RU2020937C1 - Nootropic antialcoholic drug - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: essence of this invention resides in using already known L-pyroglutamic acid amide as claimed nootropic drug. Though this medicine is already known in the art, its nootropic properties have not been described in literature and it has not been previously used for treating any diseases. L-pyroglutamic acid amide produces no toxic effects when administered in doses up to 12,000 mg/kg. To put it otherwise, this drug is less toxic than pyracetame (8,000 mg/kg). In passive avoidance conventional reaction test, this drug advantages learning ability by 50 % as compared with control figures, whereas pyracetame taken in substantially greater doses encourages leaning ability solely by 20 %. Therapeutic value and range of claimed medicine (2,000) is considerably greater than those of pyracetame (60). Novel drug exhibits nootropic activity when administered perorally and produces protective effect in experiment against amnesia provoked by either electric convulsive shock or administration of L-proline cetyl ether. Dosage in this case is also lower than that of pyracetame. L-pyroglutamic acid amide administered in experiment produces protective effect in case of alcoholic intoxication in dosage smaller than that of pyracetame. EFFECT: highly effective small doses of claimed drug improve learning ability and memory and capable of protecting central nervous system from amnesic effects and alcoholic intoxication; low toxicity is another advantage of this drug which is of certain interest in sphere of psychoneurology and reanimatology. 5 tbl

Description

 The invention relates to medicine, namely to nootropic drugs that stimulate learning and memory processes, increase brain resistance to damage and amnesic effects. The basic object is piracetam - a drug that stimulates the highest integrative activity of the brain, facilitates learning disrupted by damaging effects, and weakens the toxic effect of ethanol. Piracetam is used to restore intellectual-mnestic functions in patients who have suffered strokes, brain injuries, in children with mental retardation, to remove patients from alcoholic coma, etc. However, the doses at which piracetam causes a nootropic effect are high. In addition, the therapeutic effect of piracetam is not always reproduced.

 The purpose of the invention is to obtain an effective tool that improves learning and memory, protects the brain from amnesic effects, as well as from alcohol intoxication, acting in small doses and non-toxic.

Соединение I синтезировано было ранее. Ноотропные свойства соединения I не описаны. В качестве препарата для лечения каких-либо заболеваний соединение I не использовалось.This goal is achieved by the use of a nootropic agent amide L-pyroglutamic acid (compound I)

Compound I was synthesized previously. The nootropic properties of compound I are not described. Compound I was not used as a drug for the treatment of any diseases.

 The proposed compound I, in comparison with piracetam, exhibits a more pronounced nootropic effect at a greater therapeutic latitude, its effectiveness as a nootropic agent is shown by the stimulating effect on the learning and memory of rats in the test of conditioned passive avoidance reflex (passive avoidance reaction) both in conditions of incomplete training and to prevent amnesia caused by chemical and physical agents. Like piracetam, the claimed compound I protects the body from alcohol intoxication. The severity of the latter effect of compound I also exceeds that of piracetam.

PRI me R 1. The acute toxicity of the claimed compounds was determined in experiments on white male mice weighing 18-24 g. Due to the fact that the literature on the toxicity of piracetam is ambiguous (it is indicated that LD _{50 is} 8000 mg / kg; there are evidence that it exceeds 12,000 mg / kg, in the experiments conducted, along with the determination of the acute toxicity of the claimed compound I, the acute toxicity of piracetam was also determined.

 Both compounds were administered at doses of 6000 mg / kg, 9000 mg / kg and 12000 mg / kg as a 30% solution. Each dose was administered to a group of 6 mice, injection was carried out intraperitoneally in a volume of 0.2 ml / 10 g, 0.3 ml / 10 g and 0.4 ml / 10 g of animal weight. The number of deaths was evaluated after 24 hours. It was shown that the claimed compound I in the entire studied value of the doses does not cause deaths, piracetam at a dose of 6000 mg / kg and 8000 mg / kg also showed no toxic effects, with the introduction of piracetam at a dose of 12000 mg / kg after 24 hours the death of 50% of the animals.

