RU2130314C1 - Remedy possessing nootropic and adaptation properties and method for producing the remedy - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: remedy is extracted from not defibrinated dried Siberian stag, Manchurian deer or sika deer blood. To produce the not defibrinated Siberian stag, Manchurian deer or sika deer blood, it is to be taken during the time interval from June to October and dried at 40-45 C during 1.5-2 h until it is transformed into paste-like state. The additional drying process lasts during 4- 5 h to reach 4-5% humidity. EFFECT: prolonged action time.

Description

 The invention relates to medicine and specifically to preventive pharmacology, and relates to agents that improve mental and physical performance of both healthy and sick people.

 Known nootropic drugs of various chemical structures and mechanisms of action: 1. Derivatives of pyrrolidone. 2. Derivatives of pyridoxine. 3. Derivatives of GABA. 4. Cerebrovascular agents. 5. Derivatives of dimethylaminoethanol. 6. Neutrapeptides and their analogues. 7. Antioxidants. 8. Different substances with a component of nootropic action [1].

 Known adaptogenic agents of synthetic, plant and animal origin [2].

 The closest activity agent, namely, having double activity - nootropic and adaptogenic, is Rhodiola rosea [3, 4].

 A known method of producing an extract of Rhodiola rosea by grinding the raw material and extracting it with 40% ethyl alcohol at a ratio of raw material / extractant 1: 1 [5].

 However, at present, the issue of expanding the arsenal of adaptogenic and, especially, neotropic drugs is extremely urgent, forming a social order for the development and reproduction of drugs used in psychiatry, narcology, preventive medicine, stimulating the processes of memory, learning, increasing physical and mental performance.

 The problem solved by this invention is to expand the arsenal of funds with nootropic and adaptogenic activity of prolonged action.

The problem is solved by developing a tool that has both adaptogenic and nootropic effects from dried non-defibrated blood of deer, red deer or sika deer and a method for its preparation by drying non-defibrated blood of deer, red deer or sika deer taken from June to November. Drying is carried out at a temperature of 45 - 50 ^o C for 1.5 to 2 hours to a pasty state, followed by drying for 4 to 5 hours to a moisture content of 4 to 5%.

 A more complete chemical composition is achieved in that the blood is not defibrated. As a result of drying, the blood does not lose its biological properties and does not deteriorate for a long period of time.

New in the present invention is that as a nootropic and adaptogenic agent, dried non-defibrified blood of deer, red deer or sika deer is used, which is dried at a temperature of 45-50 ^° C for 1.5-2 hours to a paste-like mass, followed by drying in flow for 4 to 5 hours to a moisture content of 4 to 5%. Thus, the proposed solution meets the criteria of the invention of "Novelty."

Comparison of the proposed solution with the known shows that for the first time the use of dried non-defibrinated blood of maral, red deer or sika deer as a nootropic and adaptogenic agent is proposed simultaneously. It is known to use defibrinated blood of maral, red deer or sika deer mixed with ethyl alcohol, sugar syrup, fruit essence and ascorbic acid as a psychostimulating agent [6]. However, the authors for the first time experimentally showed a new property of red deer blood, red deer or sika deer, namely the nootropic and adaptogenic effect. The authors did not find in the literature they analyzed the following set of essential features: the use of red blood, raisins or sika deer taken as a nootropic and adaptogenic agent from June to November, drying it at a temperature of 45 - 50 ^o C for 1.5 - 2 hours, followed by drying for 4 - 5 hours to a moisture content of 4 - 5%. Thus, the claimed solution meets the criteria of the invention "Inventive step", as it clearly does not follow for a specialist from the prior art. The proposed solution meets the criteria of the invention "industrially applicable", as it can be successfully used in practical health care.

Nootropic and adaptogenic agent "Pantohematogen dry" is prepared as follows. Blood from a deer, red deer or sika deer is taken from June to November. The collected non-defibrinated blood immediately after collection is loaded into the dryer. Blood dehydration occurs at a temperature of the dryer body not higher than 45 - 50 ^o C for 1.5 - 2 hours to a pasty state. Pasty blood is distributed evenly over the inner surface of the drying apparatus and is dried to a moisture content of 4-5% during 4-5 hours. Dried blood is separated from the walls of the drying apparatus and ground to a powdery state. The dry final product, which is a brown-red powder with a specific smell of sour taste, is placed in a sealed container and stored at a temperature not exceeding 18 ^o C without air. The drug can be used in powders and tablets.

