Complex antibacterial agent for animals
FIELD: veterinary medicine.
SUBSTANCE: complex antibacterial agent for animals, containing a compound from the group of fluoroquinolones and auxiliary substances, characterised in that it additionally comprises a compound from the group of pleuromutilins in an effective amount.
EFFECT: invention is effective against vegetative and spore forms of bacteria, it is harmless, has no allergenic properties, has a stimulating effect on the indices of humoral immune response, and is stable during storage.
6 cl, 9 ex
The invention relates to veterinary and can be used for therapeutic or preventive treatment of respiratory and gastrointestinal diseases of bacterial and mycoplasmal etiology, including enzootic pneumonia, pleuropneumonia, salmonellosis, pasteurellosis, mycoplasmosis, colibacillosis and other infections in animals, particularly in pigs, chickens and turkeys.
Pigs and poultry are among the most intensively developing branches of the national economy. A distinctive feature of these industries are medium-sized or large farms with complex epizootic situation. The factors acting negatively in terms of complexes, is the content of a large number of animals in a limited area, the growing number of immunocompromised animals with metabolic disorders and immunodeficiencies. Additionally complicating the situation is not always favorable environmental conditions. All this often leads to the emergence and rapid spread of various diseases. Sick animal is a source of further spread of infection, even if clinical signs are seen in obliterated or latent. Thus, in the complex of measures against contagious animal pathology, along with specific prevention and veterinary-sanitary�mi events still one of the leading places should be given to the use of effective antimicrobial drugs.
Antibiotic therapy is an essential component of effective integrated treatment of animals. However, the widespread uncontrolled use of antibiotics in previous decades led to the growth of antibiotic resistance of field strains of different pathogens that form of Association. The treatment of infectious diseases caused by such microorganisms and their associations, remains a challenge both in terms of productive, and for small Pets. Because these diseases cause significant economic damage, the fight against them is an urgent task.
In accordance with the above, due to the widespread resistance of infectious agents applied to many antibiotics are constantly searching for new chemotherapeutic antibacterial drugs with different mechanism of action.
Research of domestic and foreign authors suggest that the most effective are comprehensive preparations on the basis of modern highly active substances, the combination of which produces a synergy effect and a wide range of sensitive drug microflora.
Currently due to high cha�tote use in clinical practice and significant role in the treatment of infectious processes in the first ranks of fighters with microbes" are quite rightly fluoroquinolones. Quinolones and fluoroquinolones in particular have no analogues in the natural environment, which ensures their high activity against multidrug-resistant strains of microorganisms. Also described cases of the formation of resistance in microorganisms after prolonged use of fluoroquinolones.
Famous drugs with a broad spectrum of action, which include fluoroquinolones (see, for example, CN 102846615 A, 02.01.2013, WO 2009136408 A1, 12.11.2009, KR 20090102053 A, 30.09.2009, EP 1880722 A1, 23.01.2008, drug Ciproral - Internet address: http://vetsintez.com.ua/catalog/at2 LTD. vaccines, 18.10.2011).
The closest analogue of the claimed drug is Ciprocal.
The drug is produced in Ukraine and contains a compound from the group of fluoroquinolones - ciprofloxacin and polypeptide antibiotic is colistin sulfate and excipients.
The disadvantage of the drug is the inconvenience of its use - the drug is available in capsules and it is recommended to use in combination with ascorbic acid (vitamin C), first dissolved in water ascorbic acid, then the drug.
The object of the invention is the development of domestic antibacterial drug with a combined mechanism of action, highly effective against mixed antibiotic-resistant infections in animals, maloto�lichnogo and stable during storage.
The problem is solved in that the developed complex antibacterial drug for animals, which contains a compound from the group of fluoroquinolones, auxiliary substances and, according to the invention further comprises a compound from the group of pleuromutilins in effective amounts.
The problem is solved also by the fact that the drug contains compounds from the group of fluoroquinolones and out of a group of pleuromutilins in a ratio (in wt.h.) 1:3.0-1:225.0
In addition, the problem is solved in that the fluoroquinolones claimed the drug contains ciprofloxacin or pefloxacin or ofloxacin, or enrofloxacin or norfloxacin, or lomefloxacin, or levofloxacin, or moxifloxacin or sparfloxacin, or enoxacin.
The task can be solved by the fact that as pleuromutilins the claimed preparation contains tiamulin hydrogen fumarate or tiamulin.
As auxiliary substances for the task it is advisable to use sugar and sugar - powdered sugar, or glucose, or fructose, or dextrose, or lactose or lactulose.
The technical result obtained by implementing the claimed invention, is that the drug has a pronounced antimicrobial action on gram-negative and gram-positive microflora, this effectively acts as on vegetative and spore forms of bacteria are harmless, can effectively treat a wide range of diseases of bacterial etiology in animals in the absence of data on the pathogen and its sensitivity to antibiotics, has no allergenic properties, has a stimulating effect on the humoral immune response and stable during storage.
The mechanism of action of the claimed preparation is based on the ability of fluoroquinolones to inhibit the activity of gyrase enzyme that replicates DNA in the bacterial cell, as well as the disruption of the membrane of bacterial cells and elimination of R-plasmids, which hinders the development of microbial resistance to the drug, and the suppression pleuromutilins protein synthesis of bacteria by binding to 70S-ribosome subunit of microorganisms and violations of the process of formation of the complex m-RNA-tRNA" microbial cell.
Fluoroquinolones have a broad spectrum antibacterial and antimycoplasmal action. Active against gram-positive and gram-negative bacteria, including Echerichia coli, Salmonella spp., Shigella spp. Klebsiella spp. Enterobacter spp. Proteus spp. Yersinia spp, Haemophilus spp., Pseudomonas aeruginosa, Pasteurella multocida, Plesiomonas shigelloides, Campylobacter jejuni, Brucella spp., Chlamydia trachomatis, Listeria monocytogenes, Mycobacterium spp., Corynebacterium diphtheriase, Staphylococcu aureus and Streptococcus spp. as well as Mycoplasma spp.
The maximum concentration of fluoroquinolones in serum is celebrated, usually in 1.5-2 hours, therapeutic concentration is maintained for 24 hours after oral drug administration. Excreted mostly unchanged and partly in the form of metabolites in urine and bile.
