GB2166953A

GB2166953A - Feedstuff and feed premix with anticoccidial efficacy

Info

Publication number: GB2166953A
Application number: GB08527910A
Authority: GB
Inventors: Istvan Hutas; Laszlo Nemeseri; Istvan Varga; Maria Homoki
Original assignee: BCR MUEVEK
Current assignee: BCR MUEVEK
Priority date: 1984-11-13
Filing date: 1985-11-12
Publication date: 1986-05-21
Also published as: DE3540105A1; CS816985A3; CS276344B6; FR2572895A1; GB2166953B; NL8503099A; DD239715A5; HU191576B; BG47520A1; GB8527910D0

Abstract

The feedstuff or feed premix contain a synergistic mixture of an ionophorous antibiotic and the compound (I), <IMAGE> wherein R1 is hydrogen, C1-4alkyl, nitro, CF3, OCF3, OCF2CF3 or OCF2CHF2; <IMAGE> R3 is hydrogen, C1-4alkyl, phenyl, aminophenyl, benzyl, nitroaminophenyl, dinitroaminophenyl or fluoroalkoxydinitrophenyl; and n is 1 to 3. The antibiotic may be monensin, narasin or salisomycin.

Description

SPECIFICATION Feedstuff and feed premix with enhanced anticoccidial efficacy This invention relates to a feed and a feed premix which contain the synergistic mixture of an ionophorous antibiotic compound and a quinoline derivative, and thus are of enchanced anticoccidial efficacy.

The efficiency of animal husbandry depends, besides genetic factors, on feeding and on veterinary sanitary keeping conditions. Poultry coccidiosis is a difficult problem in broiler production and in rabbitbreeding. Nowadays, however,the loss caused by mortality due to intestinal coccidiosis is far surpassed by the loss due to coccidia which cause growth depression and poorfeed utilization in apparently healthy stock. Chickens or rabbits, heavily infected with coccidia, are much less resistant and cannot be sufficiently immunized against infectious diseases.

Thus, at present, the loss caused by hidden,subclinic- al infection is much greaterthanthatdueto clinical coccidiosis.

In broiler production and rabbit-breeding, the substantial loss caused by coccidiosis demands a planned system of preventive measures. Regular and continuous keeping on mixed feed which contain up-to-date anticoccidial agents is the preventive measure currently used against coccidiosis. The main criteria of up-to-date anticoccidial preparations are as follows: high efficacy, broad spectrum low level toxicity and residual effects, improving of feedutilization and weight-gain.Furthermore, such preparations should be applicable by admixture in feed; they should be stable within the blend formed with the feed; they should not be incompatible; they should be easy to detect in the blend which contains them; they should not impede the development of immunity; no resistance against them should develop; and their application should be economical.

Prophylaxis against coccidiosis used to consist in the addition of synthetic anticoccidial preparations, or combinations of these, to e.g. chicken feed.

Lately, so-called ionophorous antibiotics begin to take the placeofsyntheticanticoccidial preparations.

These are, for example, monesin, narasin, salinomycin or lasalocid. The most often applied one is monensin.

Monensin-sodium is a biologically active compound with a polyetherstructure. It has been isolated in 1967 from a special growth of the microorganism Streptomyces cinnamonensis (c.f. Antimicrob.

Agents and Chemother., 349, 1967). Its chemical properties have been described by A. Agtarap and J.

W. Chamberlin (c.f. Antimicrob. Agents and Chemother., 359, 1967). Its production by a fermentation process is described in the Hungarian patent specification No. 154,327.

Generally, anticoccidial preparations act by inhibiting metabolism in various stages of the parasite or inhibitthe action of enzymes.

In the course ofthe biological mechanism of ionophorous antibiotics, the important role is played by the transport of certain alkali metal ions and the derangement of their repartition within the cell. The basis of efficacy residesthereinthatthese antibiotics can carry with them certain alkali metal ions through the cell-membrane ofthe coccidia, e.g. monensin and salinomycin can do this with Na+ and K+, lasalocid does with Ca++ and Mg++ ions. The change in the intracellular colloid osmotic pressure leads to the decay ofthe coccidia.

Surprisingly, we have found that if not only an ionophorous antibiotic alone is administered but also at least one of the compounds of the formula (I),

wherein R1 stands for hydrogen, C14 alkyl, nitro, CF3, OCF3, OCF2CF3 or OCF2CHF2; R2 stands for

or -NH-; R3standsforhydrogen, C14alkyI, phenyl, aminophenyl, benzyl, nitroaminophenyl, dinitroaminophenyl orfluoroalkoxydinitrophenyl; and is equal to a whole number between 1 and 3, then the number of coccidia to be detected in the intestinaltract of the animals is substantially reduced, the measure of infection reaches sometimes zero level.

