Note: Descriptions are shown in the official language in which they were submitted.
29,259
I
METHOD FOR IMP OWING MILK PRODUCTION
IN LACTATING RUMINANTS
This invention relates to a method for in-
creasing milk production in lactating ruminant animals
such as dairy cattle, goats, and sheep
ore particularly, this invention relates to a
method for increasing milk production in lactating rum-
Nat animals by orally administering thereto, during the
lactating period, from about 0.04 my to 0.33 my and
preferably 0.0~ my to .25 my of avoparcin or a salt or
complex thereof, per kg of animal body weight per day.
The antibiotic avoparcin is also sometimes referred to as
antibiotic AVOW and is generally prepared by a ferment
station process.
Avoparcin (AVOW) consists essentially of two
water-soluble glycopeptides, hereinafter referred to as
the and Components of avoparcin. These components are
discussed in the following publications: W. J. McGahren,
et at., "Structure of Avoparcin Components," Journal of
the American Chemical Society, 102, 1671 (1980) and
"Avoparcin," Journal of the American Chemical Society,
01, 2237 (1979).
The structure of avoparcin (AVOW is thus-
treated in Figure I below. The to component has the
configuration shown in Figure I, wherein R' and R are each
hydrogen, and the component is similar excepting that
R' is hydrogen, and R is chlorine.
I, I
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owe; owe
owe
owe "; I Cut
1-0~ 0
~-avoparcin R'- R = Hydrogen
~-avoparcin R'= Hydrogen; R = Chlorine
3 I I
In accordance with the present invention, avow
porcine is orally administered to lactating ruminants in
or with their feed as an animal feed premix or concern-
irate. It may also be offered in the form of a top
dressing for the animal's feed or administered thereto
incorporated in a slow release bonus designed to contain-
usual provide the animal with the desired quantity of
antibiotic throughout the lactating period.
The antibiotic may be used in its essentially
pure crystalline form or may be employed as a pharmacy-
tidally acceptable salt such as the hydrochloride salt of
the antibiotic or as an antibiotic complex such as the
alkylated sulfate, suntan or Truman complex of avopar-
gin. In the conduct of the present invention, it has
likewise been found that the antibiotic avoparcin is
effective for increasing milk production in lactating
ruminants when the antibiotic is orally administered in
any of the above-said forms but associated with the dried
solids of the whole harvest fermentation mash in which it
was produced.
Administration of from about 0.04 my to 0.33 my
of avoparcin per kg of animal body weight per day (i.e.,
0.04--0.33 mg/kg body weight per day) amounts to approxi-
mutely 24 to 200 mg/kg per head per day for lactating
dairy cattle and from about 2.4 my to 25 my per kg per
head per day for lactating goats or sheep.
When the antibiotic is administered in the
form of a salt or complex, the amount of salt or complex
used should, of course, be adjusted to provide the dosage
level of avoparcin previously indicated.
I ~2~3~
Although avoparcin has been an important, come
Marshall available antibiotic used in the feed of meat-
producing animals to accelerate the growth rate thereof,
we have found that when said antibiotic is administered
5 to lactating dairy cattle at the dosage levels recomb
mended for growth promotion in beef cattle, milk pro-
diction and/or milk quality is measurably reduced.
Therefore, the concept that all glycopeptides
including: actoplanin, avoparcin A-35512, vancomycin,
10 ristocein A-477, K-288, and AM-374 are essentially equip
valet as milk production enhancing agents for lactating
dairy ruminants as suggested by the applicant in United
Kingdom Patent Application AYE, published October
27, 1982, is erroneous and/or misleading, at least with
respect to the inclusion of avoparcin amongst the glyco-
peptizes indicated.
As will hereinafter be demonstrated, avoparcir,
administered to lactating dairy cattle at dosage levels
from about 50 my and 150 my per head per day increases
20 milk production and/or milk quality; whereas, ad minis-
traction of avoparcin to lactating dairy cattle at 300 my
per body weight per day to 600 my per body weight per day
reduces milk production and/or the quality of the milk of
the treated animals.
The invention in the subject application is
further demonstrated by the examples set forth below.
I 5~31
EXAMPLE 1
Evaluation of avoparcin for increasing milk productionand/or the quality of milk of lactating dairy cattle.
The experimental design utilized in this oval-
ration consisted of three periods. Period I was a
pre-experimental 28-day period when all the cows in the
milking herd were recorded, and selection of suitable
subjects for the trial occurred. Period II consisted of
28 days where the avoparcin treatments were given, and
Period III constituted a following 28-day post-avoparcin
treatment. The entire experiment took place over a
three-month period.
