Medicinal agent

FIELD: medicine.

SUBSTANCE: invention relates to medicine and pharmaceutical industry, and more specifically to making tableted dosage form with prophylactic effect for arresting primed reaction to radiation and early transient incapacity. The agent contains ondansetron, methacin and caffeine in weight ratio ondansetron:methacin:caffeine 4:1:20-300.

EFFECT: reduced adverse reaction, more specifically vomiting, diarrhea and reduction of physical activity.

5 cl, 11 tbl

 

The present invention relates to a new combination drug, which can be used as a means of protection from ionizing radiation, in particular for the prevention of primary reaction to radiation and the early transient incapacitation, especially in military medicine for relief of the primary reaction to radiation.

Known application of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-it or its hydrate or its salts (I) as a means of acute emetic response caused by the use of drugs or other means of chemotherapy and/or rentgenoterapii tumors, or irradiation. Most often this purpose hydrochloride dehydrate 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-it (ondansetron, Latran (Patent of great Britain No. 2153821, 2290963; European patent No. 191562, 219929; the patent of Russia №1528319, 2041876, 2159614 and other Order of the chief of gumu MO of the Russian Federation No. 224 from 01.06.1996 "Of acceptance for the supply of medical services of the Armed forces of the Russian Federation tablets latrine 0,004 coated").

Known applications for the prevention of primary reaction to radiation and the early transient incapacitation of several compositions of physiologically active substances on the basis of ondansetron.

One which of such medicines is a combination of ondansetron and benzamide or its derivatives (Patent RF №2229882). The disadvantage of this tool is the poor efficiency in protecting against diarrhea.

Renowned pharmaceutical composition comprising ondansetron and metacin (iodine-methylate 2-dimethylaminoethanol ether benzyl acid) (Patent RF №2185825), which has improved antiemetic properties and a significant reduction in diarrhoeal syndrome (closest equivalent).

Described pharmaceutical composition containing ondansetron, metacin and benzamid (RF Patent No. 2234315)with improved antiemetic activity, especially at high doses of ionizing radiation.

The disadvantages of the last songs is that under the action of radiation, along with vomiting and diarrhea, there is a sharp decrease physical, including physical activity. This is specifically indicated in the description to the patent of Russian Federation №2234315 (p.8) "adverse effects of large doses of ondansetron and metacin appear, as a rule, decrease motor activity, tachycardia ...".

The objective of the invention is the creation of a medicinal product for human protection from early transient incapacitation and for the prevention of primary reaction to radiation in the form of a tablet dosage form (as is most convenient in a military context), devoid of the decree is the R of the disadvantages. The task is dictated by the modern methods of warfare, especially the ability to use in combat so-called tactical nuclear weapons. Under these conditions, soldiers must maintain combat readiness for some time, during which it must be suitable reinforcements. Decreased performance in these conditions is unacceptable. In terms of warfare and, in particular, in the use of nuclear (including neutron) weapons, especially important is the use of such funds in the form of a pill, because in these conditions dramatically reduced critical opportunities and possible panic that could lead to uncontrollable consequences.

The problem is solved by creating a combo drug consisting of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-it or its hydrate or its salts (I) and metacin (II); in which added caffeine (III) if the ratio of ingredients in a 4:1:20÷300.

According to the invention offers the drug composition I:II:III=4:1:20÷300 (weight ratio), preferably composition II:III=1:50-100.

It is most convenient to solve the problem to use in order to themselves and others, tableted dosage form, in which the th but the active ingredients must enter the required pharmaceutical additives and components. Been tested on artificial mixtures of different ratios of caffeine without changing the pre-selected ratio ondansetron: metacin. When using the quantity of caffeine less than 20 effects on locomotor activity slightly, and when the amount of caffeine more than 500 tablet size becomes uncomfortable to receive. The required dosage form obtained by studying the compatibility of excipients with the active principles and to each other.

Tablets can be manufactured by conventional means, using one or more auxiliary components. Tablets can be made using the appropriate hardware pressing, in which active substances are used in easily movable, for example in the form of powder or granules, possibly mixed with a binder component, a sliding additives, inert diluent, surface-active agent or dispersing agent. Molded tablets may be coated by a shell consisting of a sugar or a special film.

It is most convenient to use a tablet dosage form coated with a gastric-soluble coating. The required dosage form obtained by studying the compatibility of excipients with active on Alamy and among themselves. As a stabilizer may be used sodium thiosulfate.

As auxiliary substances used calcium carbonate, kaolin, gelatin, starch, magnesium carbonate, microcrystalline cellulose, milk sugar, Aerosil and other Use as excipients microcrystalline cellulose, Aerosil and starch; the mixture of Aerosil, starch and magnesium stearate as moving and an aqueous solution of starch as a binder gave the opportunity to obtain core tablets needed to cover properties in strength. Based on hydroxypropylcellulose developed coating tablets and matched the conditions of its application.

On the basis of preclinical studies is optimal kernel tablet:

1. Ondansetron hydrochloride dihydrate0,010 g (0.008 g of base)
2. Metacin0.002 g
3. Caffeine grounds0,100 g

The advantage of this structure is the use of known drugs in their usual recommended doses. It is established that at a lower caffeine content physical performance is not restored, more content is of oreina leads to a number of side effects and the difficulties of creating a tablet dosage form. Microcrystalline cellulose, Aerosil, magnesium stearate, sodium thiosulfate, polyvinylpyrrolidone enough to obtain core tablets weighing 0,2,

To cover was used colorless film-forming ingredients: hydroxypropylcellulose (hyprolose), castor oil, tween-80, tropeolin About sufficient to obtain a homogeneous film in the fluidized bed.

After coating the tablets obtained tablets are raspadaemost 10±2 min and release active substances to 96±2%. Received the drug received in the study name Lamzin. Experimental examples illustrate but do not limit the claims of the applicant.

