The present invention is directed to a method for increasing the milk producing capacity of a female bovidae, by administering an effective amount of an active agent to the bovidae during its mammary glands' allometric growth phase preceding first conception. The active agent is ractopamine or a physiologically acceptable salt.

BRIEF SUMMARY OF THE INVENTION 
The rearing of female bovidae, in a manner to maximize their milk 
production, is a matter which has received a great deal of attention. This 
is because the parenchyma, the functional milk-secreting portion of the 
mammary glands, is to a substantial degree developed prior to puberty. 
Studies have been undertaken to enhance parenchymal development. 
Surprisingly, increased feed consumption in the prepubertal period, while 
it may lead to increased growth rate and earlier puberty, results in 
decreased milk production. 
There has now been discovered a method by which pre- and peripubertal 
female bovidae can be treated, with the result that parenchymal tissue is 
increased and the ultimate milk producing capacity of the animal 
increased. This method is the administration of an active agent which is 
1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanol, or 
a physiologically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION 
The active agent to be employed in the present method is 
1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanol, or 
a physiologically acceptable salt thereof. The compound has the following 
formula: 
##STR1## 
It is known by its USAN name of "ractopamine." It has two asymmetric 
carbon atoms. In the present invention, an individual isomer can be used, 
but preferably the compound is employed as a mixture of the isomers. The 
hydrochloride is the preferred salt. 
The compounds to be used in the present invention are the subject of U.S. 
Pat. No. 4,690,951, which is incorporated herein by reference. 
The development of the mammary gland is a complex process. A good review is 
presented in the Apr. 6, 1992, issue of Feedstuffs, pages 12, 13, and 17. 
In summary, from shortly after birth until somewhat after puberty, the 
growth of the mammary glands occurs at an "allometric" rate, that is, at a 
rate greater than the general growth rate of the animal ("isometric"). See 
Acta. Agr. Scand., 28, 41-46 (1978). During this allometric growth phase, 
growth is directed to both the parenchymal tissue, the ductular epithelial 
tissue on which actual milk secretary tissue will later form, as well as 
to the fat pad in which the parenchyma is embedded. Subsequent milk 
production is maximized by increasing the growth of the parenchyma and 
minimizing the growth of the fat pad during this allometric growth phase. 
Higher milk production is desirable for those breeds that are used for 
dairy purposes, since the milk is sold. Higher milk production is also 
desirable for those breeds in which the practice is to allow the offspring 
to suckle. The offspring has a larger supply of milk for sustenance, and 
achieves a higher weight by weaning. 
In the present invention, the active agent is administered to a female 
bovidae during its mammary glands' allometric growth phase preceding first 
conception. The age at which each species reaches puberty and can be bred 
is known. Females from Bos taurus generally reach puberty when they are 
two-thirds of "adult" size for the particular breed. This will occur in a 
period ranging from 4 months to 14 months of age. In sheep and goats, 
puberty is only in part controlled by size, being also controlled by 
seasonality; in general, these species reach puberty at 40 to 70 percent 
of their adult size, which is generally attained at 5 to 10 months. 
However, cycling may be delayed for a year if the necessary size is 
reached late in autumn. Buffaloes reach puberty at 1 to 3 years of age. In 
addition to these species differences, there are additional variations 
among particular breeds and also depending on the management practices 
used. The attainment of puberty by any individual animal can be determined 
by observation for behavioral signs of estrus, or by methods known to 
those skilled in the science of animal management, notably by analysis of 
blood samples for progesterone. 
In the preferred practice, the present active agent is administered in the 
latter portion of the allometric growth phase, which will include the 
period prior to puberty (first estrus) and may include the early post 
puberty period. However, around puberty, the allometric growth phase is 
gradually converted to an isometric phase, and the opportunity for 
beneficially altering the development of the mammary glands is reduced. 
Therefore, in a particularly preferred practice, the present active agent 
is administered in the period prior to puberty. The length of this period 
will vary with the particular bovidae to be treated. In bovidae which are 
Bos taurus, the period will generally be two to four months preceding 
puberty. 
