of the period of immobility were noted with the introduction of Noofen and tryptophan. So, the introduction of Noofen led to an increase in immobility time by 35.5% compared with the control (p <0.05). Administration of tryptophan led to an increase in immobility time by 30.5% compared with the control 0X0.05).

Thus, the studied drug - a combined agent of thiotriazolin and tryptophan (1: 4) reduces the level of anxiety, fear and despair more significantly than the comparison drugs - anxiolytic and nootropic Noofen and anxiolytic tryptophan.

Example 2. The study of stress-protective, nootropic, anxiolytic and antioxidant effects

The experiments were conducted on 40 male Wistar rats weighing 210-230 g at the age of 6 months. Chronic immobilization stress (CHI) was modeled by brutal two-hour immobilization on the back for 10 days [3, 10, 12]. The combined agent of thiotriazolin and tryptophan (1: 4) (NPO Farmatron, Ukraine), the reference drug of nootropic, stress-protective and anxiolytic action is Noofen (Olainfarm, Latvia), as well as the combined drug containing an equivalent amount of thiotriazoline - Thiocetam , was administered at a dose of 250 mg / kg orally with a metal probe in 0.5 ml of water for 10 days, once a day 30 minutes before immobilization. On the first day of the experiment, 30 minutes before stressing, the animals developed a conditioned passive avoidance reaction (passive avoidance reaction) in a two-shuttle chamber. 10 days later, 2 hours after the last stress, an open field test was performed in rats. Within 3 minutes, the number of vertical and horizontal movements was recorded, as well as the number of peeps into the “mink”, grooming (acts) and the number of bowel movements. At the same time, the safety of passive avoidance reaction was evaluated by the latent period of entry into the dark compartment of the two-shuttle chamber [10, 14]. Then the animals were withdrawn from the experiment under nembutal anesthesia (40 mg / kg). For biochemical studies, the brain was washed in a chilled isotonic KCl solution (+ 5 ° C), then homogenized in a Potter homogenizer (1500 rpm) for 3 min in 5 volumes of buffer containing 50 mM Tris-HCL, 2 mM EDTA and 2 mM dithiothreitol (pH 7.4). Aliquots of these homogenates were centrifuged for 10 min at 11000 g [4].

In the supernatant (5 mg / ml), the products of oxidative modification of the protein (OMB) were determined by the level of aldehyde phenylhydrazone (APH) and ketonphenylhydrazone (CPH) by the reaction of the interaction of oxidized amino acid residues with 2,4-dinitrophenylhydrazine [4]. Stable NO metabolites were also determined by the level of nitrates in the Griss reaction [4] and the activity of NO synthase (NOS). NOS activity was determined by the difference between the NADPH oxidation rate, recorded fluorometrically, in two parallel samples, both not containing and containing a NOS inhibitor, N-nitro-L-arginine [4]. Protein concentration was evaluated according to the Bradford method. The degree of oxidative DNA modification was determined by daily excretion of 8-hydroxyguanine (8-OHG) in urine [4].

The results of the studies showed that ChIS is characterized by a change in motor activity, which is expressed in a decrease in horizontal activity by 82.3%, vertical - by 77%, inhibition of research activity (number of peeks) by 90%, as well as an increase in anxiety, as evidenced by a decrease grooming acts by 43% and an increase in bowel movements by 112.5%. It was also found that the transferred HIS depresses the cognitive-mnestic functions of the central nervous system, as evidenced by a 79% decrease in the latent period of passive avoidance reaction and a 70% decrease in the number of trained animals. The introduction of a combination agent of thiotriazoline with tryptophan (1: 4) into rats with chis is statistically significant in relation to the control group of animals (p <0.05) increased the tentative research activity. So, in this group of animals the number of horizontal movements increased by 2.54 times, vertical - by 2.57 times, which indicated an increase in motor activity. Under the influence of the combined preparation, the number of peeks into the “mink” increased by 5.75 times. The results of the introduction of Noofen were inferior to the study drug in terms of the degree of influence on the studied indicators of orientational research activity in animals with HIS. Also, the introduction of a combined agent of thiotriazoline and tryptophan (1: 4) led to an increase in grooming by 57% and the number of bowel movements by 47%, indicating a decrease in anxiety after stress. Reproduction of passive avoidance reaction, conducted after 10 days of daily stress, showed that in the control animals reproduction of the commemorative trace was impaired, as evidenced by a decrease in passive avoidance reaction by 79%. Almost all rats in this group quickly entered the dark “dangerous” chamber. The administration of a combination of thiotriazoline and tryptophan (1: 4) to animals weakened the passive avoidance reaction amnesia caused by ChIS, statistically significantly increasing the latent time of the reflex during reproduction (Table 3). Thus, the introduction of a combined agent of thiotriazoline and tryptophan (1: 4) increased the latent period of passive avoidance reaction by 2.38 times, and the introduction of Noofen by 1.44 times. It is worth noting that the introduction of a combined agent of thiotriazolin and tryptophan (1: 4) significantly increased the number of trained rats in the group to 90%, and the introduction of Noofen to 60%. The data presented confirm the nootropic and stress-protective activity of the proposed combination agent.