The degree of impact on the body fluoroquinolones are moderately hazardous substances (3 hazard class according to GOST 12.1.007-76).
Pleuromutilin bacteriostatic activity against mycoplasmas, including M. hyopneumoniae, M. hyosynoviae, M. hyorhinis, M. gallisepticum, M. synoviae, M. meleagridis, spirochetes (V. huodysenteriae, B. pilosicoli), of gram-positive aerobes, including Staphylococcus spp., Streptococcus spp., Corynebacterium pyogenes, and anaerobes (Clostridiym perfringens), gram-negative anaerobes, including Lawsonia intracellularis, Bacteroides spp., Fusobacterium spp. and aerobes Actinobacillus pleuropneumoniae, Pasteurella multocida; no effect on bacteria of the family Enterobacteriaceae, including Salmonella spp. and Echerichia coli.
After oral administration pleuromutilin quickly absorbed in the gastrointestinal tract and penetrate into most tissues and organs, reaching maximum concentrations in the organism of birds after 4 hours in the body of pigs - in 2 hours, and maintained at therapeutic level for 18-24 hours. Excreted mainly in the faeces.
Pleuromutilin on St�interest effects on the body are moderately hazardous substances (3 hazard class according to GOST 12.1.007-76): LD50 when administered orally to white mice 700 mg/kg weight of the animal.
The invention is characterized by the following exemplary embodiments, which, in turn, limit the scope of the claims of the applicant.
Example 1. Receiving drugs
The drug is produced by mixing of the components. The composition in one of the variants of its implementation are the following (mg/g of powder):
|of tiamulin hydrogen fumarate||365|
|powdered sugar||to 1 g|
Example 2. The study of drug toxicity
Experimental investigations were carried out on four species: white rats, white mice, pigs and chickens. Original weight of laboratory animals ranged: for rats: 180-210 g; for mice of 18-20 g. the experiment was clinically healthy animals, which previously stood at fifteen days quarantine.
Studies were performed in the acute, subacute and chronic experiments with the drug in the stomach.
Experience on determination of acute toxicity were carried out on white rats. The animals were observed for 2 weeks after administration, noting the time of death or recovery animals. Take into account the General condition of the animal�, preservation of motor function, appetite, condition of coat, breathing, reaction to external stimuli.
The study of the tolerability of the drug was conducted in a single injection of the drug in therapeutic and three to fivefold higher doses. Once the experiment was conducted on pigs and chickens.
The study of the subchronic toxicity was performed on rats, pigs and chickens with the introduction of the drug into the stomach.
In the first series of experience were involved male albino rats weighing 130-140 g. In the second series, when tested, used pigs and chickens.
The preparation was given to the animals for 20 days at doses 0,136 g DW per 1 kg weight of the animal (pigs) and 0.33 g per kg weight of the animal (chickens), which, respectively, 3 times more single recommended dose. The third group of animals served as a control, was used.
Monitoring the condition of the animals was performed for 20 days.
Using indicators of both General and specific effects of the drug.
As an integral indicators used the following: determination of body weight and evaluation of the peripheral blood of animals.
The peripheral blood was assessed using standard techniques. Determined: the amount of hemoglobin, white blood cells and red blood cells. For vychisleny� of leukogram blood were fixed with alcohol swabs and stained by Giemsa. Specific can be considered a functional state of the liver, kidney and metabolic processes in the body (protein and nitrogen exchanges).
The functional state of the liver was assessed mainly through biochemical studies.
About belkovosvazavatei liver function was measured by the protein content in the serum. This figure was determined by color reaction with orthotoluidine.
The study of the functional state of the kidneys was performed on a complex of methods: diuresis was measured, was determined by urine specific gravity and pH, the content of urine protein, sugar and acetone bodies and indican.
Definition of protein in the urine based on the interaction of proteins with sulfosalicylic acid, in which the degree of turbidity was analyzed using photocolorimetric analysis.
The sugar content was determined by the rapid method.
Of all the products of protein metabolism the most important are contained in animal blood urea and creatinine.
In the study of the preparation took into account the impact on the content in the body K, Na, Ca, which are known to ensure the normal implementation of all functions of the body.
Data obtained from the above studies, were analyzed by the method of mathematical statistics with calculation of mean values (M), its error (±m) and level values� R.
The study of acute drug toxicity
The drug was administered into the stomach of albino rats in the form of a 50% aqueous suspension. Were tested the dose - 4,0; 6,0; 10,0 and 12,0 g/kg-BW (volume of injected suspension was 1,6; 2,4; 4,0; 4,8 ml for a rat weighing 200 g, respectively).
As a result of the research showed that the LD50funds is 8.5±0.84 g/kg-BW According to the classification (GOST 12.1.007-76) claimed the drug is a low toxic compound (4 class).
Example 3. Evaluation of the functional state of the liver after a single dose of the drug
To detect toxic effects of drugs used hexenal sample, based on the definition of hexenal sleep, and conducted experiments on white mice.
The duration of hexenal sleep due, primarily, liver function and depends on the time required for the concentration of hexanal in the blood below the level causing anesthesia. When liver disease any toxic substances disposal of hexenal is slowed, which increases the duration of sleep.
Defining the functional state of the liver of white mice after oral administration of the claimed preparation was carried out according to the method Rosina 90 nonlinear white mice weighing 18 - 20 g, which were divided into 9 groups with an equal number of mice in each: group 3 - control, 6 g�SCP - experienced. Control animals orally received saline at a dose of 1 ml per head. Half of the experimental animals were injected claimed the drug orally at a dose equal to LD (15000 mg/kg), and the second half - dose LD50 (20000 mg/kg) of body weight. The drug, the mice were injected on an empty stomach and after 1, 3 and 6 hours was administered hexenal intraperitoneally at a dose of 60 mg/kg of body weight.
The duration of hexenal narcosis considered since the adoption of the mice, the lateral position of the first attempts to change it.
When assessing the functional state of the liver of white mice of the control groups, it was observed that after 1 hour after injection of saline duration of hexenal narcosis was 32.3±4,4 min, after 3 hours was 30.3±4,6 min and 6 hours to 33.7±4.5 min As shown by the data, with increasing time of the study, after administration of saline liver function has not changed.
