Note: Descriptions are shown in the official language in which they were submitted.
HECHST AKTIENGESELLSCHAFT HOE 86/F 086 Dr.AU/mU
COCG idiocidal ~gents
Sal;nomycin and narasin ~s 4-methyLsalinD~ycin) ~re known
~s ~ polyether ~ntibiotic from German O~fenl~ungsschrift
2,353,998 ~nd ~A Antibiotics 30, pages 53D-532 t1977), see
also Merck lndex 10th edition, page 920, 1200 (1983).
Their use as ~nticsccidiosis ~gents is ~lso descr;bed
there. These antibiotics ~r~ prepared by fer0entation,
see ~ritish Patent 1,37R,413 and German Patene 2,525,095.
lt has now been found that the attion of salinomycin and
narasin ~hen combined ~ith other known coccidiocidal
active compQunds is increased beyond ~he expected degree.
The invention thus rel~tes to cocr,idiocidal 3gents which
contain ~ polyether ~ntibiotic ~elected from the group com-
prising salinomycin, nar~sln or their physiologically ac-
ceptable salt or ester ln combinatlon with one or more
actlve compounds æelected from the group comprising meticlor-
pindol, m~thyl benzoquate, nicarbazin, amprolium, beclo-
tiamine or halo~uginone or its salt.
T~o-component comb;nations are of particular interest.
Three-component combinations can ~lso be used ~ccording
to the invention; of the latter, the combination of
salinomycin or narasin with meticlorpindol and methyl
benzo~uate is preferred.
Instead of ~ m its muxture with ethopabate can be used in these
combinations. The o~ination p~ers ~o be used according to the
inv~ntion for salinomycin and nar~sin have ~een kno~n in
veterinary ~edicine for ~ relatively long ti~e. They are
~ll described in the Merck Ind~x, 10th editi~n, pubLished by
Merck ~ Co., Inc. ~S~ (1983): ~etitlorpindol l3,5-dichloro-
2,6-dimethyl-4-pyridinol) ~n pD9~ ~41; ~ethyl benroquate
~nequinate; 3-~ethoxyc~rbonyl-6-n-bu~yl-7-ben~yloxy-4-
Z~6
oxoquinoline~ on page 928; nicarbazin (complex of N,N'-
bis(4~nitrophenyl)urea with 4,6-dimethyl-2(1H)-pyrimidi-
none) on page 931; ethopabate ~methyl-(4-acetamido-2-
ethoxy-benzoate~on page 544; amprolium (1-~4-amino-2-propyl-
5-pyrimidinyl)methyl~-2-methyl- piperidinium chloride~ on
page 613; beclotiamine ~3~(4-amino-2-me~hyl-5-pyri~idinyl)-
methyl~-5-(2-chloroethyl)~-4~methyl-thiazolium chloride on
page 144; and halofuginone (7-bromo-6-chloro-febrifugine)
on page 662. In addition to ~alofuginone, physiologically
acceptable salts thereof, such as the hydrohalides, in
particular hydrobromide, acetate, lactate, alkali metal or
alkaline earth metal salts and salt of aceturic acid, see
German Offenlegungsschrift 2,934,069, are also included
according to the invention, as well as all the optical iso-
mers and mixtures thereof. Amprolium or beclotiamine can
also be used as their hydrochloride addition salts. Instead
of heclotiamine also its analogous naphthalene-1,5-disul-
fonate salt can be used accordin~ to the invention.
'l'he combination of meticlorpindol and methyl benzoquate is
known as the commercial product ~R~Lerbek (ICI). The com-
bination of amprolium and ethopabate is known as the com-
mer c~l product (R)Amprol Mix Super (Merck, Sharp & Dohme
AGV~T)
The combinations according to the ;nvention exhibit syner-
gist;c effects in combating toccidiosis, in particular
coccidiosis in poultry.