The results of preclinical research drug

Acute toxicity tableted dosage forms Lacocina

Experiments made on 44 males and 35 females of Wistar rats. Suspension tablets Lacocina in 1% starch gel was injected into the stomach in doses 330, 385,440 and 495 mg/ kg

Males dose of 330 and 385 mg/kg caused decreased motor activity, increased anxiety, depression, slight dyspnea, cyanosis. Most of the rats after 3-4 hours active enough. However, some continuing lack of exercise, shortness of breath, cyanosis. These animals die within the first two days. (Respectively 1 and 2 rats from doses 330 and 385 mg/kg).

PR is a dose of 440 mg/kg phenomena of intoxication develop 30-60 minutes animals sitting or lying on his belly with his eyes closed, anxiety increased, gradually increasing shortness of breath and cyanosis, there is a tremor. In one animal after 1.5 hours after administration of the drug has developed clinico-tonic convulsions and came death from cardiac arrest. Two rats died during the first day.

With increasing doses up to 495 mg/kg oppression, shortness of breath and cyanosis occur slightly faster. Typically the appearance of tremor of the head. The death of animals (6/9) was observed after 2 hours and within 1-2 days. (In all probability from cardiac activity).

With the introduction of Lacocina females the symptoms of intoxication were similar to those described above. The death of animals occurred within the first day.

All surviving rats, both males and females, after 2 days, looks no different from control animals. In the future, during the two-week observation in rats revealed no signs of delayed toxicity, violations of behavioural responses (table 2), changes the weights of the internal organs (table 3), the appearance of death. Females have also not found significant changes in weight gain, while males of all experimental groups had a statistically significant decrease in the dynamics of body weight in comparison with control (table 1).

Quantitative indicators of mortality in vnutri lidochem rats dosage forms (tablets) Lacocina presented in table 4.

As can be seen from the table, males were less sensitive to Lacocina than females. Indicators LD50 for them are, respectively, 475 mg/kg 316 mg/kg

Table 1
Dynamics of body weight of Wistar rats males and females within 2 weeks after a single injection in the stomach Lacocina
Dose, Mg/kgnInitial mass, gn1Growth(%) weight in 1 weekGrowth (%) weight in 2 weeks
MALES
Control5208,6±11,2517,5±1,533,3±3,8
33010197,4±6,897,5±1,7*18,3±2,7*
38510196,4±6,680,6±1,6* 24,5±1,5
44010205,3±8,0710,5±1,4*23,2±2,4*
FEMALE
Control5203,8±10,958,7±1,815,4±1,02
33010198,9±5,169,0±0,814,6±1,2
38510193,6±5,725,4±0,913,4±0,7
4010201,2±6,225,4±1,8515,2±1,6
* the significance of differences from control P≤0,05

Table 2
Performance test "open field" in rats Wistar males and females in 2 weeks after a single injection in the stomach Lacocina
Dose, mg/kgnTime out from the center (s)Vertical racksQuantity. acts of groomingQuantity. posiden. centerQuantity. visited. the peripheryΣQuantity. visited. corners
MALES
Pin.59,4±1,36,2±0,75,6±0,55,0±1,938,6±7,343,6±9,110,6±2,1
33094,0±0,611,9±2,611,9±2,33,8±0,848,1±9,951,9±10,512,9±2,5
38 88,4±1,49,9±2,07,2±0,86,0±1,758,0±8,065,6±8,215,5±2,2
44077,0±2,410,4±1,66,3±1,13,7±1,435,6±8,039,3±9,29,7±2,0

385
FEMALE
Control58,0±2,419,6±2,76,2±1,514,6±1,9of 99.4±10,9114±12,525,4±2,2
33064,7±0,917,5±1,93,2±0,77,2±2,7for 77.2±8,2of 84.3±10,819,3±1,6
218,0±7,019,0±1,05,0±2,08,0±2,078,5±10,586,5±12,521,5±3,5
440212,5±1,515,0±1,02,5±1,53,5±0,574,5±11,578,0±12,019,0±3,0

Table 3
Weights of organs of Wistar rats, males and females 2 weeks after a single injection in the stomach Lacocina
Dose, mg/kgnNadmocan., mg %The thymus, %HeartSpleenKidneyGonadLiver
MALES
Control5 0,218±0,02of 0.337±0,010,785±0,06China 0,686±0,031,038±0,054,1±0,05
330918,8±0,80,153±0,010,339±0,010,633±0,030,752±0,021,119±0,14,1±0,19
385818,69±0,70,172±0,010,330±0,01China 0,686±0,040,663±0,021,125±0,024,2±0,08
440718,2±1,20,176±0,020,326±0,010,695±0,06of 0.625±0,011,093±0,034,3±0,14
FEMALE
Control30,8±1,7 0,200±0,020,308±0,030,544±0,050,649±0,034,4±0,19
33030,6±1,00,199±0,020,341±0,010,636±0,060,661±0,034,4±0,12
38530,9±2,40,250±0,020,330±0,010,704±0,010,766±0,124,6±0,15
44028,6±300,272±0,010,316±0,040,614±0,10,660±0,034,8±0,12

Table 4
Indicators of acute toxicity of combined drug Lamzin at cu is with Wistar
GroupLD, mg/kgLD50, mg/kg
Males362 (315÷416)475 (402÷560)
Female253 (214÷298)316 (282÷363)

Classification Sapelnikov Lamzin refers to preparations of moderate toxicity.

