Phosphonium salt preparation for treating mastitis in veterinary medicine

FIELD: medicine.

SUBSTANCE: invention relates to veterinary science, namely to obstetrics and gynaecology. A preparation for treating and preventing sub-clinical, clinical, acute and chronic mastitis in farm and domestic animals contains an active substance that is - triphenyl-(3,5-di-tert-butyl-4-hydroxybenzyl)phosphonium bromide and a pharmaceutically acceptable carrier that is Vaseline in ratio 1:2000.

EFFECT: invention provides the higher antimicrobial effectiveness and the lower toxicity of the ointment with the lower concentration of the active substance.

3 tbl, 5 ex

 

The invention relates primarily to veterinary medicine, namely to obstetrics and gynecology, is intended for the treatment and prevention of subclinical, clinical, acute and chronic mastitis in cows and other farm and domestic animals, caused by exogenous or endogenous infectious factors leading to painful inflammation, redness, swelling nipples; in cows and other dairy farm animals milk in this disease vydelaetsia with great difficulty; they received milk depending on the type of mastitis watery; contains flakes or blood clots.

The inventive tool can be used to treat mastitis in humans.

Objective of the claimed technical solution is to develop tools based on vaseline ointment and phosphonium salts of for the treatment and prevention of subclinical, clinical and acute mastitis in cows and other farm and domestic animals with strong antibacterial, antifungal and antioxidant activity with low therapeutic doses (at a ratio of active substance is a salt of Quaternary phosphonium and vaseline basics 1:2000).

Clinical manifestations of all types of mastitis caused by exogenous and endogenous infectious factors [Danilevskaya, NV, Boxes, AV, St is renkow SV, Shcherbakov, Handbook of veterinary physician. 4th ed., SPb.: DOE, 2005, - 384 C.]. The disease is accompanied by redness, soreness (stagnation) and puffy teats and udder of the animal. Patients milch animals milk vydelaetsia with great difficulty, the animal does not admit - kicking. They received milk depending on the type of mastitis watery, contains flakes and blood clots. Sample mastitis test [Usha BV, Feldstein M.A. Clinical examination of animals. - M.: Agropromizdat, 1986. - 303 S.] shows the presence of mastitis (by the presence of flakes and mucus in the sample of milk in connection with the reagent). Disease teachnig cows with acute mastitis in severe case can lead to death as an adult animal and offspring.

Improving the efficiency of treatment of mastitis in cows and other milk of farm animals is a task that is important for ensuring high productivity of dairy animals and milk quality [Vasiliev, V.V. Economic damage from milk during mastitis in cows // veterinary medicine. - 2008. No. 1. - P.32-34]. Therefore, the development of new domestic medicines for the treatment and prevention of all types of mastitis affecting different parts of the pathological process that combines simultaneously antibacterial, antimycotic and EN is Occidente action is an important task as veterinary medicine and pharmacy, can effectively be treated animals at different stages of the pathological process caused by exposure to pathogenic microflora, leading to redness, swelling and pain during milking, unusable milk feeding of young animals and in a very severe case of acute mastitis lethal.

It is known that for the treatment of clinical mastitis cows offered the use of antimicrobial drugs that are injected intracisternally (nativemenu) [Sirenko, SERGEY Treatment of cows with mastitis / Sirenko SV, Safronov S.L. // Agrarian Bulletin of the Urals. - 2006. No. 1. - P.55-56; Sokolov E Clinical farmacologia M.: Kolos. - 2002. - 227 S.].

There is a method of treatment of mastitis in cows medicinal drug Dipomat, containing in its composition dioxidine (2%), furatsilin (0,04%), beeswax and vaseline oil. In appearance it is a buttery yellow suspension which is produced in bottles of neutral glass 100 ml (20 doses) and the syringes 10 ml (2 doses). Enter intracisternal: if subclinical, serous, catarrhal mastitis in 5 ml of 1 times a day for 3-4 days; if purulent-catarrhal mastitis produce the first injection of 10 ml, then 5 ml with an interval of 24 hours for 5-6 days. Before the introduction of the drug from bol is Noah quarter of the udder secret vydavat, and teats are disinfected with 70% ethanol. Preparation before applying heat to 36-39°C and shaken, then suck from the bottle with a sterile syringe and injected through the nipple of the affected quarter of the udder via catheter [http://www.veterinar.ru/pharmacy/52/11/].

The disadvantage of this method is:

- high cost due to its high content of drugs in the drug;

- the need for special devices for injection (syringe) and pre-treatment of the nipple ethyl alcohol;

- complexity vnutrivennogo (intracisternal) introduction, which is carried out by expert veterinarians and is very painful for the animal;

- long term treatment - up to 1-2 months [Worms D.K. Drugs in veterinary medicine. M.: Kolos, 1977].

There is a method of treatment of mastitis in cows [patent RU 2230571 published 20.06.2004]. The method includes vnutriserdechne introduction staphylococcal and streptococcal anatoxins in a mixture with 25% solution of aspirin in a dose of 2 ml and 4 ml Method is highly effective in the treatment of mastitis in cows only coccoid etiology.

