Intravenous solution that diminishes body protein loss

The present invention provides compositions and methods of decreasing the nitrogen loss in a mammal which is normally associated with the administration of isocaloric solutions. Specifically, the present invention provides compositions comprising from about 4% to 10% dextrose and from about 1/2% to 2% glutamine. Such compositions, when administered to a mammal, reduces dehydration and nitrogen loss to approximately 25% of that found when no solution is administered.

FIELD OF THE INVENTION 
The present invention relates to field of fluid replacement therapy and 
nutrition. Specifically the present invention provides a novel composition 
which is capable of diminishing protein loss when administered 
parenterally or enterally, to a patient. 
DESCRIPTION OF THE BACKGROUND ART 
The transition from the fed to the fasting state is accompanied by several 
important metabolic changes. Glucose is the preferred energy source of the 
brain, red blood cells, and the renal medulla. Muscle and liver stores of 
glycogen are rapidly depleted and this leaves the fasting individual with 
two sources of body fuel: protein (primarily from skeletal muscle), and 
fatty acids (which are deposited in adipose tissue). Despite large 
triglyceride energy stores, fatty acids cannot be converted into glucose; 
although the glycerol moiety of triglycerides can be converted into 
glucose, this supply is quite limited. The only remaining sources of 
glucose are the gluconeogenic amino acids derived from the breakdown of 
protein. 
Protein is essential to the organism and consists of either functional or 
structural cellular elements. Protein-containing tissue is referred to as 
the body cell mass (BCM), and it is this tissue that is active and 
functional and thus maintains the organism (Moore, F., The Metabolic Care 
of the Surgical Patient, W. B. Saunders Co., Philadelphia, Pa. (1959)). 
The utilization of protein for endogenous fuel results in a gradual 
erosion of the BCM, which eventually results in dysfunction. 
Unfortunately, the energy derived from the oxidation of endogenous fat 
stores is not sufficient to maintain the BCM. In his classic study of 
fasting subjects on a life raft in the 1940s, Gamble demonstrated that by 
providing 100 grams of glucose to the fasting subjects, he could decrease 
protein loss by 50% (Gamble, J. L., Harvey Lectures 42: 247 (1946-1947)). 
Based on his work, 5% dextrose has become the universal intravenous fluid 
used in the hospital. Two or three liters of this solution provide 100-150 
g dextrose (50 g/L) which reduces net nitrogen breakdown and excretion by 
one-half. 
A variety of studies have been performed in an attempt to further decrease 
the nitrogen loss in patients who cannot or do not eat. First, it should 
be noted that Gamble added 40 g protein to the 100 g of carbohydrate and 
did not observe improvement in nitrogen retention. Others have 
administered varying amounts of glucose and/or amino acids in a similar 
attempt to reduce protein loss. The most comprehensive data comes from 
Moore's Laboratory (Wolff, B. M., et al., Ann. Surg. 186: 518 (1977)) and 
is shown below. 
TABLE 1 
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Total Total Nitrogen 
Nitrogen 
Calories carbohydrates 
intake balance 
Diet kcal/day calories, kcal/day 
g/m.sup.2 /day 
g/m.sup.2 /day 
______________________________________ 
Starvation 
0 0 0 -6.44 
Low-dose 568 568 0 -4.14 
glucose 
High-dose 
2278 2278 0 -3.06 
glucose 
Amino acids 
378 0 6.8 -3.22 
Amino acids 
888 540 7.4 -0.68 
+ low-dose 
glucose 
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As noted from the above table, the administration of calories alone has an 
effect of reducing negative nitrogen balance. The same is true with the 
administration of nitrogen; when the two nutrient sources are given 
together, there is an additive effect which greatly reduces the net 
negative nitrogen balance. 
Glutamine is a nonessential amino acid that is the most abundant amino acid 
in whole blood and accounts for 60% of the total amino acid pool in 
skeletal muscle (Bergstrom, J., et al., J. Appl. Physiol. 36: 693-696 
(1974)). Glutamine has a central role in several metabolic pathways. It 
contains two nitrogen groups which are readily transferred among tissues, 
provide a substrate for ammoniagenesis in the kidney, and enhance its role 
as a precursor for nucleotide synthesis (Marliss, E. B., et al., J. Clin. 
