RU2275902C2 - Preparation for treating and preventing metritis-mastitis-agalactia in sows and puerperal endometritis in cows - Google Patents

Abstract

FIELD: veterinary science.

SUBSTANCE: the suggested preparation contains enrofloxacin, dimethyl sulfoxide, furacriline and distilled water at the following ratio of components, weight%: enrofloxacin 0.3-0.5, furacriline 0.021-0.027, dimethyl sulfoxide 38-50%, distilled water - the rest. The preparation should be introduced due to intrauterine injections, in sows - with the help of special equipment for artificial insemination. Against other analogs the preparation is of wider range of anti-microbial action and high anti-microbial activity.

EFFECT: higher efficiency of therapy and prophylaxis.

6 ex, 6 tbl

Description

The invention relates to the field of veterinary medicine, in particular to preparations for the treatment and prevention of metritis-mastitis agalactia in sows and postpartum endometritis in cows.

Metritis-mastitis-agalactia is an acute disease of sows that occurs as a general syndrome in the first two days after farrowing and manifests itself as inflammation of the uterus, mammary gland, as well as a decrease (hypogalactia) or cessation (agalactia) of milk secretion. The disease is manifested by an increase in body temperature to 39.8-40.8 ° C, increased heart rate and respiration, inhibition of the general condition, decreased or terminated intake of food and water. Sows are lying, not allowing piglets to the nipples. From the genital tract, mucopurulent exudate of a liquid or semi-liquid consistency is allocated in an amount of 10-20 to 200-300 ml. The external genitalia, the mucous membrane of the vagina are hyperemic. The main form of breast inflammation is subclinical mastitis, which affects up to 40-60% of the functioning lobes of sows. Clinically expressed mastitis is recorded in 12-20% of sick sows.

Acute postpartum endometritis is an inflammation of the predominantly uterine mucosa. Depending on the nature of the inflammation, postpartum endometritis is divided into catarrhal, purulent-catarrhal and fibrinous. Purulent-catarrhal endometritis is believed to be the main form of postpartum endometritis in cows. Acute postpartum endometritis is clinically manifested on the 8-10th day after childbirth, less often on the 6-7th day and is characterized by abundant secretion of exudate (mucous, purulent-mucous, fibrinous) of a liquid consistency of gray-brown or yellow-brown color. Postpartum endometritis is recorded in 20-57% of calving cows.

For the treatment and prevention of postpartum diseases in sows, antimicrobial agents are used, including antibiotics, sulfonamide, nitrofuran agents. But not all of them give the expected effect. This is primarily due to a decrease in the sensitivity of the uterine microflora to drugs. Therefore, a periodic replacement of drugs is necessary as their therapeutic effectiveness decreases and a sufficient arsenal of rotational agents is used. In this regard, there is a need to develop new effective drugs. As analogues, we took two drugs used to treat sows with metritis-mastitis-agalactia and treat cows with postpartum endometritis.

Neofur is a complex preparation containing neomycin, furazolidone and a gelatin-glycerin base. Used for the treatment and prevention of inflammatory process in the uterus of animals. The main disadvantage of neofur is the rapid decrease in its therapeutic and prophylactic effectiveness due to a decrease in the sensitivity of microflora and the need for its repeated administration due to the absence of penetrating substances at the base of the preparation / 1 /.

Lefuran is a complex preparation containing chloramphenicol and furagin dissolved in dimethyl sulfoxide / 2 /.

The main disadvantages of lefuran are:

a) a decrease in its therapeutic effectiveness due to a rapid decrease in the sensitivity of microflora to chloramphenicol due to the long-term (more than 20 years) use of this antibiotic in pig farming;

b) the high cost of the drug due to the high concentration (65%) of dimethyl sulfoxide (DMSO).

The closest analogue of the developed drug is the drug enrocid / 3 /. Enrocid is 0.4% enrofloxacin in a solution of dimethyl sulfoxide and distilled water.

