CS239619B1 - Pharmaceutical agent for fodder for cattle with grow-stimulating effect - Google Patents

Abstract

contains the active ingredients cyanoacetylhydrazone-2-formylquinoxaline-1, 4- -dioxide (generically labeled as Cyadox) in combination with antibiotics or sulfonamides and in an excellent way to suppress and prevention of microbial infectious diseases diseases, especially the digestive tract, significantly improves overall animal health weight gains and improves conversion feed.

Description

BACKGROUND OF THE INVENTION The present invention relates to a composition for medicating livestock feeds with a strong growth-stimulating effect which, if desired, has further additives in addition to the carrier substances and / or excipients. Cyanacetylhydrazone contains 2-formylquinoxaline-1,4-dioxide (generically designated Cyadox) as one of the active ingredients.

The composition of the invention is excellently suited for the control and prevention of microbial infectious diseases, particularly the digestive and respiratory tract, coccidiosis, while stimulating the growth of livestock and improving feed conversion. The composition according to the invention significantly improves the general health of the animals, reduces deaths, increases weight gains and feed utilization.

These novel compositions are primarily used as feed additives and compound feed for livestock, such as pigs, calves, poultry and others, and can be used both to treat infested breeds and to prevent, while stimulating growth and improving feed conversion.

It is known from the literature (AO No. 195 508; US Pat. No. 4,225,604; DE Pat. No. 2,829,580) that Cyadox is effective on Gram positive. and gram-negative microorganisms and has significant coccidiostatic effects and is highly effective as a growth promoter for livestock. Its great advantage is that it is practically nontoxic, since its LD 50 q = 15 g / kg (rat).

The use of a variety of antibiotics of various types for the treatment of infectious diseases and as growth promoters for livestock are generally known. The use of sulfonamides to control infectious diseases in animals is also well known. However, not all antibiotics used have stimulating efficacy. For example, neomycin alone does not act as a growth promoter (GB Pat.

140 315). Sulfonamides generally do not have growth stimulating activity.

It has now surprisingly been found that the combination of Cyadox with some antibiotics, such as tylosin, bacitracin, oxytetracycline, chlortetracycline, flavomycin, virginiamycin, spectinomycin, thiamulin or apramycin, and a combination of Cyadox with some sulfonamides / e.g. thiazole) or sulfadimidine (4,6-dimethyl-2-sulfanilamidopyrimidine) have unexpected advantages. For example, when Cyadox alone at 100 ppm / kg feed and tylosin alone at 100 ppm / kg feed are applied to early weaned piglets, and the combination of Cyadox + 100 ppm tylosin compared to control, both weight gain and weight gain are combined. even feed conversion higher than the sum of the effects of the individually administered components. It is therefore a true synergistic effect that could not be predicted in advance.

An analogous effect was observed when the feed was medicated with the Cyadox-sulfonamide combination. For example, when pre-fattening pigs weighing about 50 kg, Cyadox alone at 100 ppm / kg feed and phtalazole alone at 100 ppm / kg feed and a combination of Cyadox 100 ppm + 100 ppm phtalazole per kg feed are applied compared to the untreated control , the combination weight gain is greater than the sum of the effects for the individual components.

Again, there is a synergistic effect.

As used herein, tylosin refers to either a base or an equivalent amount of an acid salt such as hydrochloride, sulfate, phosphate, tartrate, or a dried fermentation broth with an antibiotic. The term bacitracin means a substance as such or complexes thereof with metals, for example Zn-bacitracin. Likewise, the other antibiotics and sulfonamides mentioned herein are understood as being amphoteric, basic or acidic, but also as pharmaceutically acceptable salts with organic or inorganic acids or bases, or complex salts or chelates, optionally as an antibiotic-containing mycelium.

Due to the very low toxicity of Cyadox and the disclosed antibiotics and sulfonamides, there is no risk of harm in the event of an unintended overdose of medicated feed, and when administered as a veterinary drug, appropriate doses can be used to control infectious diseases in infested breeds, and generally in systemic diseases.

The synergistic composition of the invention may contain a mixture of Cyadox and the antibiotic or Cyadox and the sulfonamide in any weight ratio to each other, for example in the range 1:10 to 10: 1, especially about 1: 1, but may contain both antibiotic and sulfonamide. In the preparation of medicated feedingstuffs, this mixture is preferably added as a premix to nutritionally balanced compound feedingstuffs with biofactors in an amount of 20 to 500 g of each ingredient per ton of feed, optionally in an appropriate veterinary dosage form of 1 to 100 mg of active substances per kg bodyweight daily.