 Experimental data confirming the identified nootropic and adaptogenic properties of dried non-defibrinated blood are presented in example 1.

Example 1. The studied preparation "Pantohematogen dry" obtained by drying the blood of maral (cervus elaphus sibiricus), red deer (cervus elaphus xanthophigus) or sika deer (nippon hortulorum, pseudaxis hortulorum) taken at different periods during the year: in April - Pantohematogen-1 ", in June, during the antler cut-off period -" Pantohematogen-2 ", in July - Pantohematogen-3", in September - "Pantohematogen-4", in November - "Pantohematogen-5" and in January - "Pantohematogen-5" -6 "
The official hematogen, in tiles at a dose of 15.0 g / kg, was taken as reference preparations; Rhodiola rosea extract - prototype - at a dose of 2.0 ml / kg; piracetam - the basic drug for nootropic activity - at a dose of 400 mg / kg. Pantohematogen dry was studied at a dose of 200 mg / kg. These doses of drugs were determined as optimal in terms of biological activity based on preliminary studies (for panthematogen on the example of "Pantohematogen-2"). The large difference in doses between the official hematogen and pantohematogen is explained, in addition to the higher biological activity of the latter, by the fact that the composition of the official hematogen includes a large number of fillers (up to 40% of the total mass), such as condensed milk, sugar, starch.

 The effect of drugs on the development of a stress response [7], adaptation to physical activity by a swimming test [8], reproduction of a conditional passive avoidance reaction under amnesia caused by a violation of cholinergic regulation as a result of scopolamine administration [9], hypoxic trauma [10], and the development of posthypoxic encephalopathy [10], the development and reproduction of a conditioned drinking reflex in a T-shaped labyrinth in an intensive mode of training loads [11] and with alcohol intoxication [12].

 The experiments were performed on 798 male CBA mice weighing 18–22 g and 100 Wistar rats weighing 200–250 g. All animals were divided into groups according to the data presented in Tables 1–8. In experiments to study the effect of drugs on physical performance and the stress response in the groups was an equal number of animals in 12 mice. The purpose of these experiments was not only to compare pantohematogen with reference nootropic, adaptogenic drugs and official hematogen, but also to find out the optimal timing of blood sampling during the year. For this, 6 pantohematogen samples with different timing of production were studied. In experiments with learning and memory under conditions of scopolamine amnesia, the initial number of groups was 20 individuals each, and the different numbers of groups in the data presented are explained by the exclusion of some animals from the experiment due to accidental death or for methodological reasons specified in the description of the methods. The conditioned drinking reflex was studied in rats of 10 animals per group. The preparations were introduced into the stomach with a probe during the 5 days preceding the study once a day in the form of a suspension or solution in distilled water, control animals received water in an equivalent amount.

 Immobilization stress was created by hanging mice by the neck fold. One hour after the last administration of the preparations, the mice were suspended by the neck fold for 22 hours. After the time, the animals were removed and 15 minutes after removal, they studied the orientation and research behavior in the open field, recorded the emotional response according to the Brody method, and the number of leukocytes in the peripheral area was calculated blood, after which the animals were sacrificed and the weight of the adrenal glands, spleen, thymus was determined and the weight coefficients of organs per 20 g of body weight were calculated. Then, according to the method of Dobryakov [7], the severity of stress in points was calculated. When assessing behavioral indicators, a scale was used similar to that adopted in the Dobryakov method. With an increase in motor activity in a shortened version of stress, for every 20% deviation from the corresponding indicator of intact control, 1 point is awarded. If the indicator increased by more than 200%, then 6 points were awarded. With a prolonged variant of stress, when a decrease in behavioral activity was noted, for each 16.7% decrease in activity, 1 point was assigned [10].