The overall pharmacological activity of Lacocina

The pharmacological activity of the combined funds of Lacocina investigated in mice and rats. In this case, as a rule, used 1 and 5 therapeutic doses, recalculated on the surface of the body of animals. One therapeutic dose for mice and rats respectively 18,86 and 9.43 mg/kg

The impact on the overall excitability and some neurotransmitter systems of the CNS

To study the effect of drugs on CNS function method is used pharmacological analyzers, based on the fundamental principle of physiology, according to which physiological reaction depends not only on the force of the impact (in this case the dose of the pharmacological agent), but, significantly, from the initial functional state of the Central nervous system.

Below is a study of the influence of Lacocina basic neuro-mediator system goal the main brain of animals (choline-, dopamine - and GABAergic) and the sensitivity of the Central nervous system of animals to the action of convulsant agents (strychnine, korazol) and drugs (geksenal).

Effect on sensitivity to drugs and convulsive tools

Narcotic agents

One of the criteria for the assessment of Central nervous system when exposed to any pharmacological substances is to study the sensitivity of animals to drugs. For this purpose, we studied the drug effect geksenala according to the criterion of duration narcotic sleep on the background of a single injection of Lacocina. Experiments were performed on 30 mice (CBAxC57B16)F1 - males weighing 20-22, Lamzin was introduced into the stomach in starch gel 40 minutes before geksenala (70 mg/kg intraperitoneally in a volume of 0.1 ml per 10 g of body weight).

It is established that Lamzin used in doses does not affect the duration geksanalem sleep.

Analepticheskih tools

The analeptics are Central nervous system stimulants General steps. They either increase the excitation process, facilitating neuronal transmission of nerve impulses, or depress the brake mechanisms. There are analeptics on almost all levels of the Central nervous system, however, each of the products is more pronounced trapnest for certain parts of the Central nervous system. T is to, korazol has a predominant effect on the centers of the medulla oblongata, strychnine - on the spinal cord.

Based on the foregoing, korazol is the appropriate analyzer to assess the overall excitability of the CNS under pathological conditions and the introduction of drugs.

Korazol directly excites the various departments of the Central nervous system and is analeptics a wide spectrum of action. Although the mechanism of stimulating effects on the Central nervous system remains largely unclear, it was found that the effects of corazol associated with extrasynaptic effect on the membrane structure of neurons, increasing their conductivity for sodium ions and oppression for chlorine ions.

Thus, the effect of corazol is generalized and non-specific in relation to various neurotransmitter systems of the brain. From this point of view korazol is the appropriate analyzer to assess the overall excitability of the Central nervous system in the application of the studied drugs.

The study convulsive action of corazol held on 30 mice (Swahs B16) F1male weighing 20-23 g Korazol dose of 50 mg/kg was administered subcutaneously (0.1 ml aqueous solution of 10 g of body weight) after 40 min after intragastric administration of Lacocina, registered convulsions.

Served as control mice, in which the stomach was introduced starch gel 0.1 ml/10 g found that Lamzin in ADNOC is based therapeutic doses has no effect, and five times therapeutic dose was increased convulsive effect of corazol.

The effect on the cholinergic system

Central M-cholinergic system

Along with the action on postganglionarnyh parasympathetic nerves M-cholinomimetic arecoline has a Central action, which is manifested, in particular, in the tremor. This is based on the use of arecoline as analyzer status of the cholinergic system.

The experiments were conducted on 54 mice CBAxC57Bl6(F1) weighing 20-24, Lamzin was introduced into the stomach 40 minutes before arecoline. The latter was used at a dose of 20 mg/kg in 2% aqueous solution of 0.1/10 g subcutaneously. Register beginning tremor and completion rates for each mouse individually, and then calculated the duration of the tremor. Compared the duration arecoline tremor control and experimental animals. The obtained results show that the sensitivity of Central M-cholinergic system to the action of arecoline under the influence of Lacocina not significantly changed.

Central N-cholinergic system

To study the effect of the studied drugs on the N-cholinergic system of the brain used N-cholinomimetic Central actions of nicotine.

The experiments were performed on 28 mice - males (CBAxC57Bl6)F1weighing 20-23, Lamzin was introduced in guludo is in starch gel 40 minutes before application of nicotine (10 mg/kg subcutaneously). N-cholinergic effects were assessed for the effect on the duration of convulsions caused by nicotine.

It is established that Lamzin in both tested doses increased the duration of nicotine convulsions.

Effects on the GABAergic system

γ-Aminobutyric acid (GABA) - biogenic substance contained in the Central nervous system and is involved in the metabolic processes of the brain. According to current data GABA is a neurotransmitter of the Central braking. On the state of the GABAergic system was judged by the severity of the actions thiosemicarbazide (a substance that inhibits the formation of GABA).

The experiments were conducted on 30 mice (CBAxC57Bl6)F1male weighing 20-23, Thiosemicarbazide was administered at a dose of 10 mg/kg, intraperitoneally, in the form of a 0.1% aqueous solution of 0.1/10 g weight. The influence of thiosemicarbazide were taken into account individually for each mouse on the stopwatch. Were recorded during the administration of the drug, the symptoms of his actions (tremor, jerking, convulsions), the time of the disappearance of symptoms. For each mouse was calculated period of hyperexcitability. Lamzin was introduced into the stomach for 40 min to TJC. The introduction of Lacocina 1 and 5 times the dose significantly affect the effects of thiosemicarbazide.

Impact on serotoninergicescuu system

The influence of Lacocina on the serotonergic system in mice studied what about the test Head twich" (nodding). The experiments were conducted on 34 mice (CBAxC57Bl6)F1male weighing 20-23, 5-Oxidation (5-Hydroxy-DL-tryptophan, the company Sigma) was administered intraperitoneally at a dose of 150 mg/kg (15 mg/1 ml, 0.1 ml/10 g weight). Lamzin was introduced into the stomach 40 minutes before oxidation 1 and 5 doses in a volume of 0.1/10 g mouse. Registered average number of kiwani in the control and experimental groups for 2 minutes. Studies have shown that Lamzin in both doses enhances the effect of 5-oksitriptofana.