Invest. 50: 814-817 (1971); Pitts, R. F., Am. J. Med. 36: 720-742 (1962); 
Levintow, L., et al., J. Biol. Chem. 227: 929-941 (1957)). In addition, 
glutamine is actively consumed by dividing cells such as lymphocytes and 
intestinal epithelial cells. During catabolic states, glutamine plasma 
concentrations may be markedly decreased, intracellular stores may be 
decreased by 50% while whole plasma levels fall 20-30% (Askanazi, J., et 
al., Ann. Surg. 192: 78 (1980)). This depletion persists long after 
recovery from the catabolic process (Askanazi, J., et al., Ann. Surg. 191: 
465 (1980)). Glutamine concentrations in skeletal muscle have been found 
to correlate well with the rate of protein synthesis (MacLennan, P. A., et 
al., FEBS Lett. 215: 187-191 (1987)) and its administration has been found 
to inhibit muscle protein breakdown in rats and dogs (MacLennan, P. A., et 
al., FEBS Lett. 237: 133-136 (1988)). This protein loss is not prevented 
by administering standard total parenteral nutrition (TPN) which is devoid 
of glutamine (Vinnars, E., et al., JPEN 4: 184-187 (1980)). Studies 
utilizing muscle biopsies in patients undergoing elective surgery have 
shown that glutamine-supplemented TPN diminished the decline of 
intracellular glutamine in muscle and counteracted the decrease in protein 
synthesis (Hammarqvist, F., et al., Ann. Surg. 209: 455-461 (1989)). 
SUMMARY OF THE INVENTION 
The present invention is based on the novel observation that the nitrogen 
loss a mammal experiences during fluid replacement therapy using 
intravenously administered 5% dextrose can be significantly decreased by 
supplementing the intravenous solution with the amino acid glutamine, or a 
glutamine equivalent, and reducing the amount of dextrose in an isocaloric 
amount. Based on this observation, the present invention provides novel 
compositions and methods for reducing nitrogen loss in a mammal when the 
mammal would normally be administered an intravenous solution of dextrose, 
for example during rehydration therapy. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
In one embodiment, the present invention provides novel compositions which 
are capable of reducing nitrogen loss in a mammal in need of rehydration 
therapy or under conditions which would necessitate the administration of 
a 5% dextrose solution intravenously. In detail, the compositions of the 
present invention comprise from about 4% to 10% dextrose and from about 
1/2% to 2% glutamine. The most preferred composition of the present 
invention consists of 1% glutamine and 4% dextrose. Alternatively, a 
glutamine equivalent can be substituted for the glutamine in the present 
composition so long as the glutamine equivalent is capable of being 
converted to the appropriate amount of glutamine within the mammal. 
As used herein, a "glutamine equivalent" is defined as an analogue, 
substitution product, isomer, homologue, metabolite, or derivative of 
glutamine which can donate an amine group and be metabolized in the Krebs 
cycle. Most preferred are compounds which process at least one glutamine 
residue such as small polypeptides or dipeptide containing glutamine. 
As used herein, the term "mammal" is intended to include, but not be 
limited to, humans, pigs, cattle, cats, dogs and rodents. 
As used herein, the term "reducing nitrogen loss" is defined as any 
decrease in the net amount of nitrogen loss by the body when compared to 
the level of nitrogen loss observed with starvation, i.e., no rehydration 
therapy. For example, it has been previously shown that a 50% reduction in 
nitrogen (protein) loss during rehydration therapy can be achieved by 
administering to the mammal an appropriate amount (approximately 2 liters 
for a human subject) of 5% dextrose. The present invention discloses that 
this net loss can be decreased to approximately 25% when the solution 
which is administered consists of from about 4% dextrose and from about 1% 
glutamine. 
A mammal is said to be suffering from protein loss when the net nitrogen 
balance of the mammal decreases ore becomes negative over a specific 
period of time. A variety of tests can be employed to determine if a 
mammal is suffering from nitrogen loss. However, in general, protein loss 
is measured by comparing the amount of nitrogen administered to the mammal 
with the amount of nitrogen excreted from the mammalian urine. 
The compositions of the present invention may be administered by any means 
so long as the composition achieves the intended purpose of reducing net 
nitrogen loss. In a preferred embodiment, the compositions of the present 
invention are administered parenterally; more preferably intravenously. 
The preferred route of administration is intravenous administration. 
However enteral, i.e. oral, administration can be employed as well. The 
amount and the regime used for the administration of the compositions of 
the present invention can be readily determined by those with ordinary 
skill in the art. 
The compositions of the present invention can be formulated so as to be 
administered by any means or routes so long as the composition achieves 
the intended purpose of reducing nitrogen loss during rehydration. 
Further, the amount and regimes employed for the administration of 
glutamine, or a glutamine equivalent in a dextrose solution can be readily 
determined by those with ordinary skill in the art. 
As used herein "parenteral" is defined as that region outside the digestive 
tract. 