A total of 28 Fruition dairy cows was selected
from a milking herd of over 60 animals. Each cow had been
calved for a minimum of six and no longer than 22 weeks
and currently had a daily milk yield in the range of 17
- 32 liters. Four balanced treatment groups were care-
fully composed so that each contained animals which were
paired with respect to milk yield and stage of lactation.
Each balanced group was then assigned at random to one of
four experimental treatments. Group A received no avow
porcine and acted as an untreated control group. Groups B,
C, and D received 50, 150, and 300 my of avoparcin per
head per day, respectively, over a consecutive 28-day
period. Each of the experimental cows received its
allocation of avoparcin in one meal at the afternoon
milking. Carefully weighed amounts of avoparcin (i.e.,
1 g, 3 g, and 6 g AVOTAN~ 50, avoparcin, the I active
ingredient premix, for treatments B, C, and D respect
lively) were included in 250 g lots of a palatablemaize-based concentrate.
-6- ~25~3~
At the start of the study, the cows were at
grass. During the first week of Period II, they were
fully changed over onto the winter basal ration con-
sitting of 35 kg fresh silage which was estimated to
supply maintenance alone. A balanced dairy concentrate
(180 g CP/kg) was given for all the milk produced at the
rate of 0.4 kg per lithe throughout the experiment.
Milk yields were recorded, and milk samples
were taken on four occasions in the pre-experimental
Period I and daily for the first three days of avoparcin
feeding. Thereafter, milk yields and samples were taken
on alternate days until the end of the entire experiment
tat period. Milk yields and samples continued to be taken
periodically during the I days immediately following
the end of avoparcin feeding (Period III).
Milk samples, where taken, were collected at
both morning (05 30 h) and evening milking (15-30 h) and
combined for any one day. Compositional analyses for
butterfat, protein, and lactose were performed by stank
dart automated techniques.
During the course of the trial, five cows
required antibiotic therapy for misstates. Two cows were
seventy affected and were removed from the study. Con-
sequently, final data are reported on seven cows from
each groups A and Do and six cows each from groups B and
C.
I
Tables I and II detail the mean daily yields
and butterfat of the four treatment groups as recorded
during the trial. Table III details an obvious consider-
anion of that data in presenting mean group milk yields
and butterfat contents of the cows immediately pro-
treatment, during the 28 days of avoparcin feeding; and,
similarly, during the 28 days following the end of
avoparcin treatment. The groups were closely matched
during the pretreatment phase; but, clearly after avow
porcine treatment, it appeared that the untreated con-
trots, group A, and the group which received 300 my of
avoparcin per head per day, group D, showed a sub Stan-
tidally greater decline in milk production and some de-
press ion in butterfat content, compared to groups B and
C. The milk yield decline, in particular, is continued
in these groups (A and D) for the 28 days following the
end of treatment. During the avoparcin feeding period
(II), both groups, B and C, declined in yields at a slower
daily rate than the untreated control group A. When the
overall yield decline is examined (by averaging milk
yields during both the period of avoparcin feeding (II),
and the 28 days following the end of this period (III),
and comparing said averages with the average milk yields
obtained in period I), it can be seen that the decline in
overall milk yields obtained with groups B, 50 my per head
per day; and C, 150 my per head per day, is only about l/4
to 1/2 of the decline obtained with the untreated con-
trots, group A and group D, treated with avoparcin at
300 my per head per day. Actually, the greatest declines
3Q in both milk yield and butterfat were observed in the
group receiving 300 my per head per day.
Table III provides group mean values of milk
yield and butterfat immediately pretreatment, during the
last two Willis of avoparcin treatment, and during the
final two weeks of the period following the end of avow
porcine treatment.
The data from Tables I and III are also
graphically illustrated below.