The partially new, partially known compounds of the formula (l)can be prepared by condensing trimethyl-1, 2-dihydroquinoline or an appropriate derivative thereof with an aliphaticaldehydeaccord- ing to the Japanese published patent application No.

8114516-orthe Hungarian application No. 3638/84.

The compounds offormula (I) are mixtures of positional isomers ascribed to the carbon atom to which R1 and R2 are attached. These isomeric mixtures are the products ofthe above-mentioned condensation procedure and are usually not sub jected to angfurtherstep for recovering the individual isomers.

The increased anticoccidial efficacy evident at a simultaneous application of an ionophorous antibiotic and a condensation product oftheformula (I) can be ascribed to the synergistic effect of the two.

Furthermore we have found that if, in a sinergistically effective preparation,the ionophorous antibiotic is added in the usual dose of 100 mg/kg of feed a surprisingly improved anticoccidial effect is evident but a slight reduction of weight gain also occurs. If, however, the usual dose ofthe ionophorous antibiotic in the feed is substantially diminished and a compound oftheformula (I) is admixed in a dose of 10to 130 mg/kg of feed, the improved anticoccidial effect is retained butthe weight gain is not reduced, it is even slightiy improved.

The synergistic blend of an ionophorous antibiotic and a compound of theformula (I) can be added directly to the feed, or, alternatively, the synergistic blend may be mixed with a carrier or any other additive to form a premixwhich is then added to the feed.

Thus, the invention relates to a feed composition which is ofimproved anticoccidial activity. Tb is feed contains, calculated for 1000 g of a known type of feed, at least 5 mg of an ionophoric antibiotic, preferably monensin, narasin or salinomycin, and 10 to 130 mg of at least one ofthe compounds of the formula (I)

Wherein R1 stands for a hydrogen, C1-4 alkyl, nitro, CF3, OCF3, OCF2CF3 or OCF2CHF2; H stands for

or -NH-; R3 stands for hydrogen, C14alkyl, phenyl, aminophenyl, benzyl, nitroaminophenyl, dinitroaminophenyl orfluoroalkoxydinitrophenyl; and - nisequaltoawholenumberbetween land 3.

Furtheron, the invention relates to a feed premix containing, together with e.g. vitamins, inorganic substances and micro-elements, at least 5 mg of an ionophorous antibiotic, preferably monensin, narasin orsalinomycin,and lotto 130 mg of at least one compound oftheformula (I),

wherein R1 stands for hydrogen, CiA alkyl, nitro, CF3, OCF3, OCF2CF3 or OCF2CF2; R2 stands for

or -NH-; Rsstands for hydrogen, Cl 4 alkyl, phenyl, aminophenyl, benzyl, nitroaminophenyl, dinitroami nophenyl,orfluoroalkoxydinitrophenyl; and n is equal to a whole number between 1 and 3, related to 100 g of a feed to which the premix is added.

Preferred compounds are those oftheformula (IA)

wherein Ri, Rz and R3 are as defined above. Referred to 1 kg ofthefeed, from monensin 5to 120 mg,from narasin 5 to 70 mg, from salinomycin 5 to 60 mg doses are used; from a compound oftheformula (I) doses of 10 to 130 mg are admixed each time. The invention will be exemplified by the aid ofthe following non-limiting examples.

Example 1 To 1 kg of chicken feed 100 mg of monensin and 120 mg ofthecompound oftheformula (I), wherein R, stands for hydrogen, R2 for a

group, R3 for methyl and n = 2, are added.

This feed is used for Hybrococks.

Example2 To 1 kg of chicken feed 100 mg of monensin and 120 mg ofthecompound of the formula (I), wherein R1 standsforthe nitro group, R2for a

group, R3for hydrogen and n = 2, are added.

Example3 We proceed as described in Example 2 but use 50 mg of monesin instead of 100 mg, and admix compound (I), wherein R1 stands for -CF3, R2for a

group, R3forethyl and n = 2. Example4 We proceed as described in Example 2, but use 70 mg of narasin instead of 100 mg of monesin, and admix compound (I), wherein R1 standsfor-OCF3, R2 fora

group, R3forhydrogen and n = 1. Example 5 We proceed as in Example 2 but use 40 mg of narasin instead of 100 mg of monensin, and admix a 1 ::1 mixture of the compounds of the formula (I), wherein R1 stands for ethyl, R2for

R3 for hydrogen and n = 2, and R1 stands for OCF2CF3, R2 for

R3forhydrogen and n = 1, respectively.