The disadvantages of this method is;

narrow spectrum of antimicrobial activity (only in respect of coccoid bacteria), while the cause of mastitis are not only streptococci and staphylococci, but also is acteria group of Escherichia coli, found Corynebacterium, Mycoplasma, fungi of the genus Candida, Nocardia and others, as well as specific pathogens infections [Counsel for the diagnosis, therapy and prevention of mastitis in cows. The Russian Ministry of agriculture, veterinary Department, No. 13-5-2/1948, 30.03.2000, http://www.cap.ru/home/65/aris/bd/vetzac/document/371.html];

- high cost due to the high content of dipyrone in pharmaceutical drug;

- the complexity and pain of injection, which requires a special device and participation veterinary specialists.

The closest (prototype) to the claimed means is the drug for the treatment of mastitis in animals [patent RU 2200546 published 20.03.2003]. The drug is in the form of ointment contains components in the following ratio, wt.%: colloid 1,5-2,0, salicylic acid 1.0 to 1.5, trimekain 0,45-0,55, Hemofarm or levamisole 0,03-0,5, carbon dioxide extract of chamomile 2.0 to 2.5, the juice of celandine 1,5-2,0, dimexide 29,0-33,0, anhydrous lanolin 46,9-47,65 distilled water - the rest.

The disadvantage of this drug are:

- mnogonapravlennostj;

- high cost,

- the risk of adverse reactions to the drug components (levamisole can cause agitation, increased salivation, increased defecation and urination, ataxia [http://www.vetlek.ru/directions/?id=223], lanolin may have allergenic and sensitizing on the op perate [Technology of medicinal forms: a Textbook in 2 volumes. Volume 1 / FT Kondratiev, L.A. Ivanova, SCI Zelikson and others; Ed. by T.S. Kondratieva. - M.: Medicine, 1991. - S.285]. When mixed with salts of heavy metals (in this example with silver contained in the product "colloid") lanolin its shades and formed metal Soaps increase the toxicity of ointments [Reference pharmacist / Ed. by A.I. Tenzaloy. - M.: Medicine, 1981. - P.14]).

Thus, for applicable drug (including the prototype), as a rule, follows:

- high cost;

- mnogonapravlennostj;

- pain intracisternal introduction did;

- the need for special devices for injection (syringe) and the presence of a specialist;

- limited spectrum of activity against parasitic and pathogenic microflora;

- long term treatment;

- toxicity.

Therefore, the creation of new efficient and easy to use domestic products for the treatment of mastitis in cows and other farm and domestic animals is important.

The analysis of the prior art, carried out by the applicant have shown that structural analogues of the proposed pharmaceutical agents for the treatment of mastitis on the basis of Quaternary phosphonium salts of known prior art on the filing date does not exist.

However, known for their antibacterial, protiva icovia, antimicrobial and antioxidant properties as such [Galkina I.V. Synthesis and antibacterial activities of phosphonium salts on basis of triphenylphosphine and 3,5-di-tert-butyl-4-hydroxybenzyl bromide / I.V. Galkina, Y.V. Bakhtiarova, V.V. Andriashin, V.I. Galkin, R.A. Cherkasov // Phosphoms, Sulfur, and Silicon and Related Elements. - 2013. - V. 188. N 1. - P.97-101. DOI: 10.1080/10426507.2012.740694.], from the investigated prior art does not disclose specific properties of these compounds, showing their efficacy in the treatment of animals suffering from mastitis, caused by exposure to pathogenic organisms are exogenous or endogenous infectious factors.

Objective of the claimed technical solution is to develop a new, unknown in the prior art generation antimastit ointments funds, mainly for veterinary use, characterized by:

- simple manufacturing technology (consists of two ingredients), and as a result of low cost of production;

- lower cost (inexpensive ingredients and manufacturing);

- less pain and trauma for the animal;

low therapeutic doses (0.05% of active substance - Quaternary salts of phosphonium);

- ease of use (does not require special tools and assistants);

- antibacterial, antifungal and antioxidant properties against a wide spectrum of pathogenic and the criminal pathogenic microflora;

- short term treatment of animals;

- relatively low toxicity.

The essence of the claimed technical solution is to create a pharmaceutical composition tools for treatment and prevention of subclinical, clinical, acute and chronic mastitis in veterinary medicine in the form of ointments, including the active ingredient and pharmaceutically acceptable carrier, characterized in that the active substance is triphenyl-(3,5-di-tert-butyl-4-hydroxybenzyl)phosphonium bromide of the formula I as an active ingredient and pharmaceutically acceptable carrier is petrolatum at a ratio of 1:2000.

This pharmaceutical composition is high in antibacterial, antifungal and antioxidant activity at low concentrations and may find application in the field of veterinary medicine.