 Approximate research behavior was studied in an open field technique. The experimental setup "open field" was a camera measuring 40x40x20 cm with a square floor and white walls [13]. Its floor, divided into 16 squares, had a circular hole in diameter of 3 cm in each. The camera was illuminated from above by an electric incandescent lamp with a power of 100 watts, located at a height of 1 m from the floor. The mouse was placed in one of its corners and within 2 minutes the number of movements from square to square (horizontal activity), the number of hole examinations (mink reflex), the number of hind legs rising (vertical activity), the number of washing (grooming) and the number of bowel movements by the number of fecal balls, the coefficient of asymmetry of behavior was calculated, in the form of the ratio of the number of horizontal movements to the total motor activity, expressed as a percentage.

 The emotional reaction was studied by the method of Brady and Nauta [14], in which the reaction to 4 types of effects was evaluated in a semi-quantitative way: capture in the cage where the animal constantly lives, capture in the hand after placing the animal on a flat surface, reaction to the approach of tweezers, reaction to the push tweezers, while defecation with urination, squeak and muscle tension were additionally recorded (a total of 7 reactions). Each reaction was evaluated using a 4-point system, after which all scores were summed up, giving a general assessment of the emotional reaction.

The effect on physical performance was investigated under the conditions of the forced swimming technique [8]. Swimming was carried out with a weighting load, equal in weight to 10% of the body weight of a particular mouse. The animal swam until exhausted (until it began to sink). After the first swimming, they were allowed to rest for 1 hour, after which the swimming was repeated. Thus, the mice swam for 5 days at a temperature of 20 ^o , on the 6th day a “collision” of adaptation was made, which was achieved by increasing the water temperature to 40 ^o C. The performance was judged by the duration of swimming in seconds. The increase in the duration of swimming every day characterized the process of fitness. A decrease in the indicator on the 6th day after an increase in water temperature indicates a violation of the adaptation process due to changed conditions. Drugs were administered throughout the study. The effect of drugs was judged by differences with control groups.

 Violation of the process of memorizing and reproducing the skill during interventions in the cholinergic mechanisms of higher nervous activity caused by the introduction of scopolamine is one of the most common methodological techniques in the study of memory mechanisms [9]. For this, 30 minutes before the development of the reflex, all mice, except for the intact control, were injected with scopolamine at a dose of 2.5 mg / kg. The technique of the conditioned reflex of passive avoidance is based on the suppression of the innate reflex of preference for the dark space available in rodents. The experimental setup was a camera consisting of two compartments - large light and small dark. The animal was placed in the light compartment and after some time, due to the innate reflex, turned into the dark one, after which the hole connecting the two compartments was blocked by a door and the floor of the dark compartment, which was a lattice of parallel alternating electrodes, was supplied with electric current pulses of 50 Msec duration. with a frequency of 5 Hz and an amplitude of 50 MA, after 10 seconds the door was opened and the animal could jump out into the bright compartment with the usual floor. As a result of the described procedure, a conditioned reflex of avoiding dark space was developed in the animal. Reflex production was checked after 24 hours. For this, the animal was placed in the bright compartment, in the corner of the chamber opposite from the entrance, and was observed for 3 minutes. The time of the first entry into the dark compartment (latent entry time - LT), the total time spent in the dark compartment, and the number of animals with a developed reflex were recorded. A reflex was considered developed if, during all three minutes of observation, the animal did not make the transition from the bright compartment to the dark or latent time of approach exceeding 150 s. Animals that, after being placed in the bright compartment, remained motionless and did not approach the entrance to the dark part of the chamber, were not taken into account when calculating the results.

 The effect of hypoxic injury on the production and preservation of the conditioned reflex was carried out on a hermetic hypoxia model. For research, two versions of the technique were used.

 In the first case, the goal of the work was to study the effect of hypoxic injury on the consolidation of conditioned reflex skill (conditioned reflex of passive avoidance - passive avoidance reaction) in case of its violation caused by hypoxic injury. In this case, a short version of hypoxic exposure was used using a pressure chamber with a volume of 250 ml, the passive avoidance reaction was produced immediately before being placed in the pressure chamber, and the reflex was checked 24 hours after production.

 In the second case, the course of posthypoxic encephalopathy was studied in distant periods after a hypoxic injury. In this embodiment, a 500 ml pressure chamber was used; 1 hour after extraction from the pressure chamber, a passive avoidance reflex was developed in all animals of this series. The reflex was tested 24 hours, 1, 2, and 3 weeks after the development of the reflex. An additional criterion for the condition of animals in the conditions of this technique was the delayed death of mice.

