HU207445B - Method for producing preparation and fodder mixture of synergetical effect suitable for medicinal treatment of bacterial sicknesses of domestic animals - Google Patents

Abstract

Synergistic prepns. for treatment of bacterial and prosaw ailments in domestic animals and to cure certain respiratory infections and digestive complaints (especially Choli-infections) and to prevent and cure mycoplasmosis in poultry and pigs (to increase their yield), contain tiamulin and a quinoling-carboxylic-acid deriv. (1), pref. flumequin or buytoilic acid in 30:1-1:2 ratio, pref. in 5:1-1:1 proportion. The prepns. are administered orally or parenterally at a level of 1-100 mgs/kg body wt. pref. 5-50 mgs/kg body wt. - In formula (I), R1 = hydrolic or fluorine atom; R2 = pyrazino or 4-ethyl-pyrazino gp.; R3 = hydrogen atom; R4 = alkyl or cyclo-propyl gp. X = =CH gp. or R1 = fluorine atom; R2 = pyrazino gp. R4 = alkyl gp., or R1 = fluorine atom; R2 = hydrogen atom; R3 and R4 = -CH2-CH3-CH2-CH3- gp. X = =CH-gp.

Description

The present invention relates to a novel antimicrobial synergistic composition for the treatment and prevention of gastrointestinal, respiratory, urinary, udder, uterine and uterine diseases of domestic animals. More particularly, the present invention relates to a process for the preparation of a synergistic drug combination comprising a mixture of tiamulin, a diterpenic antibiotic, and a quinolone carboxylic acid derivative of general formula I.

In the general formula I, the substituents R _b R ₂ , R ₃ , R ₄ and X have the following meanings:

Rj = hydrogen, fluorine

R _{2 is} piperazino or 4-ethylpiperazino

R ₃ = hydrogen

R ₄ = ethyl or cyclopropyl

X = carbon or 25

R ₁ -X and R ₃ -X = N

R ₂ = piperazino

R ₄ = ethyl or 30;

R 1 = fluorine R ₂ = hydrogen

CH ₃

I

R ₃ and R ₄ = -CH ₂ -CH ₂ -CH-

X = carbon

The acid addition or basic salts of tiamulin and the quinolone carboxylic acid derivatives of the general formula I and the esters of the quinolone carboxylic acid derivatives of the general formula I under physiological conditions, preferably C 1 -C 4 alkyl esters, are also synergistic, Thus, hereinafter, when describing the active ingredients and their effects, these derivatives are included in the specification. When using antibacterial or protozoal agents, the risk of developing resistance over a shorter or longer period of time is expected, resulting in a reduction in the efficacy of the formulations and, in some cases, ineffectiveness. All of this requires the development of new drugs and new drug combinations based on known drugs.

Tiamulin is a semisynthetic derivative of pleuromulin, which, besides Gram-positive bacteria, has excellent activity against microplasmas and treponemes, but has little effect on the growth of Gram-55-negative bacteria (Antimicr. Ag. Chemother. 7, 507 (1975)). and used to prevent and treat diseases caused by various mycoplasmas [Zbl. Bakt. Hy „I, Abt. Őrig. A. 236. 127 (1976) + 60

Poultry Sci. 56, 1209 (1977)]; Dtsch. Tierárztl. Wschr. 84. 345 (1977).

The quinolone carboxylic acid derivative of general formula I, such as flumequin [Antimicr. Ag. Chemother. 13, 475 (1978)], wherein in general formula I R 1 = fluorine

R ₂ = hydrogen

R ₃ and R _{4 are} -CH ₂ -CH ₂ -CH-

CH ₃

X = carbon atom in pipemic acid [J. Antimicr. Chemother. 11: 369 (1983)], wherein in general formula I

R 1 -X = N

R ₃ -X = N

R ₂ = piperazino

R ₄ = ethyl group of norfloxacin [Antimicr. Ag. Chemother. 25,399 (1984)] where in the general formula I