The problem is solved by the creation of anti-inflammatory drugs for the prevention and treatment of subclinical, clinical and acute mastitis in the form of vaseline ointment consisting of salts of triphenyl-(3,5-di-tert-butyl-4-hydroxybenzyl)phosphonium bromide of the formula I in a pharmaceutically acceptable carrier:

For the purposes of the synthesis of the claimed anti-inflammatory drugs the applicant used an improved method of obtaining salt phosphonoformate I, consisting of two stages, which was partially reproduced by known literature methods described in [Stames W.H., Lauff J.J. Reactions of a Quinone Methide with Tri-n-butylphosphosphine. J. Org. Chem.Vol.35, N6, 1970. - P.1978-1986].

It should be noted that in the works of American authors were not studied antibacterial, antifungal and antioxidant properties of these compounds and studied their properties for use as a fat burner for weight loss, it should be noted that their experiences were negative.

The following is the method of synthesis of the claimed anti-inflammatory agents.

The first stage of synthesis of the compounds of formula I was bromination of 2,6-di-tert-butyl-4-METHYLPHENOL (BHT) in carbon tetrachloride resulting in quantitative yield 3,5-di-tert-butyl-4-hydroxybenzamide in the form of a yellow crystalline product with a melting point 55-56°C.

The second stage to obtain the product of formula I was quaternization of triphenylphosphine synthesized benzylbromide.

The quaternization reaction was carried out in acetonitrile after distillation of the majority (2/3) of the solvent, the product of formula I is precipitated with ether. The obtained colorless crystalline powder with a high melting point, a31P NMR spectra which recorded only one signal is the DRA of phosphorus in the area 23,47 ppm field.

Source 2,6-di-tert-butyl-4-METHYLPHENOL (trademark "BHT", "Agidol-1", "alkoven") is cheap tonnage widely known drug that is used as antioxidant in food production (food additive E-321), lubricating oils, plastics (produced technical "ionol" GOST 10894-76). With the ability to neutralize free radicals and terminate the chain reaction involving free radicals 5%liniment "Dibunola" was widely used as external burns and anti-inflammatories. "BHT" has also been used successfully to treat some types of cancer, radiation and trophic lesions of the skin and mucous membranes [V. Ershov, G. A. Nikiforov, A.A. Volodkin. "Spatial-employed phenols". M.: Chemistry, 1972. 352 S.; Emanuel N.M. "Kinetics experimental neoplastic processes". M.: Nauka, 1977; Mashkovsky PPM Medicines. Edition 16. M: New wave, 2010. S]. Triphenylphosphine and bromine is relatively cheap available domestic commercial preparations.

The invention is illustrated by the following specific examples, but is not limited to them. Example 1 illustrates the method of synthesis of the main active substances ointment - phosphonium salts of formula I, example 2 shows a method of obtaining vaseline is Azi, example 3 shows the means and methods for the determination of acute toxicity and irritant Quaternary phosphonium salts of triphenyl-(3,5-di-tert-butyl-4-hydroxybenzyl)phosphonium bromide in example 4 shows a method of treatment of mastitis in cows, in example 5, we studied the biological activity of phosphonium salts of the formula I, studied antimicrobial (antibacterial and antifungal) and antioxidant action.

Example 1

Step 1.

Synthesis of 3,5-di-tert-butyl-4-hydroxybenzamide.

To a solution of 2.20 g (0.01 mol) of 2,6-di-tert-butyl-4-METHYLPHENOL in 20 ml of carbon tetrachloride are added dropwise a solution of 1.60 g (0.01 mol) of bromine in 20 ml of carbon tetrachloride with such speed that it was bleached as additions. After the reaction mixture is refluxed for one hour, the solvent was removed in vacuum. Precipitated oily product crystallizes during freezing. Yield 2.75 g (92%). TPL 54-56°C.

Elemental analysis of C15H23BrO. Found, %: C at 60.54; H 8.01. Calculated, %: C 60.21; H 7.75.

Stage 2.

Synthesis of triphenyl-(3,5-di-tert.-butyl-4-hydroxybenzyl)phosphonium bromide of formula I.

To 0.299 g (0.001 mol) of 3,5-di-tert-butyl-4-hydroxybenzyl bromide in 5 ml of acetonitrile, add a solution of 0.262 g (0.001 mol) of triphenylphosphine in 5 ml of the of clonicel. The reaction mixture is left for 10 minutes. The solvent is removed in vacuum at 2/3, then the product is precipitated with ether. The precipitation of the product I is filtered off and washed with a small amount of ether. Output 0.533 g (95%). TPL 225°C (decomp.), δ31ppm 23.47.

Elemental analysis of C33H38OBrP. Found, %: C 70.70; H 7.00; P 5.62. Calculated, %: C 70.58; H 6.82; P 5.52.

Example 2

A method of obtaining a vaseline ointment.

All work is carried out in sterile conditions. In a porcelain mortar weighed 1 g of salt - triphenyl-(3,5-ditretbutyl-4-hydroxybenzyl)phosphonium bromide of the formula (I), triturated and mixed with 100 g of vaseline until a homogeneous mass (concentrate). In the capacity maselesele weighed 1900 vaseline, heated to 40°C, stirred and gradually, in small portions when the stirrer type of mortar concentrate. The ointment is stirred for 20 minutes and Packed in sterile glass jars.

