JPS63239218A - Coccidiocide - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Salinomycin and Narasin (Narasin = 4-methylsalinomycin) as polyether antibiotics in German Patent Application No. 2.355,998 and J.
Anti-biotics '30, 530-532
('1977) (Merck
Index 10th edition, pages 920 and 1200 (19
(See B). Their use as anti-coccidiosis agents is also described therein. These antibiotics are produced by fermentation (see British Patent No. 1,578,413 and West German Patent No. 2,525,095).

Now, salinomycin? It has now been discovered that the effects of Coccidiocide and Narasin are enhanced beyond the scale expected when they are combined with other known coccidicidal actives.

Therefore, the present invention provides methychlorpindole (Meti-
chlorpindol), methylbenzoquae) (M
ethylBenzoquat), Nicarbazine (Ni
carbazin), Amprolium (carbazin), Amprolium (carbazin)
um), BaclO-tiamine
) or Halo fuginon
or a polyether antibiotic selected from the group consisting of salinomycin, narasin or their physiologically acceptable salts or esters in combination with one or more active substances selected from the group consisting of or salts thereof. The present invention relates to a coccicidal agent containing.

A combination of two components is particularly suitable. According to the invention, 3
Combinations of bottom portions may also be used. Of the latter, a combination of salinomycin or narasin with methychlorpindole and methylbenzoquatate is preferred.

Instead of amprolium its mixture with ethopabate can also be used in these combinations.

The combination partners for salinomycin and narasin to be used according to the invention have been known for a relatively long time in veterinary medicine. These are all Merck Ind.
ex 10th edition (Merck & Co, Publisher 1 USA, 1
983). Methychlorpindole (
'5,5-cyclo2,6-dimethyl-4-viridinol) is on page 341, methylbenzoquatate (Nequinate), 6-medoxycarbonyl-6-n-butyl-7-benzyloxy-4- Nicarbazine (N,N'-
Bis-(4-nitro-phenyl')urea 4.4- )
Complex with methoxyh-2(IH)-pyrimidinone) is listed on page 931, etopabate [methyl-(4-acetamido-2-ethoxy)-benzoate] is listed on page 544, amprolium (1-C(4-amino -2-propyl-
5-pyrimidinyl)-methyl]-2-methyl biboridinium chloride) is listed on page 615 as beclotiamin (3-
[(4-amino-2-methyl-5-pyrimidinyl)-methyl)-5-(2-chloroethyl)]-]4-methyl-thiazolium chloride is on page 144, and halofuginone (7-bromo-6-chloro -7 Every Hugin (fe
The brifugine is described on page 662. In addition to halofuginone, according to the invention, its physiologically acceptable salts, such as hydrohalides, in particular hydrobromides, acetic acid salts, lactate salts, alkali metal or alkaline earth metal salts, salts of acetic acid (Rooster German Patent Publication No. 2.
934,069), as well as all optical isomers and mixtures thereof. Amprolium or beclotiamin can also be used as their hydrochloride salts. Instead of beclotiamin, its analogous naphthalene-1,5-disulfonate salt may also be used according to the invention.

The combination of methyl chlorpindole and methyl benzoquate is available from the commercial product Lerbek@ (ICI).
company products). A combination of amprolium and etopabate is also available as a commercial product, Amprol Mix φSuher (AmprolMix 5uper■).
(Merck, 5harp & Dohme AGV
ET Corporation).

Salinomycin or narasin can be used as the free acid, or as a salt, especially an alkali metal (Na, K) salt, an alkaline earth metal (Mg, Ca) salt, or an ammonium salt, or as an ester, especially (01-C4,). It can be used as an alkyl ester or a benzyl ester.

Preferably, Na-salts are used. The product can be used in purified form or as mycelium or as a crude product.

The combination according to the invention exhibits a synergistic effect in combating coccidiosis, especially avian coccidiosis.

In mass rearing of birds in confined spaces, e.g. in bird fattening or bird rearing, there is always a possible risk of coccidial infections caused by Eimeria species, which, without eradication by chemotherapy, can lead to serious economic losses. will come. Coccidial infections mostly cause weight loss and hematochezia, which appears as a result of lesions of the intestinal mucosa.

