Sedative agent and method for preparing it

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmacology and pharmaceutics, and concerns a sedative agent representing glycine immobilised on detonation nanodiamond particles 2-10 nm in size, and to a method for preparing it.

EFFECT: preparing the sedative agent.

4 cl, 7 dwg, 13 tbl, 4 ex

 

The invention relates to medicine, in particular, pharmacology, and relates sedatives, which represents glycine, immobilized on particles of detonation nanodiamond.

Currently psychotropic drugs that cause sedation - suppression response to constant stimuli with reduced levels of spontaneous activity and thinking while reducing anxiety, widely used in medical practice, primarily for the treatment of various neurotic conditions. It is believed that such sedatives, reduces anxiety and has a calming effect, affect the Central nervous system (CNS) without appreciable disturbance of its functions, however, their action is characterized gradually dose-dependent suppression of Central nervous system function. The mechanism of action of sedative drugs to date are not completely elucidated. Sedatives can reduce the excitability of the Central nervous system, increase the inhibitory processes and to provide a regulating effect on the Central nervous system, restoring the balance between the processes of excitation and inhibition [1].

Despite wide application in medicine, a large assortment of sedative drugs, good drugs are still not available. In some cases, some drugs are inadequate those who piticescu effect in others too "hard" and in their application, there are various side effects [1].

It is known that nonessential amino acid glycine (NH2CH2COOH), being the Central neurotransmitter braking action type, has sedative effect and improves metabolic processes in the brain [2]. In modern therapeutic practice glycine used as a means of weakening the attraction to alcohol, reducing the phenomenon of withdrawal, depressive disorders, irritability, normalizing sleep, as well as in treatment of disorders of cerebral circulation [2]. In the basis of the pharmacological action of glycine is the effect of amplification of metabolic and neurotransmitter processes by strengthening its endogenous synthesis. To increase the intracellular synthesis of glycine is possible only by using the transmission path of the signal resulting from the interaction with the receptor systems. His interaction with glycine receptors leads to the opening of chloride channels, hyperpolarization of the membrane and proliferation inhibition. Along with this, glycine can act as allosteric of coagonist glutamate receptors. Linking to a specific website, it enhances the ability of glutamate and N-methyl-D-asparate (NMDA) open cation channel [3,4].

Used pharmacopean the th glycine is administered in the form of tablets (0.1 g) under the tongue 3-4 times a day.

Known glycine, immobilized on particles of detonation nanodiamond size 2-10 nm, used as a binder component in polymer composites [5, 6]. The method thereof is as follows [6]. A portion of the nano-diamonds are placed in a reactor at a constant current of helium and annealed at a temperature of 150-470°C for 3-4 hours Then hold the fluoridation of samples nd at a temperature of 50-500°C for 1-24 hours by contacting with a mixture of fluorine gas and hydrogen. To obtain glycine, immobilized on particles of nd, fluorinated nanodiamond treated with ultrasound in o-dichlorobenzene for 20-30 minutes, add the hydrochloride of the ethyl ester of glycine (NH2CH2COOCH2CH3·HCl) and a few drops of pyridine. The resulting mixture is stirred at a temperature of 130-140°C for 8-12 hours the Resulting product is filtered, washed with ethanol and dried under vacuum at 70°C.

An additional characteristic of this substance is the amount of particles in suspension, equal, according to the dynamic light scattering (ODCs), 310 nm [6].

The peculiarity of this matter is the presence on the surface of nanodiamond particles in addition to the molecules of glycine well as fluorine atoms. Although a number of authors declare less than 1% at., in fact, it is found experimentally that the concentration of fluorine is and the surface of the nanodiamond can reach 14% at. and more. This is due to the fact that the connection C-F (ESt.=115 kcal/g-atom) is durable and ftoroproizvodnykh carbon is inert with respect to many substances. Therefore, when the chemical immobilization of glycine on the surface of nanodiamond containing fluorine atoms, molecules of glycine are replaced by fluorine atoms only partially. It is known that the presence of organic matter fluoride and its derivatives increases its toxicity and can change the performance of microsomal system biotransformation of xenobiotics in the liver [7]. Thus, the presence of fluorine atoms in the near nanostructured similar nd - fullerene (C60increases its overall toxicity of 2,4-5 times [8]. In addition, fluorine and its compounds can accumulate in various environmental objects and present them in different quantities [9]. Therefore, glycine, immobilized on particles of nd, which contain fluorine atoms, it is undesirable to use in medical practice as a medicine.

So getting glycine, immobilized on particles of detonation nanodiamond containing no fluorine atoms, with increased dispersion in suspensions used as a medicine, as well as reducing environmental and endoecological hazard, simpler and cheaper method of its production, pre which are relevant and practically important task.

The aim of the invention is to increase the efficiency of the sedative action of glycine without showing any adverse and toxic effects, reduction in the dosage of the drug and the expansion of the range of sedative drugs.