As used herein, "enteral" is defined as that portion of the alimentary 
canal including the stomach and the portion distal to the stomach. 
The amount of glutamine or glutamine equivalent and the frequency of 
administration will vary depending upon the needs of the mammal. For a 
mammal suffering from dehydration, it is preferable to administer the 
compositions of the present invention continuously or at frequent 
intervals throughout the day. Depending upon the severity of the 
dehydration and the complications associated therewith, it is generally 
preferred that the compositions of the present invention be administered 
intravenously. 
Enteral administration can be accomplished by tubing placed via the nose 
into the gastric or duodenal regions whereas parenteral administration 
include, but are not limited to, routes such as subcutaneous, 
intramuscular, or intravenous injection. Preparations for parenteral 
administration include sterile aqueous or non-aqueous solutions, 
suspensions and emulsions. 
In another embodiment, the present invention provides methods of reducing 
nitrogen loss in a mammal when the mammal would normally be administered 
an intravenous solution of dextrose, such as a means of alleviating 
dehydration which is associated with post-operative trauma or with 
pathological infection such as cholera. 
In detail, a mammal fed solely with an intravenous solution of 5% dextrose 
can be expected to have a net nitrogen loss of approximately 50% of the 
loss which would be observed without the administration of the dextrose 
solution. As stated above, when the compositions of the present invention 
(4% dextrose and 1% glutamine) are administered to the mammal, the net 
nitrogen loss will be reduced to approximately 25% of that observed 
without the administration of an intravenous solution. 
The methods of the present invention and compositions employed for reducing 
nitrogen loss can be used to decrease the nitrogen loss and dehydration 
associated with any state or pathological condition in which dehydration 
and nitrogen loss occurs or where there has been recognized in the past a 
need to administer an intravenous solution of 5% dextrose. These include, 
but are not limited to post-operative trauma, bacterial infection such as 
cholera, and various malabsorption syndromes of the gut. In the preferred 
embodiment, the present methods and compositions are employed to decrease 
the nitrogen loss and dehydration which is associated with post-operative 
intravenous rehydration therapy. 
The methods of the present invention are used to reduce the dehydration and 
nitrogen loss which is associated with condition which mimic starvation. 
Since the methods and compositions of the present invention are directed 
to the dehydration and nitrogen loss which is present, and not to the 
condition itself, the methods and compositions can be utilized to treat 
all conditions which resulting in nitrogen loss and dehydration. An 
illustration of this is the use of the methods and compositions of the 
present invention in treating the dehydration and nitrogen loss which is 
associated with surgical operations.

Having now generally described the invention, the methods and agents will 
be more readily understood through reference to the following examples. 
These examples are provided by way of illustration and are not intended to 
limit the present invention unless specified otherwise. 
EXAMPLE 1 
All of the previous studies that have been performed have used amino acid 
solutions devoid of glutamine. In an effort to determine the effect of 
this amino acid when added to standard peripheral intravenous solutions, 
we have studied 10 healthy male volunteers who were randomized to receive 
isocaloric infusions of either 5% dextrose (standard hospital treatment) 
or 4% dextrose plus 1% glutamine during a 5-day fast. All subjects 
received 1400 ml solution/m.sup.2 body surface area. Electrolytes were 
standardized and were also added to all solutions. The patients were 
weighed daily and all urine was collected. 
TABLE 2 
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N Balance 
% Change in 
Sodium balance 
g/m.sup.2 /day 
Body Weight 
g/m.sup.2 /day 
______________________________________ 
5% Dextrose -4.20 -2.62 +1.5 
4% Dextrose -2.75* -1.89 +18.1* 
+ 1% glutamine 
______________________________________ 
*p &lt; 0.05 vs dextrose, by convention (-) means loss, (+) means gain. 
GLN supplementation improved nitrogen balance by 35% relative to volunteers 
receiving dextrose alone. Losses in body weight also were decreased in the 
GLN group. GLN volunteers had a 12-fold increase in sodium balance, when 
compared to the volunteers receiving dextrose alone. This study 
demonstrates that the addition of GLN to peripheral IV fluids improves 
nitrogen balance compared to standard therapy of 5% dextrose. The single 
administration of dextrose with one amino acid is more efficient than 
administering a large quantity of amino acids (see Table 1, amino acids 
alone). This solution approaches the nitrogen sparing effects observed 
with solutions of amino acids and low-dose glucose, although the quantity 
of calories and nitrogen is much less. The 4% dextrose plus 1% glutamine 
solution provides only 380 glucose calories/day, and only 2.24 g 
nitrogen/m.sup.2 /day. Thus, this solution represents a much more 
efficient mixture to enhance nitrogen sparing than previously realized.