When administered drug dose LD it was found that the duration of hexenal sleep an hour after administration was 31.8±4,1 min, and after 3 hours - 30,2±3,8 min and 6 hours of 32.4±4,1 min, and although a few decreases, but not significantly different (P>0.05) from the control group.
When increasing doses of the drug to LD50 duration of hexenal narcosis in an hour was 32.6±4,1 min, which is not significantly different (P>0,05) odontology group. However, 3 hours after the injection there was an increase in the duration of hexenal sleep to 39.6±4,1 min, and after 6 hours - reduction of hexenal sleep to 30.2±4,6 min, which differs significantly (P<0.05) from the control group. Apparently there's a stated dose of the drug initially causes an inhibition of the activity of mitochondrial enzymes, leading to a sharp increase in sleep time. Subsequently, due to the rapid destruction of the drug the number of enzymes remains in hepatocytes in large quantities, quickly destroys the hexenal, and sleep duration decreases.
Thus, the claimed drug in doses close to LD50, causing a short depression of liver function is restored in 6 hours after drug administration. Smaller doses of the drug (LD) do not cause functional changes in the liver.
Example 4. Assessment of local irritating and skin-resorptive action of the claimed preparation
Experience conducted on Guinea pigs and rats, which the day before the start of the experiment concave scissors cut off the hair on the skin area of 3×4 cm2in the back area.
Claimed the drug at a dose of 0.045 g/kg LW on the twin were applied to each surface and lightly rubbed. After application of the drug, each animal is placed separately on a 4 hours to avoid sweat�Pb of the drug. Further animals were kept in conventional cages.
Within 30 days after the start of the experiment conducted visual observation of the appearance, condition and behavior of animals. The time, the degree of manifestation of signs of toxicity and deaths of animals.
Skin reaction was considered on the scale of evaluation of skin samples.
As a result of experiments carried out by standard methods, it was shown that a single application of the drug to the skin of Guinea pigs at a dose of 0.045 g/kg LW for 4 hours did not cause changes of state of the animals. Not revealed in death of the animals in all groups, indicating the absence of local irritation of the product in a single use.
Skin-resorptive action was studied on rats. Rats of the experimental group were fixed in special houses, and their tails were immersed 2/3 of the length in the tube with the drug made on the twin in the ratio of 1:10. The exposure time was 4 hours for 5 days. The tails of rats of control group were loaded on 2/3 of the length in the tube with the twin.
Studies have shown that experienced rats during the experiment did not differ from control.
Surveillance for two weeks after application of the drug did not reveal any manifestations of intoxication, the skin covered with smooth uniform coat, the animals were� active and ate well.
Consequently, the drug does not cause local irritation and skin-resorptive action in a single application to the skin at a dose of 0.045 g/kg LW and belongs to the 4th class of hazard.
Example 5. The study of the subchronic toxicity of the drug on laboratory animals, pigs and chickens
The experiments were performed on white outbred male rats with initial weight of 130-140 g. in the stomach daily for 2 months via gavage was administered the drug in the form of suspension of the starch paste in doses 1/10 and 1/100 of the LD50, which corresponded to 200 and 20 mg/kg of Each experimental and control group consisted of an equal number of animals. Animals of the control group, under the same conditions of keeping and feeding, were injected an equal volume of the starch paste.
Signs of toxicity and no deaths were observed that gives the basis to speak about the absence of drug in the dose effect of cumulation on toxic symptom.
Examination using clinical and biochemical methods animals treated for 2 months in a dose of 0.01 and 0.001 from LD50, showed no statistically significant differences between experimental and control groups. Tests carried out on the 60th day experience after decapitation.
As a result of the research showed that the drug does not affect the body weight gain alive�on the Internet.
Blood samples were taken from the tail vein, the number of erythrocytes and leukocytes was determined in the cell Goryaeva, the level of hemoglobin - photometric method.
Hematological parameters of rats treated with the claimed preparation, did not differ from those in the control group (P≥0,05).
Biochemical parameters of animals was also studied after administration of the drug in doses of 1/100 and 1/1000 from the LD50. The activity of alanine aminotransferase (Alat) and aspartate aminotransferase (AST) were determined by Reitman and Princely, pyruvic acid (PVA) - according to Friedman and Haugen, lactic acid according to the method of Barker and Summerson.
The results showed that the lack of difference in blood parameters of rats in different groups (P≥0,05).
Renal function after prolonged administration of the drug in doses of 0.01 and 0.001 from the LD50was assessed by the indicators of the daily urine output, protein and urea. Urine was collected over 24 hours in a metabolic chamber at normal water load. Determination of the urea and the protein was done by conventional methods.
As a result of the research showed that the drug has no negative effect on renal function.
The study of the subchronic toxicity of the claimed preparation was carried out on pigs weighing 8-32 kg, equally divided on the principle of analogues into 3 groups. The drug for 20 days animals were injected once daily with food at a daily dose of:
I group 0.135 g/kg of body weight (three times therapeutic dose);
Group II - 0.045 g/kg of body weight (therapeutic dose);
Group III - control group (drug one).
Monitoring the clinical condition of the animals were within 30 days from the start of the experiment. In a day and ten days after the last injection of the drug underwent clinical blood analysis (number of erythrocytes, leukocytes, hemoglobin, leukocyte formula deduced).
In the same period has been evaluated by the functional state of the kidneys in the urine, which determined the content of protein, carbohydrates, bilirubin, urobilin, ketone bodies, specific gravity, and by definition in the serum of creatinine and urea.
About the functional state of the liver was measured by the change of activity hepatospecific enzymes (cholinesterase, aspartate aminotransferase, alanine aminotransferase), the definition of the content of bilirubin in the blood.
The introduction of the drug in doses 0,135 g and 0.045 g per kg of body weight for 20 days did not cause visible clinical changes in the body of pigs. Animals were actively moving, well and completely were eating food foods� to external stimuli.
As a result of the conducted researches it is established that the introduction of the drug in doses 0,135 g and 0.045 g per kg of body weight, blood picture in piglets is almost constant and is within the physiological norm.