Dosage forms suitable for administration of the synergistic composition of the invention may be solid or liquid, eg granules, capsules, bols, oral pastes, suspensions and the like, and may contain compatible solvents or diluents, carriers of organic or inorganic origin, eg ground limestone, kaolin, talc, starch, sugars, cellulose, comminuted plant residues and the like commonly used in the preparation of dosage forms, conventional excipients and other pharmaceutically active substances. Of the excipients, it is particularly important to emphasize the addition of pharmaceutically acceptable surfactants such as nonionic, cationic or anionic surfactants with good emulsifying, dispersing and wetting properties, or mixtures thereof. Surfactants may also form part of premixes and compound feeds and may be selected from a wide variety of known compounds. Surfactants are added in an amount of 0.5 to 10 kg per ton of feed.

The dosage forms of the synergistic composition according to the invention, such as conventional veterinary dosage forms, premixes, concentrates, compound feeds containing the necessary biofactors, and other preparations of this type are prepared in a known manner, e.g. by thoroughly mixing or grinding the active ingredients with solvents, diluents, carriers, adjuvants, biofactors, surfactants.

The invention also relates to the use of the synergistic composition of the invention.

The synergistic composition of the invention can be advantageously used for the treatment and prevention of diarrheal diseases and salmonelloses in pigs and other livestock, coccidiosis and other systemic diseases. It also stimulates the growth of livestock at a higher rate than the individual components, improves utilization feed and overall animal health, preventing the loss of animal death in the early stages of life, thereby increasing the efficiency of poultry, pig and cattle breeding.

The following examples illustrate the use and efficacy of the invention, but do not limit its numerous possible variations and scope.

Example 1

Early weaned piglets, crossbreeds of white noble x landrasse, born within 6 days, were brought from the farrowing house on the 5th day after weaning and after 7 days of the adaptation period at the biostation, the experiment was started. The piglets were divided into boxes into groups of 8 to 12 pieces. The boxes were fitted with a slatted floor and wooden heated floors. For the whole 4 weeks of the experiment, the complete mixture for the early weaned piglets of COS 2 was fed in all groups.

Group I - control, mixture alone

II. - Cyadox at a dose of 100 mg per kg of the mixture

III. - technical tylosin at a dose of 100 mg of active substance (base) per kg of mixture

IV. Cyadox at a dose of 100 mg per kg of the mixture in combination with technical tylosin at a dose of 100 mg of active ingredient (base) per kg of the mixture.

Animals were weighed individually at the beginning and at the end of the experiment (day 28). Feed consumption was monitored daily by group and feed conversion was calculated. The overall health of the piglets was monitored daily. The results are summarized in the table below.

Table 1

Group AND. II. III. IV. Used substances Control Cyadox Tylosin Cyadox <100) + (doses in ppm) (01 (100) those. (100) Tylosin of those. <100) Number of piglets 12 12 11 5x8 Duration of the experiment in days 28 28 28 28 Starting weight x (kg) 10.30 10.28 9.13 7.10 Increment Index (%) 100.00 109.80 125.90 150.60 Conversion of mixture x 2,0 1.99 1.90 1.61 Index (%) 100.0 99.5 (0,5) 92.2 (-7.8) 84.3 (-15.7)

Example 2

In pig fattening, 20 to 25% of animals have a stationary occurrence of bloody diarrhea. These are pigs in the pre-fattening breed BU x PC + L, weighing about 50 kg, housed in pens of 10 to 15 heads. The diagnosis of the disease was determined on the basis of pathological-anatomical, bacteriological and bacterioscopic examination. Vibrio coli has been identified as the causative agent of diarrhea.

Organization of the experiment: The pigs were divided into 4 groups of different numbers of animals (see Table 2) and fed a SOL mixture to which the premixed active ingredients were mixed as follows:

Group I - SOL mixture alone

II. Phtalazole group 100 ppm

III. group - Cyadox 100 ppm

IV. Group - Combination Cyadox 100 ppm + Phthalazole 100 ppm

The substances were applied for 14 days. In group III. (Cyadox) and IV. (Cyadox + Ftalazol) no bloody diarrhea was observed, the test substances had 100% therapeutic effect. In groups I (control) and II (phthalazole), bloody diarrhea was observed in 20-30% of the animals. At the end of the experiment, 20 pigs from both groups had to be sent to the necessary slaughter due to poor health (from group I 15, from group II 5 pigs). The health status and weight gains of the animals treated with the composition of the invention over the other groups are shown in Table 2 below.