The use of glycine, immobilized on particles of detonation nanodiamond as sedatives in the scientific and patent literature are not described.

The goal is solved by means described in accordance with the invention, sedatives, which represents glycine, immobilized on particles of detonation nanodiamond size 2-10 nm, containing no fluorine atoms and having a shell thickness of 1 nm, with the content of glycine to 21±3% of the mass, and method of its production.

Described sedative in the form of glycine, immobilized on particles of detonation nanodiamond, not containing on its surface fluorine atoms, is an ultra-fine powder (1) dark-gray or dark gray with a greenish or dark blue shades with a particle size of from 2 to 10 nm, with a shell thickness of 1 nm (Figure 2), the size of aggregates in aqueous suspension to 100 nm (Figure 3) and the content of glycine to 21±3% of the mass, part of the surface of the shell.

Figure 1 clearly shows the presence of the described sedatives of ultradisc ersey structure of the particles, lower the resolution of the used device (20 nm).

Micrograph of particles described sedatives obtained by field emission scanning electron microscope high resolution Zeiss Ultra Plus (Carl Zeiss, Germany).

Figure 2 shows that the particle size described sedatives, coated in a thickness of 1 nm, equal to 2-10 nm.

Micrograph of particles described sedatives obtained with a transmission electron microscope Jeol 1011 (JEOL, Japan).

Figure 3 shows the distribution curve of the particle sizes in the suspension described sedatives, from which it follows that the size of the particles in suspension do not exceed 100 nm.

Measurement of the size distribution of the particles described sedatives in suspension was performed by the method of the DSU on the instrument ZetaSizer (Malvern Instruments, USA). On the x-axis is a logarithmic scale of the particle size in nm. On the y - axis the percentage of particles with defined size.

The elemental composition of the surface of the particles described sedatives according to rentgenofotoelektronnoj spectroscopy (XPS) are given in table 1.

Table 1
The elemental composition and the binding energy of the surface the atoms described sedatives
Name characteristicsChemical elements
AboutN
Atomic %77,5-94,54-141,5-8,5
The binding energy, eVRUB 285.2±0,5530,7±0,5399,8±0,5

Surface investigation described sedatives were performed on the instrument LAS-3000 (Riber, France)equipped with a hemispherical analyzer ORH-150. For excitation of photoelectrons used nemonokhromaticheskogo x-rays aluminum anode (AlKα=1486,6 eV) when the voltage of the tube 12 kV and current emissions of 20 mA. Calibration photoelectron peaks was carried out by the line carbon 1s with a binding energy of 285 eV. The vacuum in the chamber was 6.7·10-8PA. To obtain a high vacuum was used ion pump.

Amount of glycine in the described sedative agent is determined as follows. Prepare a mixture of nd with different content of glycine. Take a sample of each mixture of equal mass. Register their IR spectra, choose the most intensive nature of the tourist signals, which are correlated with the bands of the infrared spectrum of the original glycine. Then build the calibration curves of signal intensity in the infrared spectrum from the content of glycine in the sample. Further, according to the intensity of the selected characteristic bands of the investigated sedatives from calibration curves to determine the quantitative content of glycine. According to the received data to determine an average value content of glycine in the described sedative agent.

The described method of obtaining sedatives is the following. Detonation nanodiamond annealed in a stream of hydrogen gas at a temperature of 500-1200°C for 1-8 h, then subjected to liquid-phase chlorination of molecular chlorine in photochemical exposure to visible light at a temperature of 50-70°C for 36-60 h followed by rinsing carbon tetrachloride,

the centrifugation and drying under vacuum. Modified chlorine nanodiamond dissolved in a polar solvent to form a suspension. Add the tertiary amine and glycine and treat the mixture with ultrasound for 5-60 min, followed by keeping at 50-80°C for 12-48 h, centrifugation, washing with a solvent and drying. The sonication are within 5-60 min, as the tertiary amine used and triethylamine as the e of the polar solvent used pyridine, the lower aliphatic alcohol, water-alcohol mixture or water.

Described sedative does not contain fluorine atoms (table 1), and other halogen atoms, in amounts exceeding the error of the instrument (0.1% at.), because in the process of obtaining sedatives all of the chlorine atoms are replaced by molecules of glycine and leave the surface of nanodiamond in the form of molecules of HCl.

In the process of pharmacological research work has been done on the study of specific sedative described the medicinal product and its safety in comparison with pharmacopoeial glycine.

Assessment of sedation were conducted according to the guidance for the study of the activity of substances possessing drugs is got with activity, described in [10].

Specific action was studied in outbred mice-males using certified methods - actometry Opto-Varimex (Colambus Instrument, USA). Statistical processing of results was performed using the software patch BIOSTAT for Windows. Expected average for the group and the standard errors of the parameters.

The results obtained indicate that the pharmacopoeial glycine at a dose of 10 mg/kg sedative activity in hectometre shows (table 3-5). He also did not show statistically significant sedative effect after 1, 4 and 8 h the donkey injection.