The disadvantages of enrocide are a decrease in its therapeutic efficacy associated with the development of resistance of microorganisms to enrofloxacin. It was found that this is due to a violation of the structure of DNA gyrase, an enzyme that causes the replication of bacterial DNA, as well as a decrease in the penetration of quinolones through the bacterial cell wall / 4 /.

In addition, it is known that in single-component preparations containing one drug, bacterial resistance develops faster.

One of the measures preventing the development of resistance of microorganisms is the development of dosage forms that include several components with different mechanisms of antimicrobial action. In the case when the combination of antibiotics does not lead to a synergistic effect, but is limited by an adaptive effect, the spectrum of action of complex drugs expands, which is important for mixed infections. The complex use of antibiotics is also effective when exposed to resistant forms of microorganisms. In this case, various mechanisms of action on the microbial cell are used. Combined antibiotic therapy reduces the possibility of drug resistance of microorganisms / 5 /.

Due to the mutually reinforcing effect of the components of complex preparations and the achievement of a therapeutic effect in smaller doses, it becomes possible to reduce the toxicity of individual components / 6 /.

In connection with the above, in the composition of the claimed drug, in addition to enrofloxacin, a drug of the nitrofuran series is introduced - furacryline, which also has a wide spectrum of antimicrobial action.

The technical result of the invention is to increase efficiency, expand the spectrum of action and enhance antimicrobial activity.

The goal is achieved by the use of a complex preparation consisting of enrofloxacin, furacryline, dimethyl sulfoxide and distilled water. The drug is used by introducing it into the uterine cavity in sows with metritis-mastitis-agalactia patients and in cows with postpartum endometritis for cows for therapeutic purposes and animals after farrowing and calving for prophylactic purposes.

The inventive preparation consists of the following components, wt.%:

Enrofloxacin 0.3-0.5

Furacrilin 0.021-0.027

Dimethyl sulfoxide 38-50

Distilled water

In this case, the optimal ratio of the components included in the preparation is the following, wt.%:

Enrofloxacin 0.4

Furacrilin 0.025

Dimethyl sulfoxide 40

Distilled water

Enrofloxacin, a derivative of quinol carboxylic acid, belongs to the group of fluoroquinolones of the third generation and consists of one fluorine radical at position 6, one piperazinyl radical at position 7 and a cyclopropyl radical at position 1/7 /.

Enrofloxacin is sparingly soluble in water; sparingly soluble in ethanol; well soluble in chloroform, in acidic and alkaline solutions.

Due to its structure, enrofloxacin has the following advantages over many antibacterial drugs:

- active against gram-positive and gram-negative microorganisms, as well as mycoplasmas;

- active when administered orally, as it is well absorbed from the gastrointestinal tract and penetrates into all organs and tissues of the body;

- low toxicity for animals and birds.

Enrofloxacin has a wide spectrum of antibacterial activity, inhibits the growth and development of gram-positive and gram-negative microorganisms, including E. coli, Haemophilus, Klebsiella, Pasteurella, Pseudomonas, Bordetella, Campylobacter, Erysipelothrix, Stobobocococcus, Staphocococtocococtoprobocum, Stocobocococulus, Stocobococida, Stocobococida as well as Mycoplasma gallisepticum, Mycoplasma synoviae, Mycoplasma meleagridis, Mycoplasma iowae.

Enrofloxacin blocks the action of a specific bacterial enzyme, DNA gyrase. This enzyme is necessary for the promotion of a folded double helix of DNA before its replication. Enrofloxacin acts directly on subunits A, which leads to stop DNA replication and the emergence of new bacteria.

Enrofloxacin is directly linked to specific regions of DNA to which DNA gyrase usually attaches. Thus, fluoroquinolone prevents the onset of replication.

The specific mechanism of action of fluoroquinolones, which differs from other antibacterial drugs, ensured for enrofloxacin the absence of cross-resistance with all antibiotics, sulfonamides and nitrofurans.

The absence of DNA gyrase, a target for enrofloxacin, in mammalian and avian cells makes the drug practically non-toxic to the macroorganism.