About the functional state of the liver was assessed by determining the content hepatospecific enzymes and bilirubin in serum. Animals in groups I and II, the activity of aspartate aminotransferase and alanine aminotransferase and bilirubin content were within the physiological range and did not differ significantly (P>0.05) from the control group.
Thus, the 20-day application of the claimed drug in doses 0,135 g and 0.045 g per kg of body weight does not affect the liver function.
Urine is collected from animals of all groups were consistent with physiological norm: transparent, yellow color, peculiar smell, the weight rate of 1.018-1,021, pH 8,6-8,7: protein, carbohydrates, bilirubin. The creatinine and urea in blood serum of piglets experimental groups were within the physiological range and did not differ significantly (P<0.05) from the control group.
No change in the urine, the normal level of creatinine and urea in the serum indicates that the claimed drug is not nephrotoxic effect in piglets in all tested doses.
As a result�e of the conducted researches it is established, that 20 - day announced the introduction of the drug in therapeutic and triple therapeutic dose has no functional changes in the organism of piglets.
The study of the subchronic toxicity of the drug was carried out on chickens weighing 220-230 g, under the same conditions of feeding and maintenance. Experimental birds on the principle of analogues were divided into 3 equal groups. The preparation was given to each chick from the first two groups daily for 20 days by gavage into the crop in the following doses:
Group 1 - 0.33 g/kg body weight (three times therapeutic dose);
Group 2 - 0.11 g/kg body weight (therapeutic dose);
Group 3 - control group (drug one).
Monitoring the clinical condition of the birds have conducted over 25 days from the start of the experiment. A day after the last administration of the claimed preparation was carried out the clinical study of blood (number of erythrocytes, leukocytes, hemoglobin, leukocyte formula).
In the experience of the deaths of birds were noted. The clinical condition of the chickens during the experience did not change. During the experiment, the experimental Chicks were very active, appetite was saved. The consumption of water and feed in the experimental and control groups was the same.
The results of the research showed that the 20 - day introduction p�of Ephrata three times larger dose (group 1) and therapeutic dose (group 2) all clinical and biochemical blood indices in experimental groups are within the physiological range and did not differ (P< 0.05) from the control group.
Example 6. The stated tolerance of the drug pigs and chickens
Under the experiments were pigs and chickens. The animals were divided into 3 groups (two experimental and one control). As control was used the research data obtained in the experimental groups before giving the drug. The preparation was given by mouth in two versions: the first - in therapeutic dose: for piglets - 0.045 g per kg of body weight of the animal, chick - 0,112 g per kg of body weight, and in the second variant - to 5-fold increased.
Data obtained from the above studies, were analyzed by the method of mathematical statistics, by calculating the arithmetic mean value (M), its error (+m) and the level value P. In connection with the fact that the data obtained by hematological studies were in the same range as that of the control animals was carried out statistical processing of their summirovanie across the days of each dose.
Within 10 days the animals were watching, was taken blood and investigated hematological and biochemical parameters.
Deviations in behavior and condition of animals first and the second groups were noted, except for the depressed state in one pig from group within 24 hours. In hematological picture was noted for a much smaller�further developments in pigs of the second group in leukotriene (eosinophilia reached to 4.4% over the day). However, these changes were within the physiological norm.
The preparation was given once when administered on an empty stomach in the craw. The observations were carried out within 10 days. Blood was taken before giving the drug, after 1, 5 and 10 days, calculated hemoglobin, erythrocytes, leukocytes and drew blood cell count
A single application of the drug at the recommended dose did not cause clinical changes in the condition of chickens: animals actively move and respond to external stimuli, appetite was saved. If you increase the recommended dose 5 times in experimental animals have also been observed deviations from the physiological norm.
Hematological parameters of blood of animals of experimental groups were within the physiological range and did not differ from the control group.
Example 7. The study of the allergenic properties of the drug
Experiments on the study of the allergenic properties of the drug were carried out on Guinea pigs by the method of histamine shock in mice by indirect degranulation of mast cells. The essence of the method of histamine shock is that in Guinea pigs subcutaneous administration of histamine in a dose of 5 mg/kg histamine causes shock, terminating in death. If the study drug has antihistamines, prior to its introduction should prevent death alive�Togo from histamine, otherwise, the death of the animal occurs in a shorter time and smaller doses of histamine.
In the experiment used clinically healthy Guinea pigs weighing 180-220 g Guinea pigs asked the drug orally at a dose of 0.045 g per kg of body weight of the animal. Control animals the drug is not injected. Histamine was injected subcutaneously at a dose of 5 mg/kg at the same time as the experimental and control Guinea pigs after 6 and 12 hours after drug administration.
The test results indicate that the claimed drug in therapeutic dose has antihistamine activity, since it does not prevent the death of animals from the administered dose of histamine as well and it accelerates that would indicate histamine allergenic effect.
All animals of the experimental and control groups fell at approximately the same time. So, with the introduction of histamine Guinea pigs after 6 hours after drug administration the time of onset of histamine shock was equal to 18.9±0,12 min, after 12 hours was 18.8±0,15 min, while the control animals, respectively 18,8±0,15 and 19.0±0,12. The difference in performance of animals in experimental and control groups were insignificant (P>0,05).
The reaction of the experimental and control groups of animals on the introduction of histamine was the same. All Guinea pigs were observed symptoms of the development of shock: severe depression, Sanli�axis, anxiety, shortness of breath, lateral position, convulsions, dyspnea and death.
The reaction degranulation of mast cells was carried out on mice lines of the IAS, which asked the drug is dissolved in the starch paste is 1:10 at a dose of 0.045 g per kg of body weight of the animal on DV. After 2 days, mice were killed, gathered blood serum. Fat cells were isolated from peritoneal fluid of rats-males weighing 180-200 g after intraperitoneal injection of saline with heparin in an amount of 10 ml.
Then on glass slides, covered with a 0.3% neutralatom in absolute alcohol, applied 1 drop of fat cells, serum from experimental mice and the drug in a dilution of 1:10. The control sample took fat cells and serum from the same mice (1 drop) and the difference in the percentage of degranulation of mast cells in the experiment and in control to assess sensitization. To control the accuracy of the obtained data was calculated the percentage of degranulation of mast cells in peritoneal fluid (10%) and complement fixation (8%).