Severe coccidial infections usually result in high mortality in birds.

By using the combinations according to the invention, significant advantages arise compared to the corresponding active substances alone, since relatively small amounts of coccidiocide can be used. This results in reduced toxic side effects of the formulation compared to applying individual active substances, increased profitability, and reduced residue in the edible tissues of birds.

In the medicaments according to the invention the weight ratios of the active substances can be varied within wide limits. The weight ratio is 5:1 to 1: in combination of salinomycin or narasin and a) methychlorpindole.
25 especially from 15:1 to 1:5, b) in combination with methylbenzoquatate from 100=1 to
1:3 especially 60:1 to 5:1, C) in combination with nicarbazine: 1 to 1:15 especially 5:1 to 1:4, d) 160:1 to 3:1 especially in combination with halofuginone 100 :1 to 8:1, e) 20:1 to 1:204 in combination with a mixture of methychlorpindole and methylbenzoquatate
? f) 1=1 to 1:5 in combination with amprolium, g) 1:1 to 1:5 in combination with beclotiamin, and h) in combination with a mixture of amprolium and etopabate. and 1:1 to 1:5 (polyether antibiotic to combination partner ratio, respectively).

The ratio of methylchlorpindole to methylbenzoquatate can vary from 20:1 to 7:1 in e), while h)
The weight ratio of amprolium to etopabate is 30
:1 to 10:1.

The compounds according to the invention are suitable quite generally for the protection of birds, ie for the treatment of agriculturally useful birds such as chickens, turkeys, ducks or geese, or also other birds such as pheasants, penguins or guinea fowl. The latter birds are now kept for economic profit on farms and, like chickens, are often and extensively infected with coccidia.

The agents according to the invention can be used at any time to effectively protect birds against coccidiosis. These may be used in poultry farming operations or breeding houses, especially for young hens, where high infection pressure on the bird population arises due to persistent forms of coccidia (cysts) that are continuously excreted in the faeces. It is from. Since washing under these conditions always poses a risk of coccidiosis outbreaks, the coccidiocide according to the invention should be used continuously in birds and before the onset of coccidiosis. However, the medicament according to the invention can also be administered at short time intervals, ie over a relatively small number of days.

The use of the medicament according to the invention and the method for eradicating coccidiosis are carried out by conventional methods. Oral administration is the first option because coccidia is localized in the intestinal tract. The active substance combination according to the invention can then be mixed with the feed or drinking water.

The active substance concentration of the combination in the feed or drinking water can be varied within defined limits.

They generally contain from 5 to 300 pI) m of active substance combination based on the feed or drinking water.

Particularly preferred concentrations for the eradication of coccidiosis are 15 to 70 p each of salinomycin or narasin in the feed.
pm, especially 25-45 ppm, and a) Methychlorpindole 15-150 ppm, especially 60-12
5 ppm.

b) Methylbenzoquatate 1-30 ppm especially 1.2
5-5ppm.

c) Nicarbazine 15-150 ppm especially 30-1
100pp.

d) Halofugino 70.5~31)]) m Especially 0.75~
1.5ppm % e) Methychlorpindole/methylbenzoquatate 5~
1.20 ppm especially 8-15 ppm.

f) Amprolium 10 CI to 150 ppm.

g) beclotheamine 40-125 ppm, and h
) Amprolium/Etopabate 30-100pm. For use in drinking water, preferably about half of each of the above-mentioned concentrations is used.

All mentioned concentrations, proportions, parts, amounts or quantities are by weight.

The active substance concentration of the coccidicidal agent is optionally related to the feed or drinking water preparation, ie feed or drinking water is available ad libitum during the fattening or rearing period customary in practice. However, because of the individual factors involved in practice, if the birds are fed with different feed or water stocks, the avian trader must adapt the concentrations used above. In that case only part of the feed or water stock contains the agent according to the invention.

All feed formulations customary for the avian industry are suitable as carriers for the synergistic coccidicidal agents according to the invention. The formulations for bird feed shown below are examples of formulations that are conventional in practice. In addition, any other grain-based feed containing vitamin concentrates, mineral concentrates or other active substances and feed additives in any concentration may also be used. Conventional dry, powdered or pelleted feeds, including feeds such as distillers and pore organisms, as well as liquid suspension feeds can be used in the medicament according to the invention.