Example 6 We proceed as in Example2 but use 40 mg of salinomycin instead of 100 mg of monensin, and add a 10 mg dose of compound (I), wherein R1 stands for -OCF2CHF2, R2fora

group, R3for methyl and n = 2.

Example7 We proceed as described in Example 3 but instead ofthe 120 mg dose of compound (I) we used a 1:1 mixture of the compounds ofthe formula (I) defined in Examples 1 and 3, respectively.

Example 8 We proceed as described in Example 2 but use compound (I), wherein R1 stands for hydrogen, R2for

groupandn=2. Example 9 We proceed as described in Example 2 but use compound (I), wherein R1 standsforhydrogen, R2for -NH- group and n = 2.

Example 10 The following compounds are mixed together: Monensin-Na/20%/ 50,00 g Compound oftheformula (I) as defined in Example 1 (98% pure) 24,50 g Carrier substance (cereal meal) to make 100,00 g From this preparation an amount to make 0,5 per cent ofthe total is added to the mixed poultry feed.

Example 11 The following ingredients are mixed together: Vitamin A 1,000,000 IU Vitamin D-3 260,000 IU Vitamin E 1,000 IU Vitamin K-3 150 mg Vitamin B-1 200 mg Vitamin B-2 460 mg Vitamin B-3 1,200 mg Vitamin B-6 150 mg Vitamin 8-12 1 mg Nicotinic acid 3,500 mg Folic acid 100mg Antioxidant BHT 8,000 mg Choline chloride 30,000 mg Narasin (20%) 20,000 mg Blend of the compounds of the formula (I), as defined in Example 6 12,000 mg Zinc sulphate 28,000 mg Calcium iodate 100 mg Sodium selenite 20 mg Copper sulphate 2,000 mg Iron sulphate 10,000 mg Carrier (cereal meal) to make 1,000 g.

From this preparation an amount to make 1,0 per cent ofthetotal is added to the mixed broiler chicken feed.

Example 12 (test example) Hybro cocks are fed with the composition described in Example 1. Groups of 11 of Hybro cocks are infected under laboratory conditions with about 150 thousand oocystas of Eimeria tenella that causes coccidiosis in the caecum. Chickens kept on feed containing no anticoccidal substance but otherwise having the same composition are infected to serve as reference (R), a group of non-infected chickens (NI) are also kept in order to compare the weight gains.

Thetest lasts for 8 days.

The average body-weightofthe NI group is considered 100 percent.

Furthermore, in groups of eleven chickens, the ratios showing macroscopic caecal lesions are studied.

Groups studied Average Ratios body- showing caecal weight lesions 100 2 0 a 11 Kept on 100 mg of monensin in 1 bg of feed 91,7 % 4 t1 Kept on feed described in Example 1 78,4 0 Ir R 67,Z 11 Ir no lesions detectable The data show that the average body-weightofthe chickens kept on the feed prepared according to this invention decreases in a small degree butthe infection ofthis population is reduced to nil. Thus, the dangerof loss by deaths is significantly less.

Example 13 (test example) Astudy of efficacy as described in the preceding Example is carried out on chickens in groups of eleven.The results are asfollows: Groups studied Average Ratios body- showing caecal weight lesions NI 100 X 0 * 11 Kept on 100 mg of monensin in 7 1 tg of feed 96,4 2 11 Kept on feed described in 1 Example 2 81,8 % 11 Kept on feed described in 2 Example 3 1;;0N,0 2 11 Kept on 70 mg of narasin in 8 1 kg of feed 83,0 X 11 Kept on feed described in Example 4 92,7 2 11 Kept on feed described in 5 Example 5 107,0 % 11 Kept on feed described in 4 Example 6 105,0% 11 Kept on feed described in 2 Example 7 103,5 2 Ir R 70,0 2 11 11 no lesions detectable The above data show that when a feed prepared according to the invention is used, the degree of infection is substantially reduced in every instance, the average body-weight diminishes but slightly or, certain cases, even increases. Atthe same time, with a population kept on the feed prepared according to this invention the danger of loss through deaths is reduced in every case.