~hen large numbers ~f poultry ~re kept in a confined
space, for ~xa~ple in the f~ttening of poultry or rearing
of poultry, there is alw~ys the potential danger of a
coccidial inf~ction c~used by Eimeria species, and if not
combated the~other2Peutically this l~ds eo serious
economic lssses. Coccidi~l infections ~s a rule cause
depressed weigh~ Dnd excretion of bloodstained dropPings,
~hich srise ~s ~ cons~quence Dt lesisns in the inteseinal
~29~;21~;
~ucous ~embrane. Severe coccidial in~ections ;n poultry
as a rule ~lso le~d to ~ high m~rtality.
~y using the conlbinations ~ccording t~ the invention,
considerabl2 ~dvanta~es result in co~p~rison ~;th the
corresponding individu~l sctive comp~unds, since smaller
amounts of coctidiocidal ~ents tan be e~ployed This
resu(ts in ~ reduction in the ~oxic s;de e~fetts of the
pr~duct in compar;son ~ith odministration of the individual
~ctive compounds, sn incre~se in profitability and ~ reduc-
t;on of the residues in ehe edible tissues fro~ th8 poultry.
~he ~eight rdtios of the 3ctive compounds can v~ry ~ithin
wide limits in the ~g~n~s according ~o the inven~ion. In
combinations o~ ~alinomycin or nar~in with the other in-
gredients, t~ey are
a) ~ith meticlorpindol, bet~een 5:1 and 1:25, in particu-
lar bet~een 1.5:1 ~nd 1:5,
b) ~ith ~ethyl ben~oquate, bet~een 100:1 3nd 1:3, in par-
ticular bet~een ~0:1 and 5:1,
c) ~ith nicnrb~zin, between 6:1 and 1:15, in particular
bet~een 3:1 ~nd 1:4,
d) with h~lofuginone, bet~een 160:1 ~nd 3:1, in particular
between 100:1 and 8~ nd
e) ~ith a mixeure of ~etielorpindol and ~ethyl b~n~oquater
bet~een 20:1 and 1:20, in particulsr 10:1 and 1:5
f~ with amprolium, between 1:1 and 1:5
g) with beclotiamine, between 1-1 and 1:5~
h) with a mixture of amprolium and ethopabate, between
1:1 and 1:5.
(in each case the values refer to the ratio of he polyether
antibiotic to the combination partner).
The weight ratio of meticlorpindol to methyl benzoquate in
case
3~ e) can vary between 20:1 and 7:1 whereas ~he weight ratio of
amprolium tO ethopabate in case h) can vary between 30:1
and 10:1.
~4~
-- 4 --
The compounds ~cc~rding to the invention are quite gener-
ally suitable for the protection of poultry, that is to
say for the treatment of ~r;cultural commerci~l poultry,
such 3s chic~ens~ turkeys~ ducks or ~eese, ~s ~ell as other
birds, such as, for example, phe~sants, quail or guinea-
~o~l; the latter species of birds have recently aLso been
reared in far~s for economic use and, like chickens, are
affected Srequently snd massively by Coccidia.
~or success~ul protetti~n of the poultry fr~ coccidiosis,
the sgent~ ~ccording to the invention can be used at any
ti~e. In p~rticul~r, they c~n be used in broiler farms
or houses for r~ring young hens, since there is ~ high
risk of infection for the poultry population there because
o~ the per~anent forms of th~ Cocc;dia toocysts) continu-
ally excreted in the droppings. Since there is al~ays the
risk of an ou~bre~k of toccidiosis under thes~ c~nditi~ns,
the coccidiocid~l ~gents according to the invention should
be used tontinuously on the poultry and before ~n outbreak
of coccidiosis. Mo~ever, the agents according to the
;nvention c~n also be administered over short intervals
of time, that is to say over a fe~ d~ys.
The use ot the agents according to the invention and
methods for combating coccidiosis are carri~d out in the
custom~ry m~nner. Oral administr~tion is pri~rily sui~-
~ble, in accordanc~ with the location of ehe Coccidia in
the intestinal eract. The ~ctive co~p4und combin~tions
according to the invention can thereby be ~ixed ~ith feed-
3û stuf~s or ~ith drinking ~ater.
~he active co~pound concentr~tions of ~he co~binations inthe feedstuffs or in the drinking ~ater c~n vary ~ithin
cert~;n linits. They ~re in gener3l bet~een S ~nd 300 ppm
o~ the active compound ~ombina~ion, bas~d ~n t~e feeds~uf~
or drink~ng wat~r.