Described sedative caused a significant decrease in horizontal (67%) and vertical (93,6%) locomotor activity after 10 min after injection. Decrease horizontal and vertical locomotor activity remained valid and was more than 50% of control and after 4 and 8 hours after a single injection described sedatives (table 3-5).

The study of the acute toxicity described sedatives was conducted in accordance with the Methodological guidance on the study of acute toxicity, described in [10].

When the experiment was recorded the following parameters: the nature of the coat, the status of the mucous membranes, upper eyelid ptosis, increased urinate, increased defecation, increased salivation, piloerection, vocalization, lateral position, rhythm, and depth of respiratory movements, aggression, fearfulness, tremor, convulsions, changes in the thresholds of pain response, changing poses, catalepsy, violation of coordination of movements in the test of the rotating rod, holding for 5 seconds on the inverted mesh platform, pereletnie with inverted mesh platform upward, the presence of the pineal, corneal reflex, sedation, stereotypie and grooming, the death of the animal.

Statistical processing of results was the implementation is and with the help of statistical packages "patch BIOSTAT" for Windows. Expected average for the group and the standard errors of the parameters.

The results convincingly show that the described sedative intraperitoneal injection to mice at doses of 75, 150 and 225 mg/kg, as well as pharmacopoeial glycine did not cause signs of toxicity and mortality for 14 days. the observation.

The results of pharmacological studies established the presence of the described sedatives expressed specific sedative effect, superior sedative effect pharmacopoeial glycine, and lack of side effects and toxic effects in doses exceeding therapeutic more than 20 times.

Described sedative not only can improve therapeutic efficacy of the pharmaceutical preparation of glycine, but also to expand the range of effective and safe sedation.

A brief description of graphic materials.

Figure 1. Electron micrograph described sedatives, obtained by scanning electron microscope.

Figure 2. Electron micrograph described sedatives, obtained with a transmission electron microscope.

Figure 3. The distribution of particle sizes described sedatives in aqueous suspensions according to the method of the PC.

Figure 4. The IR spectra of mixtures of nd with glycine used to construct the calibration curves. I, II, III spectra of mixtures containing glycine 1:1,75:2,5, respectively. Within the identified characteristic peaks.

Figure 5. Calibration curves for each characteristic bands of the IR spectrum of a mixture of nd with glycine, a, b, C - calibration curves for bands 1407, 1332 and 504 cm-1respectively.

The invention is illustrated by the following examples.

Example 1.

300 mg initial detonation nanodiamond annealed in a stream of hydrogen gas with a speed of 3.0 l/h at 1000°C for 6 h and Then annealed nano-diamond is subjected to liquid-phase chlorination of molecular chlorine, dissolved in 40 ml of CCl4up to 6% of the mass. Cl2. The chlorination reaction is carried out at photochemical exposure to visible light for 60 h at 60°C. the sample was Then washed with CCl4by centrifugation of the suspension at 6000 rpm and dried under a pressure of 0.1 mm Hg to a constant weight. Then from chlorinated nd get a suspension, using 40 ml of water-alcohol mixture (water:methanol=1:1), which contribute 300 mg of glycine in the form of free amino acids (NH2CH2COOH) with the addition of 1 ml of triethylamine. The resulting mixture is treated with ultrasound (50 W) for 60 min and maintained at constant is ω stirring at 65°C for 30 hours The obtained product is washed with a large amount of ethanol, centrifuged and dried under vacuum at 70°C overnight. Residual moisture of the product is 2.2%. The yield of the target product is 279 mg (93%). The product is a dark grey with a bluish tinge ultrafine powder (Figure 1) with the size of the primary particles of 2-10 nm (Figure 2), which has a shell surface layer to 1 nm. In suspension, the particle size of the powder is not larger than 100 nm (Figure 3). The elemental composition of the surface of the particles of the obtained product are shown in table 2.

Table 2
XPS data of the obtained product
Name characteristicsChemical elements
AboutN
Atomic %80,1±0,111,5±0,18,4±0,1
The binding energy, eVRUB 285.2±0,5530,7±0,5399,6±0,5

To determine the mass fraction of glycine in the resulting product is prepared 3 mixture is nd with a glycine content of the last 1:1,75:3,5, respectively. For each mixture, we take the sample mass 0,0035 g and carefully grind in a mortar with 0,090 g KBr. 0,070 g of the obtained mixture is pressed into a tablet and removed the IR spectrum (Figure 4). Characteristic bands choose when 1407, 1332 and 504 cm-1accordingly, and build for them the calibration graphs (Figure 5). The intensity of the corresponding characteristic bands in the IR spectrum of the received sample weight 0,0035 g amounted to 0.23 and 0.22 and 0.10 PU, respectively. From the calibration curves a, b, in figure 5 determines the amount of content of glycine in the resulting sample, which is 0,00057±8·10-5, Therefore, the mass fraction of glycine in the weighed sample is 21±3% of the mass.