According to the data obtained, the percentage of degranulation of mast cells was 7.6±0,12, which suggests that the drug does not have sensitising properties.
Example 8. Immunotoxic properties of the drug
Immunotoxic properties of the drug were studied in 4 experiments on mice lines SVA weighing 18-20 g.
On the influence of the drug �and cellular immunity was judged by the induction of delayed-type hypersensitivity (DTH) and by changing the number authorizationresponse cells (autologous-ROCK) by the method of Jondal M. et al. (1972), as erythrocytic marker in this test applied a 1.5% suspension of autologous red blood cells.
Influence of the preparation on antibody formation was studied by the method of local hemolysis and hemagglutination reaction by immunization of mice with sheep erythrocytes (SRBC). Titers of agglutinins was determined in microbalance direct reaction of hemagglutination, was calculated suppressive index (SI).
The accuracy of results was assessed by student's criterion.
For determination of antibody-forming cells (ASC) in the spleen of mice was orally given in a therapeutic dose of the drug in conjunction with intraperitoneal immunization of their sheep erythrocytes (SRBC) - 2% suspension in a volume of 0.5 ml/mouse. On the 4th day removed the spleen, received lymphocytes and conducted research. Around each antibody-forming cells is a zone of hemolysis, visible on the agar in the form of transparent pixels. The increase in the number of producers of antibodies in the spleen of mice injected medicine, demonstrates the stimulating effect of the drug on the antibody, a decrease compared with the control (DL) - about his oppression. Stimulation index (IP) was defined as the ratio of the number of ASC in the experience among the ASC in control (introduction only DL). IP 1.5 and above - stimulant, below 0.7 - immunosuppressant.
The reported introduction of prep�rata leads to the activation of the transformation of b-lymphocytes in the ASC compared to control, resulting in a statistically significant increase in the number of ASC in the spleen. IP increased by 3.85 times, which shows the stimulating effect of the drug on the antibody, i.e., declared the drug increases the humoral immune response in animals. The increase in the content of ASC precursors of B-lymphocytes is caused by increased functional activity of T-lymphocytes.
It is established that the claimed product has a stimulating effect on humoral immune response, resulting in the increase of the stimulation index to 5.2.
Study of the effect of immunomodulators on the cellular component of the immune response involves the use of model systems, providing insight into the functional activity of lymphocytes T-series. Such tests include the reaction of delayed-type hypersensitivity (DTH) and determines the change in the number authorizationresponse cells, which in mice is similar to T-lymphocytes.
At the same time with intragastric introduction of the tested preparation mice were immunized intraperitoneally with 2% suspension of SRBC. On the 5th day introduced a resolving dose of DL - 10% suspension in a volume of 0.02 ml in paw right paw, collateral paw was injected with 0.9% NaCl solution. After 24 hours was determined by the shift of IP.
The drug in therapeutic dose causes the induction of DTH in mice, i.e. local vespoli�individual reaction which is caused by infiltration of inflammatory cells to the lesion, and non-vascular reaction. In mice that polymorphonuclear leukocytes, mononuclear cells, which after a few days turn into tissue macrophages. The introduction of the drug caused the shift to IP is 32.4%, which differed significantly from those of control animals was 8.8%. Strengthening RGST under the influence of the drug indicates its ability to stimulate the production of lymphokines-mediators of cellular immunity. The intensity of synthesis and secretion by lymphocytes of factors of cellular immunity corresponds to the severity of inflammatory reactions in the introduction of the resolving dose of antigen (SRBC) and characterizes the activity of a population of helper cells responsible for the manifestation of a hypersensitivity reaction of the delayed type.
Example 9. Evaluation of antimicrobial activity of the claimed medicinal product
In work was used as the test strains cultures of S. aureus ADS R (FDA R), Ps. aeruginosa ADS 9027 and E. coli ATSS 25922, You.subtilis ADS 6633 from all-Russian collection of industrial microorganisms FSUE "Gosniigenetika and culture Salmonella abony No. 103/39 obtained from the collection of commissions mibd fsbi "scientific center of expertise and control" of the Ministry of health.
Investigations were carried out on nutrient media production, state scientific center of applied Microbiology and biotechnology, no. 8 state Russian Museum, reg. certificate number f�R 2007/00839 from 27.12.2011. and the No. 1 timing belt, reg. SP No. SDF 2011/11415 from 27.12.2011.
Sample preparation (20-30 mg) was dissolved in sterile water and prepared serial dilutions in liquid nutrient medium No. 8 timing.
For inoculation used a fresh 24-hour cultures of microorganisms grown in an environment No. 8, with the definition insulinoma dose titration on environment No. 1 surface method. Insulinoma dose of microorganisms ranged from 1.0×105to 2.5×106SOMETHING.
As a result of the conducted researches it is established that the drug has a pronounced antimicrobial action on gram-negative (Ps. aeruginosa, E. coli, Salmonella abony) and gram positive (S. aureus, You.subtilis) microflora. The drug works effectively on both vegetative and spore forms of bacteria.
The drug is stable for three years from the date of manufacture when stored at temperatures between 5°C and 25°C.
It should also be noted that the connection of several fluoroquinolones in the composition of the drug were tested, the following compounds: pefloxacin, ofloxacin, enrofloxacin, norfloxacin, lomefloxacin, levofloxacin, moxifloxacin, sparfloxacin, enoxacin. As to the connection of pleuromutilins in the composition of the drug was also tested tiamulin, and as auxiliary substances - glucose, fructose, dextrose, lactose, lactulose.
The results of the research component�of investments with the above ingredients, provided the ratios of compounds from the group of fluoroquinolones and out of a group of pleuromutilins (mass.h.) in the range of from 1:3.0 to 1:225.0 significantly similar to the results of studies of the drug according to example 1 and are therefore not reflected in this description.