Example 14 (test example) Atest as described in Example 11 is carried out with groups comprising 69 to 71 test animals.

The percent measure of infection is given on the basis of animals harbouringforms of coccidial development in scrapings ofthe mucous membrane ofthe caeca.

Groups studied Average Chickens body- harbouring weight coccidia NI 100 S O d Kept on 100 mg of monensin in 1 kg of feed 90,3 2 67,1 Kept on feed described in Example 3 89,7 2 50,7 R 60,8 2 100,0 The rate of infection,thusthe risk of deaths, in the grou p kept on feed according to this invention is reduced, at the same time average body-weights do not change significantly when compared to the group which is kept on a feed containing monensin alone.

Example 15 We proceed as described in Example 1, but to each kg offeed we add 50 mg ofmonensin instead of 100 mg, and 90 mg ofthe compound oftheformula (I), wherein R1 stands for hydrogen, R2for

group, R3for methyl and n = 1.

Example 16 We proceed as described in Example 15, but to each kg of the feed we add 50 mg monensin and 45 mg of the compound oftheformula (I), wherein R1 stands for hydrogen, R2foragroup

R3for methyl and n = 2, and 45 mg ofthe compound of the formula (I), wherein R1 stands for hydrogen, R2 for a group

R3formethylgroupandn = 1. Example 17 (test example) 7-day-old Hybro cocks are kept on the feeds described in Examples 15 and 16. The groups, each of 35 animals, are infected orally with about 150,000 oocystas of Eimeria tenella under laboratory condi tions. For the purpose of reference, chickens (R) are similarly infected and kept on the same feed contain ing no anticoccidial agent.Non-infected chickens (NI) are also kept in orderto be able to compare the weight gains ofthe g roups. The test lasts for 8 days. The average body-weight of chickens NI is taken for 100 per cent. Furtheron, the rate of chickens harbouring forms of coccidial development in the scrapings of caecal mucosa is checked by means of microscopic tests in each group.

Groups tested lAvorage Chickens body- harbouring weight coccidia NI 100 0 Kept on lûO op of monensin in 27 each kg of feed 87 S Kept on 50 mg of munensin in bg of feed 72 S 35 35 Kept an feed described in Example 15 92 S 20 79 Kept on feed described in Example 16 89 S 32 35 R 65 S 35 79 No coccidial infection in group NI is detected.

The table shows that the body-weight of chickens kept on the feed according tothis invention does not significantly decrease and that infection is prevented byhalfofthe hitherto usedamountofthe ionophor ous anticoccidial agent.

Example 18 To 1 kg of rabbitfeed sold underthe name "54-4 Környei" in Hungary 10 mg of monensin and 80 mg of a compound oftheformula (I), wherein R1 stands for ethyl, R2fora-,cH- group, Rs for methyl and n = 2, H3 are added.

The composition ofthe said rabbitfeed is as follows: ;ihojt 20 Bran 19 Grass meal 25 Soy-beans 5% Sunflower 8 Sugar-beet slices 18 S Premix 5054-5 9 100 Crude protein content 15 % Crude fibre context 13 Example 19 To 1 kg ofthe rabbitfeed described in Example 185 mg of salinomycin and 80 mg ofa compound ofthe formula (I), wherein R1 standsfornitro, R2for a

group, R3for ethyl and n = 2, are added.

Example 20 We proceed as described in Example 18 but instead of adding 10 mg ofmonensin we add 7 mg of narasin.

Example 21 We proceed as described in Example 18 but instead of adding 80 mg ofthecompound oftheformula (I) as defined in Example 18 we add a blend of compounds oftheformula (I). This blend consists of40 mg ofthe compound oftheformula (I) as defined in Example 19 and of 40 mg ofthecompound oftheformula/l1, wherein R1 stands for -CF3, R2fora

group, R3 for ethyl and n = 1.

Example 22 (test example) Groups of rabbits weaned when fourweeksold are kept on the fattening-feed described in Example 18.

The 20 rabbits of a group got infected naturally by oocystas of coccidia. Forthe purpose of reference, we keep a group (R) reared on feed which does not contain any anticoccidial agent; also we keep a group (F) on rabbit-feed which contains 100 mg offurazoli- done in each kilogram.

The duration ofthetestis eight weeks.

Results of these tests show that in the faeces of rabbits kept on feed which contains the ionophorious antibiotic and the compound ofthe formula (I) the number of coccidian oocistas decreases by 90 to 100 per centwhile there is zero reduction with groups R and F, i.e. infection does not decrease.

