UA55983A - Cerebroprotective and nootropic drug nootril in the form of coated tablets - Google Patents

Abstract

The cerebroprotective and nootropic drug Nootril in the form of the coated tablets contains the active ingredients Pyracetam and Thiotriasolin and the excipients for preparation of the core and its coating.

Description

The invention relates to medicine, in particular to pharmacotherapy, namely to nootropic, cerebroprotective drugs.

A known nootropic medicine in tablets "Piracetam", registration number Me95/174/6/82/624/24 dated 09/29/95. (drugs of Ukraine 1999 - 2000, volume 2, pages 303 - 306). Piracetam affects metabolic processes, blood supply and bioenergetic processes of the brain.

The disadvantages of this medicinal product are: it does not have an antioxidant effect, a pharmacological effect, it is detected only after an hour, as well as a side effect - exacerbation of coronary insufficiency and the occurrence of dyspeptic phenomena.

The well-known medicinal product "Tiotriazolin" in tablets, registration number Me94/85/4 (medicinal preparations

of Ukraine - Kyiv, 1995, Pharmaceutical Journal Me4 - p. 43). "Tiotriazoline" tablets contain thiotriazoline as an active ingredient.

Thiotriazoline has antioxidant, hepatoprotective, cardiotonic, anabolic, anti-ischemic, membrane-stabilizing, immunomodulatory, chola-stimulating, wound-healing, antiviral and other effects.

Piracetam tablets are taken as a prototype.

The invention is based on the task of developing a medicinal product that has cerebroprotective, nootropic, and antioxidant effects.

The solution to the given problem ensures the creation of the combined medicinal product "Nootril" in the form of tablets containing piracetam and thiotriazoline.

The composition of "Nootril" coated tablets, wt. gram same 59:

Thiotriazoline 0.05

Piracetam 02

Auxiliary ingredients: (microcrystalline cellulose, low molecular weight polyvinylpyrrolidone, methylcellulose or oxymethylcellulose, stearic acid or magnesium stearate, polyethylene oxide 4000) 0.106

The pharmacological advantages of the medicinal product according to the invention are due to the mutually potentiating action of thiotriazoline, which has antioxidant and cerebroprotective effects, and piracetam, which has a nootropic effect, which, along with the metabolic mechanism of blood supply regulation, promotes the emergence of the nervous mechanism of its regulation, increases the speed and strength of the drug's effect on improving the blood supply of the main brain

At the same time, the drug according to the invention not only preserves, but also expands the spectrum of the pharmacological effect of thiotriazoline and excludes the exacerbation of coronary insufficiency and dyspeptic phenomena, which are possible when using piracetam.

The essence of the proposed invention is explained by the following results of pharmacological tests.

The study of the nootropic and cerebroprotective effects of the medicine "Nootril" in tablets was conducted on 285 white Wistar rats weighing 180 - 200 g, obtained from the kennel of the Institute of Pharmacology and Toxicology of the Academy of Medical Sciences of Ukraine.

Assessment of nootropic effect.

To assess the nootropic effect, we used the conditioned passive avoidance response (CRES) method, followed by the use of electroshock and scopolamine as an amnesic factor.

For this purpose, the animal was placed in the light compartment of the two-chamber installation and the latency time of entry into the dark compartment of the chamber was recorded, where the rat received an electric shock through the electrode floor (training).

Experienced groups of animals 60 minutes before training received the studied drugs - thiotriazoline in a dose of 50 mg/kg, piracetam - 200 mg/kg, nootril - 250 mg/kg in terms of the content of active ingredients.

Immediately after training, amnesia was induced by electric shock (1108, 50Hz, 500mA). Another group of rats received an injection of scopolamine (2.5 mg/kg). The safety of the reflex reproduction was carried out 24 hours after training.

Studies have shown that electric shock and scopolamine cause forgetting of the skill in animals when playing the URPU 24 hours after training (Tables 1 and 2). Prior administration of thiotriazoline, piracetam, or nootril to an experienced animal and the subsequent application of amnestic factors caused a significant increase in the latent time of the reflex, i.e., preservation of learning skills compared to control animals.

The most effective was the previous introduction of "Nootril", which almost 2 times increased the time of preservation of the learning skill in amnesia induced by scopolamine and more than three times in amnesia induced with electric shock (tables 1 and 2).

Assessment of cerebroprotective action.

The cerebroprotective properties of Nootril were studied in two models of experimental stroke in rats.

The first - cerebral ischemia was caused by bilateral ligation of the common carotid arteries.

The second - caused a hemorrhagic brain injury by injecting autologous blood into the region of the internal capsule.

The study was conducted under nembutal anesthesia (40 mg/kg). The drugs were administered orally every day for 18 days after the operation, in the following doses: thiotriazoline 5mg/kg, piracetam - 200mg/kg, nootril - 250mg/kg. Animals were slaughtered on the 4th and 18th day of the experiment under nembutal anesthesia, blood and brain tissue were used for the study. The cerebroprotective effect of the drugs was judged by the reduction of hyperenzymatemia of the cerebral isoenzyme creatine phosphokinase (BB - CFC) in the blood plasma, and by the reduction in the accumulation in the brain tissues of the final product of the free radical oxidation of malondialdehyde (MDA), as well as by the integral indicator - the percentage of survival of animals in conditions of acute experimental violation of cerebral blood circulation (CBP).