Example 2.

Study of specific sedative activity of the described tools.

The study was carried out on outbred adult mice-males weighing 25-28 g

Animals were obtained from the Central nursery of laboratory animals "Pillar", the Moscow region. The animals comply with the rules of good laboratory practice in preclinical studies in Russia (GOST 3 51000.3-96 and 51000.4-96), the regulations of the Sanitary regulations on the organization, equipment and maintenance vivarium"approved by the Chief State sanitary doctor 06.04.1973, No. 1045-73, and the Ministry of health of the Russian Federation No. 267 from 19.06.2003, "On approval of the rules of La is oratorial practice" (GLP) compliance with the International recommendations of the European Convention for the protection of vertebrate animals used in experimental studies (1997). The animals were kept in a vivarium at temperatures of 20-22°C, With a light cycle of 12 hours light and 12 hours dark periods in plastic cages T/4 And size 580×375×200 mm from the top stainless steel cover and dust-free litter of wood shavings. The animals were kept at constant access to feed and water, using the full ration extruded briquettes feed (GOST feed R 50258-92) and drinking water. In the experiments we considered the requirements of the Committee on the ethical treatment of animals of the Russian national Committee on bioethics at the Russian Academy of Sciences and the ethical standards set out in International recommendations for the conduct of biomedical research using animals" (1985). The experiments were carried out in the first half of the day.

To study specific sedative activity of the product obtained in example 1 was used certified methodology to evaluate different types of physical activity, using actometry Opto-Varimex (firm "Columbus Instrument), USA), which is recommended for exploring the sedative action of the substances according to the "guidance for the study of the neuroleptic activity of pharmacological substances" [10].

As criter the EB, characterizing sedative effect, was used indicators of horizontal and vertical motor activity. The movements of the animals were recorded on the counter in conventional units. The experiment lasted for 8 hours

The product obtained in example 1 was injected once intraperitoneally or orally (intragastric using a special probe) in doses of 5 and 10 mg/kg Check horizontal and vertical locomotor activity in hectometre Opto-Varimex was carried out after 10 minutes, 30 minutes, 1, 4, and 8 h after injection of the substance. To avoid habituation to the situation and the phenomenon of quench of physical activity, to assess the effects of the product obtained according to example 1, at each point in time used a separate group of animals: 10 mice in each group on monitoring and research of pharmacological activity described sedatives, 6 mice in group - on study of pharmacological activity of pharmacopoeial glycine. Just used the 88 animals. As the comparison drug used pharmacopoeial glycine. As control was used distilled water. Statistical processing of results was performed using the statistical package "patch BIOSTAT" for Windows. Expected average for the group and the standard errors of the parameters.

When exploring the mountains of the horizontal motor activity intraperitoneal injection installed, in the control group of animals average horizontal activity after 1 h after injection of distilled water was 230,96 movements. This figure was not significantly changed and after 8 hours (table 3).

Table 3
The study of sedative substances obtained in example 1, after a single intraperitoneal injection on indicators of horizontal locomotor activity of mice in hectometre Opto-Varimex
SubstanceDose, mg/kgCheck-in time effect hThe average horizontal activity (movement) units% reduction in locomotor activity relative to the control
Control1230,96±10,23-
Sedative101/675,78±10,76*67,19
Sedative10½ 43,46±9,35*81,18
Sedative10121,98±6,4*90,48
Sedative10425,49±7,66*88,96
Sedative10874,68±10,51*67,62
Pharmacopoeial glycine101/6190,62±18,2617,47
Pharmacopoeial glycine101227,08±17,411,68
Pharmacopoeial glycine104211,14±14,708,59
Pharmacopoeial glycine108219,54±12,424,95
Control 108204,57±14,53-
* - p<0,01 compared with the control group, the test of Mann-Whitney

Described sedative obtained in example 1, at a dose of 10 mg/kg caused a significant decrease (67%) horizontal locomotor activity after 10 min after injection. After 30 min and after 1 h the lower horizontal locomotor activity was gradually increased and decreased by 81% and 90% compared to control, respectively (table 3). The decrease in horizontal locomotor activity remained valid and was more than 50% of control and after 4 and 8 hours after a single injection described sedatives.

Pharmacopoeial glycine at a dose of 10 mg/kg after a single intraperitoneal injection caused no reduction of motor activity after 10, 30 min, 1, 4, and 8 h after injection (table 3).

When studying vertical motor activity intraperitoneal injection of substances, it was found that in the control group of animals average horizontal activity after 1 h after injection of distilled water amounted to 4.28 movements. This figure was not significantly changed, and 8 h after injection of distilled water (table 4).