Conclusion. The composition and fabrication technology products for the prevention and treatment of acute mastitis in cows and other farm and domestic animals, containing activetestsuite substance of the formula I and vaseline. Advantages of the proposed pharmaceutical composition in the form of ointments is that it is simple in manufacture, use and has therapeutic activity at low concentrations (0.05%, the which makes it a promising drug in veterinary medicine for the treatment of mastitis.

Example 3

Determination of acute toxicity and irritant Quaternary phosphonium salts of triphenyl-(3,5-di-tert-butyl-4-hydroxybenzyl)phosphonium bromide.

The claimed technical solution was investigated by carrying out experiments with the results, relevant to the objectives (tasks) for the development of a new generation antimastit vaseline ointments on the basis of salts of Quaternary phosphonium low therapeutic doses.

The method of determining the toxicity

Work on the study of acute toxicity was carried out at the Department of Parasitology and radiobiology of the Kazan state Academy of veterinary medicine named after. AD Bauman in September 2011. The experience was used 70 white mice, males and females, weighing 18-21, phosphonium Salt of formula (I) in the form of an aqueous suspension was injected into the stomach once using the probe. Laboratory animals, taking into account gender, age, body weight, were divided into 7 groups: 6 experimental and one control (10 animals each). Mice experimental groups were administered a suspension of the salt in ascending doses of 50, 100, 150, 200, 250 and 300 mg/kg of body weight according to the current matter (DW), respectively. The control group mice in the stomach was administered distilled water. The condition Zdor the outcomes of laboratory animals were observed for 14 days after administration, considering appearance, motility, food intake. Deaths were recorded, dissected dead animals. The results are shown in table 1.

Single oral administration of the drug in group 1 mice at a dose of 50 mg/kg body weight according to the current substance did not cause changes in behavior and General condition of the animals. Until the end of the experiment there were no recorded deaths of animals. This dose was defined as the upper level. In group 2, which was administered 100 mg/kg body weight, was observed inhibition of motor activity and appetite of animals, which lasted up to 5 days. Three of ten mice fell on the second and third day. In group 3 was also observed inhibition of motor activity and appetite of the animals. Until the end of the experiment were killed 4 out of 10 mice. In group 4, there have been case 7 out of 10 mice in the period from the first through the seventh day after injection. In group 5 showed a significant deterioration of the General condition of animals, reduction of motor activity and feed intake. 9 out of 10 mice fell within the first five days. In group 6, which was introduced to the drug at a dose of 300 mg/kg body weight, was observed a short period of physical activity, which then gave way to a period of deep oppression and loss of appetite. All mice died within the first and second day after injection. At necropsy all animals 6 GRU is dust marked distention of the gastrointestinal tract gases throughout, stagnation content in the stomach, venous stasis in the vessels of the abdominal cavity.

Table 1
The results of studies of acute toxicity of salt - triphenyl-(3,5-di-tert-butyl-4-hydroxybenzyl)phosphonium bromide of the formula I on white mice
no groupDose, mg/kgThe number of animals in the group at the beginning of the experimentPalo animals (animals)Survived animals (animals)Mortality, %
150100100
2100103730
3150104640
4200107 370
5250109190
630010100100

Calculation sredneseriynoe dose produced by the method of Cerberus [Ashmarin I.P., A. Vorobyev Statistical methods in microbiological research. - L.: Medgiz, 1962. - 180 S.], using the formula:

LD50=LD100-(Σ(Z×D))/m, where

D is the interval between every two adjacent doses;

Z - average number of animals, which saw a considered reaction under the influence of every two adjacent doses;

m is the number of animals in each group.

When administered orally LD50preparation of a formula I was 160 mg/kg of body weight according to the current matter.

Thus, it was established that the phosphonium salt of formula I when administered orally, in accordance with GOST 12.1.007-76 [Sapelnikov S.D., Kochanov M.M., Lost S.A., Stavchanskiy I.I. Harmful substances. Classification and General safety requirements. Experimental methods for determining the toxicity and hazards of chemicals. M; Medicine, 1978. - 184 S.] on the Toxicological characteristics of class III risk - substances, moderately dangerous for warm-blooded animals.

Studying irritating phosphonium salts of formula (I) was carried out on five rabbits at the age of 12 months, of the same sex and approximately the same body mass (2.5 to 3 kg). The drug is in the form of an aqueous suspension by using the eye dropper was introduced under the right eyelid one drop.

To control under the left eyelid similarly injected distilled water. The animals were observed for one hour. During this time, was not revealed redness of the conjunctiva of the eye, none of the rabbits. After 12 and 24 hours was not observed obvious differences between the left and right eyes in the experimental rabbits. This allowed to conclude that the drug substance suppositories comprising the salt of the formula (I), which has a strong irritant effect.

Example 4

The method of treatment of acute mastitis in cows.