~;29~;216
The particularly preferred concentrations tor combating
coccidiosis are, in the case of the feedstuffr in each
case 15 to 70 ppm, in particular 25 to 45 ppm, of salino-
mycin or narasin ~nd
a) 15 to 150 ppm, in particul~r 30 to 125 ~pm, of
meticlorpindol,
b) 1 to 30 ppm, in particular 1.25 to 5 ppm, of ~ethyl
benzoquate,
c) 15 to 150 ppm, in p~rticular 30 to 100 pp~ ~f nicar-
baz ln,
d~ 0~5 to 3 ppm, in p~rticuLar 0.75 to 1~5 pp~O of halo-
fuginone~
e) 5 to 120 ppm, in particulAr 8 to 30 ppm, ot ~eticlor-
pindol/nethyl ben20quate~
f) 100 to 150 ppm of amprolium~
g) 40 to 125 ppm of beclotiamine,
h) 30 to 100 ppm of amprolium/ethopabate.
If drinkin~ w~ter 15 used, ln each case abo~t hal~ of the
concentratlons stated ls pre~erably used.
All the concentr~tions, ratios, p~rtst a~ounts or percen-
tages mentioned ~re based on weight units.
The active compound concentr3tions of the coccidiocidal
~gents are based on feed or drink;ng ~ater ~or~ulations
~d libitum, that is to say for free intake of feed or
drinking ~ater over ~ fattening or re~ring period cus-
tomary in practice. Ho~ever~ because of particular factors
resulting in practice, ;~ ~y be that the poultry expert
~ust ~ake ~n up~ard adjust~ent in these use concentr~tions
if the poultry is suPplied ~ieh different stocks of feed
or ~ter. ~n that case, ho~ever~ only so~e of ~he feed
or ~ater stocks contains ~the ~gents accGrding ~c the inven-
tion.
~4;~16
Suitable vehicles for the synergisticalLy active coccidio-
eidal agents ~ccording to the invention are all the feed
formulations customary in the poultry industry. The for-
~ulations for poultry feed described belo~ are e~amples
of ~ormulations ~hich and customary in practice, Ho~ever,
it is ~oreover ~lso possible to US2 other feedstuffs based
on ~ny c@real grains and tontaining vitamin concentrates,
~ineral concentrates or other ~ct;ve tompounds and feed
~dditives in ~ny desired concentration. 80th conventional
dry, ~ealy or pelleted ~eedstuffs and liquid suspension
feeds, ;ncludin~ f~edstu~s such as distillation pulp and
~;lk by-products, c~n be used with the agents according to
the invention.
To prepare the poultry feed according to the invention,
A concentrated premix contDining the synergistically
active coccidiocidal agents in a high concentrstion, for
example from 0~2 to 75Z, is usually f;rst prepared. For
this purpose, the coccidiocidal agents and physislog;cally
2~ ~ccept~ble vehicles, such ~s propylene glycols, polyethy-
lene glycols, inert oils, such ~s v~getable oils, highly
refined ~ineral oils, ethanol, ~ater or ~queous alcohols,
either are dispersed or ~re 0ixed into inert ~ehicles,
such as vermiculite, diatomaceous earth, attapulgite,
c~lcium carbona~e or bolus alba. Organic vehicles, such
as ~heatbran, co~rse cornmeal, soybean flour, lucerne
flour, rice husks or ground corn cobs, ~nd uny other
desired or~anic veh;cles from vegetable prnducts, ~re
like~ise suit~ble for this purpose.
~2~Zl~
-- 7 --
The synergist;cally ~ctive agents ~ccording to the inven-
~ion can furthermore also be administered to poultry
together ~ith the drinking ~ter~ They ~re incorporated
into the drink;ng ~aeer by ~dd;ng ~ su;table ~mount of a
~ater-soluble or w3ter^suspendable form of the particular
agent to the drink;ng ~ater. 5uch ~or~ulat;ons Are in
~ener~l prepared by sel~ctiny a ~a~er-soluble form of the
bgents. lf this is undesir~ble or cannot ~e prepared, ~ater-
insoluble forms, for example suspens;ons, can also be used.