Table 4
The study of the sedative action of the described tools with a single intraperitoneal injection on the performance of vertical locomotor activity in mice hectometre Opto-Varimex
SubstanceDose, mg/kgCheck-in time effect hThe average horizontal activity per minute, a unit% reduction in locomotor activity relative to the control
Control1014,28±0,29-
Sedative101/60,27±0,0993,67
Sedative10½ 0±0*100
Sedative1010±0*100
Sedative1040,01±0,01*99,77
Sedative1080,37±0,08*91,36
Pharmacopoeial glycine1013,34±0,35#21,73
Pharmacopoeial glycine1042,38±1,32*44,39
Control108to 3.73±0,35-
* - p<0,01 compared with the control group, criteria Mann-Whitney
# - p<0.05 compared with the control group, the test of Mann-Whitney

Described sedative dose of 10 mg/kg after a single intraperitoneal injection caused a marked significant decrease (93,6%) vertical is Oh locomotor activity after 10 minutes after injection. After 30 minutes and 1 hour after a single injection, it eliminated the vertical locomotor activity. Significant reduction in vertical locomotor activity was retained after 4 h (99%) and after 8 h (89,9%) (table 4).

Pharmacopoeial glycine at a dose of 10 mg/kg after a single dose intraperitoneally, as after 1 h and 4 h after injection, statistically significant reduced vertical locomotor activity compared to control (table 4).

Example 3.

Study of specific sedative activity described by means of oral (intragastric) administration.

The study was carried out on outbred adult mice-males weighing 25-28, Experimental animals were kept as in example 1. At each point in time used a separate group of animals: 10 mice in each group on monitoring and research of pharmacological activity described sedatives, 6 mice in group - on study of pharmacological activity of pharmacopoeial glycine. Just used 62 animals.

In the study of horizontal locomotor activity in oral (intragastric) the introduction of substances, it was found that in the control group of animals average horizontal activity after 30 min after the injection of distilled water is left 208,4 movements (table 5).

Table 5
The study of the sedative action of the described tools in a single oral (intragastric) the introduction of indicators of horizontal locomotor activity of mice in hectometre Opto-Varimex
SubstanceDose, mg/kgCheck-in time effect hThe average horizontal activity (movements) per minute unit% reduction in locomotor activity relative to the control
Control½ 208,40±21,52-
Sedative10½ 110,03±19,94*47,21
Sedative10167,76±11,12*67,51
Sedative10483,67±9,81* 59,85
Sedative10894,34±7,56*54,73
Pharmacopoeial glycine101189,24±23,1317,47
Pharmacopoeial glycine104201,75±21,643,21
* - p<0.05 compared with the control group, the test of Mann-Whitney

Found that already after 30 min after administration (oral) described sedatives in the dose of 10 mg/kg there was a statistically significant decrease in the locomotor activity of animals in 1.9 times compared with the control group. Within 1 hour after administration, a statistically significant decrease in the locomotor activity of animals kept and the level of activity was also 1.9 times lower than in the control group. After 4 hours locomotor activity remained statistically significantly reduced at the same level. After 8 hours, there was a statistically significant decrease in the locomotor activity of animals in 1,5 times in comparison with the control GRU is sing (table 5). The results indicate that a single oral (intragastric) administration described sedatives in the dose of 10 mg/kg causes persistent statistically significant sedative effect within 8 h of observation.

Pharmacopoeial glycine at a dose of 10 mg/kg in a single oral (intragastric) as after 1 h and 4 h after injection, statistically significant reduced vertical locomotor activity compared to control (table 5).

Example 4.

Studying the side effects and toxic effects described sedatives

The study was carried out on outbred adult mice-males weighing 20-24 g aged 2-3 months. Experimental animals were kept as in example 2. Only used 42 animals - 7 groups of 6 mice.

Registration changes behavior, reflexes, possible side effects, signs of toxicity and mortality were performed after 1, 4, 24 h, 4, 10 and 14 days. after intraperitoneal administration described sedatives in comparison with pharmacopoeial substance glycine in the same doses.

The study found that the described sedative intraperitoneal injection to mice at doses of 75, 150 and 225 mg/kg did not cause signs of intoxication and mortality in length and 14 days. (6-11). When described this sedative is also not caused in mice changes woolen cover, condition of the mucous membranes. There was also no ptosis of the upper eyelid, increased urinary, defecation, salivation, piloerection, vocalization, lateral position. Within the normal range were the rhythm and depth of breathing, there was no aggression, fearfulness, tremor, convulsions, catalepsy, stereotypes and grooming. Was not observed changes in posture. Animals were saved pineal, and painful corneal reflexes. Throughout 14 days. observations the animals were maintained on a reversed net platform for 5 s (6-11).

When studying reactions to pain by squeezing the base of the tail of the mouse tweezers found that in animals after administration described sedatives in the first 4 h of observations noted reduced response to painful stimulus, compared to control, turn head to tail and squeak. After 24 h of observation showed normalization of the response of an animal to painful stimulus. Pharmacopoeial glycine at a dose of 75 mg/kg did not cause a change in the reaction to painful stimulus during 14 days. after injection.

