Note: Descriptions are shown in the official language in which they were submitted.
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The present invention relates to a synergic growth-
promoting feed supplement composition for farm animals that
may consist essentially of an effective amount of 2-formyl-
quinoxaline-1,4-dioxide cyanoacetylhydrazone, which has the
generlc designation cyadox, in combination with c~rtain
additional biologically active substances. The invention
also relates to the use of this feed supplement composition
and of supplemented feed mixtures comprising the same in
feeding farm animals such as, e.g., pigs, calves and poultry.
1~ The composition of the invention can be used for increasing
of liveweight gains, enhancing of the feedstuff utilisation
and for the prevention or treatment of microbial and other
infections.
The present invention, in particular, provides a
synergic growth~promoting feed supplement composition suitable
for farm animals, comprising an effective amount of 2-formyl-
quinoxaline-1,4-dioxide cyanoacetylhydrazone and a component
selected from the group consisting of an antibiotic component
a sulfonamide component and mixtures ther~of. The composition
~0 may, if desired additionally include common auxiliaries and
carriers; ie biologically acceptable carriers etcO
The present invention also provides a growth-
promoting feed mixture, suitable for farm animals, comprising a
(i) a feedstuff
2S (ii) 20 to 500 grams per ton of feed mixture of
2-formylquinoxaline-1,~-dioxide cyanoacetyl-
hydrazone and
(iii) 20 to 500 grams per ton of feed mixture of a
component selected from the group consisting
of an antibiotic component, a sulfonamide
component and mixtures thereof
The feed mixture can make use of any common feedstuffs
and can include common auxiliairiesand carriers.
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The feed supplement composition of the p~esent
invention can be advantageously used for increasing liveweight
gains, enhancing the feed utilisation, suppression of microbial
infectionsl improving the general health state of farm animals
and reduction of lo~;ses by early mortality, especially in
large-scale breeding~ conditio~ns.
It is kno~ from literature /CS 195 508, ~E 2 829 580,
US 4 225 604/ that cyadox efficiently promotes the growth of
farm animals and suppresses both gram-positive and gram-
negative microorganisms; it also has markedly pronouncedcoccidiostatic propert.ies. Advantageously, the compound is
almosk nontoxic: in rats, its L~50 is as high as 15 g/kg p.o.
The mentioned favorable effects of cyadox on the
growth and health o~ farm anin~als have recently been found
to increase surprisingly by its combination with antibiotics
and/or sulfonamides, even those which per se elicit little
or no growth promotion. The observed increase in activity
is substantially higherthan _t could have been predicted on
the basis of known properties of the components. The desirable
effects of cyadox alone are markedly promoted in the above
mentioned combination since the additional components contribute
synergically to the growth stimulation as well as to the
suppression of pathogenic microorganisms by said compound.
This synergism, similarly as the unexpected slight toxicity
and improved stability of cyadox, belongs to extraordinary
characteristics of the substance.
This synergic effect occurs in combination of cyadox
with quite a number of antibiotics such as, e.g., tylosin,
bacitracin, oxytetracycline, chlortetracycline, virginiamycin,
spectinomycin, flavomycin, thiamulin or apramycin, and
sulfonamides such as, e.g., phthalazole or sulfadimidine Thus,
for example, when test groups of early weaned piglets were
treated, in parallel experiments under otherwise identical
conditions, respectively with cyadox alone, tylosin alone
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and with a combination of both, at the same dosage level of
1~0 mg per kg of feed mixture, the liveweight gains as well
as the feedstuff utilisation in the group treated with the
~ombination proved to be substantiall~ higher than the sum
of these effects of the individual components dosaged separately.
Also, when pigs in t:he starting period of fattening, of approx.
50 ~g weight, were fed a mixture supplemented with cyadox
and/ox phthalazole in equal llD0 mg per kg doses of either
substance applied individuall1y or in combination, the re-
spective effects of administering the combination as comparedwith the untreated control group were substantially higher
than the sum of the effects of the individual dosage. This
clearly indicates synergism, which could not have been ex-
pected on the basis of the available data.
The feed supplement composition according to the
invention contains the antibiotic and/or sulfonamide
component in a suitable dosage form such as, e.g., the cor-
responding acidic, basic or amphoteric substance, an acid
addition salt, a base addition salt, a complex sal~ or a
metal chelate. The antibiotic can also be present as a
dried fermentation medium or an antibiotic-containing mycelium
previously separated therefrom. Thus, the term tylosin
designates the base or the corresponding quantity of an
acid addition salt such as, e~g., hydrochloride, sulphate,
phosphate or tartrate, or a dried tylosin-containing mycelium.
The term bacitracin stands for this substance as such or its
complex compounds with metals such as e.g., Zn-bacitracin.
Due to the extremely low toxicity of cyadox and of
antibiot~cs and sulfonamides including those listed herein
above, the administration of the feed supplement composition
does not involve any hazard of injurious effects even on un-
intentional overdosaging of the supplemented fead mixture.
Also, its use as a veterinary medicament in convenient doses
is xeliably free of any risk.
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The synergic growth-promoting feed supplemen~
composition according to the present invention may contain
cyadox and the antibiotic ancl/or sulfonamide component in
any practical proportion of quantities such as within a range
of 1 : 10 to 10 : 1. For enc;uring balanced effects and
potent synergism, h~wever, a harmonic ratio of approx. 1 : 1
is as a rule preferable. The composition may contain both
an antibiotic and a sulfonamide. In Eormulating of supplemented
feed mixtures, the composition is advantageously added, in
the form of a premix to nutritionally balanced feed mixtures
with a required content of essential biologically active
substances /biofactors/, in aL quantity xanging substantially
~rom 20 to 500 grams of each per ton of feed. Also, the
principal components of the composition may be adjusted
into a convenient veterinary medicament form and dosaged
eac~ at a level ranging from approx. 1 to 100 mg. per kg of
liveweight daily.