Table 2

Group AND. II. III. IV. Substances (doses in ppm in feed) Control (0) Ftalazol (100) Cyadox (100) Cyadox + Phthalazole (100) (100) Number of pigs 73 20 May 12 74 Duration of the experiment in days 14 14 14 14 Starting weight x kg 50.48 50.62 47.80 53.13 Final weight x kg 59.43 59.61 57.90 64.93 Total increment x kg 8.95 8.99 10.10 11.80 Daily Increment x g 639 642 721 843 Increment index in% 100 ALIGN! 100.5 112.8 131.8

Example 3

MMA, bronchopneumonia and diarrhea in piglets have diarrhea. The occurrence of diarrhea is regular when weaning piglets.

Organization of the experiment: Weaned piglets of BD x L breed weighing 7 to 12 kg were housed in two pens of 18 pieces each. One pen served as a control, in the other 1% by weight was added to the feed mixture of COS 1 and COS 2. % of a premix containing 1.0 wt. % Cyadox and 1.0 wt. tylosin, corresponding to doses of 100 ppm Cyadox and 100 ppm tylosin. Piglets were weighed individually before the start of the experiment and on the 22nd day after the end of the experiment.

After placing the weaned piglets in the pen, diarrhea was observed in about 40% of the piglets in both groups after 48 hours. In the experimental group, diarrhea disappeared as early as 3 days after placement in the pen. The piglets were in good health, with no clinical signs of disease until the end of the experiment.

Diarrhea persisted in the control group until day 11 of the experiment. The rapid cessation of diarrhea in the experimental group was reflected in the weight gain and also in feed conversion as shown in Table 3.

Table 3

Group Pokusná Checklist Duration of the experiment 22 days 22 days Dose of substances in feed Cyadox 100 ppm Tylosine 100 ppm - Initial weight x in kg 9.61 9.58 Final weight x in kg 21.30 18.19 Total increase x in kg 11.69 8.61 Increment daily x in kg 0.530 0.390 Increment index x in% 135.89 100.0 Feed conversion in kg 1.59 2.03 Index in% 78.33 100.0

Example 4

On a pig breeding farm, a regular incidence of colienterotoxemia is observed from day 5 to day 7 after weaning piglets in pens, bronchitis and bronchopneumonia, debris and parakeratosis.

The weaned piglets, PC x L x D, weighing 7 to 10 kg, were housed in group pens. The piglets were divided into two groups of 33 pieces and individually weighed before the experiment and on day 21 (after the experiment). When the weaned piglets were placed in pens, all piglets were treated with Axetocal (an injectable vitamin preparation). The test preparation was administered in the form of a premix containing 1.0 wt. % Cyadox and 1.0 wt. tylosin and added in an amount of 1 wt. to the feed mixture of COS 1 and COS 2, which corresponds to 100 ppm Cyadox and 100 ppm tylosin per kg feed mixture.

The medicated piglets were calmer, more adaptable, better able to withstand temperature fluctuations in the stable. The occurrence of diarrhea and other diseases has not been observed. Control piglets occurred from

Diarrhea in 20 to 30% of animals on day 2, and diarrhea was sporadic from day 8 to day 12. The feeding piglets were treated with Carbo medicinalis + Celaskon pulv.

The good health of the piglets treated with the test formulation resulted in an increase in weight gain and improved feed conversion, as shown in Table 4.

Table 4

Group Pokusná Checklist Duration of the experiment 20 days 20 days Dosages in feed Cyadox 100 ppm Tylosine 100 ppm - Initial weight x in kg 6.10 5.96 Final weight x in kg 14.03 10.98 Increment daily x in kg 0.400 0.250 Increment index x in% 160.0 100.0 Feed conversion in kg 1.79 2.13 Index in% 84.04 100.0

Example 5

In the feed shop, a steady occurrence of bloody diarrhea is observed in about 5 to 10% of the animals. These are pigs in the pre-fattening breed BU x PC x L weighing about 40 kg, housed in pens of about 15 pieces. The diagnosis of the disease was determined on the basis of pathological-anatomical, bacteriological and bacterioscopic examination. Vibrio coli has been identified as the causative agent of diarrhea.

Organization of the experiment: The pigs were divided into two groups, the control group of 38, the experimental group of 31, and fed a mixture of SOL to which 1% by weight was mixed in the experimental group. % of the preparation to be tested in the form of a premix containing 1 wt. % Cyadox and 1 wt. sulfadimidine. The test preparation was administered for 21 days.

No other bloody diarrhea was observed in the experimental group, the test formulation had 100% efficacy. In the control group, bloody diarrhea was observed throughout 5 to 10% of the animals. At the end of the experiment, one pig for very poor health was sent for slaughter.

Ί

The good health of the treated animals was reflected in the performance indicators in Table 5.