Study of the effect described sedatives in comparison with pharmacopoeial glycine on motor activity and coordination magic cube MOV is th was carried out using a rotating rod test (Rota Rod firm Ugo Basile, Italy). Fixed speed of rotation of the rod was 10 rpm/min Criterion job was to hold the animal on the rotating rod for 120 sarasinee coordination was observed one hour after the introduction of the described sedation at a dose of 75 mg/kg 16.7% of the animals and 50% with the introduction of the drug in doses of 150 and 225 mg/kg After 24 h, 4, 10 and 14 days. disorders of motor activity under the influence of the described sedatives at all doses was observed (table 6-12).

Table 6
The study of the possible side effects and death of mice within 1 hour after the introduction of pharmacopoeial glycine and described sedatives (a measure of the change in the group in %)
IndicatorsGroup
ControlSedative/dose, mg/kgPharmacopoeial glycine/dose, mg/kg
7515022575150 225
The changing nature woolen cover0000000
Changing the state of the mucous membranes0000000
Ptosis of the upper eyelid0000000
Increased urinary0000000
Increased defecation0000000
Increased salivation0000000
The presence of piloerection0000000
The presence of vocalizations0000000
The presence of lateral position0000000
The rhythm and depth of respiratory movements0000000
The presence of aggressiveness 0000000
Change in response to tapping on the cell00033,3*0033,3*
Increased fearfulness0000000
The presence of tremor0000000
The presence of seizures0000000
The changes in the thresholds of painful reaction066,7* 100*100*0100*100*
Changing poses, catalepsy0000000
Violation of coordination of movements in the test of the rotating rod016,750*50*33,3*33,3*50*
Hold 5 seconds at the inverted mesh platform100100100100100100100
Pereletnie with inverted mesh platform top10066,7*66,7*50*66,7*66,7*66,7*
100100100100100100100
The presence of corneal reflex100100100100100100100
The presence of sedation066,7*100*100*0100*100*
The presence of stereotypia0000000
The presence of grooming0000000
The death of an animal0 000000
*- P<0.05 to relatively control χ2

Table 7
The study of the possible side effects and death of mice 4 hours after the introduction of pharmacopoeial glycine and described sedatives (a measure of the change in the group in %)
IndicatorsGroup
ControlSedative/dose, mg/kgPharmacopoeial glycine/dose, mg/kg
7515022575150225
The changing nature woolen cover00000 00
Changing the state of the mucous membranes0000000
Ptosis of the upper eyelid0000000
Increased urinary0000000
Increased defecation0000000
Increased salivation0000000
The presence of piloerection0000000
The presence of vocalizations0000000
The presence of lateral position0000000
The rhythm and depth of respiratory movements0000000
The presence of aggressiveness0000000
Changing reactions to postalia is on their cell 00016,70016,7
Increased fearfulness0000000
The presence of tremor0000000
The presence of seizures0000000
The changes in the thresholds of painful reaction066,7*100*100*0100*100*
Changing poses, catalepsy0 000000
Violation of coordination of movements in the test of the rotating rod016,716,750*33,3*16,733,3*
Hold 5 seconds at the inverted mesh platform100100100100100100100
Pereletnie with inverted mesh platform top10066,7*66,7*50*100*83,366,7*
The presence of the pineal reflex100100100100100100100
The presence of corneal reflex100100100100100100100
The presence of sedation066,7*83,3*100*083,3*100*
The presence of stereotypia0000000
The presence of grooming0000000
The death of an animal0000000
*- P<0,05 - relative control by Cree is a series of χ2

Table 8
The study of the possible side effects and death of mice 24 hours after injection pharmacopoeial glycine and described sedatives (a measure of the change in the group in %)
IndicatorsGroup
ControlSedative/dose, mg/kgPharmacopoeial glycine/dose, mg/kg
7515022575150225
The changing nature woolen cover0000000
Changing the state of the mucous membranes0000 000
Ptosis of the upper eyelid0000000
Increased urinary0000000
Increased defecation0000000
Increased salivation0000000
The presence of piloerection0000000
The presence of vocalizations0000000
The presence of lateral position0000000
The rhythm and depth of respiratory movements0000000
The presence of aggressiveness0000000
Change in response to tapping on the cell0000000
Increased the th fearfulness 0000000
The presence of tremor0000000
The presence of seizures0000000
The changes in the thresholds of pain0000000
reaction
Changing poses, catalepsy00 00000
Violation of coordination of movements in the test of the rotating rod000033,3*16,733,3*
Hold 5 seconds at the inverted mesh platform100100100100100100100
Pereletnie with inverted mesh platform top100100100100100100100
The presence of the pineal reflex10010010010010010066,6*
The presence of corneal reflector is sa 100100100100100100100
The presence of sedation0000000
The presence of stereotypia0000000
The presence of grooming0000000
The death of an animal0000000
*- P<0.05 to relatively control χ2