So LD ₅₀ with a single oral administration for chickens ranges from 2000-2500 mg / kg body weight, which is hundreds of times the therapeutic dose.

Furacrilin is a broad-spectrum antimicrobial agent that has an antimicrobial effect on gram-positive and gram-negative bacteria, especially pyogenic organisms. Highly active against pathogens of dysentery, colienteritis, listeriosis and antibiotic-resistant microbes. Furacryline is low toxic. It does not have a cumulative effect. When administered orally in therapeutic doses, it is well absorbed and is stored in blood in effective concentrations for 6 hours. Increases the phagocytic activity of leukocytes, does not affect the composition of the blood.

The mechanism of the antimicrobial action of furacrilin is based on blocking cellular respiration. Being hydrogen acceptors, they compete with flavin enzymes, disrupt nucleic acid synthesis, blocking the DNA structural gene, inhibit pyruvate metabolism, dehydrogenase activity, aldolase and transketolase, which negatively affects the energy exchange of the microbial cell, its growth and reproduction) / 8 /.

Dimethyl sulfoxide (DMSO) is used as a solvent. It is the only low-toxic substance that has the ability to penetrate intact tissues and carry dissolved medicinal substances (penetrating and transport properties) / 9 /.

The inventive drug is administered to sows intrauterine using a device for artificial insemination of pigs - POS-5. During treatment, a single dose of 0.7 ml / kg of body weight is reintroduced if necessary after 24 hours. For prevention, the dose is 0.5 ml / kg body weight 6-12 hours after farrowing, once.

The drug for the treatment of cows with acute postpartum endometritis is administered intrauterine using a Janet syringe 3-4 times (the first two times at a dose of 200 ml, and then 150 ml each) with a 48-hour interval until recovery.

For the prevention of postpartum endometritis, the cows should be intravenously injected with a dose of 200 ml immediately after the operative separation of the placenta or 6-12 hours after normal birth in cases of a wide spread of this pathology on the farm.

The drug is made as follows (components in wt.%). Furacrilin 0.025% is added to DMSO (40%) and mixed until completely dissolved, 0.4% enrofloxacin is gradually added to it in the form of an aqueous solution, and distilled water is added up to 100%.

The effectiveness of the preparation was tested on sows of the Krasnodonskoye breeding farm of the Ilovlinsky District of the Volgograd Region and cows of the Voronezhpishcheproduct LLC of the Novousmansky District of the Voronezh Region.

The essence of the proposed technical solution is illustrated by examples.

Example 1

The experiment was carried out on large white pigs in the second and fourth farrowing. The diagnosis was made on the basis of a clinical, obstetric and gynecological examination.

The drug was injected into the uterine cavity using POS-5 at a dose of 0.7 ml / kg of body weight in a heated form to 40%. If the effect after administration of the claimed drug is not obtained, then the drug was re-administered. The experiment was carried out using three compositions of the active components of the claimed drug:

No. 1 contains (wt.%): Enrofloxacin 0.3, furacryline 0.021, dimethyl sulfoxide 38 and distilled water up to 100;

No. 2 contains (wt.%): Enrofloxacin 0.4, furacryline 0.025, dimethyl sulfoxide 40 and distilled water up to 100;

No. 3: contains (wt.%) Enrofloxacin 0.5, furacryline 0.027, dimethyl sulfoxide 50 and distilled water to 100.

Animals of the control group were treated using the base drug neofur. A neofur suspension prepared at the rate of 3-4 suppositories per 150 ml of distilled water was administered at a 24-hour interval until recovery in accordance with the instructions for the drug / 1 /.

The animals underwent daily clinical examination, taking into account the time of disappearance of the clinical signs of the disease (t, pulse, respiration, excretion from the external genitalia, general condition, intake of feed and water, the condition of piglets).

The results of the experiment are presented in table 1.