The influence of Lacocina on the function of the cardiovascular system and respiration

The effect of Lacocina after intragastric administration

Experiments performed on rats male Wistar mass 250-330, Lamzin was administered as a suspension in 1% starch gel once in the stomach 1.5 or 10 doses.

Control animals received placebo orally introduced a 1% solution of starch gel. Rats were narcoticyou by thiopental sodium (60 mg/kg/b) and recorded the frequency of respiratory movements (NPV), heart rate (HR), blood pressure in the left carotid artery, systolic and diastolic (SBP and Add), as well as characteristics of the electrocardiogram in three standard leads (ECG) through 40, 60, and 90 minutes after administration of one dose of Lacocina.

To monitor and control processing of the investigated physiological parameters COI is litovali device Polygraph RM-6000 (Nihon Kohden, Japan) and cardiograph (Nihon Kohden, Japan). Statistical processing of the research results was performed using parametric criteria: t - student criterion (applied Statistica 5.5).

Studies have shown that a single oral administration of Lacocina in a single, five-and ten-fold doses did not cause rats visible sharp differences of indices of cardiovascular activity and respiration in comparison with the control animals. Procedure of introduction of the mixture did not cause adverse reactions in animal behavior.

Hemodynamics and respiration.

After 40 minutes after administration of a single dose of Lacocina blood pressure (SBP and Add) were lower than control values, and the breathing frequency was higher. This trend has increased to 60 and 90 minutes of observation: the BPA experienced rats significantly below control, Add significantly lower, and the breathing frequency was higher than in the control animals. When this pulse rate had a tendency to decrease.

A five-fold increase in dosage of the investigational formulations did not cause such changes: the value of the BPA for 90 minutes after injection of the mixture did not differ from performance monitoring, the value of the Add is moderately lowered, the indices of heart rate and breathing rate practically does not differ from the control. All study is pokazateli remained stable throughout the 90 minutes of observation.

A tenfold increase in dosage formulations did not cause abrupt changes of indicators. The BPA for 90 minutes research almost not changed, remaining at the level of the control, Add, as in the previous group, moderately reduced. Noteworthy clear dynamics increase heart rate and breathing rate in animals of this group, increasing to 90 minutes of observation.

Biological and Electromechanical activity of the heart.

Analysis of the features of automaticity, conduction and excitability of the myocardium, to ensure a proper coordination of the cuts between the different portions of the heart muscle and the heart, showed that the studied formulation in the tested doses did not have them expressed negative impact: all animals cardiocel regular heart rhythm correct, sinus. Rate RR in all experimental animals did not differ significantly from controls throughout the study period.

Conductivity fibrillation under the influence of formulation components increases slightly: all experimental rats tendency to shortening of interval PQ. In the group that received 1 dose of the formulation, this distinction reliably, in other groups is not due to the large difference Sigma.

Anxiety fibrillation in rats that received one dose Rotz the tours, also slightly increased: increasing the amplitude of P in all experimental rats. The difference is significant according to the t-criterion of student groups that received 1 and 5 doses of the formulation. In the group "10 doses" dispersion comparable indicator differ significantly.

The duration of P in the group " 1 dose of" Lacocina slightly shortened, and in group 5 doses - slightly increased.

Depolarization of the ventricles of the heart has hardly changed under the influence of formulation components. This is evidenced by the strong performance of the amplitude of the R-wave and the duration of the ventricular QRS complex.

The fading processes of excitation of the ventricles and periods of slow depolarization and rapid ventricular repolarization in animals in group 5 doses" and especially "10 doses differ from control (increased ST segment and an increase in the amplitude of the T). It is seen that increasing cardiotonic action at higher doses causes moderate myocardial ischemia.

These changes are confirmed by the rotation of the electric axis of the heart: most experimental animals she takes a horizontal position.

Thus, studies have shown that oral fivefold dosage Lacocina in 1% solution of starch gel almost no vivinet animals changes of hemodynamics and respiration.

Single dose results in the reduction of blood pressure and an increased frequency of breathing (level trends).

A tenfold increase in dosage has virtually no effect on the parameters of blood pressure, however, tends to increase heart rate and breathing rate.

Lamzin has a distinct cardiotonic action, which is manifested by an increase in the excitability and conductivity of the Atria, the rotation of the electric axis of the heart in the horizontal position.

The effect of Lacocina intraperitoneal injection

Experiments were performed on 14 rats male Wistar mass 230-300 g, received intraperitoneally once one or five doses of Lacocina in physiological solution.

Rats were narcoticyou by thiopental sodium (60 mg/kg/b) and record the original settings of the frequency of respiratory movements (NPV), heart rate (HR), blood pressure in the left carotid artery, systolic and diastolic (SBP and Add), as well as characteristics of the electrocardiogram in three standard leads (ECG). Then intraperitoneally injected with Lamzin (1 or 5 doses) and continued registration of these indicators within 40 minutes.

To monitor and control processing of the investigated physiological parameters used the Polygraph instrument RM-6000 (Ninon Kohden, Japan) and cardiograph (Ninon Kohden, Japan). Statistical processing of the research results was performed using t-test, t-test and Fisher's exact test, and nonparametric U-KRI is a series of Mann-Whitney (application package Statistica 5.5).

Studies have shown that a single intraperitoneal injection of recipes in single or five doses did not cause rats visible sharp differences of indices of cardiovascular activity and breathing.

Hemodynamics and respiration.

