Oral energy rich therapy for diarrhea in mammals

A hyperosmotic oral veterinary composition in liquid form that provides easily absorbed and metabolized energy substrates comprising 70 to 90 percent of an actively absorbed monosaccharide, 1 to 7.5 percent of an actively absorbed naturally occurring amino acid, 0.1 to 5 percent of citric acid, 4 to 12 percent of a non-toxic alkali metal salt of acetic acid which, when diluted with water for administration and is present in a concentration of 30-90 grams per liter useful for the treatment of diarrhea in animals such as calves.

FIELD OF THE INVENTION 
Diarrheal diseases in mammals cause severe dehydration and 
electrolyte-energy imbalances. The instant invention concerns a therapy 
which restores the electrolytes which have been lost and, in addition, 
provides a sufficiency of energy substrates in a readily absorbable and 
utilizable form. 
BACKGROUND OF THE INVENTION 
Several prior investigators have been concerned with diarrheal diseases. 
These investigators have proposed oral therapeutic intervention to reduce 
the serious impact of diarrheal diseases. Generally, these systems are 
directed primarily toward solving the problem of dehydration and, in some 
cases, to providing electrolytes and a minimal amount of energy sources 
such as glucose. However, the principle reason for including organic 
molecules which might provide some energy has been to enhance absorption. 
It is generally believed today that oral fluids must be supplied as 
essentially isoosmotic fluids (approximately 300 mOsm/l) since that is the 
concentration of solute in body fluids. Hyperosmotic fluids are considered 
detrimental since they are believed to cause increased secretion. This is 
brought out in a paper by R. J. Bywater entitled: Pathosphysiology and 
Treatment of Calf Diarrhea, Proceedings XII World Congress of Diseases of 
Cattle, Amsterdam, Sept. 1982, pp. 291-297. In discussing oral therapy for 
diarrhea, Dr. Bywater reiterated that "solutions for this purpose should 
be approximately isotonic (300 mOsm/kg) since, before they can be 
absorbed, hypertonic solutions must first become isotonic,". In another 
paper presented at the same World Congress by C. Demigne, C. Remesy and F. 
Chartier entitled: Interest of Acetate in Oral Glucose-electrolytes 
Formulations for Treatment of Dehydration in Diarrheic Calves, Proceedings 
XII World Congress of Diseases in Cattle, Amsterdam, Sept. 1982, pp. 
305-309, it is stated "Osmolarity is also an important factor, the optimum 
being possible in the range of 300 to 350 mOsm". However, if an isotonic 
fluid is given, some benefit is derived, but an insufficient amount of 
energy or electrolytes or both will be provided to the diarrheic animal. 
This is a particularly serious problem in young neonates who have a 
greater tendency to become diarrheic. In another paper in this field, G. 
Alexander, N. W. Bennett and R. T. Gemmell, discuss Brown Adipose Tissue 
in the Newborn Calf (Bos taurus J. Physiol. 244:223-234, 1975, and state 
that young neonates do not have sufficient energy reserves in their body. 
In addition, these animals have difficulty in mobilizing the energy that 
is present. 
U.S. Pat. No. 3,898,328 to Beigler et al, describes a dry stable 
composition for the treatment of scours and dehydration, and U.S. Pat. No. 
4,164,568 to Bywater, describes an oral scour formulation with citrate. 
These oral products provide only 20-30% of the animal's basic maintenance 
energy requirement and, therefore, will contribute to continuing body 
weight loss and energy deficit. 
In my U.S. Pat. No. 3,928,574, I disclose a method and composition for 
treating diarrhea in bovine animals. The composition consists of sodium 
chloride, a potassium salt and glucose in aqueous solution. The solutions 
are buffered to maintain a basic condition, such that pH does not exceed 
10. These solutions are formulated for use intravenously or 
subcutaneously. The formulation described in this patent does not include 
acetate for rapid energy and absorption, nor glycine and citric acid. 
A prominent clinical sign of diarrhea is acidosis due to intestinal 
bicarbonate loss, anerobic metabolism and decreased renal function. Blood 
bicarbonate levels are often decreased by 50%. The prior art investigators 
contend that acidosis may be corrected by providing organic acids alone 
which will be converted by bicarbonate. However, this is not the case, for 
metabolism of organic acid leads only to the production of carbon dioxide. 
It is critically necessary to supply sufficient sodium ion or other alkali 
metal cations as a salt of the organic acid. The metabolism of that acid 
will provide one bicarbonate for every monovalent cation such as sodium. 