Among the Bos genera, the present invention can be practiced with dairy 
breeds such as the Holstein, Jersey, Guernsey, Brown Swiss, Ayrshire, 
Friesian, Dutch Red and White, Danish Red, and Normande. The present 
invention can be practiced with beef breeds such as the Angus, Hereford, 
Chianina, Penzgauer, Red Angus, Polled Hereford, Devon, South Devon, Santa 
Gertrudis, Galloway, Maine-Anjou, Brangus, Brahman, Gelbvieh, Charolais, 
and Limousin, as well as crossbreds. Additionally, some breeds, such as 
the Simmental and Shorthorn, are used for both dairy and beef purposes. 
The present invention can also be practiced on other female bovidae, such 
as goats, sheep, and buffaloes. 
The present active agent can be administered in any of a number of ways. 
The compound can be administered orally, as part of a complete feed, as a 
topdress, as a supplement, or in drinking water. The compound can be 
combined with a physiologically acceptable carrier and injected into the 
animal to be treated. The compound can be formulated as part of an 
implant, which is inserted subcutaneously and from which the active agent 
is delivered over a period of time. The most preferred manner of delivery 
is orally, in the feed. For such purposes, an effective amount of the 
active agent can be delivered in feeds containing the present active agent 
in a concentration of from 5 to 200 ppm, and preferably from 20 to 125 
ppm. 
The present invention is exemplified by the following example. Forty 
prepubertal Holstein heifers were used in this experiment. Average weight 
and age at the beginning of the study were approximately 249 kg and 244 
days (8 months). Heifers were paired according to weight and age and 
assigned to either a control or experimental treatment. Heifers were 
maintained in pens of four. The experimental treatment was ractopamine fed 
at 80 ppm of the diet on a dry matter basis. Duration of the treatment was 
70 days. 
Heifers were fed ad libitum each day a complete mixed ration (% of total on 
a DM basis) consisting of corn silage (21.1%), alfalfa silage (15%), and 
supplement (60%) as a complete mixed ration plus topdress (3.9%). 
Composition of the supplement (CA-95) and topdress (DA-74) is shown in 
Table 1A. A premix containing ractopamine (composition, Table 1B) was 
mixed with sufficient DA-74 to provide 184.7 mg ractopamine per kg of 
topdress. An identical topdress without ractopamine was fed to control 
heifers. The amount of topdress was such as to provide 80 ppm of 
ractopamine, based on the entire diet. The mixed diet was offered once 
daily. Immediately prior to feeding, the amount of feed refusal from the 
previous day's feeding was determined. The required amount of topdress was 
added to the fresh feed and mixed in the feed bunk immediately after 
feeding. 
Body weight of heifers was determined beginning on the first day of the 
study and continuing at seven day intervals throughout the 70 d treatment 
period. Body weights at the beginning and end of the study were the 
average of two consecutive day weighings. Height at the withers was 
determined at the beginning and end of the study. 
At the end of the study, heifers were euthanized and the mammary gland and 
ovaries removed. Mammary glands were trimmed, removing medial and lateral 
suspensory ligaments and excess skin. Trimmed glands were weighed and 
dissected. The skin and teats were removed first. Next, extraneous tissue 
(mostly fascia) was removed from the dorsal surface of the gland. The 
remainder of the nonmammary tissue was separated physically from the 
anterior and lateral portions of the gland and fat pad. The supra mammary 
lymph nodes were removed as well. The gland was then separated into left 
and right halves and weighed. 
The right half of the mammary gland from 36 heifers was dissected into 
parenchymal and nonparenchymal tissue. Each component was weighed and 
tissue portions submitted for analysis of water by oven drying at 100 C. 
for 24 hr and of lipid by ether extract, and of protein by Kjeldahl. 