To prepare the bird feed according to the invention, the synergistic coccidicide is usually first applied at a high concentration, for example from 0.2 to 75%.
Prepare a concentrated premix containing . For this purpose, the coccidicidal agents are dispersed in physiologically acceptable carriers, such as propylene glycol, polyethylene glycol, inert oils such as vegetable oils, highly refined mineral oils, ethanol, water or aqueous alcohols, or vermiculite, Incorporated into an inert carrier material such as diatomaceous earth, attapulgite, calcium carbonate, or kaolin. For this purpose, any other desired organic carrier material such as wheat bran, corn grits, soybean flour, alfalfa flour, rice hulls, or ground corn ears and any other desired organic products obtained from vegetable products may also be used. Carrier materials are also suitable.

The synergistic agent according to the invention can also be administered to birds together with drinking water. Their incorporation into drinking water is accomplished by adding an appropriate amount of a water-soluble or water-suspensable form of the respective drug to the drinking water. Such preparations are generally made by selecting a water-soluble form of the drug. If these are not desired or cannot be prepared, water-insoluble forms, such as suspensions, may be used. To prepare the formulation, physiologically acceptable auxiliaries are used, with which the coccidiocide according to the invention is kept in suspension in water for a relatively long time.

Suitable auxiliaries for this purpose are swelling agents such as alginates, gelatin, carboxymethylcellulose or polyvinylpyrrolidone. However, the agents according to the invention can also be suspended using various surface-active compounds, such as, for example, lecithin, naphthalene sulfonates, alkylbenzene sulfonates, alkylphenol-polyethylene oxide adducts or polyoxyethylene sorbitan esters. first preparing a concentrated suspension or dry formulation from the coccidicidal agent and suspending agent according to the invention in a customary manner in a given mixing ratio and then diluting this with potable water to the desired use concentration; or The premix is mixed with practically conventional feed to a suitable concentration. The thus dosed drinking water or feed is then given to the bird ad libitum for the time being or for a defined period of time.

The treatment method according to the invention can be extended to other treatments and feeding methods for birds. Thus, for example, the compositions according to the invention can also be combined with other active substances, such as growth promoters or anthelmintics, which are, on the one hand, synthetic drugs or, on the other hand, fermentation products in the broadest sense.

The present invention relates on a particular scale to the protection of birds against coccidial infections, but also to other birds, domestic rabbits,
It is also of significant use in pigs, and other livestock and useful animals such as the Antiformes.

The invention therefore also relates to a method for the treatment of coccidiosis in birds, which consists in administering the abovementioned active agents orally to the birds, but also in the feed or ad libitum in the drinking water.

The invention will be illustrated by the following examples.

A. Examples of animal feed compositions The following examples relate to animal feed compositions which can be used for administering the active substance combinations according to the invention.

■, Broiler fattening feed Fishmeal (60-65%) 6.0 Feed yeast 2.0 Beef tallow
4.7 Soybean flour (44%) 24.0 Murasaki Umago Sprout 1.0 Corn
44.89 Wheat 6.65 Wheat 2 Flavor Flour 8.5 Calcium Phosphate 1.4 Calcium Carbonate
0.96 trace element mixture $
0.04 Livestock salt 0.09D
L-Methionine 0.07100, O a) Amount added per 1Kg of feed Vitamin A International unit 12.000D3 International unit 1.500E 1Kg
1
8B1 1 to 9 1・5B2 Wing g6 Pantothenic acid, 9 9 Nicotinic acid 11g24 Vitamin B6 II9 4・
5B12mcf 24 to 31g3 Choline chloride, 1
, 300*b) Feed 1.0 initially contains the following: Mn 106 Zn 119
71Fe Tomi9 44 Cu ■ 3.561
mg, 0.4Co19
' 0.16■, feed for raising chickens (0-8
Week) Fishmeal (60-65%) 5.0 Purple Umago Palm Flour 6.0 Soybean Ground (44%) 15.0 Feed Yeast
2.8 Beef tallow 2.0 Barley 6.0 Oat 6.0 Corn 670 Wheat 16.
0 Wheat bran z5LI-1 or above-
-・・^l 199 hosta male (
Hostaphos@) 0.57 trace element mixture” 0.04 ・1
00.0 m See Example 1b); further vitamins are added as described in Example 1a).