Thus, the conducted researches allow to draw the following conclusions:
- LD50the claimed drug is 8.5±0.84 g/kg-BW - low-toxic compound (4th grade) - according to the classification (GOST 12.1.007-76);
- the drug does not cause functional changes in the liver (performed by the sample);
- the drug has no allergenic properties;
- in one country five times larger dose (for piglets - 0,225 g per 1 kg of animal weight and chick - 0.55 g per 1 kg of animal weight) the drug does not cause any changes of hematological and biochemical parameters of blood of the body of pigs and poultry;
- twenty-day provision of the drug (subchronic toxicity) swine and poultry does not cause changes in hematological and biochemical parameters of blood and urine;
- the drug in therapeutic dose 0.045 g per 1 kg weight of the animal has a stimulating effect on the humoral immune response, increasing IP AOK of 4.88 times, and the reactions of heterophile agglutinins in 5,22 times and especially the T-system of immunity, resulting in increased activity of immune cells, interaction which leads to the development of the immune response in animals (IPDTH32,4%);
- the drug has pronounced antimi�more action on both gram-negative (Ps.aeruginosa, E. coli, Salmonella abony) and gram positive (S. aureus, You.subtilis) microflora;
- the drug is effective both at vegetative and spore forms of bacteria;
- can effectively treat a wide range of diseases of bacterial etiology in animals in the absence of data on the pathogen and its sensitivity to antibiotics;
- the preparation is stable when stored.
1. Complex antibacterial drug for animals containing compound from the group of fluoroquinolones and excipients, characterized in that it further comprises a compound from the group of pleuromutilins in effective amounts.
2. Complex antibacterial drug for animals according to claim 1, characterized in that it contains compounds from the group of fluoroquinolones and out of a group of pleuromutilins in a ratio (in wt.h.) 1:3.0-1:225.0.
3. Complex antibacterial drug for animals according to claim 1, characterized in that as compounds from the group of fluoroquinolones contains ciprofloxacin or pefloxacin or ofloxacin, or enrofloxacin or norfloxacin, or lomefloxacin, or levofloxacin, or moxifloxacin or sparfloxacin, or enoxacin.
4. Complex antibacterial drug for animals according to claim 1, characterized in that as compounds from the group of pleuromutilins contains tiamulin hydrogen f�Marat or tiamulin.
5. Complex antibacterial drug for animals according to claim 1, characterized in that as auxiliary substances it contains sugars.
6. Complex antibacterial drug for animals according to claim 5, characterized in that the sugar contains sugar, or glucose, or fructose, or dextrose, or lactose or lactulose.
FIELD: veterinary medicine.
SUBSTANCE: agent comprises enrofloxacin and excipients. The agent additionally comprises humates of peat or sapropel, with the following ratio of the components, wt %: enrofloxacin substance - 0.5; alkaline solution of humates (pH=12-13) - 80; succinic acid - to pH 10-11; propylene glycol - the rest. The agent is administered with the liquid feed once a day for three to five days at a dose of from 0.5 to 1.0 ml per 1 kg of body weight.
EFFECT: manifestation of pronounced therapeutic effect.
5 tbl, 2 ex
SUBSTANCE: invention relates to method of obtaining 7-hydroxyroyleanon, possessing antimicrobial action. said method includes extraction of crushed roots of salvia officinalis with 96% ethyl alcohol with further extract evaporation, processing with water, alcohol distillation and processing with hydrophobic solvent or extraction of said raw material with chloroform with further extract processing with water and evaporation; after which target product is extracted from organic phase by transfer into water-soluble phenolates, with processing with sodium hydroxide water solution; alkali solution is washed with chloroform; acidified with hydrochloric or sulphuric acid; obtained sediment is filtered; dried and crushed.
EFFECT: invention is characterised by improved process manufacturability and provides obtaining individual substance with higher antimicrobial activity than previously extracted royleanon derivatives from salvia officinalis.
2 tbl, 6 ex
SUBSTANCE: invention relates to a strain of the pathogen of pseudomonosis of pigs of the collection of Federal state budgetary institution "VGNKI", deposited under the name "Pseudomonas aeruginosa No.9" and the registration number "No.9-DEP", intended for production of a vaccine against pseudomonosis of pigs.
EFFECT: invention provides high immunogenic activity and the ability of production of the vaccine against pseudomonosis of pigs.
4 ex, 3 tbl
SUBSTANCE: invention refers to medicine, namely to clinical microbiology and antimicrobial chemotherapy, and concerns developing and creating new combinations providing potentiating bactericidal action and effectively inhibiting the purulent infection caused by methicillin-resistant S. aureus by using two classes of compounds possessing the essentially different mechanism of antimicrobial action.
EFFECT: developing and creating the new combinations providing potentiating bactericidal action and effectively inhibiting the purulent infection.
2 dwg, 6 tbl
SUBSTANCE: drops possessing antiviral and immunomodulatory effects characterised by the fact that they represent a 95% ethanol infusion of wild strawberry leaves and fruit specified in: red raspberry fruit, mountain ash fruit, bilberry fruit, blood-red hawthorn fruit, cinnamon rose fruit; 15-25 mg of the substance in 1 ml of the infusion.
EFFECT: drops possess pronounced antiviral and immunomodulatory effects.
15 tbl, 5 ex
SUBSTANCE: invention relates to polymer ketimine derivatives of doxycycline, which are obtained by condensation of doxycycline hydrochloride with cationic copolymers of acrylamide with 2-ammine-ethyl methacrylate (MW=16-20 kDa) with a molar ratio of copolymer/antibiotic equal to 1.1-2.0/1 in aqueous solution with pH 8.0 at 23°C. where: m=(78.0-80.0) mol %; n=(10.0-14.0) mol.%; k=(6.0-12.0) mol %.
EFFECT: polymer ketimine derivatives of doxycycline, which are non-toxic and combine the antimicrobial and immunosuppressive properties.
2 cl, 1 tbl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to a peptide, a peptide mimetic or an amino acid derivative, which contain di-substituted β-amino acid, wherein each of substituting group in the β-amino acid, which can be identical or different, contains at least 7 non-hydrogen atoms, is lipophilic and contains at least one cyclic group; one or more cyclic groups in the substituting group can be bound or condensed with one or more numbers of cyclic groups in the other substituting groups, and when the cyclic groups are fused so that an aggregate total number of non-hydrogen atoms for these two substituting groups makes at least 12, wherein the above peptide, peptide mimetic or amino acid derivative consist of 1-4 amino acids or length-equivalent sub-units.