For example: 
______________________________________ 
##STR1## 
##STR2## 
##STR3## 
sodium bicarbonate (NaHCO.sub.3) 
______________________________________ 
SUMMARY OF THE INVENTION 
I have found that contrary to the teaching of the prior investigators, when 
dealing with oral therapy, a formulation consisting of an actively 
absorbed monosaccharide, an actively absorbed naturally occurring amino 
acid, citric acid, a non-toxic alkali metal salt of acetic acid, inorganic 
salts such as sodium chloride and potassium chloride, when prepared in dry 
form and added to water prior to use, can be used to make a hypertonic 
oral solution which should be from 600 to 1200 mOsm/l or 2 to 4 times 
normal body osmolality. The formulation provides an adequate easily 
absorbed metabolized substrate and the energy substrate, as administered, 
provides 50 to 110% of the calve's maintenance energy requirements. The 
major component of this formulation is the monosaccharide as it provides 
the most usable energy per Osmole. There is also a significant quantity of 
a non-toxic alkali metal salt of acetic acid which is most rapidly 
utilized for immediate energy following absorption and, thus, provides a 
very immediate energy supply and also an immediate source of bicarbonate. 
The metabolism of the acetate in the body is over 5 times as fast as the 
metabolism of glucose on a molar basis and, thus, provides immediate 
energy as well as bicarbonate.

DETAILED DESCRIPTION OF THE INVENTION 
The easily absorbed and metabolized composition useful in treatment of 
diarrhea in animals comprises 70 to 90 percent of an actively absorbed 
monosaccharide, which, when diluted with water for administration, is 
present at a concentration of 30 to 90 grams per liter, 1 to 1.75 percent 
of an actively absorbed naturally occurring amino acid, 0.1 to 5 percent 
of citric acid, 4 to 12 percent of a non-toxic alkali metal salt of acetic 
acid which, when diluted with water for administration, is present at a 
concentration of 3 to 12 grams per liter and 3 to 8 percent of inorganic 
salts such as sodium chloride and potassium chloride. The sum of the 
sodium and potassium is 120 to 160 mOsm per liter with the potassium being 
present as 10 to 30 mOsm per liter and the sodium 110 to 150 msO per 
liter. Examples of suitable actively absorbed monosaccharides include 
dextrose and galactose. 
The actively absorbed natural occurring amino acid includes glycine and 
related compounds. Examples of non-toxic alkaline metal salt of acetic 
acid are sodium acetate, potassium acetate and lithium acetate. When these 
formulations are prepared and administered in the recommended quantities, 
they provide approximately 80% of the animal's energy requirements. 
Metabolism of the acetate component will yield a substantial amount of 
bicarbonate which can rapidly and significantly improve the bicarbonate 
condition of the diarrheic animal. This is an important factor, since it 
is widely recognized that diarrheic animals are acidotic with low 
bicarbonate levels. The present invention is illustrated by the following 
specific but non-limiting examples. 
EXAMPLE I 
A formulation was prepared containing the following components: 
TABLE I 
______________________________________ 
% Gram Kcal/two liters 
mOsm/l 
______________________________________ 
Glucose 81.8 130 520 361 
Glycine 4.72 7.5 23 50 
Na Acetate 
6.20 9.84 18 120 
Citric Acid 
.44 .7 3 2 
NaCl 4.42 7.02 -- 120 
KCl 2.43 3.72 -- 50 
Water 2 liters 564 703 
______________________________________ 
The composition of remaining replacement fluid after metabolism of the 
organic constituents is set out in the Table below. 
TABLE II 
______________________________________ 
mEq/liter 
Electrolytes 
Invention 
Normal Plasma 
Diarrheic Plazma 
______________________________________ 
Sodium 120 135 135 
Potassium 25 5 8 
Chloride 85 100 100 
Bicarbonate 
60 25 15 
(from acetate) 
TOTAL 290 
______________________________________ 
The therapy therefore provides an extracellular fluid with added potassium 
and bicarbonate. This is important as most fluid is lost from the 
extracellular fluid pool. 
The hematocrit declined rapidly in the first hour after therapy, and 
remained lower throughout the test as is shown in Table III. 