1~ Physiologit~lly ~ccept3bLe ~uxiliaries~ ~ith which the
coccidiocidal a~ent~ according to the invention ~re kept
in suspensions in ~ater over ~ prolonged period, are used
to pr~p~re the for0ul~tions. ~uxiliaries which ~re suit-
able for this ~re s~elling ~3ents, such as ~l~in~tes,
gelatin, carboxymethylcellulose or polyvinylpyrrolidone.
Ho~ever, the agents ~ccording to the invention c~n also
be suspended ~ith various surface-active compounds, sueh
as, for example, ~i~h the aid of Lecithin, naph~halene-
sulfonates~ ~lkylben~enesul~onates, alkylphenol-poly-
ethylene oxide adducts or polyoxyethylene sorbit~n esters.A concentr~ted suspension or ~ dry formulat;on of the
coccidiocid~l 2gen~s accord;ng to the invention ~nd the
suspending agonts in cert~in ~ixin~ ratios is usually first
prepared, and is then diluted wieh the drinking ~ter to
the desired use ccncentration, or the premixes ~re ~ixed
in suit~ble concentrations ~ieh the feedstuffs tustomary
in practice. The drinking ~ater or feed oædit~ted in this
~ay is then offered to the poultry, either initi~lly ad
libitum or ov~r ~ c~rt~in ~r;od~
The tre~t~ent ~ethod according to the invention can also
be ex~ended tG other methods for the treatment ond feeding
of poultry. If, for examp~e, the compositions according
to the invention can be combined with other active com-
pounds, such as, for example, ~i~h gro~th-promoting agents
or antiparasit;cs, uhich on the one hand are 3ynthet;c
agents or on the other hand are fermentation products in
the broadest sense.
~lthough the invent;on is particularly directed to~ards
ehe protection of pouLtry from coccidial infections, it
can also accordingl~ be used on other domest;c Dnd commer-
eial ~nimals~ such ~s, for example~ o~her birds, rabbits,
hogs and rumin~nts.
The inveneion thus ~lso relaees to a ~ethod for ehe treat-
~ent of poultry coccid;osisO ~hich comprises administering
the abovementioned ~ctive ~gents orally ad libitum to
poultry, and in particular either as a feedstuff or by
~eans of the drinking ~ater.
The inventicn is illustrated by the follo~ing examples.
A. Examples of animal feed compositions
, ~ . _
~he follouing e~amples relate ~o ~nimal feed compositions
~hich can be used for administration of the active compound
combination according eO the invention.
I ~
.
Fishmeal ~60-65X) ~.0
Feeding yeast 2.0
Beef tallo~ 4.7
Soybean ~eal (44~) 2400
Luc~rne ~eal 1.0
C~rn 44.89
Wheat 6.35
~2~ 16
g
~heat ~hite shorts 8.5
Calcium phosphate 1.4
Calcium carbonate 0.96
Trace elsment premix 0.04
S Cattle salt 0-09
DL-methionine 07
100.0
a) ~ :
V;tamin A I.U. 12,DD0
93 I.U. 1,500
E ~9 18
~1 ~9 1.5
~2 ~9 6
P~ntothenic ~cid ~9 9
Nicotinic acid ~g 24
Vitamin B6 ~9 4.5
e~2 ~cg 24
K3 mg 3
Choline chloride m9 10300
b) 1.0 kg of_feed contains
.
Mn ~g 106
Zn mg 71
Fe mg 44
Cu mg 3.56
I mg 0.4
Co mg 0.16
lI. ~ (0-8th ~eek)
~Fishme~l (60-~S~) : 5,0
Lucerne ~eal ~.o
Soybean meal ~4bX~ 13.0
feedin~ ye3st 2.8
~eet tallo~ 2~0
Barley 6.0
- 10-
Oats 6.0
Sorn 37.0
~heat 13.0
Whea~bran 703
Calcium carbonate feed talc 1.29
tR)Nostaphos
Trace element premix* 0 04
10D.O
See Example Ib); Yit~mins as described in
Example la) are furthermore added.