EFFECT: preparing the peptide, peptide mimetic or amino acid derivative, which contain the di-substituted β-amino acid.
17 cl, 4 dwg, 10 tbl, 4 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions relates to the field of pharmaceutics and medicine and deals with the application of cysteamine in the treatment of a microbial infection, caused by a microbial biofilm, as well as to a product, containing at least two anti-biofilm agents, where at least one anti-biofilm agent represents an antimicrobial peptide, and the second anti-biofilm agent represents cysteamine. Also claimed are the application of the said product in the treatment of a microbial infection and a method of preventing the formation of the microbial biofilm in a medium.
EFFECT: group of inventions provides higher antibacterial activity in comparison with the activity of any compound separately.
13 cl, 33 dwg, 2 tbl
SUBSTANCE: invention relates to organic chemistry, specifically to bensyl aralkyl ether of formula or to its pharmaceutically acceptable salt, where: Ar represents imidazolil; R1, R2, R4 and R5 independently stand for hydrogen; R3 stands for a halogen; R6 stands for trifluoromethyl or trichloromethyl; n is an integer from 0 to 2; and m is 1. The invention also relates to the use of the compound of formula (1) for the treatment and/or prevention of diseases caused by fungi, or bacteria.
EFFECT: obtained new heterocyclic compounds with useful biological properties.
4 cl, 4 dwg, 9 tbl, 8 ex
FIELD: veterinary medicine.
SUBSTANCE: method comprises intramuscular administration of the tylosin-containing preparation at a dose of 0.05 ml/kg body weight once a day for 3-4 days in all forms of mastitis. The tylosin-containing preparation is used as the preparation of the following composition, wt %: colistin sulphate - 4.0-6.0; tylosin base - 4.0-6.0; benzyl alcohol - 4.0; water for injection - 15.0; 1,2-propylene glycol - 100.0%.
EFFECT: use of the claimed invention enables to improve the therapeutic efficacy of treatment of mastitis.
3 tbl, 3 ex
SUBSTANCE: invention refers to a method of treating tuberculosis with multiple drug resistance characterised by prescribing a combination of six anti-tuberculosis preparations in the intensive phase of chemotherapy and five preparations - in the phase of the 20-month therapy continuation, wherein the intensive phase duration makes at least 8 months until obtaining four negative culture results every month in tuberculosis with multiple drug resistance and until obtaining two negative culture results in all other cases of tuberculosis with multiple drug resistance, the phase of the therapy continuation makes 12 months.
EFFECT: higher clinical effectiveness.
1 tbl, 9 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to compounds, which possess an inhibiting activity with respect to anti-apoptotic Bcl-2 proteins. The invention also relates to a pharmaceutical composition, containing the said compounds, and to a method of treating urinary bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukaemia, colorectal cancer, oesophageal cancer, hepatocellular cancer, lymphoblast leukosis, follicular lymphoma, lymphoid malignant diseases of a T-cell or B-cell origin, melanoma, myelogenous leukaemia, myeloma, oral cavity cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small-cell lung cancer or spleen cancer.
EFFECT: obtaining the compounds, possessing the inhibiting activity with respect to anti-apoptotic Bcl-2 proteins.
4 cl, 5 tbl, 405 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a compound of formula , wherein A and V independently represents H or a halogen; Q is absent; R4 independently represents H, a C1-C6 alkyl or C3-C6 cycloalkyl; R7 represents H; and R8 represents a C1-C10 alkyl substituted by OH or C1-C6 alkoxy; or C1-4 alkyl substituted by a 5-6-merous aromatic heterocyclic ring containing 1-2 heteroatoms specified in N and S, wherein the above aromatic heterocyclic ring is optionally substituted by a C1-C10 alkyl; or in -NR7R8, R7 and R8 together with N can form an optionally substituted azacyclic ring containing where applicable an additional heteroatom specified in H, O and S, as a cycle member, optionally substituted by a C1-C10 alkyl, which is substituted by a C1-C6 alkoxy; m is equal to 0; n is equal to 0. The invention also refers to a compound of formula (wherein the substitutes are those as specified in the patient claim), to a pharmaceutical composition containing a therapeutically effective amount of the compounds of formula (VIII), and to a method of treating or relieving a cell-proliferative disorder.
EFFECT: compound of formula (VIII) inhibiting cell proliferation or cell apoptosis.
12 cl, 1 dwg, 14 tbl, 55 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a compound of formula , wherein Y and Z are independently specified in a group of a) or b) so that one of Y or Z is specified in the group a), and another one - in the group b); the group a) represents i) substituted C6-10aryl; ii) C3-8cycloalkyl; iii) trifluoromethyl or iv) heteroaryl specified in a group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furasan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl and [1,2,3]thiadiazolyl; the group b) represents i) C6-10aryl; ii) heteroaryl specified in a group consisting of thiazolyl, pyridinyl, indolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, imidazo[1,2-a]pyridin-2-yl, furo[2,3-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, thieno[2,3-b]pyridinyl, quinolinyl, quinazolinyl, thienyl and benzimidazolyl; iii) benzofused heterocyclyl attached through a carbon atom, and when a heterocyclyl component contains a nitrogen atom, the carbon atom is optionally substituted by one substitute specified in a group consisting of C3-7cycloalkylcarbonyl; C3-7cycloalkylsulphonyl; phenyl; phenylcarbonyl; pyrrolylcarbonyl; phenylsulphonyl; phenyl(C1-4)alkyl; C1-6alkylcarbonyl; C1-6alkylsulphonyl; pyrimidinyl and pyridinyl; C3-7cycloalkylcarbonyl, phenyl, phenylcarbonyl, phenyl(C1-4)alkyl and phenylsulphonyl are optionally substituted by trifluoromethyl, or by one or two fluor-substitutes; iv) phenoxatiynyl; vi) fluoren-9-on-2-yl; vii) 9,9-dimethyl-9H-fluorenyl; viii) 1-chlornaphtho[2,1-b]thiophen-2-yl; ix) xanthen-9-on-3-yl; x) 9-methyl-9H-carbazol-3-yl; xi) 6,7,8,9-tetrahydro-5H-carbazol-3-yl; xiii) 3-methyl-2-phenyl-4-oxochromen-8-yl; or xiv) 1,3-dihydrobenzimidazol-2-on-5-yl optionally substituted by 1-phenyl, 1-(2,2,2-trifluoroethyl), 1-(3,3,3-trifluoropropyl) or 1-(4,4-difluorocyclohexyl); 1-phenyl is optionally substituted by one or more fluor-substitutes or trifluoromethyl; or xv) 4-(3-chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl; R1 represents C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo or aryl(C1-3)alkyl; or when s is equal to 2 and R1 represents C1-3alkyl, the substitutes C1-3akyl is taken with a piperazine ring to form 3,8-diazabicyclo[3.2.1]octanyl or 2,5-diazabicyclo[2.2.2]octanyl ring system, and its pharmaceutical compositions.