 The comparison results of piracetam and compound I are presented in table 1.

 PRI me R 2. To determine the nootropic effect of compound I in conditions of incomplete training in a rat, compound I was administered intraperitoneally at a dose of 6.5 mg / kg in the form of a 0.33% solution in isotonic sodium chloride solution or piracetam at a dose of 200 mg / kg in the form of a 2% solution in an isotonic sodium chloride solution; after 15 minutes, the animal was placed in the illuminated compartment of the two-section chamber. During the 180 s observation of the rat, the latent period of the first entry into the darkened compartment and the total residence time were recorded. After 180 s, at the time the rat was in the darkened compartment, it was subjected to irreparable electric pain irritation (5 strokes of 50 V each with an interval of 2 s) through the floor, after which the animal was removed from the chamber. The trained animal was tested after 24 hours for 180 s, while the same indicators were recorded as on the first day, as well as the number of animals that did not enter the dark compartment. The experiment was carried out on 3 groups of rats with 10 animals each. The same number of animals was injected with isotonic sodium chloride solution (control). Under these conditions, an average of 50% animal learning was achieved in the control.

· 100 % ,
где А_т - ноотропная активность соединения по времени нахождения в светлом отсеке;
Т_оп - среднее время нахождения животных в светлом отсеке в опыте, с;
Т_конт - то же, для контрольных животных;
180 - время тестирования, с.The improvement in memorization under the influence of drugs was determined by the following formulas, which are a modification of the known formula
A _t =

· 100 % ,
where And _t is the nootropic activity of the compound by the time spent in the bright compartment;
T _op - the average time spent by animals in the bright compartment in the experiment, s;
T _cont - the same for control animals;
180 - testing time, p.

· 100 % ,
где А_л - ноотропная активность соединения по латентному периоду захода в темный отсек;
Л_оп - средний латентный период захода животных в темный отсек в опыте, с;
Л_конт - то же, для контрольных животных
A_N =

· 100 % ,
где А_N - ноотропная активность по числу животных, не зашедших в темный отсек;
N_оп - число животных, не зашедших в темный отсек в опыте, нормированное по общему числу опытных животных;
N_конт - то же, для контрольных животных.A _l =

· 100 % ,
where A _l is the nootropic activity of the compound according to the latent period of entry into the dark compartment;
L _op - the average latent period of entry of animals into the dark compartment in the experiment, s;
L _cont - the same for control animals
A _N =

· 100 % ,
where A _N is the nootropic activity according to the number of animals that have not entered the dark compartment;
N _op - the number of animals that did not go into the dark compartment in the experiment, normalized to the total number of experimental animals;
N _cont - the same for control animals.

 From the data presented in Table 2, it follows that the administration of compound I at a dose of 6.5 mg / kg leads to an increase in learning ability in the passive avoidance reaction test compared to the control by 50% of the maximum possible effect. The activity of piracetam in the parameter T is only 20%, and this effect is detected in doses of 200 mg / kg. The choice of a parameter only slightly affects the magnitude of the nootropic activity, which emphasizes the objective nature of this quantity. From a comparison of the toxicity data of the claimed compound I and piracetam (see example 1) with the level of effective doses for the nootropic effect, it follows that the therapeutic breadth of compound I (2000) is significantly higher than that of piracetam (60).

 PRI me R 3. The possibility of oral administration of compound I was shown on the example of the passive avoidance reaction with incomplete training of rats in the control. Compound I in the form of a 1.5% solution was administered to rats orally in a volume of 0.2 ml / 100 g weight 30 minutes before training at a dose of 30 mg / kg. Control animals received a 0.9% sodium chloride solution also 30 minutes before training. The production of passive avoidance reaction and testing was carried out as in example 2. In the experiment, 1 group of 10 animals was used. The results obtained indicate the preservation of the nootropic activity of compound I when administered orally (see table 2).