III. ~ ~9th-20th ~eek)
Lucerne ~eal 6.0
Soybe~n meal (44X) 10.24
Feeding yeast 1~8
Beef tallo~ 2.0
8arley 8.0
Oats 6.0
Corn 40.0
~heat 15.0
~he3tbr~n 8.3
Calcium carbonate 1.53
~R)Host~phos 1.02
Trace element prem;x 0.04
DL-methionine 0 07
100 . O
: : See Example Ib); vitamins are furthermore added,
see Example Ia)
:
IV. ~ (from the 21st ~eek)
tomposit_on in X by wei~ht
Fishme~l ~60-65X) 1.5
Soybean ~eal S4bX) lQ.31
~eef tallo~ 1.0
Oats 6.7
Corn 40.0
Wheae lB.O
S ~heat ~hite shorts 3~
DL-methionine 0007
Feed paprika 0,3
Salcium carbonate 8.16
~R)Hostaphos 1.91
Trace element premix 0.05
100.0
Vitamins as described in Ex3mple Ia3 are furthermore
~dded~
V. Feed for_turkeys ~composition in ~ by weight3
Turkey Turkey ~urkey
starter fatten;ng fattening
feed feed I feed II
0-8th ~eek 9th-12th 13th-16th
~ eek _ week
Fishmeal 9.0 5.0 2.0
Feeding yeast 4.5 2~ .0
Fflt 3.1 g.7
Soybean ~eal 26.0 23.9 23~87
Lucerne ~eal 4.~ 2.0 0.95
~arley 5.3 4.5 5.0
: Oats 1.0 ~.45
Corn 3S.04 40.02 39.9D
~he3t 5.3 S.O 5.0
Wheat ~hite shcrts 5~95 470 3.8
~heatbran 4.0
Calcium phosph3te 1.58 1~30 2.71
Calcium c~rbon~te 1.35 1.~ D.9$
Trace ele~ent pre-
~ix~ 0.04 n.o4 \ 0.04
C~ttle s~lt 0.24 0.84 O.b4
Uethionine 0.1 0.1 0 18
100,0 100.D 100.0
- 12 -
Vitamin mixture per kg of feed
_ . . . _
Vitamin A ~.U. 12,0D0 8,0D0 8,000
D3 I.U~ 1,500 1,DOD 100~0
E mg 1~ 12 12
B1 ~9 1.5
~2 ~9 b.O 4 4
Pantothenic acid mg 9.0 6 6
Nicotinic acid ~9 24.0 16 16
Vitamin ~ ~9 4.5 3 3
B12 mcg 24.0 16 16
K3 ~9 3~0 2 2
Choline ehloride mg ~,3D0 1,300 1,300
1 kg of feed contains: 106 ~g of Mn; 71 ~g of Zn;
44 mg of Fe; 3.56 ~9 of Cu; 0.4 mg of I3 D.16 mg
of Co.
. Biological ex3mples
The coccidiostatic effect of the present agents has been
investigated on chickens infected ~ith Coccidia, The
experimental investig~tions described below demsnstrate
the efficacy of the v~rious combinations according to the
invention with the aid of a few examples. The salinomycin
is used here in the form of ~ sodium salt of the mycelium
~hich has been prepared by fermentation and has not been
separ~ted.
To deeer~ine and evaluate the coccidiostatic effect of the
agents according to the invention, so-called in~ection
controls (untreated~ ;n~ected birds) 3nd ~ero controls
tuntre3ted, non-intected birds) ~re used in ~ll the
gxperimental investig~tions descr;bed belo~. The birds
of both sexes used for ~hese (LSL chickensO Loh~nn,
~allau, FRG) ~ere randomi~ed and groups of 16 Dnimals each
~ere ~ade up~ The infected groups treated ~ith the agents
: ~ccording to th~ inv~ntion ~ere ~de uP by the s~me
~ethod. The bir~s, ~xcluding those of the ~ero control,
- 13 -
~ere infected with a viru~ene Eimeria tenella strain,
which leads to severe (reProducible) lesions in the ceca
in S-days old chickens. The coccidiocidal 3gents ~ere
mi~ed ~ith the feed for pou~ry in ppm amounts; the
particular concentrations can be seen from the follo~ing
Tables la to 1e.