Table 1 Therapeutic efficacy of the claimed and known drugs in the treatment of metritis-mastitis-agalactia in sows Indicators Using the base case Using various ratios of the components of the claimed drug No. 1 Number 2 Number 3 The number of sick animals 17 twenty 19 twenty Therapeutic effect after a single intrauterine injection 11 (64.7%) 13 (65.0%) 16 (84.2%) 16 (80.0%) Therapeutic effect after repeated administration to unhealthy animals 13 (76.5%) 16 (80.0%) 19 (100%) 19 (95.0%) Did not recuperate after double administration 14 (23.5%) 4 (20.0%) - 1 (5.0%) Affected shares mol. sow glands after 5 days from the start of treatment (%) 70.3 23,4 0.7 13,2

From table 1 it follows that the best therapeutic effect was achieved with the use of composition No. 2, containing (wt.%): Enrofloxacin 0.4, furacrilin 0.025, dimethyl sulfoxide 40 and distilled water to 100.

Example 2

The experiment was carried out on sows of large white breed in 2-5 farrowing with a body weight of 180-230 kg. Prevention of metritis-mastitis-agalactia was carried out by a single intrauterine injection of the drug using POS-5 4-6 hours after farrowing at a dose of 50 ml per 100 kg of body weight. The experiment was carried out using three compositions of the active components of the claimed drug:

No. 1 contains (wt.%): Enrofloxacin 0.3, furacryline 0.021, dimethyl sulfoxide 38 and distilled water up to 100;

No. 2 contains (wt.%): Enrofloxacin 0.4, furacryline 0.025, dimethyl sulfoxide 40 and distilled water up to 100;

No. 3: contains (wt.%) Enrofloxacin 0.5, furacryline 0.027, dimethyl sulfoxide 50 and distilled water to 100.

The animals of the control group, using the basic version, were once intrauterine injected with a neofur suspension prepared at the rate of 1 suppository per 50 ml of distilled water 4-6 hours after farrowing.

Animals of the control group without the use of the prototype, no preparations were administered after farrowing.

The animals underwent a daily clinical examination, taking into account the incidence of sows with metritis-mastitis-agalactia and endometritis.

The results of the experiment are presented in table 2.

table 2 The effectiveness of the claimed and well-known drugs for the prevention of metritis-mastitis-agalactia in sows Indicators The claimed drug composition Using the base case Without the use of the drug No. 1 Number 2 Number 3 The number of animals in the experience 25 27 27 29th 28 Endometritis 10 10 eleven eleven 16 MMA four 2 3 2 9 Healthy eleven fifteen 13 16 3

From table 2 it follows that the best preventive effect was achieved when applying the composition of the active ingredients No. 2: enrofloxacin, furacryline and dimethyl sulfoxide in a ratio of 0.4: 0.025: 40.0.

Example 3

The experiment was carried out on cows of red-motley breed 4-6 years of age. The diagnosis was made on the basis of a clinical, obstetric and gynecological examination, anamnesis.

The drug was injected into the uterine cavity using a Janet syringe for the first two times in a dose of 200 ml, and then 150 ml with a 48-hour interval until clinical recovery. The experiment was carried out using three compositions of the active components of the claimed drug:

No. 1 contains (wt.%): Enrofloxacin 0.3, furacryline 0.021, dimethyl sulfoxide 38 and distilled water up to 100;

No. 2 contains (wt.%): Enrofloxacin 0.4, furacryline 0.025, dimethyl sulfoxide 40 and distilled water up to 100;

No. 3: contains (wt.%) Enrofloxacin 0.5, furacryline 0.027, dimethyl sulfoxide 50 and distilled water to 100.

Animals of the control group were treated using the base drug neofur. A neofur suspension prepared at the rate of 3-4 suppositories per 150-200 ml of distilled water was administered at a 48-hour interval until recovery in accordance with the drug's instruction / 1 /.

The animals underwent a daily clinical examination, taking into account the time of disappearance of the clinical signs of the disease, the number of animals recovered and fertilized, the rate of fertilization, the length of time from calving to fertilization.