0
Table 9
The study of possible side effects, and mortality of mice after 4 days. after the introduction of pharmacopoeial glycine and described sedatives (a measure of the change in the group in %)
IndicatorsGroup
Pin
role
Sedative/dose, mg/kgPharmacopoeial glycine/dose, mg/kg
7515022575150225
The changing nature woolen cover0000000
Changing the state of the mucous membranes000000 0
Ptosis of the upper eyelid0000000
Increased urinary0000000
Increased defecation0000000
Increased salivation0000000
The presence of piloerection0000000
The presence of vocalizations 0000000
The presence of lateral position0000000
The rhythm and depth of respiratory movements0000000
The presence of aggressiveness0000000
Change in response to tapping on the cell0000000
Increased fearfulness000000
The presence of tremor0000000
The presence of seizures0000000
The changes in the thresholds of painful reaction0000000
Changing poses, catalepsy0000000
Violation of coordination of movements in the test of the rotating rod00 00000
Hold 5 seconds at the inverted mesh platform100100100100100100100
Pereletnie with inverted mesh platform top100100100100100100100
The presence of the pineal reflex100100100100100100100
The presence of corneal reflex100100100100100100100
The presence of sedation0 000000
The presence of stereotypia0000000
The presence of grooming0000000
The death of an animal0000000
* - P<0.05 to relatively control χ2

td align="center" morerows="2"> Indicators 100
Table 10
The study of possible side effects, and mortality of mice after 10 days. after the introduction of pharmacopoeial glycine and described sedatives (a measure of the change in the group in %)
Group
Pin
role
Sedative/dose, mg/kgPharmacopoeial glycine/dose, mg/kg
7515022575150225
The changing nature woolen cover0000000
Changing the state of the mucous membranes0000000
Ptosis of the upper eyelid0000000
Increased Orinats the I 0000000
Increased defecation0000000
Increased salivation0000000
The presence of piloerection0000000
The presence of vocalizations0000000
The presence of lateral position00 00000
The rhythm and depth of respiratory movements0000000
The presence of aggressiveness0000000
Change in response to tapping on the cell0000000
Increased fearfulness0000000
The presence of tremor000 0000
The presence of seizures0000000
The changes in the thresholds of painful reaction0000000
Changing poses, catalepsy0000000
Violation of coordination of movements in the test of the rotating rod0000000
Hold 5 seconds at the inverted mesh platform100100100100100100
Pereletnie with inverted mesh platform top10010010010010010083,3
The presence of the pineal reflex100100100100100100100
The presence of corneal reflex100100100100100100100
The presence of sedation0000000
The presence of stereotypia000 0000
The presence of grooming0000000
The death of an animal0000000
* - P<0.05 to relatively control χ2

0
Table 11
The study of possible side effects, and mortality of mice after 14 days. after the introduction of pharmacopoeial glycine and described sedatives (a measure of the change in the group in %)
IndicatorsGroup
Pin
role
Sedative/dose, mg/kgPharmaco is any glycine per dose, mg/kg
7515022575150225
The changing nature woolen cover0000000
Changing the state of the mucous membranes0000000
Ptosis of the upper eyelid0000000
Increased urinary0000000
Increased defecation0 000000
Increased salivation0000000
The presence of piloerection0000000
The presence of vocalizations0000000
The presence of lateral position0000000
The rhythm and depth of respiratory movements000000
The presence of aggressiveness0000000
Change in response to tapping on the cell0000000
Increased fearfulness0000000
The presence of tremor0000000
The presence of seizures00000 00
The changes in the thresholds of painful reaction0000000
Changing poses, catalepsy0000000
Violation of coordination of movements in the test of the rotating rod0000000
Hold 5 seconds at the inverted mesh platform100100100100100100100
Pereletnie with inverted mesh platform top100100100 10010010066,7*
The presence of the pineal reflex100100100100100100100
The presence of corneal reflex100100100100100100100
The presence of sedation0000000
The presence of stereotypia0000000
The presence of grooming00000 00
The death of an animal0000000
* - P<0.05 to relatively control χ2

16,67
Table 12
The effect described sedatives in comparison with pharmacopoeial glycine on motor activity of mice in the test torque rod
GroupDose, mg/kgGroup indicator %
1 h4 h24 hours4 d.10 days.14 days.
Control-000000
7516,670000
Sedative15050*16,670000
22550*50*0000
7533,33*33,33*33,33*000
Pharmacopoeial glycine15033,33*16,6716,67000
22550*33,33*33,33*0 00
* - P<0.05 to relatively control χ2

Pharmacopoeial glycine caused incoordination in doses of 75, 150 mg/kg 16.7% and 33% of the animals within 24 h of observation, and at a dose of 225 mg/kg in 50% of mice within 1 h after injection and 33% after 4 and 24 h after injection.

Thus, violation of coordination of movements after the introduction of the described sedatives were recorded mainly during the first 4 h of observation. Subsequent observations (24 h, 4, 10 and 14 days.) differences between the study group and the control is not marked. Violation of coordination of movements after the introduction of pharmacopoeial glycine animals were preserved and 24 hours after injection.