Research was conducted in the company of "APK " open Field" and thus/ "Yulduz" Chistopol district of the Republic of Tatarstan on 5 cows of black-motley breed in age from 3 to 8 years.

The content of the farm tethered during the day the cows are issued for a walk on the card. The artificial insemination, semen supplied from plum. economy "Chistopol". For acute infectious diseases, the economy is prosperous.

In the research there are cows, patients with clinical mastitis. Disease p is oallas redness and swelling of the udder, difficult milking off of milk, which was visualized blood clots and minimized milk in the form of flakes. Body temperature ranged from low grade to 39-40°C. Pulse, breathing acadeny. The onset of the disease, mainly because of the painful milking, which was carried out manually. Test the effectiveness of the ointment - triphenyl-(3,5-di-tert-butyl-4-hydroxybenzyl)phosphonium bromide of the formula (I) and vaseline (1:2000) was performed in the treatment of clinical forms of mastitis in 5 cows.

Ointment rubbed into the udder 2 times a day after milking for 5 minutes, combined with massage of the udder. The results of the study:

Day one: Udder inflamed, red, painful, touching him cow kick, do not admit to themselves, swollen nipple. Milk vydelaetsia with great difficulty. They received milk depending on the type of mastitis watery; contains flakes or/and blood clots. Conducted sample mastitis test revealed the presence of mastitis (by the presence of flakes and mucus in the sample of milk in connection with the reagent) [Usha BV, Feldstein M.A. Clinical examination of animals. - M.: Agropromizdat, 1986. - 303 S.].

Day two: the Udder is still inflamed, red, swollen nipple, pain in durgiana. Milk vydelaetsia with difficulty, the first stream containing a small amount of flakes.

Day three: the normal Udder R is smera, the redness is almost absent, nipple less swollen, the pain is negligible. The animal let to itself. Milk vydelaetsia with some difficulty, milk contains a small amount of flakes. Test with mastitis test shows the presence of mastitis; milk sample still slimy.

Day four: Udder normal size, painless, nipple normal size, blood is missing. Milk vydelaetsia easily and freely. They received milk from the affected quarter is no different from milk from healthy quarters. Test with mastitis test shows the presence of mastitis; milk sample contains a small amount of mucus.

Day five: Udder normal size, painless, local temperature is not increased, the nipple is normal in size. Milk vydelaetsia easily, they received milk, appearance and texture is no different from milk from healthy quarters. Conducted a test with mastitis test - mastitis test is negative.

Conclusion. Full clinical recovery occurs within 5 days. Consumption of a pharmaceutical composition consisting of a salt of phosphonium-triphenyl-(3,5-di-tert-butyl-4-hydroxybenzyl)phosphonium bromide of the formula (I) and vaseline (1:2000), - 100 g ointment in the treatment of 1 cow.

Example 5

Study of biological activity: bactericidal, fungicidal, anti zidantas.

Fungicidal and bactericidal activity of the compounds of formula I were investigated on the test-cultures of pathogenic and conditionally pathogenic microflora of man. We used Museum strains of the Department of Microbiology, Kazan state medical Academy: Escherichia coli, Salmonella paratyphi, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans. [Pershin GN. Methods of experimental chemotherapy. - M.: Medicine, 1971. - 245 C.]. To evaluate the activity immediately before the study was prepared by 0.01% solutions of the compounds of formula I in alcohol. Daily culture Museum strains were standardized to an optical density of 0.5 on the Mcfarland (1.5 x 108CFU/ml). Petri dishes with nutrient medium Saburo (Candida albicans) and Mueller-Hinton for all other microorganisms were seeded standardized suspension of the test cultures, using a tampon. After 5 minutes on the surface of the agar bacteriological loop was applied drop of analyte. One Cup was placed 5 chemical compounds, in the center of the Cup inflicted solvent (to control for possible antibacterial effect) or a standard drug for comparison. After 24-48 hours incubation at 37°C was assessed by the magnitude of the zone of growth inhibition of microorganisms. The results are presented in table 2.

Table 2
Antimycotic and antibacterial activity of phosphonium salts of formula I (1% solution in ethanol)
ConnectionMicroorganisms zone of inhibition of growth (diameter, mm)
Staphylococcus aureusEscherichia coliPseudomonas aeruginosaSalmonella p.BCandida albicans
4318161646
Chlorhexidine1915131416.5
Penicillin23-810-
Griseofulvin----19

Antioxidant activity was determined by the method of conometrics the th titration electrogenerating bromine [Ziyatdinova G.K., Budnikov G.K., Pogorel'tzev V.I., Ganeev T.S. The application of coulometry for total antioxidant capacity determination of human blood. Talanta. 2006. V.68. No. 3. P.800-805]. The generation of bromine was carried out on the potentiometer P-M at a constant current of 5.0 mA of 0.2 M KBr in H2SO4. The end of the titration was determined by amperometric cell with two polarized platinum electrodes (ΔΕ=300 mV). The results are presented in table 3.