In all the groups kept on the feed described in Example 18 and composed according to this invention, thefeed conversion is better by 5 to 10 percents when compared to thatfoundin groups Rand F.

As far as weight gain is concerned, no significant difference can be observed between the groups.

Example 23 We proceed as described in Example 18 but use a compound oftheformula (I),wherein Stands for phenyl instead of methyl.

Example 24 We proceed as described in Example 18 but use a compound oftheformula (I), wherein R3 stands for aminophenyl group instead of methyl.

Example 25 We proceed as described in Example 18 but use a compound ofthe formula (I), wherein R3stands for benzyl group instead of methyl.

Example 26 We proceed as described in Example 18 but use a compound oftheformula (I), wherein Rs stands for nitroaminophenyl instead of methyl.

Example 27 We proceed as described in Example 18 but use a compound oftheformula (I), wherein R3stands-for dinitroaminophenyl instead of methyl.

Example 28 We proceed as described in Example 18 but use a compound oftheformula tl),wherein R3 stands for fluoroalkoxydinitrophenyl instead of methyl.

Example 29 We proceed as described in Example 18- but use a compound ofthe formula (I), wherein R2 stands for a

group.

Example 30 We proceed as described in Example 18 but use a compound of the formula (I), wherein R2standsfora -NH- group.

Claims

1. Feedstuffwith enhanced anticoccidial effect containing, calculated for 1000 g of a known type of feed, at least 5 mg of an ionophorous antibiotic, preferably monesin, narasin or salinomycin, and 10 to 130 mg of at least one compound oftheformula (I),

wherein Ri standsforhydrngen,C1alkyl, nitro, CF3, OCF3, OCF2CF3 or OCF2CHF2; R2 stands for

or-NH-; R3 stands for hydrogen, CiA alkyl, phenyl, aminophenyl, benzyl, nitroaminophenyl, dinitroaminophenyl orfluoroalkoxydinitrophenyl; and n is equal to a whole number between 1 and 3.

2. Afeedstuffas claimed in claim 1, characterized by containing as a compound of the formula (I) a compound oftheformula (IA),

wherein R1, R2 and R3 are as defined in claim 1.

3. Afeedstuffas claimed in claim 1, characterized by containing at least 10 mg of an ionophorous antibiotic and 10 to 130 mg of at least one compound oftheformula (I), wherein R1 stands for hydrogen or C1 4alkyl; R2standsforagroupoftheformula

R3 is hydrogen or methyl and n is equal to 1,2 or 3.

4. Afeedstuffas claimed in claim 3, characterized by containing at least one compound of the formula (I), wherein n is equal to 2.

5. Feed premix, characterized by containing, together with usual premix components like vitamins, inorganic substances and micro-elements, at least 5 mg of an ionophorous antibiotic, preferably monesin, narasin or salinomycin, and 10 to 130 mg of at least one compound oftheformula (I),

wherein R1 stands for hydrogen, CiA alkyl, nitro, CF3, OCF3, OCF2CF3 or OCF2CHF2; H2 stands for

or -NH-; R3 stands for hydrogen, CiA alkyl, phenyl, aminophenyl, benzyl, nitroaminophenyl, dinitroaminophenyl orfluoroalkoxydinitrophenyl; and n is equal to a whole number between 1 and 3, related to 1000 g of a feed to which the premix is added.

6. Afeed premix as claimed in claim 5, characterized by containing as a compound of the formula (I) a compound oftheformula (IA),

wherein Ri, R2 and R3 are as defined in claim 5.

7. Afeed premix as claimed in claim 5, characterized by containing at least 10 mg of an ionophorous antibiotic and 10 to 130 mg of at least one of a compound ofthe formula (I), wherein Ri stands for hydrogen or CiA alkyl; R2 stands for a group of the formula

R3 iS hydrogen or methyl and n is equalto 1,2 or3.

8. Afeed premix as claimed in claim 7, characterized by containing at least one compound of the formula (I), wherein n is equal to 2.

9. Afeedstuffcomprising, in addition to nutritional ingredients, an ionophosphorous antibiotic and a compound ofthe general formula las defined in claim 1.

10. Afeedstuffadditive comprising an ionophosphorous antibiotic and a compound ofthe general formulalasdefined in claim 1.

11. Afeedstuffand/orfeedstuffadditive as claimed in claim 9 or 10 substantially as hereinbefore described in any one of Examples 1 to 11,15 or 18 to21 or23to30.