 In these experiments, drugs were administered in three different modes of administration: a) 5 times before hypoxia, b) 5 times immediately after hypoxia, and c) 5 times 2 weeks after hypoxia. At the same time, 3 groups of mice received the appropriate drug in the time periods indicated above, 3 groups served as controls according to the regimen of drug administration, and one group was an intact control. The mechanism of reflex production and the criteria for its presence were the same as in the previous experiment.

 The study of the processes of generation and reproduction of a complex conditioned reflex was carried out on the model of a drinking reflex in a T-shaped labyrinth. The experiments were performed on rats against the background of water deprivation. According to existing concepts, the behavior of animals under the conditions of this technique mainly reflects the functional state of integrative mechanisms controlled by the emotional system of goal achievement or behavioral activation and which is phylogenetically the youngest and most complex behavioral system of a motivational nature [15].

 The labyrinth was an installation consisting of one starting chamber and two systems of corridors, each of which included 3 T-shaped knees, spirally connected to each other and ending with target cameras [11]. The training procedure was as follows. Rats were previously left without water for two days. Then, for 2 days, each rat separately twice a day for 20 minutes with an interval of 1 hour was placed in a maze, where 6 drinkers were randomly placed (the first stage of training). On the third day, the animal was placed in the starting chamber of the labyrinth, while all the drinkers from the latter were removed. The rat began to search for a drinker, left the launch chamber and made the first turn to the right or left side of the maze. The direction of the first rotation was fixed and was considered the preferred direction of rotation for this animal. Immediately after this, a drinker was placed in the target chamber, located in half opposite to the one into which the rat turned for the first time. For all subsequent runs, the drinker was placed for this rat in this target chamber. This was done in order to exclude the influence of the preferred direction of rotation upon the formation of the conditioned reflex. Each animal was tested in the maze in this way for 15 minutes, if it did not find a drinker earlier. If the animal did not find a drinker within 15 minutes, it was placed in the target chamber so that the rat could get drunk. Rats that refused to search for a drinker during the first 4 runs were excluded from further experiments. On the same day, the animal after 1 hour made the second run. Thus, each rat was trained for 3 days (2nd stage of training - a total of 6 runs). At the same time, the time to reach the drinking bowl, the number of errors (entries into the wrong labyrinth sleeves and dead ends), the number of vertical stands and grooming were recorded. The quality of training was judged by reducing the time to reach the drinker and the number of errors. Grooming and vertical struts characterized biased and tentative research activity, respectively. The effect of drugs was judged by the difference in the indicators of the 6th run. Refusal to perform a reflex after 2 successful finding of a drinking bowl was considered a manifestation of a neurotic reaction [15] and was assessed as an independent indicator of the number of neurotic reactions during training, counting after the 2nd run. The introduction of drugs began with the deprivation of animal water (a total of 7 injections).

 The results of the studies are presented in tables 1 - 8. The experiments showed that the proposed preparation - pantohematogen dry has a pronounced nootropic and adaptogenic activity, reducing the severity of the stress response and increasing the performance of animals, especially pronounced in the first days of training and with a sharp change in swimming conditions (increase temperature). At the same time, it slightly exceeds the activity of piracetam and somewhat more rhodiola extract, especially on the 4th day of swimming. Pantohematogen-1 and Pantohematogen-6, quite obviously, are significantly inferior to the remaining 4 samples in biological activity in both tests.

 Pantohematogen dry more effectively than piracetam restored mnemonic functions when they were impaired as a result of scopolamine administration, and the radiola extract was inactive in this technique, as well as the official hematogen.

 All 4 drugs (pantogematogen dry, officinal hematogen, rhodiola extract, piracetam) did not affect the life expectancy in the hermetic space, however, they provided a high preservation of the conditioned reflex developed before hypoxic exposure with respect to hypoxic control. Pantohematogen dry in this method showed a higher activity compared to the official hematogen, was equal in activity to the rhodiola extract and was somewhat inferior to piracetam.