TABLE III 
__________________________________________________________________________ 
Changes after Therapy 
Pre Hour 1 Hour 2 Hour 3-4 
__________________________________________________________________________ 
Plasma Sodium mEq/l 
138.9 .+-. .3 
140.3 .+-. 1.0 
140.5 .+-. 0.6 
139.9 .+-. 1.0 
Plasma Potassium mEq/l 
5.21 .+-. .20 
4.59 .+-. 0.4 
4.65 .+-. 10 
4.56 .+-. 1.2 
Hematocrit % 
58.7 .+-. 1.3 
51.2 .+-. 2.4 
48.9 .+-. .4 
50.7 .+-. 1.2 
__________________________________________________________________________ 
These data, when considered with the lack of change in plasma sodium 
concentration, provide firm evidence that secretion into the 
gastrointestinal tract and hemoconcentration were not occurring. The 
animal was hypoglycemic with a very low blood glucose (55 mg/dl) prior to 
therapy indicating a precarious energy state. Plasma glucose began to 
increase within 15 minutes of therapy and remained elevated for the 
duration of the test. The plasma glucose was still at 100 mg/dl four hours 
after therapy indicating a sustained benefit. Minor hyperkalemia was 
corrected. This data is confirmed in Table III above. FIG. 1 is a graphic 
illustration of the benefit of this therapy. It shows the restoration of 
normal fluid and energy metabolism as seen by the increase of skin 
temperature on the extremities without modification of rectal temperature. 
The increase in extracellular fluid volume including blood, allowed for 
normal blood circulation pattern to be reestablished and, as blood flow to 
the limbs was increased, their temperature increased. 
EXAMPLE II 
This example compares the beneficial effects of the formulation set out in 
Table I with the formulation set out in U.S. Pat. No. 4,164,568 consisting 
of the following composition: 
TABLE IV 
______________________________________ 
Formulation of U.S. Pat. No. 4,164,568 
% gram kcal/2 liters 
Osm/l 
______________________________________ 
Glucose 69.9% 44.6 178 124 
Glycine 9.7% 6.2 19 41 
Citric A 0.8% .5 3 1 
K.sub.3 Citrate 
.2% .1 -- &lt;1 
NaCl 13.3% 8.5 -- 145 
KH.sub.2 PO.sub.4 
6.4% 4.1 -- 30 
2 liters H.sub.2 O 200 342 
______________________________________ 
The composition of remaining replacement fluid after metabolism of the 
organic constituents is set out in the table below. 
TABLE V 
______________________________________ 
U.S. Pat. No. 
mEq/liter diarrheic 
4,164,568 
normal plasma 
plazma 
______________________________________ 
Sodium 72 135 135 
Potassium 15 5 8 
Chloride 72 100 100 
Bicarbonate 
&lt;1 25 15 
(from K.sub.3 Citrate) 
Phosphate 15 5 mg/100 mls 
5 mg/100 mls 
TOTAL 175 
______________________________________ 
This formulation is a commercially available product and was used according 
to label directions. Both the formulations set out in Table I and the 
formulation covered in U.S. Pat. No. 4,164,568 were administered as two 
quart doses to neonatal diarrheic calves less than 75 lbs and 3 quart 
doses to neonatal calves greater than 75 lbs twice a day for two days. 
After the end of the two-day period, the dosage was changed to a mixture 
of equal quantities of the therapy fluid with whole cows milk. During the 
first two days of therapy, when the products were administered alone, the 
efficacy can be more clearly delineated. One of the principle advantages 
of the therapy of the instant application is that the hyperosmotic 
solutions enhance net absorption. This is contrary to current thought as 
is pointed out above. The effect is shown by following the concentration 
of stable components in the blood plasma, which reflect this effect. This 
data is set out in Table VI. 
TABLE VI 
______________________________________ 
Changes in plasma protein concentration one hour 
following therapy. 
pretherapy 
1 hour post 
decrease 
______________________________________ 
Formulation of 
4.9 .+-. 0.3 
4.6 .+-. 0.4 
-.3 
Table I 
Formulation of 
4.8 .+-. 0.3 
4.6 .+-. 0.2 
-.2 
Table IV 
______________________________________ 
If the formulation of the instant invention causes proteins to become more 
concentrated, then net secretion, not net absorption, has occurred. 
However, the formulation of the instant invention, on the average, caused 
more dilution of plasma proteins in the first hour after administration 
than the formulation covered in U.S. Pat. No. 4,164,568. This phenomenon 
demonstrates rapid net absorption as further evidence of rapid absorption 
by the diarrheic calves. 