The dispensing forms suitable for the application
of the oomposition may be solid or liquid such as, e.g.,
granulations, capsules, pills, oral pastes, suspensions and
the like. They may contain compatible solvents or diluents,
carriers of organic or inorganic origin such as, e.g., ground
limestone, kaolin, talc, starch, sugar, cellulose, crushed
plant residues or similar substrates used in formulating of
veterinary dosage forms, as well as usual excipients
/auxiliaries/ and, if required, other biologically active
components. Among said excipients there should be particularly
emphasized the addition of suitable surface-active substances
such as cationactive, anionactive and nonionogenous tensides
or tenside mixtur~s with good wetting and dispersing or
emulsifying properties. These tenside substances, advantageously
chosen from among a large amount of commercial products, may
also form a part of the premixes, feed supplements and feed
mixtures. The tensides are admixed preferably in a ~uantity
43
ranging f~om approx. 0.5 to 10.0 ~g per ton of ~eed.
Said dispensing forms of the composition are manu-
factured similarly as common veterinary medicament forms,
biofactor concentrates, premixes, feed supplements or supple-
mented feed mixtures by any of the known methods, predominantly
by mixing or grinding of the active constituents with the
other components such as, e.g., solvents, carriers and tensides.
The feed supplement composition according to the
invention promotes the growth of farm animals in a substantial-
ly higher degree than its individual components and signifi-
cantly enhances the feedstuff utilisation. In addition to
this, the composition can advantageously be used for the
prevention and treatment of systemic diseases of farm animals,
especially of diarrhoeic diseases such as enterites and
salmonelloses as well as of coccidiosis. This feed supplement
composition also improves the general health of farm animals,
diminishes the losses by their early mortality and so increases
the efficiency of farm animal breeding, particularly of large-
scale breeding of pigs, cattle and poultry.
The following examples illustrate the utility and
effects of the invention, but are in no respect limitative
as to the scope thereof. - The percentual values sofar in-
~icated herein below represent percents by weight.
Example 1:
Early weaned piglets, crossbreds of the large white
x landrasse, born within an interval of 6 days, were transfer-
red from the delivery station to the experimental ~iostation
on the fifth day after weaning. The animals were divided
into groups of 8 to 12 and each group was placed into a
separate box; the boxes were provided with grate floors and
heated through wooden floorings. After an adaptation period
of additional 7 days the experiment was started. Over the
entire te~t period of 4 weeks, all groups under test were fed
a commercial feed mixture COS-2 designed for feeding of early
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weaned piglets. The feed mixture was supplemented, by
admixture of the respective premix, a~ follows:
Group I - /reference group/ mixture alone
II - cyadox, 100 ppm /100 mg per kg of
the mixture/
III - feed-grade tylosin, 100 ppm of pure base
IV - cyadox and feed-grade tylosin, 100
ppm of each.
The animals were weighed individually at the start and at the
end /on the 28th day/ of the experiment. The feed consumption
per group was followed daily and the feed utilisation rate
was calculated. Also, general health of the animals was
examined daily. The test results are summarized in the fol-
lowing Table I.
Table I
Group I II III IV
Substance reference cyadox tylosin cyadox /100/
/dosage, ppm/ /0/ ~100/ /100/+tylosin /100/
Number of animals 12 12 11 5 x 8
Initial weight 10.30 10.28 9.13 7.10
x, kg
Weight gain index 100.0 109.8 125.9 150.6 %
Feed utilisation x 2.0 1.99 1.90 1.61
/consumption per
gain unit/
2S
Feed utilisation lOl~.0 99.5 92.2 84.3 %
index ~-0.5J /-7.8/ /-15.7/
Similar results were obtained with the use of tylosin,
b~acitracin, chlortetracycline and oxytetracycline together with
cyadox for supplementing of feed mixtures fed to pigs, calves
and broilers.
Example 2:
In a pig fattening station there was observed the
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occurrence of diarrhoea with bleeding in 5 to 15% of the
BU x PC + L race starter pigs, approx. 50 kg liveweight,
placed in boxes each for 10 to 15 animals. The disease was
diagnosticized histolotically and microbiologically; the
disease originator was identiiied as Vibrio coli.
The test pigs were clivided into 4 groups and fed
a commercial SOL feed mixture, which was supplemented by
premixes as ollows:
Group I - /reference group/ mixture alone
II - phthala~zole, 100 ppm
III - cyadox, 100 ppm
IV - cyadox and phthalazole, 100 ppm
of each.
Said biologically active substances were administered for 14
days. After that time, groups III /cyadox/ and IV /cyadox +
phthalazole/ had no case of diarrhoea with bleeding /100
therapeutical efficiency/ whereas in groups I /reference/
and II /phthalazole alon~/ the disease was still observed in
20 to 30% of the animals. At the end of the e~periment,
altogether 20 pigs from the latter two groups tl5 from group
I and 5 from group II/ ha~ to be sent to emergency slaughter
because of bad state. The test results are summarized in the
subsequent Table II.
Similar results were obtained with the use of
phthalazole and sulfadimidine together with cyadox for sup-
plementing of feed mixtures fed to pigs, calves and broilers.
. ~
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