The introduction of a single dose of Lacocina did not modify the values of arterial blood pressure during the entire observation period. Introduction five doses caused a moderate but significant decrease in SBP and indicators Add virtually no different from the original. The pulse rate of the rats in both groups were increased in the group receiving 5 doses in 15 minutes observing these differences are significant and reliable. Respiratory rate, high enough source in this sample of rats was also increased in both groups, for 40 minutes reaching significant differences. This effect is probably due to some stimulation of the respiratory and vasomotor centers and increased cardiac activity by caffeine, which is part of Lacocina.

Biological and Electromechanical activity of the heart.

Analysis of the features of automaticity, conduction and excitability of the myocardium, to ensure a proper coordination of the cuts between the different portions of the heart muscle and the heart, showed that Lamzin in tested doses as it turns out the l on them noticeable effect: all animals cardiocel regular, heart regular rhythm, sinus. Rate RR in all experimental animals had a distinct tendency toward shortening, its values in the group "5 doses significantly below the original (tabl, 4.12). This is due to the cardiotonic action of caffeine.

Conductivity fibrillation under the influence of Lacocina practically unchanged (PQ interval).

Anxiety fibrillation in rats that received one or five doses, almost not changed (amplitude and duration P).

Depolarization of the ventricles was almost unchanged. This is evidenced by the strong performance of the amplitude of the R-wave and the duration of the ventricular QRS complex.

The fading processes of excitation of the ventricles and periods of slow depolarization and rapid ventricular repolarization in animals in group 1 dose" almost does not change the performance of the ST segment amplitude and wave T, and in group 5 doses have been a clear trend to increase of these indicators, which is probably associated with increasing cardiotonic effect of the drug.

These changes did not, apparently, a pronounced negative impact on the cardiovascular activity of the animals: all the experimental rats in studies of the electrical axis of the heart is almost not changed its direction.

Thus, studies have shown that intraperitoneal what purpose once or five times the dosage of the combined funds of Lacocina practically does not cause animals to changes in hemodynamics and respiration.

The purpose of the investigated formulations in a single dose slightly lowers systolic blood pressure, moderately increases the heart rate and breathing.

A five-fold increase in dosage practically significantly lowers systolic blood pressure, does not affect diastolic blood pressure significantly increases heart rate and significantly speeds up breathing.

All the described effects are caused, apparently, by a moderate stimulation of the respiratory and vasomotor centers, and cardiotonic action of the components of Lacocina.

The influence of Lacocina on the motor-evacuation function of the gastrointestinal tract in mice

The experiments were performed on 30 mice - males. The day before the start of the experiment the animals were deprived of food with free access to water. Lamzin was introduced into the stomach 1 hour before injection into the stomach indicator suspension 50% barium sulfate 1% starch gel (0.2 ml per mouse). Control animals instead of medication received water. After 30 minutes, mice were sacrificed stretching of the cervical spine, were investigated and determined the distance of passage of the indicator in the small intestine in percent relative to its total length. The results of experiments on mice show that Lamzin has antiperistaltic action.

The study of immunotropic, immunotoxic and allergenic properties of Lacocina.

SV is istwa combined pharmacological tools Lacocina investigated in mice and rats. In this case, as a rule, used 1 and 5 therapeutic doses, recalculated on the surface of the animal body.

Assessing the impact of Lacocina on humoral immune response

The work was done at 40 mice-hybrids F1(CBAxC57BL6), males and females, weighing 20-25 g, kept in vivarium conditions on a standard diet. The primary humoral immune response was assessed by the ability of mice to form in the spleen antibody productive cells (AFC) on the antigenic stimulus. For this purpose, animals were injected intraperitoneally thymusdependent antigen - sheep red blood cells (EB) at a dose of 5×107cells in the mouse. After 4 days was determined by the weight and cellularity of the spleen and thymus, and the spleen - contents KLA method Cunningham. Lamzin was dissolved in distilled water and introduced into the stomach of one or five doses in a volume of 0.2 ml per 10 g of body weight for 1 day prior to immunization of the animals. The control group of mice instead of the drug was administered with an appropriate volume of distilled water. Each experimental group consisted of 10 animals. The significance of differences of the results of the experiments were determined using t-student test.

With the introduction of a single dose of the combined funds mice males - mass, cellularity of the spleen and the content of the KLA, and the thymus weight was not changed.

The introduction of Lacocina five times the dose females call which provides stimulation of the humoral immune response. The mass of the spleen and thymus remained at the control level. However, the cellularity of the spleen was slightly decreased.

Thus, Lamzin on mice-females in the high dose has a stimulating effect on the primary thymusdependent humoral immune response, but slightly reduces the cellularity of the spleen.

Assessing the impact of Lacocina on the cellular immune response

Influence of Lacocina on the reaction of hypersensitivity of the delayed type.

Cellular immunity was evaluated by the reaction of hypersensitivity of the delayed type. For this purpose mice (30 animals) were senzibilizirani intraperitoneal introduction of EB dose of 5×107cells per mouse in a volume of 0.2 ml of saline. After 5 days under aponeurotic plate of one of the hind paws (experience) EB was injected at a dose of 1×108cells in a volume of 50 μl, and in the contralateral paw of 50 ál of saline (control). After 24 h, the mice were scored by dislocation of the cervical vertebrae, cut off the legs at the level of the ankle joints was determined by their mass, and calculated the index response (IR) according to the formula:

where Mo is the mass of experienced paws, g;

MK is the mass of the control legs,

Each experimental group consisted of 10 animals. Lamzin was dissolved in distilled water. One or five mice doses of the drug enter the and per os in a volume of 0.2 ml per 10 g of body weight per day to sensitization of animals EB. Control mice received an equal volume of distilled water. As follows from the data obtained in mice exposed to Lacocina, index hypersensitivity reactions of the delayed type is not changed. Thus, Lamzin no effect on the reaction of hypersensitivity of the delayed type.