Rj = fluorine

R ₂ = piperazino

R ₃ = hydrogen

R.-- ethyl

X = carbon atom of ciprofloxacin [Arzneim. Forsch. 36, 904 (1986)] where in the general formula I

Rj = fluorine

R ₂ = piperazino

R ₃ = hydrogen

R ₄ = cyclopropyl

X - Carbon atom of enrofloxacin [Scherr, M., Bauditz, R .: Baytril (BAY Vp 2674) - Antibacterial activity as well as serum and tissue levels in calves. IPVS Congress, Barcelona, 1986)] where in the general formula I

Rj = fluorine

R ₂ = 4-ethylpiperazino

R ₃ = hydrogen

R ₄ = cyclopropyl

X = Carbon is a relatively new compound which is very effective against gram-negative pathogens in particular. These compounds are used in human and veterinary medicine primarily for the treatment of enteric, urinary and respiratory tract infections caused by Gram-negative pathogens.

Our studies have surprisingly found that when tiamulin is combined with a quinolone carboxylic acid derivative of the Formula I, preferably flumequine, the antimicrobial activity of the compounds of different spectrum of activity is enhanced in a synergistic manner in several bacterial strains.

HU 207 445 Β

Microbiological tests were performed for each judgment. The results of the studies are summarized in Table 1 below for the in vitro inhibitory effect of the compounds of Table 1 or combinations thereof on bacterial strains.

Table 1

Antibacterial activity of chemotherapeutic agents and combinations thereof (mg / l)

Bacterium Chemotherapeutic agent Synergism '' tiamulin flumequine tiamulin + flumequin (1: 1) MIC MBC MIC MBC MIC MBC MIC MBC Staphylococcus aureus 25 100 25 50 5 25 10x 4x Listeria monocytogenes 50 100 25 25 1 5 50x 10x E. coli 11 50 100 0.5 1 0.5 1 2x 2x Klebsiella pneumoniae 200 200 5 10 5 10 2x 2x Salmonella typhimurinum 200 200 1 1 0.5 1 4x 2x Bordetella bronchiseptica 50 200 5 10 5 10 2x 2x

MIC - minimum inhibitory concentration

MBC - Minimum Bactericidal Concentration - Compared to a More Effective Member of the Combination Against a Strain of Bacteria

In vitro studies clearly demonstrated the synergistic effect of the combination on certain bacterial strains.

The enhancement effect is primarily expressed in the auto- _r Reus Staphylococcus, Listeria monocytogenes and Salmonella typhimurium cultures. The degree of synergism for the bacterial strains examined is generally 2-4-fold, but occasionally reaches 25-50-fold.

The pharmaceutical combination of the present invention is prepared by mixing or pouring the active ingredients with the veterinary auxiliaries and / or carriers. The veterinary medicinal product is administered orally and / or parenterally. The ratio of tiamulin to quinolone carboxylic acid derivative of the general formula I in the veterinary preparation may be 20:11:20, preferably 5: 1-1: 1.

The daily dose of the preparation is from 1 to 100 mg / kg, preferably 5-50 mg / kg of active ingredient.

The favorable results of the in vitro studies were largely supported by the data from the field trials.

In our studies of broiler chickens, we found, for example, that tiamulin with flumequin in the first 3 days of life and fattening 26-28. administered at a dose of 150 mg / l through drinking water at a daily dose of 2: 1, increased the meat yield of the animals by 5% compared to the untreated 55 controls, improved their feed intake by 4%, and reduced the incidence of chronic respiratory disease and coli.

In our studies of broiler chickens, we found that 60 in combination with tiamulin in combination with flumequin at a dose of 225 mg / l for 5 days, virtually eliminated the clinical signs of chronic respiratory disease, significantly reduced mortality, and and significantly increased the profitability of production.

According to our studies in broiler chickens, the combination of tiamulin and flumequin 2: 1 at 120 mg / kg / kg in the feed for the first 10 days of life significantly increased meat yield, improved feed intake, mortality, has been significantly reduced.