EFFECT: preparing the new pharmaceutical compositions.
20 cl, 7 tbl, 72 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: claimed is a pharmaceutical, ear, sterile, preservative-free composition in the form of a transparent aqueous solution, containing 0.01-0.025 % of fluocinilone acetonide optionally in a combination with 0.1-0.8% of ciprofloxacin or its pharmaceutically acceptable salt, a non-ionic surface-active substance, a tonicity-regulating agent and a viscosity-increasing agent.
EFFECT: composition is useful for the prevention and/or treatment of ear inflammation, optionally accompanied with a bacterial infection, and for the introduction of a single dose from a package.
15 cl, 8 ex
SUBSTANCE: invention represents an anti-inflammatory antibacterial wound-healing agent containing a polyethylene oxide base with molecular weight 400 (PEO-400) as a forming agent, as well as polyethylene oxide with molecular weight 1,500 (PEO-1500); an active substance is chloramphenicol and methyluracil; the agent is characterised by the fact that it additionally contains rifampicin and/or cycloserine; the cycloserine content in the rifampicin mixture is specified within the range of 18 to 82 wt %, whereas the ingredients are taken in certain ratio, wt %.
EFFECT: invention provides more effective healing of open wounds, ulcers, bedsores, as well as increased necrolytic effect, reduced exudation, and also a lower risk of allergic reactions.
3 cl, 9 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new chromone derivatives of general formula
wherein: R1 represents one or more identical or different substitutes on a benzene ring, each of which independently represents a hydrogen atom, or a halogen atom, or C1-4 alkoxy group, or OH group. or group -O(CH2)nO-, wherein n=1 or 2, R2 represents a hydrogen atom, or C1-4 alkyl group; A and B independently represent either a nitrogen atom, or a carbon atom; R3 represents a hydrogen atom or one or more identical or different substitutes specified in a group consisting of: a halogen atom, C1-4 alkyl group, C1-4 alkoxy group, group -O(CH2)nO-, wherein n=1 or 2, group NO2, group NHSO2R4, group NHR5, OH group, C1-4 halogenoalkyl group, CN group, or R3 makes a ring condensed with a benzene ring bearing it, specified in a group consisting of indole, benzimidazole, carbostyril, benzoxazolone and benzoxazolone and benzimidazolone, R4 represents C1-4 alkyl group, or C1-4 dialkylamino group, or C1-4 alkoxyalkyl group, or C1-4 dialkylaminoalkyl group, R5 represents a hydrogen atom, or C1-4 alkylcarbonyl group, or C1-4 alkoxycarbonyl group, and to its pharmaceutically acceptable salts, as well as to methods for preparing them, and to based pharmaceutical compositions, and to using them as a therapeutic agent for central nervous system disorders, as long as they possess the D3 dopaminergic ligand properties.
EFFECT: preparing the compositions for treating central nervous system disorders, as long as they possess the D3 dopaminergic ligand properties.
17 cl, 1 dwg, 2 tbl, 33 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new 3-benzofuranylindol-2-one derivatives substituted in position 3 of formula wherein: R1 means a hydrogen atom; R2, R3, R4 equal or different, found in any accessible position of the phenyl ring, means independently a hydrogen atom or a halogen atom; R5 means (C1-6) alkyl group; n means 1; in the form of the base or acid-additive salt, as well as to a therapeutic agent and a pharmaceutical composition based on the above compounds possessing the ghrelin receptor antagonist activity, and to using this compounds for preparing the therapeutic agent for preventing or treating obesity, diabetes, appetite disorders and overweight.
EFFECT: preparing the therapeutic agent used for preventing or treating obesity, diabetes, appetite disorders and overweight.
8 cl, 1 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to compounds of structural formula (I), which can be used for treating diseases mediated by an androgen receptor. In formula (I), R1 means (C2-6)alkyl, (C1-6)alkyloxy, -S(O)m-(C1-6)alkyl, (C1-6)fluoroalkyl, CN or halogen, R2 and R3 are identical or different and mean a hydrogen atom or (C1-9)alkyl, R4, R5, R6, R7 are identical or different and mean a hydrogen or halogen, X means CH or N, Y means either a nitrogen atom, or a carbon atom substituted by (C1-6)alkyl, (C1-6)alkyloxy, (C1-6)fluoroalkyl, a hydrogen atom or halogen; m is equal to 0, 1 or 2.
EFFECT: invention refers to using the compounds for preparing a therapeutic agent for preventing and/or treating hirsutism, androgenetic alopecia, hypertrichosis, atopic dermatitis, disordered sebaceous gland, such as hyperseborrhea, acne, greasy skin or seborrheic dermatitis.
8 cl, 2 tbl, 26 ex
SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I
and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.
EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.
17 cl, 2 tbl, 89 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a compound of formula , which is a methylhydrofumarate (MHF) prodrug. In formula (I), radicals and symbols have the values specified in the patent claim. The invention also refers to a pharmaceutical composition containing the declared methylhydrofumarate drugs, to using the declared methylhydrofumarate drugs and the pharmaceutical composition containing them, for treating diseases, such as psoriasis, asthma, multiple sclerosis, inflammatory intestinal disease and arthritis, and to a method of treating the above diseases.
EFFECT: higher oral bioavailability and plasma MHF, dimethylfumarate and/or other metabolites.
47 cl, 1 tbl, 54 ex