The average increase in plasma glucose at the end of the first hour by the 
calves given the formulation of the instant invention was 104 mg/dl. In 
contrast, the calves receiving the formulation covered by the patent set 
out above had an average increase of only 53 mg/dl. By the end of 3 hours, 
the average elevation of plasma glucose above pretherapy levels in the 
calves receiving the formulation of the instant invention was 70 mg/dl 
versus only 20 mg/dl for the therapy using the formulation described in 
U.S. Pat. No. 4,164,568. This data is shown graphically in FIG. 2. This 
continuing three-fold elevation emphasizes the sustaining longer term 
benefits of the formulation of the instant invention in supplying much 
needed readily available energy to the initially energy deficient 
hypoglycemic calves. 
EXAMPLE III 
This example illustrates the further benefit of the increased availability 
of metabolizable glucose in the therapy of the present invention as 
compared to the therapy of the formulation covered in the above-identified 
patent. This benefit is shown in Table VII. 
TABLE VII 
______________________________________ 
Plasma potassium changes due to therapy: 
K (mEq/l) 
3 hours following therapy 
pretherapy 
change in K (mEq/l) 
______________________________________ 
Formulation of 
5.3 .+-. .6 
-1.1 .+-. 0.5 
Table I 
Formulation of 
5.0 .+-. .4 
-0.1 .+-. 0.3 
Table IV 
______________________________________ 
All animals were hyperkalemic prior to therapy. Three hours following the 
therapy the decrease in plasma potassium averaged 1.1.+-.0.5 mEq/l for the 
calves receiving the therapy of the formulation of the instant invention 
and all were within the normal range. In contrast, the calves receiving 
the therapy covered in the patent set out above had only minimal 
0.1.+-.0.3 mEq/l decrease, and several remained hyperkalemic. 
In addition, the mean blood urea nitrogen decreased precipitously following 
the initiation of the treatment of the instant application. Prior to the 
first therapy, the blood urea nitrogen was 35 mg/dl and was in the normal 
range at 9 mg/dl for 11/2 days prior to the 4th therapy. This data is 
shown in FIG. 3. A decrease of blood urea nitrogen of this magnitude may 
be due to enhanced renal function allowing a more normal excretory pattern 
or may be due to a decrease in the catabolism of protein due to the 
provision of ample energy substrates. All calves treated with the 
formulation of the instant invention had blood urea nitrogen levels in a 
normal range in the last one-half of the experiment. FIG. 3 graphically 
compares the changes in the blood urea nitrogen during the course of 
therapy with the formulation of the current invention and with the 
formulation of U.S. Pat. No. 4,164,568. 
One of the best indications of the long-term benefit of the therapeutic 
approach of the instant invention is the maintenance of body weight during 
therapy. This data is set out in Table VIII. 
TABLE VIII 
______________________________________ 
Change in body weight (lbs) following therapy: 
Formulation of 
Formulation of 
Table I Table IV 
______________________________________ 
2 days* +1.5 0 
4 days** +4.5 1 
______________________________________ 
*received therapy alone 
**sum of all 4 days: in the last two days received 50% whole milk and 50% 
therapy. 
When the calves received the therapy of the instant invention alone, the 
calves gained some weight. The gain was more pronounced in the last 2 days 
when the formulation was changed to 50% milk and 50% of the formulation in 
Table I. In this case, the animals received energy for maintenance as well 
as growth. In the first two days, it is likely that the gain in weight was 
due to rehydration without body wasting. The formulation of the prior art 
undoubtedly had some rehydration which was masked due to the energy 
deficit of the therapy and no weight change was seen. 
EXAMPLE IV 
In mildly diarrheic calves, over the entire testing period, potassium 
concentration changes were evaluated one hour following therapy. Based on 
six evaluations on each calf they were slightly hyperkalemic prior to 
therapy shown in Table VIII. One hour following the invention therapy 
potassium level of all calves had dropped to within the normal range. The 
average decrease was 0.6 mEq/L. 
The data included is set out in Table IX below. 
TABLE IX 
______________________________________ 
Potassium Concentration 
(mEq/L) changes due Mean 
to therapy 1 Hour Post 
Change 
______________________________________ 
Invention 
5.1 .+-. 0.1 4.5 .+-. 0.1 
-0.6 
Prior Art 
5.0 .+-. 0.1 4.8 .+-. 0.1 
-0.2 
U.S. Pat. No. 
4,164,568 
______________________________________ 
In the calves treated with the prior art formulation, the decrease in K was 
considerably less. On several occasions these mammals remained 
hyperkalemic. These changes were seen in spite of the higher potassium 
concentration in these treated with the formulation of the instant 
application. 