In our studies in turkeys, we found 45 that when combined with 2: 1 tiamulin in the first 3 days of life and flumequin at 150 mg / l in drinking water, it increased the body weight of the animals by 6%, improved feed sales by 4%, significantly reducing the incidence of chronic 50 respiratory diseases and coli infections.

In our studies of fattening pigs, we found that tiamulin and flumequin in a 2: 1 ratio in the feed at a dose of 150 mg / kg / kg and 10-10 days after selection and after introduction into the fattening farm significantly increased the meat yield of the animals. significantly reduced the incidence of infections and enzootic pneumonia.

HU 207 445 Β

In our experiments in fattening pigs, it was found that the combination of tiamulin and enrofloxacin at a dose of 75 mg / l in drinking water for 5 days significantly reduced the clinical symptoms of porcine dysentery and enzymatic pneumonia and significantly increased the yield of pigs.

In our studies of cows, we found that the combination of tiamulin and enrofloxacin in a 1: 1 ratio encapsulated in the uterus of newly born cows accelerated the rate of involution and prevented the development of uterine inflammation and fetal retardation. Each capsule contained 2 g of the active ingredient.

Example 1

Tiamulin and flumequin as active ingredients are used to prepare pulvis. The composition of pulvis is as follows:

tiamulin hydrogen fumarate 20.0 g flumequin 10.0 g sucrose 70.0 g

The preparation is used in the prevention or treatment of diseases of chickens, turkeys and pigs caused by E. coli and mycoplasmas, dissolved in drinking water or mixed with feed at a dose of 5-50 mg / kg.

Example 2

Tiamulin and enrofloxacin are used as active ingredients in the preparation of a medicated premix. The drug premix has the following composition: tiamul hydrogen fumarate 10.0 g enrofloxacin 5.0 g wheat flour 985.0 g

1000.0 g

The medicated premix is mixed at a concentration of 1% into feed for fattening pigs, and the feed thus prepared is fed to the animals after selection and then introduced into the fattening farm for 10 to 10 days.

Example 3

Tiamulin and enrofloxacin are used as active ingredients in the form of a bee capsule. The composition of the bee capsule is as follows:

tiamulin hydrogen fumarate 1.0 g enrofloxacin 1.0 g lactose 3.0 g

5HG

The drug mixture is filled into a capsule and the resulting capsule is placed in the uterus of cows for 1-3 days for the prevention or treatment of uterine inflammation.

Claims (2)

PATENT CLAIMS A process for the preparation of a compound having a synergistic antimicrobial activity for the treatment of bacterial diseases in domestic animals, characterized in that tiamulin and a quinolone carboxylic acid derivative of the formula I wherein R [= hydrogen, fluorine] R ₂ = piperazino or 4-ethylpiperazino R ₃ = hydrogen R ₄ = ethyl or cyclopropyl You're an X carbon atom R ₁ -X and R ₃ -X = N R ₂ = piperazino R ₄ = ethyl or Rj = fluorine R ₂ = hydrogen CH ₃ i R ₃ and R ₄ = -CH ₂ -CH ₂ -CH- X = carbon atom or physiologically acceptable esters of these compounds, preferably C 1 -C 4 alkyl esters, or their biologically usable salts, in a ratio of from 20 to 20, preferably from 5 to 1 to 1: 1; and other excipients. 2. A process for the preparation of a compound feed comprising tiamulin and a quinolone carboxylic acid derivative of general formula I wherein: Rj is hydrogen, fluorine R ₂ = piperazino or 4-ethylpiperazino R ₃ = hydrogen R ₄ = ethyl or cyclopropyl X = carbon atom R ₁ -X and R ₃ -X = N R ₂ = piperazino R ₄ = ethyl or Rj = fluorine R ₂ = hydrogen CH ₃ I R ₃ and R ₄ = -CH ₂ -CH ₂ -CH- X = a mixture of carbon atoms or physiologically acceptable alkyl esters thereof, preferably having from 1 to 4 carbon atoms, or a biologically acceptable salt thereof, in a ratio of 20: 1 to 1:20, preferably 5: 1 to 1: 1, 01-0.1% by volume.