The use of "Nootril" showed a significant cerebroprotective effect in experimental OPMK, which was evidenced by a decrease in the level of MDA in ischemic brain tissues and hyperenzymemia in the blood plasma at different times of the experiment.

Thus, with bilateral ligation of the common carotid arteries on the 4th day of the experiment, "Nootril" reduces the content of MDA by 52.395, and the antioxidant drug thiotriazoline by 38.195. During the same observation period, "Nootril" reduced the hyperenzymemia of BB-CFC by 55.195, thiotriazoline by 47.695, piracetam by 17.595, respectively (table 3).

In the model of hemorrhagic stroke, "Nootril" reduced MDA by 35,195, BB-CFC by 48,895, which was superior to thiotriazolin and piracetam (table 4).

The result of a similar effect of "Nootril" was an increase in the survival of animals under experimental conditions

OpPMK.

Thus, on the 4th day of ischemic stroke, the survival rate of animals when Nootril was prescribed was 88,895, on the 18th day of the same model - 77,790, which significantly exceeded similar indicators of thiotriazoline and piracetam (table 5).

In the conditions of the hemorrhagic model of stroke, the survival of animals when prescribed "Nootril" was 83.0905, piracetam - 50.095, and thiotriazoline - 33.39 (table 6).

Thus, the medicine according to the invention of tablets "Nootril", coated with a shell, has pronounced nootropic, cerebroprotective, antioxidant effects, in terms of the strength of its pharmacotherapeutic action it exceeds piracetam and thiotriazoline taken separately, it belongs to relatively harmless means, it has a weakly expressed species sensitivity, it does not accumulate in the body and can find wide application in medical practice.

The acute toxicity of Nootril when administered orally to rats is 32,600 mg/kg.

Table 1

The effect of drugs on scopolamine-induced URPU amnesia

Latency time

Reflex dose at

Drug mg/kg | reproduction of URPU, sec. (Control amnesia | - | 1186165

Controls with amnesia 56.7 and 60.8 9.7 82.6 2 8.8" - p.« 0.05 in relation to controls with amnesia.

The effect of drugs on amnesia caused by URPU

Table 2

Effect of drugs on electroshock-induced amnesia of URPU

Latency time

Reflex dose at

Drug mg/kg | reproduction of URPU, sec. (Control amnesia | - | 972576

Control with amnesia 21623

ZT

58.6 ad - p.« 0.05 in relation to controls with amnesia.

Table C

Activity of the cerebral isoenzyme creatine phosphokinase (CPP) in blood serum and the content of malondialdehyde (MDA) in the brain tissues of experimental animals on the 4th and 18th day of observation after bilateral ligation of the common carotid arteries

The level of VV-CFC (mmol/l/hour) according to

Group during observation MDA, (μmol/g tissue) 18th day 18th day

0.107 from 0.005 0.048 from 0.007 1.26 0.07 0.68 20.02 0.088 from 0.003 0.046 from 0.006 0.81 from 0.087 0.64 from 0.05 0.056 from 0.002 0.044 from 0.003 0.058 same 0.07 0.048 with 0.004 0.041 with 0.002 0.60 with 0.027 0.50 with 0.027 0.042 with 0.006 0.042 with 0.006 0.62 20.07 0.62 20.07 - r« 0.05 in relation to controls with amnesia.

Table 4

The activity of the cerebral creatine phosphokinase isozyme (BB-CFC) in blood serum and the content of malondialdehyde (MDA) in the brain tissues of experimental animals on the fourth day of observation after administration of autologous blood to the region of the internal capsule of the brain (Mo | Group of animals Level of BB-FCC (mmol/ l/hour) 0.090 w 0.004 0.94 50.04 0.070 w 0.003 0.74 w 0.057 0.051 w 0.002 0.70 w 0.067 0.046 w 0.005" 0.63 w 0.077 0.042 w 0.006 0.051 - 7.50 .« 0.05 relative to the control.

Table 5

Dynamics of survival of animals after bilateral ligation of the common carotid arteries and administration of the studied drugs

Me | Group animals | Total animals |-NUMBERS of rats. survivors, according to observation, 00).

RU y y oy. (Control: KMZ | 9777/7773 33)777777777 2. |Piracetam.///// | 7777/7971 5BB 77777777 777777 38321 3. |Potriazoln.// | 97777777 66711111 56551 4. |Nootril./:/ | (09577777 Ї1777171717171717171717118811 111 (5. (|intact animals.| 9 | 9 (100 9 (100 -7 yr.« 0.05 in relation to control.

Table 6

Dynamics of survival of animals during the day of observation after the injection of autologous blood into the region of the internal capsule of the brain and the administration of the studied drugs. (96) 1 Control (| 5 6 Fo | 4666 2. |Piracetam.///// | (6 | 583) | 4(666 3. |Potriazoln./// | 6 | 7 5583) | 30500 | 233 ) | 2(35) 4. |Nootvil.////// | 6 (| 583) | 5083) | 583) | 583 (5. (|Intact animals.i | 6 2 | 6(po0 6 (100 6 (100 6 (100 -7 r.« 0.05 in relation to the control.

Claims (1)

Cerebroprotective and nootropic medicinal product in film-coated tablets containing the active ingredient piracetam and auxiliary ingredients for forming the core tablet and coating it, which is distinguished by the fact that the active ingredient contains thiotriazoline with the following ratio of ingredients, by weight. 90: Piracetam 53.6 - 59 Thiotriazoline 13.3 - 14.7 Auxiliary ingredients are the rest.