Table 3
The antioxidant capacity of the phosphonium salts of formula I
No.Connection solutions in ethanol)The AOA, CL/mlSr
I286±61.7
Control 1Ascorbic acid185±32.2
Control 2α-tocopherol195±41.4

Thus, the proposed effective tool for the treatment of mastitis in veterinary medicine on the basis of salts of phosphonium and the appropriate method of treatment and prevention of subclinical, clinical and acute mastitis in cows by rubbing ointment into the udder, followed by a massage based on phosphonium salts of possessing a wide spectrum of antibacterial, antifungal and antioxidant action, which leads to the cure of animals on the fifth day. Advantages of the claimed compounds of formula I is that it has simultaneous high antibacterial and antifungal activity as well as high antioxidant activity (which is not typical for antibiotics), this effect is manifested at low concentrations against the background of relatively low toxicity of the proposed connection, it is thermally rack (according to the method of thermogravimetry and scanning calorimetry) to 225°C (I) and not collapse under the action of soap, making it a promising drug, anti-inflammatory and disinfectant in veterinary medicine and medicine.

The claimed technical solution meets the criterion of "novelty", presented to the invention, because of the investigated level of technology not identified technical solutions characterized by these traits, leading to the implementation of the claimed technical result of the claimed technical solution, which is the creation of funds in the form of ointment for the treatment of mastitis in veterinary medicine, the possession is the future as bactericidal, fungicidal and antioxidant activity at low doses of the active substance (0,05%) on the background of relatively low toxicity.

The claimed technical solution meets the criterion of "inventive step" presented to the invention, as it is not obvious to a person skilled in the art due to the fact that the claimed technical solution provides the practical implementation of objectively existing in science and technology contradictions, not resolvable by conventional design, namely, of the investigated prior art known to produce phosphonium salts to create drugs - fat burner to lose weight, and have not been studied antibacterial, antifungal and antioxidant properties of these compounds, and the compound obtained of the formula I according to the claimed technical solution with antibacterial, antifungal and antioxidant properties, has a high effektivnosti in the treatment and prevention of subclinical, clinical, acute and chronic mastitis in cows and other farm and domestic animals, therefore, we can conclude that the results are not obvious to a person skilled in this technical field.

The claimed technical solution meets the criterion of "industrial note nimoth", presented to the invention, as may be implemented on any domestic purpose-built facility using standard equipment known materials and industrial technologies.

For the treatment and prevention of subclinical, clinical, acute and chronic mastitis in veterinary medicine, including the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient is triphenyl-(3,5-di-tert-butyl-4-hydroxybenzyl)phosphonium bromide, and a pharmaceutically acceptable carrier vaseline with a ratio of 1:2000.



 

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19 cl, 6 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I in which R1 represents halogen, methoxy group or cyano group; each of Y1 and Y2 represents CH, and one or two from U, V, W and X represent N, and each remaining one represents CH, or in case X, cam also represent CRa, or Ra represents halogen; A represents CH2CH(OH), CH2CH(NH2), CH(OH)CH(NH2) or CH(NH2)CH2, B represents CH2CH2, CH2NH or CONH, and D represents CH2, or A represents CH(OH)CH2, and B represents CH2NH, N(R2)CO or CONH, and D represents CH2, or B represents N(R2a)CH2, and D represents CH(OH), or A represents CH(OH)CH(OH), B represents CH2NH or CONH and D represents CH2, or A represents CH2CH2, and B represents CH2CH2, CH2NR3, NHCO, CONR4, CH2O, COCH2 or CH2CH2NH, and D represents CH2, or B represents CH2NH, and D represents CO, or A also represents CH2CH2, B represents NR4bCH2 and D represents CH(OH), or A represents CH=CH, B represents CH2NR5 or CONR6, and D represents CH2, or A represents C≡C, B represents CH2NH and D represents CO, or A represents COCH2, B represents CONH and D represents CH2, or A represents CH2N(R7), and B represents CH2CH2, a D represents CH2, or B represents CH2CH(OH), a D represents CH(OH), or A represents NHCH2, and B represents CH2NH, a D represents CH2, or B represents CH2NH, a D represents CO, or A represents NHCO, B represents CH(R8)NH or CH2CH2, and D represents CH2, or A represents OCH2, B represents CH=CH or CONH, and D represents CH2; R2 represents (C1-C4)alkyl; R2a represents hydrogen; R3 represents hydrogen, CO-(CH2)p-COOR3', (CH2)p-COOR3, (C2-C5)acyl or amino(C1-C4)alkyl, or also R3 represents (C1-C4)alkyl, which can be one or two times substituted with hydroxygroup, p stands for integer number from 1 to 4, and R3 represents hydrogen or (C1-C4)alkyl; R4 represents hydrogen or (C1-C4)alkyl; R4b represents hydrogen; R5 represents hydrogen or (C2-C5)acyl; R6 represents hydrogen or (C1-C4)alkyl; R7 represents hydrogen or (C1-C4)alkyl, which can be one or two times substituted with group, independently selected from hydroxygroup and aminogroup, R8 represents hydrogen or (C1-C4)alkyl; E represents one of the following groups (a-a1) where Z represents CH or N, and Q represents O or S, or E represents phenyl group, which is one or two times substituted in meta- and/or para-position with substituents, each of which is independently selected from group, including halogen, (C1-C3)alkyl and trifluoromethyl; or pharmaceutically acceptable salt of such compound. Formula I compound or its pharmaceutically acceptable salt is applied for obtaining medication or pharmaceutical composition for prevention or treatment of bacterial infection.