Determination of the effect of Lacocina on phagocytic activity of peritoneal macrophages

In the paper, we used a mouse-males (57l6) F1 body weight 25-26, Animals were injected with the drug orally in single and five-fold (mouse) dose volume of 0.1 ml/10 g body weight. Control animals were injected with the solvent in the same amount. Through the day the animals experimental and control groups were killed with ether and washed the abdominal cavity 3-4 ml of medium 199 with 10%fetal serum. The obtained cells of peritoneal exudate were washed with medium 199 and counted in the camera Goryaeva the number of cells in the exudate, reducing their concentration to 2 million/ml Phagocytophilum particles were cells of Staphylococcus (Staph. aureus), killed by heating and opsonization polovoy mouse serum. The opsonization was performed for 10 min at 37°C, followed by money laundering and bring the concentration up to 20 million/ml For suspension cells of peritoneal exudate in the amount of 1 ml was added an equal volume of cells of Staphylococcus. After 30 minutes of th the incubation at 37°C were prepared smears (by analogy with dabs of blood), on a glass slide was evaluated by phagocytic number and index, followed by fixation in absolute alcohol and coloring according to Romanovsky-Ginza ability Lacocina affect the absorption stage of phagocytosis.

The experiments showed that in the control samples, the number capable of macrophages phagocytose ranged from 88 to 98% and the average was 93.6±1.7%, phagocytic index was 5.8±0.38 particles on faguoqitirute macrophage. In mice after injection of Lacocina in a single dose quantity faguoqitirute cells ranged from 64 to 94%, with an average of 84.0±5,2%, and the index of phagocytosis was 5.2±0,35. After the introduction of Lacocina five times the dose amount faguoqitirute macrophages ranged from 84 to 90%, on average - 87,2±1,0%, and the index of phagocytosis - 5,26±0,3.

Thus, the data obtained indicate that Lamzin in single and five-time dose does not affect the adsorption capacity of peritoneal macrophages. The introduction of Lacocina five times the dose only slightly modifies the parameters of physiological fluctuations in the number faguoqitirute peritoneal macrophages.

Thus, in these experimental conditions, Lacocina found no marked influence on the parameters of humoral and cellular immunity. Except that in mice-females in the high dose he has a stimulating effect the CT primary thymusdependent humoral immune response.

Assessment of the allergenic properties of Lacocina

Study of the effect of the drug on the total reaction anaphylaxis (anaphylactic shock)

Work done on rats male population "Wistar" weighing 140-150 g contained in vivarium conditions on a standard diet.

Each experimental group of animals consisted of 10 animals.

To obtain active anaphylactic shock in rats of the control and experimental groups were senzibilizirani subcutaneously (s/C) normal horse serum in a dose of 0.1 ml Immediately after sensitization, experimental animals were administered oral drugs in single and five-fold (rat) dose volume of 1 ml/100 g body weight. Control animals were injected with the solvent (distilled water) in the same volume.

To obtain anaphylactic shock after 19 days after sensitization animal experimental and control groups were injected intravenously resolution dose normal horse serum in a volume of 1.5 ml Estimation of the reaction was performed according to generally accepted chetyrehluchevoy scheme:

+ - intermittent scratching the nose, theresiana wool, a drop in body temperature at least 1°C;

++ - distinct frequent scratching, single sneezing, falling body temperature;

+++ - spastic cough, lateral position of the animal, the separation of feces and urine;

++++ - spasm digitalin the x ways, convulsive leaps, convulsions, an animal dies.

The intensity of anaphylaxis was assessed individually and calculate the index of the reaction according to the formula Vaigla:

where a, B, C, D, e - the number of animals with the corresponding estimation of the reaction: minimal (1+);

- B (2+); (3+); max - G (4+); the reaction is missing - D.

Studies have shown that in sensitized rats of the control group after the introduction of the resolution intravenous injection of normal horse serum in a volume of 1.5 ml was observed: 2 rats for short-term scratching of the nose (measuring response was - +)8-x rats distinct scratching and the occasional sneeze (the reaction is evaluated - ++). Accordingly, the index of response Weigle equal to 1.8.

Resolving injection in rats, which after sensitization were administered the study drug in a single dose, had 4 rats intermittent scratching of the nose (the estimation of the reaction - +). In 6 rats distinct scratching and the occasional sneeze - ++. Hence, the index of the reaction Weigle was equal to 1.6.

In rats that were administered the drug in a five-fold dose, reaction to allow the effect was absent in 8 individuals, and 2 rats was +. Index of response Weigle - 0,2.

Thus, the tests indicate that Lamzin one is five doses does not affect the intensity of the anaphylactic shock, in addition, Lamzin introduced rats in a five-fold dose, partially inhibits the sensitization foreign protein.

Assessing the impact of Lacocina on active cutaneous anaphylaxis

Work done on rats male population "Wistar" weighing 190-200 g contained in vivarium conditions on a standard diet. The study drug was administered in doses of 1.57 3.14 mg/kg (1/6 and 1/3 dose in rats) 0.1 ml/100 g body weight according to the following scheme. Sensitizing injections: the first subcutaneously into the fold on the back, two subsequent injection a day in the thigh. The control group animals according to the same scheme was introduced, the solvent is distilled water. The number of animals in groups: a control group of 16 rats, experienced by 10 individuals. 16 days after the sensitization experimental groups of rats were injected resolution dose Lacocina, is equal to the total sensitizing dose intradermally () in the clipped area on the back: one group of three, the other six, each in a volume of 0.1 ml/100 g Control animals were divided into two groups. One group of individuals in the lower part of the cropped area of the back was introduced to the solvent, and in the upper part of the drug three times the dose, the other group is solvent and the drug in the six-dose. 30 minutes after the resolution of injection, the animal was injected intravenously 0.5 ml of 1% dissolve the and Evans blue. 30 minutes after the last injection the animals were killed with ether, and determine the size colored spots on the inner side of the skin at the injection site.