The results of the experiment are presented in table 3.

Table 3 Therapeutic efficacy of the claimed and known drugs in the treatment of endometritis in cows Indicators The claimed drug composition Basic version No. 1 Number 2 Number 3 Number of animals, goal 12 13 13 12 Recovery time, days 14.8 ± 0.78 13.3 ± 0.46 13.9 ± 0.51 15.4 ± 0.67 The number of drug injections 5.24 ± 0.39 3.91 ± 0.31 4.02 ± 0.28 5.69 ± 0.24 Recover, goal 9 eleven 10 9 Therapeutic efficacy,% 75.0 84.6 76.9 75.0 The period from calving to fertilization, days 79.1 ± 3.09 65.2 ± 2.07 68.4 ± 2.47 78.9 ± 3.41 Fertilized at the first insemination: Goal 6 10 9 7 % 50,0 76.9 69.2 58.3 Fertilization rate 1.91 ± 0.19 1.48 ± 0.08 1.56 ± 0.09 1.89 ± 0.17 Toxic effect, goal 0 0 0 0

From table 3 it follows that the best therapeutic effect was achieved when applying the composition of the active ingredients No. 2: enrofloxacin, furacryline and dimethyl sulfoxide in a ratio of 0.4: 0.025: 40.0.

Example 4

The experiment was carried out on cows of red-motley breed 4-6 years of age. Prevention of postpartum endometritis was carried out by a single intrauterine injection of the drug using a Janet syringe immediately after surgical separation of the placenta or 6-8 hours after normal delivery at a dose of 200 ml. The experiment was carried out using three compositions of the active components of the claimed drug:

No. 1 contains (wt.%): Enrofloxacin 0.3, furacryline 0.021, dimethyl sulfoxide 38 and distilled water up to 100;

No. 2 contains (wt.%): Enrofloxacin 0.4, furacryline 0.025, dimethyl sulfoxide 40 and distilled water up to 100;

No. 3: contains (wt.%) Enrofloxacin 0.5, furacryline 0.027, dimethyl sulfoxide 50 and distilled water to 100.

Animals of the control group using the basic version were once intrauterine injected with a neofur suspension in a dose of 200 ml immediately after surgical separation of the placenta or 6-8 hours after normal delivery / 1 /.

Animals of the control group without the use of the prototype, no preparations were administered after farrowing.

The animals underwent daily clinical observation, taking into account the incidence of cows with postpartum endometritis, the percentage of fertilized animals, the period from calving to fertilization, and the fertilization rate.

The results are presented in table 4.

Table 4 The effectiveness of the claimed and known drugs for the prevention of postpartum endometritis in cows Indicators The claimed drug composition Using the base case Without the use of the drug No. 1 Number 2 Number 3 Number of animals, goal eleven 12 12 12 12 Has contracted postpartum endometritis: Goal, 3 one 2 3 5 % 27.3 8.3 16.7 25.0 41.7 Preventive efficacy,% 72.7 91.7 83.3 75.0 58.3 The period from calving to fertilization, days 59.8 ± 3.14 46.7 ± 2.17 49.8 ± 2.07 58.1 ± 3.04 75.6 ± 4.21 Fertilized at the first insemination: Goal, 6 9 8 7 5 % 50,0 75.0 66.7 58.3 41.7 Fertilization rate 1.51 ± 0.09 1.33 ± 0.08 1.38 ± 0.08 1.47 ± 0.08 2.14 ± 0.17 Toxic effect, goal 0 0 0 0 0

From table 4 it follows that the best preventive effect was achieved when applying the composition of the active components No. 2: enrofloxacin, furacryline and dimethyl sulfoxide in a ratio of 0.4: 0.025: 40.0.

Example 5

To test the antimicrobial activity of the claimed drug in comparison with the prototype, an experiment was conducted. The inventive preparation was taken in the optimal ratio of active components, wt.%:

Enrofloxacin 0.4

Furacrilin 0.025

Dimethyl sulfoxide 40

Distilled water

Antimicrobial activity was determined (BS - bacteriostatic activity, BC - bactericidal activity) of the claimed drug by serial dilution method.