EFFECT: derivatives of oxazolidine antibiotics for obtaining medication for treatment of bacterial infections.

15 cl, 2 tbl, 214 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry and represents a preparation possessing the anti-inflammatory action, stimulating the mucosa regeneration, and containing magnesium-chloride mineral bischofit brine 1.27±0.01 g/ml with normalised specific gravity, slastiline, menthol, thymol, and a stabilising agent differing by the fact that it contains magnesium-chloride mineral bischofit brine free from technogenic impurities, with the ingredients in the preparation are taken in specific proportions, g.

EFFECT: reducing acute daily oral toxicity in 1,7-1,9 times.

1 tbl

FIELD: medicine.

SUBSTANCE: azithromycin infusions are combined with the daily administration of metronidazole. Azithromycin is administered in a single dose of 1.0 g on the 5th post-infusion day. The treatment is combined with the daily administration from the first day of the metronidazole therapy twice a day in a dose of 500 mg for 14 days.

EFFECT: effective treatment ensured by reducing a dose and risk of side effects.

3 ex

FIELD: medicine.

SUBSTANCE: combination contains fulvic acid or a salt thereof, and an antibiotic representing oxacillin or gentamycin, or a combination thereof. The invention also refers to a method of treating or inhibiting a bacterial infection in an individual that involves administering an effective amount of a composition containing the above combination.

EFFECT: invention provides the synergetic effect of the combination of fulvic acid and antibiotics.

16 cl, 1 tbl, 7 dwg, 2 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a new derivative of β-lactam ceftriaxone antibiotic, which is presented with general formula (I), containing group R1=3-[[(2-methyl-6-oxide-5-oxo-2,5-dihydro-1,2,4-triazine-3-il)sulphanyl]methyl] (a), where R2=sodium, R3=2-amino-3-mercaptopropionate ion -HOOC-CH(NH2)-CH2-S-. Compound is synthesised with interaction of β-lactam ceftriaxone antibiotic with amino acid with cysteine.

EFFECT: derivative of β-lactam ceftriaxone antibiotic, which shows antibacterial properties in relation to bacteria Staphylococcus aureus 25923 and Escherichia coli 25922.

2 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an antiseptic drug with haemostatic action for wound cleaning. The drug contains ingredients in the following ratio, wt %: an antimicrobial substance - 0.01-3, an active complex - 1-25, glycerol - 2-35 and water - up to 100. The antimicrobial substance is specified in a group consisting of cetyl pyridinium or cetyl methyl ammonium halogenide, chlorhexidine, miramistin and other quaternary bases applicable in medical practice to treat burns and to clean open wounds, and the active complex is presented by a haemostatic preparation in the form of a mixed-ligand chelated complex of zinc, ethylene diamine tetraacetic acid and ε - aminocapronic acid. The invention also refers to a method for preparing the antiseptic drug with haemostatic action. The method consists in the fact the active complex is prepared in a water-glycerol mixture while stirring by dissolving ε - aminocapronic acid, then zinc oxide, adding powdered ethylene diamine tetraacetic acid and after dissolved completely, adding a liquid solution of the antimicrobial substance in the water-glycerol mixture.

EFFECT: preparing the antiseptic drug with haemostatic action for wound cleaning.

2 cl, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry and represents a preparation possessing the anti-inflammatory action, stimulating the mucosa regeneration, and containing magnesium-chloride mineral bischofit brine 1.27±0.01 g/ml with normalised specific gravity, slastiline, menthol, thymol, and a stabilising agent differing by the fact that it contains magnesium-chloride mineral bischofit brine free from technogenic impurities, with the ingredients in the preparation are taken in specific proportions, g.

EFFECT: reducing acute daily oral toxicity in 1,7-1,9 times.

1 tbl

FIELD: biotechnologies.

SUBSTANCE: invention refers to derivatives of oxazolopyrimidine in any of their stereoisomeric forms, or in the form of a mixture of stereoisomeric forms specified in Claim 1.

EFFECT: oxazolopyrimidine derivatives having agonistic activity in relation to Edg-1 receptor.

5 tbl, 319 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to general surgery, and can be applied in prevention of purulent-inflammatory complications of anterior abdominal wall wounds in case of strangulated ventral hernias. For this purpose, 10% solution of colloidal nanosilver is introduced into operation wound after elimination of strangulation, with preliminary injections on perimetre of hernial orifice edges in dose 0.1 ml of solution per 1 cm2 of aponeurosis. After that, after fixation of synthetic implant, injections are made along the line of sutures on periphery in dose 0.1 ml per 1 cm2 of suture. After that, subcutaneous adipose cellular tissue is infiltrated with solution of colloidal nanosilver in dose 0.1 ml of solution per 1 cm2 of wound.