Experiments have shown that in rats sensitized by Lacocina in a single dose according to the above diagram, the diameter of the colored spots on the introduction of the resolving dose ranged from 8.0 to 12.5 mm and averaged at 10,35±0,44 mm After sensitizing injections of the drug in a double dose of the diameter of the colored spots ranged from 6.0 to 14 mm, with an average of 9.6±0,95 mm

In control animals the diameter of the colored spots on the injection of a single dose of Lacocina accounted for 11.0±0.68 mm, double - 11,5±0,62 mm After the injection of the solvent, the spot diameter was equal to 4.68±0,84 mm

Thus, the results of these studies indicate that Lamzin with the introduction of single and double doses of allergenic properties is not. On the basis of the conducted research it can be concluded that Lamzin used in doses has no immunotoxic, allergenic and anaphylactogenic properties

The study of the specific activity of Lacocina

The results of experiments on dogs have shown that prophylactic (15 min) oral administration of combined HP Lamzin animals irradiated at a dose of 30 the R, reduce the severity of the syndrome without primary reaction to radiation. As can be seen from the data presented in table 5, the use of the drug Lamzin at a dose of 1 tab. the animal leads to a significant decrease in the total number of emetic acts, duration, without a period and increase the time to first vomiting act compared to animals of group Control exposure". Exposure to dogs at a dose of 30 Gy caused all the animals natural development without reaction: average time to first vomiting act was 27 minutes after the impact, the duration of the period without reactions ranged from 134 min to 177 min, and the average number of acts of vomiting was 14. Prophylactic administration of Lacocina resulted in reduced severity without reactions in irradiated dogs. Preventive action of the drug Lamzin manifested in significantly reducing the number of emetic acts (the average value in the group - 5) and the duration of the period without a response (to 22.5 min), the time of appearance of the first vomitoxin act significantly increased and amounted to 115 minutes (the average value in the group).

To address the question about the optimal dose of drug was carried out series of experiments in which dogs received Lamzin dose of 6 tablets per animal. The choice of this dose would be is due to the fact, according to data obtained Megladon (1998), the optimal dose of latrine for dogs is 2.4 mg/kg, This dose of an antiemetic is provided by the introduction of 6 tablets for animal weighing 20 kg As can be seen from the data presented in table 5, increasing the dose Lamzin to 6 tab. the animal leads to a significant reduction manifestations without reaction to radiation. At the same time, significant differences between groups of animals that received 1 tab. or 6 tab., could not be detected. Therefore, in subsequent experiments on dogs, the animals received the drug Lamzin at a dose of 1 tab. on the animal.

Table 5
The influence of Lacocina on salivation and vomiting in dogs (irradiation dose of 30 Gy, n=6 in each group, M±m)
Experimental groupThe dose of the drug, tab./animalFrequency salivation, %Vomiting
Frequency %The time of appearance, minDuration, minNumber
Control exposure 100-8100-827,5±14,4155,7±21,714±2
Lamzin133±19*83±5*115,0±59,8*22,5±20,7*5±2*
625±16*78±5*130,0±65,0*18,4±15,2*3±1*
* - the difference is significant compared to the group Control exposure (P≤0,05)

Drug Lamzin has antidiarrheal activity. As can be seen from the data presented in table 6, in animals that were administered the drug, there was no urge for defecation, decreased the average value of the acts of defecation and increased the time to first defecation compared with similar indicators of the group "Control of exposure".

Table 6
Antidiarrheal activity of Lacocina in dogs (irradiation dose of 30 Gy, n=6 in each group, M±m)
Experimental groupThe number of urgesThe time of appearance of diarrhea, minFrequency of defecation, %The number of acts of defecation
Control exposure2,0±1,037,5±12,567±71,5±0,5
Lamzin0,0±0,0*77,5±76,1*40±5*0,8±0,8
* - the difference is significant compared to the group Control exposure (P≤0,05)

In experiments on the second form of animals - rats was studied propulsive activity of the intestine and its absorption capacity. Index propulsive activity (IPA) reflects the motor-evacuation function of the intestine and is calculated as the ratio of the filled area to the total length of the colon. Experimental data show that irradiation increases the rate of passage of barium suspension in the intestine of rats 1.2 times. The introduction of Lacocina helps to slow this process. Thus, the introduction of the drug in doses of 0.5, 1 and 2 tab. per kg of body weight of the animal for 30 min before irradiation at a dose of 100 Gy leads to a decrease in the size of the IPA is about 61,42 and 32%, respectively. Differences in IPA with the introduction of 1 tab./kg 2 tab./kg differ by 10%. Thus, the optimal dose of the drug Lamzin for rats is 1 tab./kg, This dose was used in further experiments on rats. The effect of reducing the propulsive activity of the intestine after the introduction of Lacocina appears in 5 min after injection and lasts for 1 hours

Table 7
The effect of different doses and timing of administration Lacocina on the propulsive activity of the intestine of rats (irradiation dose of 30 Gy, n=12 in each group)
Experimental groupThe dose of the drug, tab./kgThe term preventive injection, minIndex propulsive activity (M±m)%
Biocontrol--71±3
Control exposure-3088±3*
Lamzin0,53061±5**
1 542±4*,**
13042±4*,**
16053±3*,**
23032±8*,**
* - differences significant (P≤0,05) in comparison with group "biological control";
** - differences significant (P≤0,05) in comparison with a group of "Exposure" (control)

Adsorption bowel function was assessed in rats according to the method, based on measurement of the fluorescence of the plasma after intragastric administration of fluorescein. As can be seen from the data presented in table 7, the irradiation leads to slower absorption of fluorescein in blood 1.4 times. Prophylactic administration of Lacocina dose of 1 tablet per kg 30 min before irradiation restores the suction function of the intestine.