■, Feed for rearing chicks (9-20 weeks) Murasaki Umagoyashi powder 6.0 Soybean grind (44%)
10.24 Feed yeast
1.8 Cow yXf12.0 Barley 8.0 Oat 6.0 Corn 40.0 Wheat 15
．． 0 Wheat bran 8.3 Calcium carbonate 1.55Ho5taphos■
1.02 trace elements in the mixture
0.04DL-Methionine
0.07 ioo.

*See Example Ib); further vitamins are added. See Example 1a).

■, Feed for rearing chicks (over 21 weeks) Fishmeal (60-6
Section 5) 1.5 Ground soybean (44%) 19.31 Beef tallow 1.0 Oat 6.7 Corn 40.0 Wheat
18.0 wheat 2nd flour
6.0DL-Methionine
0.07 Paprika for feed 0.
3 Calcium Carbonate 8.16Host
aphos ■ 1.91 trace element mixture" 0.05100.0 Further vitamins are added as described in Example 1a).

■, Turkey feed (composition, weight %) Fish meal 9.0 5.0 2.0 Feed yeast
4.5 2.91 4.0 Fat 3.1 6.7 Soybean flour 26.0 23.9
23.87 Murasaki Umagoyashi 1ψA minute 4.6
2.0 0.95 barley
5.3 4.5 5.0 Oat
1.0 4.45 Corn
56. Q4 40.02 39.90 wheat 5.3 6.0 5.0 wheat No. 2 flour
5.95 4.0 3.8 Wheat bran 4.0 Calcium phosphate 1. ss 1.3o 2.
71 Calcium carbonate 1.35 1.2
9 0.96 Trace element mixture book 0.04
0.04 0.04 Salt for livestock
0.24 0.84 0.44100.0
100.0 100.0 Vitamin mixture per 1 kg of feed Vitamin A International unit 12.000 8,000
Li00D3 international unit 1,500 1,00
0 1,000E Door W 18
12 12B1■ 1.5
1 1B2η 6. Q
4' 4 Pantothenic acid true Q
9.0 6 6 Nicotinic acid richness g24.0 16 16 Vitamin B6 ■ 4.5 3
3B12 mcs' 24.0
16 16 to 3 m9
3.0 2 2 Choline Chloride Q 1,300 1,300
106Q of blood, 71mm of Zn, 44my of Fe, 3.5611Q of Cu, 0.
Contains lf and 0.161112 CO.

B. Biological Example The coccidia inhibiting effect of this drug was investigated in young chickens infected with coccidia. The experimental studies described below demonstrate the efficacy of combinations according to various principles based on several examples. Salinomycin is used here in the form of its unisolated sodium salt and in the form of mycelium prepared by fermentation.

For the determination and evaluation of the coccidiostatic effect of the drug according to the invention, so-called infected controls (untreated, infected animals) and 101 controls (naive, uninfected animals) were used in all the experimental studies described below. used. Animals of both sexes used for this purpose (LSL pullets, Lohm
ANN, Wallau, Federal Republic of Germany) were randomized and organized into groups of 16 birds each. Groups treated and infected with the agent according to the invention were assembled according to the same method. All animals, except one in the control group, were infected with Eimeria tenella, a poisonous plant that causes severe (regenerating tendrils) lesions on the cecum in 8-day-old chickens.
) strain. The coccidicide was mixed with the bird feed in pp weight. The respective concentrations are shown in Section 1a below.
~1 can be seen from the table.

The grade of pathological and anatomical changes in the intestinal mucosa of the cecum caused by infection was evaluated in a conventional manner (Ex-periment
al Parasitology Volume 28 1970,
or The Biolog by Long, P.L.
y of the Coccidia, 1982 Un
iv, published by Park Press) Below, it is displayed in the form of damage value (=lesion value) indicated by "lesion score grade (0 to 4)". At the end of the study, 5 days after infection, the animals were sacrificed and examined for all typical pathological anatomical changes caused by coccidiosis.