TABLE I
MILK PRODUCTION DURING PERIOD I 28 DAYS PRETREATMENT
Mean milk yield (Liters/day) of untreated cows
allotted to group (A) untreated controls, group (B) 50 my
per head per day avoparcin, group (C) 150 my per head per
day avoparcin, or group (D) 300 my per head per day
avoparcin
GROUP _ B C D_
Untreated 50 mud 150 mud 300 mud
Milk Yield Milk Yield Milk Yield Milk Yield
Day Liters/Day Liters/Day Liters/Day Liters/Day
-28 26.1 26.3 24.8 21~.5
- 9 22.9 23.0 22.7 23.0
- 1 22.0 23.1 22.6 23.0
21.7 23.0 22.4 22.1
Average
Milk Yield
(L/D) 23.18 23.85 23.13 23.15
9 ~22~î03~
TABLE I (Continued)
PERIOD II MILK PRODUCTION DURING 28 DAYS OF TREATMENT
__
Mean milk yield (Liters/day) of untreated cows
group (A) and cows given either 50 my per head per day
avoparcin group (B), 150 my per head per day avoparcin
group (C), or 300 my per head per day avoparcin group (D)
over a 28-day treatment period
CROUP A B C D
Untreated 50 mud 150 mud 300 mud
Milk Yield Milk Yield Milk Yield Milk Yield
Day Liters/Day Liters/Day Liters/Day Liters/Day
1 21.8 23.8 22.1 22.2
2 21.8 23.9 23.1 21.6
3 21.9 24.9 21.9 22.3
21.3 25.3 22.7 20.1
7 23.1 25.7 24.8 22.7
9 22.7 26.3 LOWE 21.5
11 22.6 26.6 24.4 23.7
13 22.6 25.8 24.3 23.1
21.2 25.0 22.1 21.0
17 20.7 25.2 20.3 21.3
19 19.5 25.2 22.4 20.3
21 20.0 24.4 23.5 20.1
23 19.0 22.5 22.4 18.9
19.4 22.4 21.2 18.7
28 19.5 22.7 21.4 18.7
Average
Milk Yield
(L/D) 21.14 24.85 22.74 21.08
o 25~
TABLE I (Continued)
PERIOD IT MILK PRODUCTION DURING 28 DAYS_POST-TREATMENT
Mean milk yield (Liters/day) of untreated cows
group (A) and cows treated during Period II of this
evaluation with 50 my per head per day avoparcin group (B)
150 my per head per day avoparcin group (C), or 300 my per
head per day avoparcin group (D).
GROUP _ B _ D
lo Untreated 50 mud 150 my 300 mud
Milk Yield Milk Yield Milk Yield Milk Yield
Day Liters/Day Liters/Day Liters/Day Liters/Day
+ 2 18.9 22.3 20.7 19.4
+ 4 18.8 22.3 20.2 19.1
+ 7 19.3 22.9 21.3 19.1
+ 9 18.3 21.9 20.3 18.5
+11 18.9 20.4 19.7 17.4
+14 19.5 21.0 20.4 17.6
+16 19.4 20.1 20.3 17.3
+18 18.5 20.1 18.6 17.1
+20 18.3 20.4 18.8 16.3
+22 18.5 19.9 20.4 15.5
+25 18.0 20.1 19.8 15.6
+28 18.2 20.0 19.9 15.7
Average
Milk Yield
(L/D) 18.72 20.95 20.03 17.38
Croups B and C were reduced to six cows during Period III.
2~3~
TABLE II
PERIOD I PERCENT BUTTERFAT CONTENT OF MILK SAMPLES
FROM COWS DURING 28 DAYS PRETREATMENT
Mean butterfat percent of milk samples from
untreated cows allotted to group (A) untreated controls,
group (B) 50 my per head per day avoparcin, group (C)
150 my per head per day avoparcin, and group (D) 300 my per
head per day avoparcin.
10 GROUP A B C D
Untreated 50 mud 150 mud 300 my
Day % Butterfat % Butterfat Butterfat % Butterfat
-28 I~.01 3.84 3.82 4.11
_ 9 3.89 3.78 3-71 3.97
3.71 3.72 3.80 3.82
0 3.82 3.80 3.80 3.71
Average
Percent
Butterfat 3.86 3.79 3.78 3.90
-12_ ~Z5~3~
TABLE II (Continued)
PERIOD If PERCENT BUTTERFAT OF MILK SAMPLES
FROM COWS DURING 28 DAYS OF TREATMENT
Mean butterfat percent of milk samples from cows
given either no treatment group (A), or 50 my per head
per day avoparcin group (B), 150 my per head per day
avoparcin group (C), and 300 my per head per day avoparcin
over 28 days of treatment group I
10 CROUP A B _ D
Untreated 50 mud 150 mud 300 mud
Butterfat % Butterfat % Butterfat % Butterfat
1 3.79 3.78 3.78 3.87
2 3.75 3.65 3.~1 3.70
15 3 3.71 3.83 3.54 3.21
3.54 3.80 3.37 3.57
7 3.30 3.84 Lowe 3.40
9 3.27 3.97 3.58 3.42
2011 3.37 3.84 3.63 3.85
13 3.25 3.79 3.4~ 3.25
3.47 3.72 3.80 3.53
17 3.40 3.54 3.59 3.50
19 3.45 3.60 3.30 3.38
21 3.57 3.71 3.41 3.35
23 3.58 3.47 3.58 3.38
4.05 3.70 3.78 3.66
28 owe 3.76 3.67 3.66
Average
Percent
Butterfat 3.57 3.73 3.54 3.51
- 1 3 - ~503~
TABLE II (Continued)
PERIOD III PERCENT BUTTERFAT OF MILK SAMPLES
FROM COWS DURING 28 DAYS POST-TREATMENT
Mean butterfat percent of milk samples from
untreated cows group (A) and cows treated during Period II
of this evaluation with 50 my per head per day avoparcin
group (B), 150 my per head per day avoparcin group (C), and
300 my per head per day avoparcin group (D).