Simulation of ChIS for 10 days led to the development of oxidative stress in the brain of experimental animals, as evidenced by an increase in the level of marker products of oxidative protein modification. Thus, the concentration of APH and CPG in the control group of animals was 120% and 134% respectively higher than those of the intact group. The introduction of the combined agent of thiotriazoline and tryptophan (1: 4) significantly (p <0.05) reduced the concentration of OMB - AFH markers by 46%, and CFG by 36%. In terms of the degree of reduction of oxidative stress markers - AFH and KFG - the studied combination drug significantly exceeded the effectiveness of the reference drug Noofen, and in terms of the degree of decrease in AFH - and Tiocetam. Oxidative modification of proteins leads to a decrease in the function of proteins in the chain of electron carriers, the activity of ATPase, and the selectivity of the action of transport pores. Changes in the Red / Ox potential of the mitochondrial membrane can affect the dysfunction of the neuronal cell respiratory chain cascade. The above changes, ultimately, lead to a violation of the secretory, incretory, transport function of the neuron, and, as a consequence, to the development of cognitive deficit [1, 2, 10].

Hyperproduction of NO and OH ^. in some pathological conditions (ischemia, stress, neurodegenerative diseases, etc.) plays a key role in the molecular mechanisms of oxidative stress and is a trigger in the oxidative destruction of cell DNA [1, 2, 13]. Oxidative modification of DNA leads to the formation of 8-hydroxyguanine (8-OHG), which has a pronounced cyto- and genomotoxic effect, the most important consequences of which are the distortion of molecular biological processes in the cell - replication and transcription. From table 5 it is seen that CI is accompanied by a significant increase in the concentration of 8-OHG (2.42 times) in the daily urine of rats.

The introduction of a combination of thiotriazoline and tryptophan (1: 4) into experimental animals had a protective effect on nucleic acids under oxidative stress, as evidenced by a 48% decrease in daily excretion of 8-OHG (p <0.05). The introduction of Noofen led to a decrease in 8-OHG by 13.2% (p <0.05) in daily urine. The introduction of a combination drug containing thiotriazolin - Thiocetam - reduced 8-OHG by 30% (p <0.05) in daily urine. It is worth noting that in this test the proposed combination agent significantly exceeded the effect of Noofen and Thiocetam, which indicates a more pronounced antioxidant and genomoprotective effect of the combined preparation of thiotriazoline and tryptophan.

An essential role in the overproduction of NO belongs to inducible NO synthase, which is expressed under the influence of transcription factors-JunB; c-fos; AP-1 [1, 2]. These studies found that ChIS led to the activation of NO synthase by 132% and overproduction of NO, as evidenced by an increase of 170% in the brain of rats of its stable metabolites. The use of the combination agent thiotriazolin and tryptophan (1: 4) in experimental animals reduced the activity of NO synthase by 56% and overproduction of NO by 44%. The introduction of Noofen did not have a significant effect on the nitrite content and was significantly inferior in degree of influence on the activity of NO synthase. The introduction of Thiocetam reduced the activity of NO synthase by 40% and overproduction of NO by 38%. The combination of thiotriazolin and tryptophan (1: 4) significantly exceeds Thiocetam in the degree of decrease in the activity of NO synthase (Table 5).

A similar effect of the combined agent of thiotriazoline and tryptophan (1: 4) is one of the key mechanisms of its neuroprotective effect, since the nature of the action of these compounds on the processes associated with the regulation of apoptosis in a neuronal cell depends on the ratio of intracellular concentrations of NO and ROS [1, 2] .

Thus, the studied drug, a combined agent of thiotriazolin and tryptophan (1: 4), has pronounced stress-protective, nootropic, anxiolytic and antioxidant properties, and it significantly exceeds the reference drug Noofen in the strength of these pharmacological effects, and Thiocetam in the strength of the antioxidant effect.

After analyzing the results of the studies, we can conclude that the proposed combination agent of thiotriazoline and tryptophan provides a higher anxiolytic and antioxidant activity compared with the comparison drugs. In addition, the proposed tool showed new types of activity - nootropic and stress-protective actions, which separately the components of the combined means - tryptophan and thiotriazoline - did not have.