When studying miorelaksantnoe steps described sedatives and pharmacopoeial glycine in the test retention of mice inverted mesh platform within 5 seconds of differences relative to the control is not detected within 14 days. the observation.

In the study of motor activity of mice revealed that the Pharmacopoeia glycine and described sedative broke the ability of animals to climb on top of the inverted mesh platform. So, in the first hour of observation in all experimental groups showed a reduction in the number of animals that can perform the amount. 4, 10 and 14 th day. after the introduction of substances violations ability peretania on top of the mesh platform were noted.

For the study of sedative effect on the ability to move in the plane of the animal was placed on a laboratory table. The lack of animal movements within the first 5 were regarded as having a sedative effect. The results of the study are presented in table 6-11 and table 13. It is established that the introduction described sedatives (75, 150 and 225 mg/kg) and pharmacopoeial glycine (150 and 225 mg/kg) in the first 4 h was observed pronounced sedation, which was dose-dependent. Sedation during the first 4 hours was absent only in the group of animals treated with pharmacopoeial glycine at a dose of 75 mg/kg Via 1,4, 10 and 14 days. after the introduction of substances sedative effect was not registered. These data confirm the presence of the described sedatives more pronounced sedative effect in the test motor activity of mice in comparison with pharmacopoeial glycine.

Table 13
The study of the sedative effect of the described tools in comparison with pharmacopoeial glycine in mice in the test tapping cell
G is the SCP Dose, mg/kgGroup indicator %
1 h4 h24 hours4 d.10 days.14 days.
Control-000000
7566,67*66,67*0000
Sedative150100*83,33*0000
225100*100*0000
75000000
150100*83,33*0000
225100*100*0000
* - P<0.05 to relatively control χ2

In the test tap on the animal cell is established that the group, in which mice were administered described sedative dose of 225 mg/kg during the first 4 h was observed lack of response of mice tapping a pencil on the cage of the animal compared to control group, which can be seen as the expression of the sedative effect of the described tools. Subsequent observations through 1,4, 10 and 14 days. differences between groups were observed (table 6-11).

References

1. Astray freight is Katzung. Basic and clinical pharmacology: 2 TT 1. / Lane. from English. - 2nd ed., Rev. and supplementary); SPb.: Publishing house of the Binomial, Izd-vo "Dialect", 2007. S-448.

2. PPM Mashkovsky. Medicinal product. 2 so So 2. - 14th ed., Rev., cor. and extra - M.: OOO "Publishing house New wave", 2000. P.124.

3. IGOR Komissarov, Arenaria. Molecular mechanisms of action of the drug Glycine" // Terra medica. 2001. No. 1. P.23-25.

4. A. Bespalov, EE, Zvartau. Neuropsychopharmacology antagonists of NMDA receptors. - SPb.: Nevsky Dialect, 2000. 297 C.

5. USPat 7820130 B2, 24.11.2004.

6. Y. Liu, Zh. Gu, J.L. Margrave, V.N. Khabashesku. Functionalization of Nanoscale Diamond Powder: Fluoro-, Alkyl-, Amino-, and Amino Acid-Nanodiamond Derivatives // Chem. Mater. 2004. V.16. P. 3924-3930.

7. Russian encyclopedia for labour protection. 3 volume 2 ed., revised and enlarged dopt 3. - M.: Izd. NCAAS. S.

8. N.N. Karkishchenko. Biomedicine, 2009. No. 2. Pp.5-26.

9. TI Shalin, Laslau. General questions the toxic effects of fluoride // Siberian journal of medicine. 2009. No. 5. Pp.5-9.

10. The guidelines for conducting pre-clinical studies of drugs 4.1. THE FGBI "NCAMP". - M., Publishing house of the Neck, 2012. 244 C.

1. Sedative, represents glycine, immobilized on particles of detonation nanodiamond size 2-10 nm with a shell thickness of 1 nm, with the content of glycine to (21±3) wt.%.

2. The method of obtaining sedatives according to claim 1, characterized in that detonation nanodiamond annealed at the e gaseous hydrogen at a temperature of 500-1200°C for 1-8 h, subjected to liquid-phase chlorination of molecular chlorine in photochemical exposure to visible light at a temperature of 50-70°C for 36-60 h followed by rinsing carbon tetrachloride, centrifugation and drying, the obtained modified chlorine nanodiamond dissolved in a polar solvent to form a slurry, add the tertiary amine and glycine, the mixture is treated with ultrasound followed by keeping at 50-80°C, centrifugation, washing with a solvent and drying.

3. The method according to claim 2, where the sonication are within 5-60 min and keeping at 50-80°C. is carried out for from 12 to 48 hours

4. The method according to claim 2 or 3, where the tertiary amine using triethylamine as a polar solvent using pyridine, a lower aliphatic alcohol, water-alcohol mixture or water.



 

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