Results 
Animal performance is shown in Table 2. Gain was increased (P&lt;0.07) by 0.13 
kg/d in heifers fed ractopamine. The difference in ADG diminished as time 
on treatment increased. Differences in ADG between control and treated 
heifers after 28, 42 and 56 days of treatment were 0.35, 0.20, and 0.17 
kg/d, respectively. Dry matter intake between treatments was similar such 
that feed required per kg of gain was decreased (P&lt;0.06) by 8.3%. There 
was no difference between treatments in hot carcass weight or dressing 
percentage. 
Weight of the mammary gland and its tissue types are shown in Table 3. The 
total weight of mammary glands from control heifers was 7.9% greater than 
for heifers fed ractopamine. The difference between treatments in trimmed 
weight of the mammary glands was not statistically significant. Likewise, 
differences between treatments for actual weight of each tissue type and 
proportion of tissue type as a percent of the total gland were not 
statistically significant. However, the mammary glands from heifers fed 
ractopamine weighed slightly less (4.7%) than the glands from control 
heifers but contained slightly more parenchyma (3.1%) and less 
nonparenchyma (11.8%). 
The tissue types once separated were analyzed for protein, lipid, ash and 
water content (Table 4). Parenchyma from mammary glands of heifers fed 
ractopamine contained a lower percentage of lipid (P&lt;0.01) and an 
increased percentage of protein (P&lt;0.06), water (P&lt;0.01), and ash (P&lt;0.01) 
when compared to mammary glands from control heifers. While there was a 
11.8% reduction (P&gt;0.2) in weight of nonparenchymal tissue in the mammary 
glands of heifers fed ractopamine, there were no differences in the 
chemical composition of the nonparenchymal tissue. 
Actual weight of protein, lipid, ash and water in parenchymal and 
nonparenchymal tissues from mammary glands of heifers is shown in Table 5. 
There were no statistically significant differences between treatments for 
any chemical component of either parenchymal or nonparenchymal tissues. 
The percentage and weight of protein, lipid, ash and water in the total 
gland are shown in Table 6. Mammary glands from heifers fed ractopamine 
contained on a percentage basis, higher protein (P&lt;0.07) and water 
(P&lt;0.03) and lower lipid (P&lt;0.04). Feeding of ractopamine reduced (P&lt;0.03) 
the weight of total lipid in the mammary gland but the effects of 
ractopamine on protein, ash, and water were not statistically significant. 
In summary, although ractopamine-fed heifers gained (9.0%) more than 
control heifers (1.55 vs. 1.42 kg/d), parenchyma from mammary glands of 
ractopamine-fed heifers contained less (P&lt;0.01) lipid and more (P&lt;0.06) 
protein on a percentage basis than did control heifers. There was no 
effect of ractopamine on lipid content of the nonparenchymal tissue. These 
data indicate that ractopamine is useful in feeding pre- and peripubertal 
heifers for a higher rate of gain without the usual increase in lipid 
deposition in the developing mammary gland that normally occurs with such 
increases in gain. 
TABLE 1A 
______________________________________ 
Composition (%) of supplement (CA-95) and topdress (DA-74). 
Ingredient CA-95 DA-74 
______________________________________ 
Ground corn, yellow 63.0 20.0 
Soybean meal (solvent extracted) 
10.0 25.0 
Cane molasses 10.0 2.5 
Distillers dried grains 
9.0 -- 
Corn cobs -- 38.0 
Meat meal 4.6 -- 
Oats, ground -- 11.0 
Animal fat -- 2.0 
Mineral/vitamins 2.8 1.1 
Salt 0.6 0.4 
______________________________________ 
TABLE 1B 
______________________________________ 
Composition of Premix Containing Ractopamine. 
% Ingredient 
Ractopamine hydrochloride 
Ground corn cobs 
______________________________________ 
Lot #1 10 90 
Lot #2 5 95 
______________________________________ 
TABLE 2 
______________________________________ 
Growth Performance. 
Ractop- (Percent Change 
Control 
amine from Control) 
P&lt; 
______________________________________ 
Gain, kg/d 
1.42 1.55 (+9.2) 0.07 
Feed/gain 6.83 6.26 (-8.3) 0.06 
Dry matter 
9.7 9.6 (-1.0) 0.87 
intake, kg/d 
Hot carcass, kg 
188.6 193.9 (+2.8) 0.18 
Dressing Pct 
54.2 54 (-0.4) 0.77 
______________________________________ 
TABLE 3 
______________________________________ 
Weight of mammary gland and of parenchyma 
and fat in mammary gland. 