10 GROUP A B C D
Untreated 50 mud 150 mud 300 mud
Day % Butterfat g Butterfat g Butterfat % Butterfat
.
+ 2 3.94 3.50 3.86 3.91
4 3.52 3.80 3.64 3.75
+ 7 3.57 3.72 3.55 3.61
+ 9 3.71 3.74 3.66 3.76
+11 3.71 3.80 3.86 3.72
+14 3.84 3.81 3.86 3.73
+16 3.91 3.77 3.79 3.71
+18 3.93 3.87 3.74 3.70
+20 3.84 3.43 3.52 3.65
+22 3.75 4.00 3.63 4.03
+25 3.99 3.96 3.78 3.82
~28 3.82 3.98 3.84 3.77
Average
Percent
Butterfat 3.79 3.78 3.72 3.76
"
-14- 3
TABLE III
Average milk yield and percent butterfat content
of milk samples, for Periods I, II, and III, taken from
untreated cows group (A), and cows treated with 50 my per
S head per day avoparcin group (B), 150 my per head per day
avoparcin group (C), and 300 my per head per day avoparcin
group (Do.
Average Average
Milk Yield Percent
Period Group (Liters/Day)Butterfat
Pretreatment ) A 23.18 3.86
I ) B 23.85 3.79
) C 23.13 3.78
) D 23.15 3.90
Treatment ) A 21.14 3.57
II ) B 24.85 3.73
) C 22.74 3.54
) D 21.08 3.51
Post-treatment j A 18.72 3.79
III ) B 20.95 3.78
) C 20.03 3.72
) D 17.38 3.76
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EXAMPLE 2
Evaluation of the effects of 600 my per head per day of
avoparcin on milk production in lactating Fruition
dairy cows
Ten Fruition dairy cows were selected from a
herd of over 60 such that each cow had been calved for
I to 23 weeks and currently had a daily milk yield in
the range of 13 to 18 liters. The basal diet consisted
of 35 kg fresh silage which was calculated to supply
maintenance alone. A balanced dairy concentrate feed
was given for all the milk produced at the rate of 0.4 kg
per lithe of milk.
Each of the experimental cows received 600 my
of avoparcin in one meal per day on each of three
consecutive days (one, two, and three). Weighed amounts
of 600 my avoparcin (i.e., 12 g AVOTAN~ avoparcin 50, the
I active ingredient premix) were included in 500 g lots
of a palatable maize based concentrate. The 0.5 kg
avoparcin-containing concentrate replaced 0.5 kg of the
normal concentrate on each feeding occasion.
Milk yields were recorded and milk samples
taken during the avoparcin feeding period (days one,
two, and three) and on days four, five, seven, and ten
(i.e., one, two, four, and seven days after avoparcin
feeding had ceased). Mean milk yields of 52 other cows
in the herd were also taken during the experimental
period as a control.
~æ25~3~
-18-
Milk samples were analyzed for butterfat,
protein, lactose, and total solids content by standard
methods.
Only one cow on one occasion refused some of
5 the avoparcin-containing concentrate offered. On all
other occasions, the material contained in the 0.5 kg
concentrate was well consumed. At no time were any
untoward effects noted in any of the cows on the export-
mint.
The mean milk yield of the ten cows which
received avoparcin fell significantly from 15.1 kg per
day on day -one (i.e., two days before avoparcin feeding
commenced) to 12.7 kg per day on day ten of the export-
mint. This can be compared with the mean milk yield of
15 52 control cows which remained fairly constant at about
16.5 kg per day. (See Table IV).
-19--
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-21-
An examination of the compositional data given
in Table V shows no changes in protein and lactose content
of the mink over the experimental period. Butterfat
content, however, does show a marked depression clearly
evident on days five, seven, and ten. The fall in total
solids content observed (12.13% on day -1 falling to
11.7% by day lo is thus a result of the lowered milk fat
production and not any alteration in protein or lactose
production.
From the above data, it is clear that the oral
administration of 600 rung per head per day of avoparcin to
lactating cows caused a marked and noticeable effect on
milk yield (15% reduction) and butterfat (about 10%
reduction) with a consequent effect on the total solid
content of the milk. (The reduction to 11.7% total solids
from 12.1% would, in fact, be enough to incur a penalty
of 0.3 p/l based on the Scottish Milk Marketing Board
Compositional Quality Payments Scheme, 1981).