Table 5 Antimicrobial activity of the claimed drug and enrocide Culture The concentration of the drug, mcg / ml enrocid claimed drug BS Bts BS Bts Staph. aureus 1.95 3.9 1,0 1,0 E.coli O 866 0.49 0.49 0.015 0,03 E.coli O 141 3.9 7.8 1.95 3.9 Str. agalactiae 0.49 0.49 0.08 0.32

From table 5 it follows that the claimed drug has a higher antimicrobial activity compared with enrocid.

Example 6

To determine the sensitivity of microflora, isolated from the uterine cavity of patients with endometritis of cows and sows, to the claimed drug and enrocid experiment was conducted. The inventive preparation was taken in the optimal ratio of active components, wt.%:

Enrofloxacin 0.4

Furacrilin 0.025

Dimethyl sulfoxide 40

Distilled water

The sensitivity of the selected microflora is determined using indicator discs.

Table 6 The sensitivity of microflora to the claimed drug and enrocide Culture Zone of growth inhibition, mm enrocid The inventive drug E.coli O 8 6 * 24 E.coli O 126 13 27 Staph. aureus fifteen 28 Staph. epidermidis 13 24 Str. β-hemolytic 7 eighteen Str. agalactiae eighteen 24 Str. disagalactiae 12 27 * Note: with a growth inhibition zone of less than 10 mm, microorganisms are considered insensitive, with a growth inhibition zone of 10 to 15 mm - insensitive, from 15 to 20 mm - sensitive and more than 20 mm - highly sensitive.

From table 6 it follows that the claimed drug has a wider spectrum of antimicrobial action, since in relation to it, almost all the isolated microorganisms show high sensitivity.

Thus, the studies showed the effectiveness of the claimed drug and its wide spectrum of action for the treatment and prevention of metritis-mastitis agalactia in sows and postpartum endometritis in cows.

Information sources

1. Chervyakov D.K. et al. Medicines in veterinary medicine. - M .: Kolos, 1977 .-- P.342.

2. Sotnikov A.V. Diagnosis and treatment of subclinical mastitis in MMA (metritis-mastitis-agalactia) in sows. / Abstract of dissertation for the degree of candidate of veterinary sciences. - Voronezh, 1985.

3. Temporary instruction on the use of the drug enrocid for the prevention and treatment of postpartum gynecological diseases in cows and sows (in the order of a wide production test in 2000-2002) No. 13-5-2 / 2007. Approved by the Veterinary Department of the Ministry of Agriculture and Food of Russia on 05.15.2000

4. M. Gellert. DNA topoisomerases / Ann. Rev. Biocem. - 1981. - V.50. - P.879-910.

5. Kovalev V.F. and others. Antibiotics in animal products. - M., 1977.

6. Rabinovich M.I. Workshop on Veterinary Pharmacology and Prescription. / 3rd ed., Rev. and add. - Agropromizdat, 1988 .-- 239 p.

7. Sazonova E.M. Development of an antibacterial drug based on enrofloxacin, the study of its toxicity, pharmacokinetics and therapeutic efficacy. / Abstract of dissertation for the degree of candidate of biological sciences. - Voronezh, 2000.

8. Kovalev V.F., Volkov IB, Violin B.V. Antibiotics, sulfonamides and nitrofurans in veterinary medicine: Reference book // Agropromizdat, 1988.

9. Dimethyl sulfoxide: pharmacology, application in dermatology and related specialties. - Perm, 1975.

Claims (1)

A drug for the treatment and prevention of metritis-mastitis agalactia in sows and postpartum endometritis in cows, containing enrofloxacin, dimethyl sulfoxide and distilled water, characterized in that it additionally contains furacryline in the following ratio, wt.%: Enrofloxacin 0.3-0.5 Furacryline 0.021-0.027 Dimethyl sulfoxide 38-50 Distilled water Rest