Ractop- (Percent Change 
Control 
amine from Control) 
P&lt; 
______________________________________ 
Total weight, g 
3508 3231 (-7.9) 0.14 
Trimmed weight, 
2285 2177 (-4.7) 0.39 
Mammary gland, 
0.66 0.61 (-7.6) 0.19 
% of Body Wt 
Right mammary 
1134.75 1082.1 (-4.6) 0.39 
gland weight, g 
Parenchyma, g 
554 571 (+3.1) 0.8 
Nonparenchyma, 
574.7 506.9 (-11.8) 0.22 
g 
Parenchyma, % 
48.6 52.9 (+8.8) 0.31 
of Mammary 
gland 
Nonparenchyma, 
50.9 47.1 (-7.5) 0.39 
% of Mammary 
gland 
______________________________________ 
TABLE 4 
______________________________________ 
Chemical composition of parenchymal and nonparenchymal 
tissues from mammary glands. 
Ractop- (Percent Change 
Control 
amine from Control) 
P&lt; 
______________________________________ 
Parenchyma, g 
554 571 (+3.1) 0.8 
Parenchyma, % 
54.5 47.8 (-12.3) 0.01 
lipid 
Parenchyma, % 
6.46 6.99 (+8.2) 0.06 
protein 
Parenchyma, % 
37.9 43.7 (+15.3) 0.01 
moisture 
Parenchyma, % 
0.43 0.52 (+20.9) 0.01 
ash 
Nonparenchyma, 
574.7 506.9 (-11.8) 0.22 
Nonparenchyma, 
80.4 79.1 (-1.6) 0.28 
% lipid 
Nonparenchyma, 
2.64 2.59 (-1.9) 0.8 
% protein 
Nonparenchyma, 
16.1 17.5 (+8.7) 0.27 
% moisture 
Nonparenchyma, 
0.15 0.11 (-26.7) 0.42 
% ash 
______________________________________ 
TABLE 5 
______________________________________ 
Weight of chemical components in parenchymal and 
nonparenchymal tissues from mammary glands. 
Ractop- (Percent Change 
Control 
amine from Control) 
P&lt; 
______________________________________ 
Parenchyma, g 
554 571 (+3.1) 0.8 
Parenchyma, g of 
36 40.2 (+11.7) 0.38 
protein 
Parenchyma, g of 
302.4 272.3 (-10.0) 0.26 
lipid 
Parenchyma, g of 
209.4 249.4 (+19.1) 0.26 
water 
Parenchyma, g of 
2.4 3.0 (+25.0) 0.19 
ash 
Nonparenchyma, 
574.7 506.9 (-11.8) 0.22 
Nonparenchyma, 
14.8 12.8 (-13.5) 0.41 
g of protein 
Nonparenchyma, 
461.5 401 (-13.1) 0.15 
g of lipid 
Nonparenchyma, 
93.2 88.9 (-4.6) 0.73 
g of water 
Nonparenchyma, 
0.9 0.6 (-33.3) 0.34 
g of ash 
______________________________________ 
TABLE 6 
______________________________________ 
Percentage and weight of chemical 
components from mammary glands. 
Ractop- (Percent Change 
Control 
amine from Control) 
P&lt; 
______________________________________ 
Total Gland, % 
Protein 4.47 4.93 (+10.3) 0.07 
Lipid 67.5 62.5 (-7.4) 0.04 
Water 26.5 31.4 (+18.5) 0.03 
Ash 0.29 0.33 (+13.8) 0.38 
Total Gland, g 
Protein 50.8 53 (+4.3) 0.61 
Lipid 763.9 673.2 (-11.9) 0.03 
Water 302.6 338.2 (+11.8) 0.31 
Ash 3.3 3.6 (+9.1) 0.67 
______________________________________