The degree of ~everity of the pathological-~natomical
changes in the ~ucous ~embrane in the ceca caused by the
infection is usually (ExperimentaL Pardsi~ology VoLume 28,
~5 1970; or Lon~, P.L.: ~he ~iology of ehe CGCC idia, 19R2,
Univ. Park Press) expressed in the form of damage values
(= lesion vaLues)~ called " ~ " belo~ ~scaLe
from 0 to 4~. At the end o~ the investigations, the
animals ~ere s~crificed 5 ~ays ~fter infection and ~ere
: 15 investigated for all the typical pathologic~l ~natomical
changes caused by cocc;diosis.
Description and evaluation of ~he damage tlesion scores):
0 to 4
. _
0 - birds in ~hich no lesions are detectable in the
intestinal tract
1 - birds ~ith ~ few circu~scribed sm~ll lesions (pet-
echiae) in the eeca
2 - birds ~ith several, circ~mseribed lesions tpet-
echiae) some~hat larger tban described under 1
3 = birds ~i~h numerDus hemorrhagic lesions of a relatively
large area and partly tontluent.
4 = bords ~ith large ~re3 he~orrha~ic lesions, ~hith
af~ert the entire intestinal ~ucous ~embran~ of the
c~ca ~nd 2lso adj~cent sections of the intestine
; 30 tileu~ and rectu~)~ The pict~re of extremely severe
hemorrhogic ~nteritis over ~ l~r~e ~re~, ~hich 3S a
rule leads to the death of the bird, is prevented.
~z~
Liquid and bloodsta;ned dropping are ;ncreasing~Y de-
posited ~ith the damage described under 1 to 4. The
depressed ~eight as a result of refusal of food likewise
torrelates ~ith the intrease in "Lesion scores"~
The relevance of the lesion scores for evalu3ting the
coccidioc;dal actic~n of the agents accordin~ to the
invention bec~mes clear from the observations mentioned.
~he lesion scores are l;sted in Tables 1a-le, on the one
hand as individual values per snimal w;thin a group, and
on the other hand as mean values of the corresPonding
yroup o~ birds.
ln all the experi~ents, groups of 16 LSL chickens one week
old ~ere kept under constant housing cond;tions in ~;re
cages containing 4 birds each per ~ire cage. The feed
medicated ~ith the agents ~ccording to the invention uas
offered ad libitum from day D-1 (one day before infection)
untiL day D+S t5 days ~fter infection). The control groups
tzero group and infection control) received non~edicated
~eed. The particular ~roups of birds ~ere thus fed with
the same feed for 7 days. On the day of infection ~= DO),
200,000 sporulated oocysts of the abovementioned E.
tenella strain ~ere ~dministered to each bird by a stomach
eube.
~tter parti3l digestion of the oocysts in the s~all intes-
tine, the infectious sporo~oites ~ere rele~sed from these
permanent forms and then attacked the epitheli3l cells of
ehe intestinal ~ucous membr~ne and multiplied there
~assively by changing ~or~. ~he numerous schiz~nts ~hich
develop from the sporo~oites destroy ~he intestin3l epi-
~heliu~ by repe3ted division processes. ~ pe~k of the
destructive ef~ect of the schizonts on the intes~inal
epiehelium is reached 5 days ~fter infectionO ~he "lesion
scores" ~ere therefore determined at this point in time
_ ~5 -
;n the manner described above.
The synergist;c effect of the agents according to the
invention tcombinations~ is sho~n below in ~Dbles la-1e,
and in part;cular, on the one hand the effect of the indi-
vidual acti~e compounds in the use concentration rustomaryin practice, and on the other h~nd the super~dditive or
synergistic effect resulting ~rom various co~binations of
the individual active compound. The 'lles;on scores" of
~he infec~;on controls ~nd ehe zero controLs ~non-infected
animals) ære used for balancing with the particular medi-
cated and infected groups of ~nimals.
lZ~Z~qS
- 16 -
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-- 17 --
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- 18 --
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