EXAMPLE V 
Prior to any therapy administration, all of the mildly diarrheic calves had 
low-normal blood glucose concentration averaging 78 and 71 mg/dl. In FIG. 
4, changes in glucose concentration during the three hours following 
therapy have been plotted for calves treated with the formulation of the 
instant invention and those treated in the formulation of the prior art 
for a two-period period, or four treatments per calf, during the period of 
therapy alone, when the calves were receiving less than maintenance energy 
requirements. The calves treated with the formulation of the instant 
invention became slightly hypoglycemic between therapys dropping from a 
mean of 78 to a mean of 67 mg/dl. The calves treated with the prior 
formulation became severely hypoglycemic; they had entered the study with 
a mean blood glucose of 71 mg/dl, their pretherapy glucose concentration 
was 49 mg/dl during the time that they received the therapy. 
The formulation of the instant invention produced a significantly greater 
plasma glucose response. Based on the area under the curve it was twice as 
great. Further, the calves treated with the formulation of the instant 
invention had high normal glucose concentration three hours following 
therapy while the prior art calves had already become hypoglycemic again 
(FIG. 1). 
EXAMPLE VI 
Further evidence substantiating the claim that the hyperosmotic nature of 
the formulation of the instant invention does not cause hemoconcentration 
can be gleaned from Table IX which represents the average change in 
hematocrit and plasma protein concentration one hour following therapy in 
mildly diarrheic calves treated with the formulation of the instant 
invention. On the average, the therapy elicited a minor hemodilution as 
evidenced by a decrease in both hemotocrit and plasma protein 
concentrations. This establishes that the invention, in spite of its 
hyperosmolar natures does not cause excessive fluid secretion from the 
blood. 
EXAMPLE VII 
The effect of the therapy on blood gas and acid base status in mildly 
diarrheic calves is presented in Table XI below compared to prior art 
therapy. Although numerous reports attest to the prevalence of acidosis 
and decreased bicarbonate levels in more severe diarrhea, these mildly 
diarrheic calves had normal blood pH and essentially normal blood 
bicarbonate and base excess values. The calves treated with the 
formulation of the instant invention had a mean increase of 0.023 pH units 
compared to no change or a slight decrease (-0.005) pH units in the 
animals treated with the formulation of the prior art. They, in addition, 
with the formulation of the prior art had a decrease in total bicarbonate 
and no change in base excess. Thus, the therapy of the instant invention 
was able to change all of these important parameters of acid base status 
in a beneficial direction. That is, it increased alkalinity which is of 
important significance in treating diarrheic acidosis. 
TABLE X 
______________________________________ 
Therapy Induced Changes in Hematocrit 
and Plasma Protein Concentrations 
# Pre- 1 Hr. 
Pre- 1 Hr. 
Therapy Calves Therapy Post Therapy 
Post 
______________________________________ 
Day one 1 3 24.5 24.5 4.5 4.6 
2 3 28.7 29.3 4.4 4.5 
Day two 3 3 30.0 28.7 4.4 4.5 
4 3 29.3 28.7 4.5 4.4 
Day three 
5 3 30.3 28.7 5.2 4.7 
6 3 26.7 27.0 4.8 4.6 
Average 29.2 27.0 4.8 4.5 
______________________________________ 
TABLE XI 
______________________________________ 
Acid Base Changes due to Therapy* 
U.S. Pat. No. 
4,164,568 
Invention Prior Art Therapy 
______________________________________ 
pH 
Pre Therapy 7.461 .+-. 0.007 
7.470 .+-. 0.008 
Post Therapy (1 hour) 
7.484 .+-. 0.012 
7.465 .+-. 0.005 
Change in pH +0.023 -0.005 
Total Bicarbonate 
Pre Therapy 24.9 .+-. 0.5 
21.8 .+-. 0.5 
Post Therapy (1 hour) 
26.0 .+-. 0.5 
21.1 .+-. 0.4 
Change in HCO.sub.3 
+1.1 -0.7 
Base Excess** 
Changes in Base Excess 
+1.5 .+-. 0.3 
+0.1 .+-. 0.1 
1 Hour After Therapy 
______________________________________ 
*Values shown are mean .+-. S.E. 
**Base excess is a measure of total acidity and alkalinity. An increase i 
base excess indicates correction of acidosis. 
Since modifications and variations of the invention as described 
hereinabove can be made without departing therefrom, the scope of the 
invention is to be limited only by the following claims.