 PRI me R 4. To determine the protective effect of compound I in relation to retrograde amnesia caused by cetyl ether of L-proline (CEP), rats of the 1st and 2nd experimental groups were introduced at a dose of 30 mg to the rats of the 1st and 2nd experimental groups 45 minutes before training / kg in the form of a 0.3% suspension in 0.05% Tween-80 in an isotonic sodium chloride solution, and control rats (3rd group) —isotonic sodium chloride solution containing 0.05% Tween-80 . 15 minutes before training, rats of the 1st experimental group were injected with 6.5 mg / kg of compound I in the form of a 0.065% solution in isotonic sodium chloride solution, and rats of the 2nd experimental and control groups were injected with isotonic sodium chloride solution. Training and testing was carried out according to the method described in example 2, except that the rats were inflicted not 5, but 6 current shocks. The results obtained (see table 3) show that compound I at a dose of 6.5 mg / kg under the described experimental conditions almost completely (96%) prevents retrograde amnesia caused by proline cetyl ether. Piracetam under the same conditions reduces amnesia by 88%, exhibiting this effect at a dose of 200 mg / kg.

 PRI me R 5. To determine the protective effect of compound I under conditions of retrograde amnesia caused by electroconvulsive shock (ESH) to rats of the 1st experimental group 15 minutes before the production of passive avoidance reaction was administered compound I at a dose of 6.5 mg / kg in the form 0.065% solution in isotonic sodium chloride solution. Rats of the 2nd experimental group 15 minutes before training were injected with 200 mg / kg of piracetam in the form of a 2% solution in isotonic sodium chloride solution. Rats of the 3rd (control) group were also given an isotonic sodium chloride solution 15 minutes before training. Training and testing was carried out according to the method described in example 4. ECS (120 V, 50 ms) were applied transcornally after training no later than 40 s after the last electric shock was applied across the floor.

 The results obtained (see table 4) show that under the experimental conditions, compound I is three times more effective than piracetam, protects the animal from amnesia caused by ESH, exhibiting this action in a dose 30 times lower than piracetam.

 PRI me R 6. To study the effect of the claimed compound I and piracetam on the toxic effect of ethanol, white male mice weighing 18-24 g were used. Ethanol was introduced as a 32% solution at the rate of 0.3 ml / 10 g of mass animal, which corresponds to a dose of ethanol 9600 mg / kg Experimental animals 15 minutes before the introduction of ethanol and 3 hours after it was administered Compound I at doses of 30 mg / kg, or 60 mg / kg, or piracetam at doses of 1000 or 2000 mg / kg. At the same time, control animals were injected with 0.9% sodium chloride solution (0.1 ml / 10 g of animal weight). Survival in each group was determined after 24 hours.

 As follows from the data given in table 5, the claimed compound I reduces the frequency of deaths caused by ethanol at a dose of 30 mg / kg by 25%, and at a dose of 60 mg / kg by 80% compared with the control. Piracetam at a dose of 1000 mg / kg reduced mortality by 25%, and at a dose of 2000 mg / kg - by 15%. A comparison of the toxicity data of the claimed compound I and piracetam (see Example 1) with the data on the protective effect of alcohol poisoning indicates that the therapeutic breadth of compound I is greater than that of piracetam (compound I is higher than 200, and for piracetam - 6).

 Thus, an experimental study of the claimed compound I showed that it has the ability to improve learning and memory of initially untrained animals, to prevent amnesia caused by 1-proline cetyl ether and electric shock, and also to protect the body from the toxic effects of alcohol. According to the severity of all these effects, the claimed compound I exceeds the standard nootropic-piracetam. Compared to piracetam, compound I has a greater therapeutic breadth.

 Compound I is of interest for neuropsychiatric and resuscitation practice and can be used both in parenteral and oral form.

Claims (1)

 The use of amide L - pyroglutamic acid as a nootropic and anti-alcoholic agent.

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