Tablets containing tryptophan and thiotriazolin are made coated or uncoated. The tablet core is made in various ways, for example, by obtaining a powdery mixture of these active ingredients with the addition of a sufficient amount of auxiliary substances and subsequent pressing. The composition of the tablets includes various excipients that affect the physicochemical properties, for example, multifunctional excipients, fillers, disintegrants, antifriction substances, etc.

Capsules are made by dosing a mixture of the active components of tryptophan and thiotriazolin and excipients into capsules, which may contain a single or higher therapeutic dose of the proposed agent.

An injection solution containing both the active substances tryptophan and thiotriazoline is prepared with or without a stabilizer. It is possible to use substances that make it possible to achieve isotonicity of the solution. The solution is prepared in various concentrations, which contain a therapeutic dose of the proposed combination drug.

For the preparation of infusion solutions of the combined preparation of tryptophan with thiotriazoline, physiological solutions of various compositions can be used.

Thus, the use of the proposed tool will expand the domestic arsenal of drugs that can be used in neurology, and which are safe and highly effective.

Literature

1. Belenichev I.F., Gubsky Yu.I., Pavlov S.V. Toxic effects of oxidative protein modification in various pathological conditions // Sovr. prob. toxicol. - 2005. - No. 3. - S. 20-26.

2. Belenichev I.F., Cherniy V.I., Pavlov S.V., Kucherenko L.I. Neuroprotection and neuroplasticity. - K .: Logos, 2015 .-- 512 s.

3. Goikova L.A., Zoryan E.V., Anisimova E.N. // Pharmacological methods of stress correction // Vopr. biol. honey. and farm. chemistry. - 2004. - No. 3. - S. 3-5.

4. Preclinical study of the specific activity of potential neuroprotective drugs / I.S. Chekman, I.F. Belenichev, L.A. Gromov et al. - Methodological recommendations of the State Pharmacological Center of the Ministry of Health of Ukraine, Kiev. - 2010 .-- 81 s.

5. Dewsbury R. Studying the behavior of animals. M .: Nauka, 1980 .-- 376 p.

активностi таблеток "Тiоцетам" Мазур I.A.,

I.Ф., Стець В.Р. // Експер.фiзiол.та бioxiм. - 2002. - №1. - С. 7-11.6. Experimentation

the activity of the tablets "Tiocetam" Mazur IA,

I.F., Stets V.R. // Expert.physiol.ta bioxim. - 2002. - No. 1. - S. 7-11.

7. Turpaev K.T. Active forms of oxygen and regulation of gene expression // Biochemistry. - 2002. - T. 67, No. 3. - S. 339-352.

та

. - 2006. - №4. - С. 28-36.8. Mazur I.A., Belenichev I.F. To the question of the creation of neuroprotective drugs // News

that

. - 2006. - No. 4. - S. 28-36.

9. Mazur I.A., Zimenkovsky B.S., Voloshin N.A., Chekman I.S., Stets V.R. Thiotriazolinum. - Lviv: Nautilus, 2005 .-- 230 p.

10. Kaluev A.V. Stress, anxiety and behavior. Actual problems of modeling anxiety behavior in animals. - Kiev, 1998 .-- 95 s.

11. Koplik E.V., Meshcheryakov A.F., Pertsov S.S. et al. Effect of Vilon dipeptide on the resistance of rats to emotional stress // Ros. fiziol. journal - 2002. - T. 88, No. 11. - S. 1440-1452.

12. Stefanov A.V. Preclinical studies of drugs. - Kiev: State Pharmacological Center of the Ministry of Health of Ukraine, 2000 .-- 540 p.

13. Aruoma O., Halliwell B. Molecular Biology of Free Radicals in Human Diseases - St. Lucia, London: OCIA Int., 1999 .-- 345 p.

14. Bures J. Cortical spreading depression as a memory disturbing factor / J. Bures, O. Buresude // J. comp. and phisiol. - 1963. - Vol. 56, No. 2. - P. 268-272.

15. Mikava S., Kinouchi H., Kami H. et al. Attenuation of acute and chronic damage fllowing traumatic brain injuri in copper, zinc-superoxide dismutsse transgenic mice // J. Neurosurg. - 1996. - V. 85. - P. 885-891.

Claims (3)

1. The combined drug anxiolytic, stress-protective, nootropic and antioxidant effects, containing tryptophan, characterized in that it additionally contains thiotriazoline. 2. The combined drug anxiolytic, stress-protective, nootropic and antioxidant effects according to claim 1, characterized in that it contains tryptophan and thiotriazoline in the following ratio: tryptophan in the range from 1 to 7 mass fractions per 1 mass fraction of thiotriazoline. 3. The combined drug anxiolytic, stress-protective, nootropic and antioxidant effects according to paragraphs. 1 and 2, characterized in that it takes the form of tablets, capsules, injection and infusion solutions.