Description and evaluation of lesions (lesion score) 20-40 = Bird with no detectable lesions in the intestinal tract 1 = Bird with few, limited small lesions (petechiae) in the cecum 2 = Several lesions , Bird with limited and somewhat larger lesions (petechiae) than described in 1 above = Bird 6 = Bird with multiple and relatively large area, partially confluent hemorrhagic lesions 4 = Cecum and also border Birds with large areas of hemorrhagic lesions that involve the entire intestinal mucosa of adjacent intestinal segments (ileum or rectum°). Formation of hemorrhagic enteritis over a large area represents the most severe grade, usually leading to death of the animal.

In the injuries shown in 1 to 4 above, dilute and bloody feces are excreted as the scale increases. Weight loss due to nutritional deficiencies is similarly associated with increased "lesion scores."

From the mentioned observations the relevance of the lesion score for determining the coccidicidal action of the drug according to the invention will be clear.

The lesion scores are shown in Tables 1a to 16 on the one hand as individual values per animal within a group and on the other hand as the corresponding group mean values.

Treatment and Infection In all experiments, 16 1-week-old LSL-chickens per group were housed in wire mesh cages, 4 birds per wire cage, under constant spatial conditions. Feed administered with the drug according to the invention was given ad libitum from day D-18 (one day before infection) to day D+5 (day 8, 5 days after infection).

Control groups (group ○1 and infected control) were fed unmedicated feed. Each group of animals was therefore fed the same diet for 7 days. On the day of infection (=Do), each bird was administered 200,000 sporulated blastocysts of the Eimeria tenella strain by gastric tube.

After partial digestion of the vesicular bodies in the small intestine, infectious sporozoites were released from these persistent forms, which then invaded the epithelial cells of the intestinal mucosa and multiplied there by morphological changes.

A large number of premitotic bodies arising from sporozoites destroy the intestinal epithelium by repeating the division process.

The destructive effect of promitotic bodies on the intestinal epithelium reaches its peak 5 days after infection. Therefore up to this point in the method described above a "lesion score" was calculated.

The synergistic effects of the medicaments (combinations) according to the invention are shown below in Tables 1a to 1, and on the one hand the effects of the individual active substances at the concentrations customary in practice and on the other hand the various effects of the individual active substances. A more than additive effect or a synergistic effect resulting from the combination is indicated. Infected control and 0
The "lesion score" of one control (uninfected animal) is used for each dosing and adjustment to the infected animal group.

Claims (1)

[Claims] 1) Meticlorpindole
ol), Methyl Benzoquatate (Methyl Ben
zoquate), Nicarbazi
Salinomycin in combination with one or more active compounds selected from the group consisting of n), Amprolium, Beclotiamine or Halofuginone or its salts.
), Narasin or physiologically acceptable salts and esters thereof. 2) A drug according to claim 1, which contains salinomycin or narasin in the form of its physiologically acceptable salt or ester. 3) The drug according to claim 2, which contains salinomycin or narasin in the form of its alkali metal or alkaline earth metal salt. 4) The drug according to claim 2 or 3, which contains salinomycin or narasin as a sodium, potassium, ammonium, magnesium or calcium salt. 5) The drug according to any one of claims 1 to 4, which contains salinomycin or narasin as a Na-salt. 6) The drug according to claim 1, which contains salinomycin or narasin as mycelium or as a crude product. 7) A drug according to any one of claims 1 to 6, containing salinomycin or narasin in combination with methychlorpindole and methylbenzoquartate. 8) Any one of claims 1 to 7 containing salinomycin or narasin in combination with amprolium and ethopabate.
Drugs listed in section. 9) A drug according to any one of claims 1 to 8, which additionally contains bird feed or drinking water. 10) Use of the drug according to any one of claims 1 to 9 for eradicating coccidiosis in birds. 11) A method for eradicating avian coccidiosis, which comprises administering to birds an effective amount of the drug according to any one of claims 1 to 9.