 When studying the effect of drugs on the course of posthypoxic encephalopathy, pantohematogen dry in activity significantly exceeded the official hematogen and rhodiola extract to a slightly lesser extent and was close to piracetam, however, when administered remotely after a hypoxic injury, it significantly exceeded all three other drugs.

 When developing a complex drinking reflex in the T-shaped labyrinth in normal animals and against the background of alcohol intoxication, pantogematogen dry significantly improved the speed of the reflex and reduced the number of errors. Moreover, in its activity, it was close to piracetam. Rhodiola extract was slightly inferior to the first two drugs. The official hematogen was significantly inferior in activity to all three other drugs.

Conclusion
The studied drug - pantohematogen dry has a pronounced adaptogenic and nootropic activity.

 According to these types of activity, it shows obvious advantages in qualitative and quantitative terms over the official hematogen and is not inferior to the standard nootropic drug - piracetam, the prototype - Rhodiola rosea extract, and the dry pantomatogen in some respects exceeds these drugs.

 Pantogematogen dry, obtained from blood taken between June and November, is most active.

 The inventive time, temperature and technological conditions are selected by the authors experimentally and provides maximum biological activity and storage duration of a nootropic adaptogenic agent with an optimal amount of labor in its production.

Cited literature
1. Voronina T.A. Experimental psychopharmacology of nootropics // Pharmacology of nootropics (experimental and clinical study). - M., 1989, - S. 8 - 20.

 2. Yaremenko KV Adaptogens as a means of preventive medicine. - Tomsk: Publishing house Tom. University, 1990 .-- 96 S.

 3. Saratikov A.S., Krasnov E.A. Rhodiola rosea - a valuable medicinal plant: Golden root. - Tomsk: Publishing house Tom. University, 1987 .-- 254 S.

 4. Kovalev G.V. Nootropic drugs. - Volgograd: Lower. - Volzh. publishing house - 1990. - 368 S.

 5. 42-2163-84. Pharmacopoeia article. Rhodiola liquid extract.

 6. "Psychostimulating agent" Pantohematogen "/ Goldberg ED, Dygay A. M., Suslov N.I. and others // Patent of the Russian Federation N 208008 according to the application N 5064997 of September 29, 1992

 7. Dobryakov Yu. I. Screening method for assessing the antistress action of drugs // Stress and adaptation: Thes. All-Union Symposium. - Chisinau, 1978.- S. 172.

 8. Bobkov Yu.G., Vinogradov V.M., Katkov V.F. Pharmacological correction of fatigue. - M .: - Medicine, 1984, - 207 S.

 9. Shabanov P. D., Borodkin Yu.S. Memory impairment and their correction. - L .: Science. - 1989. - 127 S.

 10. Suslov N.I. Pathogenetic substantiation of the psychopharmacological effects of drugs of natural origin. - Dis ... doctor. medical science. - Tomsk. - 1995 - 407 C.

 11. Azarashvili A. A. Study of memory mechanisms using physiologically active compounds. - M.: Science, - 1981. - 183 S.

 12. Popova E.N., Polyansky VB, Nikolskaya K.A. et al. Brain and alcohol. / M.: Science. - 1984.- 224 S.

 13. Walsh R.N., Cummins R.A. The open-field test: a critical review // Psychol. Bull. - 1976, V. 83. - P. 482 - 504.

 14. Brady J.V. Nauta W.J.H. Subcortical mechanisms in emotional behavioral affective changes following septal forebrain lessions in the albino rat. // J. comparative and phisiol psichol. - 1953. - V. 46. - N 3. - P. 339 - 341.

 15. Krushinsky L.V. Biological basis of rational activity. - M .: Publishing house of Moscow University, 1986. - 276 S.

Claims (2)

 1. The tool from natural raw materials with nootropic and adaptogenic action, characterized in that it contains dried non-defibrated blood of deer, red deer or sika deer taken from these animals in the period from June to November. 2. A method of obtaining funds having a nootropic and adaptogenic effect by processing raw materials of natural origin, characterized in that the raw materials of natural origin use non-defibrated blood of deer, red deer or sika deer taken from June to November, dried to a paste-like mass at a temperature of 45 - 50 ^o C for 1.5 - 2 hours, followed by drying for 4 - 5 hours to a moisture content of 4 - 5%.

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