EFFECT: method ensures considerable reduction of risk of development of purulent-inflammatory complications in patients with said pathology, as well as acceleration of processes of tissue reparation due to application of biologically active colloidal solution of nanosilver, producing selective impact only on pathogenic microorganisms, on all layers of anterior abdominal wall and zone of synthetic implant fixation.

5 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely purulent surgery, and may be used for treating infected wounds. That is ensured by surgical treatment of suppurative focuses and exsection of necrotised tissues. Then the whole wound surface is treated with 10% colloidal nanosilver. The subcutaneous fat is infiltrated with 10% colloidal nanosilver at 0.1 ml of the solution per 1 cm2 of the wound. Additionally, the wound is covered with a sterile 10% colloidal nanosilver wipe.

EFFECT: method enables reducing the length of wound granulation and epithelisation ensured by using the biologically active colloidal nanosilver solution coating all wound layers and rendering selective action on pathogens only.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, specifically to an agent showing antimicrobial activity.

EFFECT: agent possessing antimicrobial action and representing robinia (Robinia pseudaacacia L) seed essence prepared by collecting the seeds in October and extracting them three times in petroleum benzene under certain conditions.

2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, particularly to ophthalmology. One of the objects is using 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diole (compound A), its separate isomers and a mixture of the same isomers, or pharmaceutically acceptable salts, solvates and hydrates thereof for preparing an agent for treating keratoplasty or refractive keratoplasty consequences. The second object is a method of treating the keratoplasty or refractive keratoplasty consequences in an individual in need thereof that involves administering a therapeutically effective amount of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diole (compound A), its separate isomers and mixtures of the same, pharmaceutically acceptable salts, solvates and hydrates thereof into the above individual.

EFFECT: invention provides treating the eye disorder consequences.

2 cl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and may be used for treating septic wounds and burns. A composition possessing antibacterial action contains active metal biocomplexes with 5-nitroimidazole and β-pyridine carboxylic acid and a base providing a soft dosage form. As a gelling agent, there may be used modified cellulose derivatives, additionally comprising methyl monosilane hydrogel (enterosgel) and/or polyvinylpyrrolidone, or an alloy of polyethylene oxide-400 and polyethylene oxide-1500. As a mixture of hydrophilic substances, the base contains substances specified in a group of: polyethylene oxides, dimexide, glycerol and aerosol, may comprise at least one target additive of: anaesthetic - trimecaine, pyrromecaine, lidocaine, or a mixture thereof, a repair process stimulator - methyluracil, acemine, solcoseryl, Spirulina microalgae (Spirulina platensis), or a mixture thereof, antiseptic - miramistine, chlorhexidine digluconate, dioxidine or a mixture thereof. The composition is presented in the form of an ointment or gel.

EFFECT: invention provides the improved microcirculation in wound tissues, as well as anti-inflammatory action, repair process stimulation.

5 cl, 6 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to microencapsulation of drugs through the example of rivanol which can be used as an antimicrobial, antifungal topical preparation. A method for preparing microcaplues of rivanol in a water-soluble polymer representing polyvinyl alcohol or polyvinyl pyrrolidone is implemented by physical-chemical precipitation with a solvent wherein a precipitant is acetone. The process is carried out at 25°C with no special equipment required.

EFFECT: method for preparing the microcapsules of rivanol provides simplifying the process of microencapsulation.

13 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery and can be used for prevention of postoperative wound suppuration. For this purpose perforated tube is placed on the bottom of wound surface and its ends are brought outside through formed on patient's skin counteropenings with further fixation of tube to skin and their hermetic closing. Starting from the following after operation day and further on 2-3 postoperative days, 100-150 ml of antiseptic solution are forced fractionally once daily into wound through one of tube ends, the second one being closed. Intra-wound hydraulic compression of antiseptic is created and increased to such a degree that partial leakage of solution between skin sutures takes place. After that, compressed second end of tube is opened and all antiseptic is drained from wound. Then, remaining wound and drainage tube content is aspirated completely. After that from 3-4 to 9-10 days washing of wound in flow manner without element of hydraulic compression is continued on the same daily single time basis.

EFFECT: method makes it possible to reduce number of postoperative wound suppurations, thus ensuring wound healing with primary intention.

1 ex

FIELD: biotechnologies.

SUBSTANCE: vaccine strain for influenza virus A/17/mallard/Netherlands/00/95(H7N3) is proposed. Strain A/17/mallard/Netherlands/00/95(H7N3) is harmless for laboratory animals. Strain A/17/mallard/Netherlands/00/95(H7M3) has antigenic actuality and attenuation thus meeting the requirements to vaccine strains included in influenza live vaccine, and may be used for production of influenza live and inactivated intranasal vaccine in health care service for influenza prevention.

EFFECT: temperature sensitivity and high degree of cold adaptability.

7 tbl, 3 ex

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