Table 5

Group

Pokusná

Checklist

Duration of the experiment

Dose of substances in feed

Starting weight x in kg Final weight x in kg Total increment x in kg Daily increment x in kg Index x increment in% Feed Conversion in kg

Index in% days

Cyadox 100 ppm Sulfadimidine 100 ppm

38.52

55.13

16.61

0.790

143.64

3.34

80,87 days

41.71

53.21

11., 50

AND

0.550

100.0

4.13

100.0

Example 6

In pig fattening, 10 to 20% of pigs were observed to have bloody diarrhea and bronchopneumonia. These are pre-fattening pigs weighing about 50 kg housed in pens. The diagnosis of the disease was determined on the basis of pathological-anatomical, bacteriological and bacterioscopic examination. Treponema hyodysenteriae and Vibrio coli have been identified as causative agents of diarrhea.

Experimental organization: Pigs were divided into control group - 45 pieces and experimental group 40 pieces. The test preparation was mixed in the experimental group as premixes in the pig fattening mixture SOL and administered for 17 days.

In the experimental group, bloody diarrhea disappeared within 3 days. Diarrhea occurred in the control group during the experiment, in some pigs bloody. From the control group, 1 pig (day 14) died during the experiment.

The therapeutic effect of the test product was manifested in objective performance indicators, ie weight gain and feed conversion, as shown in Table 6.

Table 6

Group Pokusná Checklist Duration of the experiment 17 days 17 days Dose of substances in feed Cyadox 100 ppm Phthalazole 100 ppm - Initial weight x in kg 61.03 58.98 Final weight x in kg 72.78 66.32 Total increment x in kg 11.75 7.34 Daily increment x in kg 0.690 0.430 Increment index x in% 160.47 100 _A 0

Continuation of Table 6

Group Pokusná Checklist Feed conversion in kg 3.35 3.87 Index in% 86.56 100.0

Explanation of abbreviations of compound feed used:

COS 1 (% by weight)

fish meal 6 skimmed milk powder 30 to 36 extracted soya meal 16 to 20 flax seed 5 wheat germ 3 oat rice (scrap) 5 to 13 potato flakes 6 to 10 sugar 5 dicalcium phosphate 0.5 biofactor supplement 1 mineral feed additive III 0.5 barley 9 to 15 100, Cos 2 (% by weight) fish meal 6 to 10 skimmed milk powder 5 to 10 extracted soya meal 14 to 19 maize 0 to 20 wheat 10 to 30 barley 12 to 25 wheat flour 5 to 10 oatmeal 0 to 10 -) Grain ₍ sprouts) 0 to 4 potato flakes 0 to 10 sugar 3 feed salt 0.2 dicalcium phosphate 0.5 biofactor supplement 1 mineral feed additive III 0.5 dried whey 0.4 100 ALIGN! SOL (% by weight) extracted soya meal 3 to 6 wheat 15 to 40 barley 20 to 60 maize 0 to 30 oat 0 to 10 rye 0 to 5 fodder legumes 0 to 3 meat - or - bone meal or poultry meal or wine lees , 0 to 3

microbial protein or yeast sulphite or potato protein 0 to 3 mineral and vitamin concentrate SOL 2 bran 0 to 10

100 ALIGN!

Biofactor supplement for feed mixtures of type COS:

vitamins A, D ₂ , C and E, essential amino acid lysine, antioxidant stabilizer (Curasan).

Biofactor supplement for SOL compound feed:

vitamin D ₂ , essential amino acid lysine, antioxidant stabilizer.

Mineral feed additive - FEM III - for feed mixtures of type COS:

% by weight of calcium carbonate and trace element salt.

Mineral and vitamin concentrate for compound feed type SOL - MVK SOL:

(% by weight)

MD I 1.5 Wheat feed flour 8.5 Feed salt 15.0 Feed limestone 50.0 SOL biofactor supplement 25.0

100 ALIGN!

Mineral supplement - MD I:

sulfate Copper 80 000 mg sulfate ferrous 400 000 mg oxide; sinečnaté 200 000 mg manganese carbonate 100 ALIGN! 000 mg iodide Potassium 1 000 mg sulfate cobaltous 100 ALIGN! mg sulfate Calcium 50 500 mg fodder flour 1 000 000 mg

Claims (2)

PREVENTION OF THE INVENTION A composition for the treatment of feedstuffs for livestock with a growth-stimulating effect, comprising, in addition to carriers and / or excipients, optionally other additives, characterized in that it contains 2-formylquinoxaline-1,4-dioxide cyanacetylhydrazone in combination with tylosin as active ingredients or a sulfonamide, wherein their weight ratio to each other is from 10: 1 to 1:10. 2. A composition according to claim 1 wherein the sulfonamide is 2- (N-phthalylsulfanilylamino) thiazole or 4,6-dimethyl-2-sulfanilamidopyrimidine.