Table 8
The effect of prophylactic administration of Lacocina on the adsorption function of the intestine of rats (irradiation dose of 30 Gy, n=12 in each group)
The experience is imentally group Ratio, %
Biocontrol22,9±2,1
Control exposure17,0±1,8*
Lamzin24,6±2,2**
* - differences significant (P<0.05) as compared with group "biological control";
** - differences significant (P≤0,05) in comparison with group Controlling irradiation"

As can be seen from the data presented in table 9, the irradiation dose of 100 Gy caused diarrhea in 83% of animals, which started already during the exposure. The introduction of Lacocina leads to a decrease in the incidence of diarrhoea in 4 times compared to the group Control exposure".

Table 9
The effect of prophylactic administration of Lacocina on the incidence of diarrhoea in rats (exposure dose of 100 Gy, n=24 in each group)
Experimental groupAbsolute valueFrequency %
Control exposure3083±6
Lamzin520±8*
* - differences significant (P≤0,05) in comparison with group Controlling irradiation"

Thus, Lamzin in the tested dose is effective antidiarrheal agent that promotes the normalization of propulsion and sucking activity of the intestine of rats. The optimal dose combination drugs Lamzin for humans is 1 tab.

To clarify the question about the influence of the drug Lamzin on radiation-induced physical inactivity experiments on rats irradiated at a dose of 100 Gy.

As can be seen from the data presented in table 10, in animals that received the drug Lamzin, moderate (1.2 times) increased locomotor activity and decreased (1.4 times) time fixed seat. Such indicators as the number of vertical columns and mink reactions was almost unchanged. Irradiation leads to reduced behavioral activity, reflected in the decline in motor activity (1.7 times), uprights (2 times) and increase the total time of the fixed seat (2.4 times) in comparison with the similar performance of the group "biological control". Prophylactic administration of the drug Lamzin leads to normalization of indicators of behavioral activity. Thus, the motor is the activity of animals, received before irradiation Lamzin, 1.7 times greater than the corresponding group index "Control of exposure". The time fixed seats animals in a group Lamzin was superior to group index "Control exposure" 3 times.

Table 10
The influence of Lacocina on behavioral activity of rats 30 min after irradiation (test "open field", the irradiation dose of 100 Gy, n=10 in each group, M±m)
Experimental groupMotor activityThe number of vertical racksThe number of mink reactionsThe time fixed seat,
Biocontrol66,8±8,78,9±2,42,3±1,645,4±19,6
Lamzin82,0±17,910,5±3,72,7±0,432,6±15,5
Irradiation39,4±17,2*4,5±1,7*1,2±0,5 107,0±34,3*
Lamzin + irradiationto 69.4±25,2**6,7±3,83,3±0,4**35,1±25,2**
* - the difference is significant compared with the group "biological control" (P≤0,05)
** - the difference is significant compared to the group of "Exposure" (P≤0,05)

Table 11 presents the indicators of behavioral activity of rats after 60 min after irradiation. As can be seen from the presented experimental data, outcomes measured in different experimental groups were almost at the same level. You should note that under Lamzin time fixed seat was 2 times lower than in the group "biological control". This fact may be due to "exhaustion" due to the stimulating effect of caffeine.

Table 11
The influence of Lacocina on behavioral activity of rats after 60 min after irradiation tests (open field, the irradiation dose of 100 Gy, n=10 in each group, M±m)
Experimental groupMotor activity The number of vertical racksHP usledThe time fixed seat,
Biocontrol68,2±18,49,2±5,42,7±1,540,2±18,4
Lamzin65,6±20,69,5±3,73.3V±1,621,6±5,4*
Irradiation56,5±30,16,0±1,42,3±1,437,6±17,0
Lamzin + irradiation60,6±21,88,1±4,82,3±1,634,1±24,8
* - the difference is significant compared with the group "biological control" (P≤0,05)

1. Medicine with preventive action for relief of the primary reaction to radiation and the early transient incapacitation containing ondansetron and metacin, characterized in that additionally introduced pharmacologically active agent caffeine in a mass ratio of ondansetron:metacin:caffeine 4:1:20-300.

2. The drug according to claim 1 characterized in, it is a tablet dosage form.

3. The drug according to any one of claims 1 and 2, characterized in that it is a tablet dosage form coated.

4. The drug according to any one of claims 1 and 2, wherein said 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-one used in the form of the hydrochloride dihydrate.

5. The drug according to any one of claims 1 and 2, characterized in that the ondansetron:metacin:caffeine use in a weight ratio of 4:1:50-100.



 

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6 tbl, 9 ex

FIELD: chemistry.

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FIELD: medicine, pharmaceutics.

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FIELD: medicine; pharmacology.

SUBSTANCE: wood of Siberian or Daurian larch is debarked, cleaved and dried at 40-50°C to residual moisture 23-27%. Dried wood is chopped, and soluble substances are extracted with 75-85% ethyl alcohol aqueous solution at temperature 45-50°C in ratio raw material:extracting agent 1:(7-10). Further extracting agent is distilled off, and sawdust is supplied to press for additional alcohol return. Then extract aqueous part is cooled to 20-25°C within 20-30 minutes for isolation of resinous impurity accompanying dihydroquercetin (DHQ). Deresined extract aqueous part is added with methyltertbutyl ether (MTBE) in ratio 1: (0.3-0.45), and DHQ is reextracted within 2-3 hours. Extract ether part is isolated separate from aqueous part through sedimentation within 2-2.5 hours and supplied to MTBE evaporation, while target product is crystallised of hot water. Invention enables to produce DHQ with yield 2.2-2.5% of bone-dry wood mass with grade 90-96%.

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1 ex

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