WO1992011773A1

WO1992011773A1 - Compositions and methods for achieving improved physiological response to exercice

Info

Publication number: WO1992011773A1
Application number: PCT/US1991/009793
Authority: WO
Inventors: Melvin J. Fregly; Malcolm R. Privette; Robert Cade
Original assignee: University Of Florida
Priority date: 1990-12-31
Filing date: 1991-12-30
Publication date: 1992-07-23
Also published as: AU9159891A

Abstract

Disclosed here are novel compositions and methods which can be used as a blood substitute to ameliorate adverse physiological effects of blood loss. The novel compositions comprise fluids containing water, electrolytes, glycerol, and additional energy sources.

Description

DESCRIPTION

COMPOSITIONS AND METHODS FOR ACHIEVING IMPROVED PHYSIOLOGICAL RESPONSE TO EXERCISE

Cross-Reference to a Related Application

This application is a continuation-in-part of our copending applicati

Serial No. 07/636,329, filed December 31, 1990, which is a continuation-in-p of application Serial No. 07/378,582, filed July 17, 1989, now U.S. Patent 4,981,687, which is a continuation-in-part of our copending application Serial N

07/226,027, filed July 29, 1988, now abandoned.

Background of the Invention In humans and other animals, strenuous exercise as well as exposure sunlight and heat can result in significant physiological changes. Subjec exercising or working in the heat are at risk for developing heat related injuri Environmental heat illnesses include heat syncope, heat exhaustion, dehydrati syndrome, and heat stroke. The potentially fatal clinical syndrome of heat stro has been described in marathon runners, military recruits, football players, a in hot industrial environments. An epidemic appearance of heat stroke has be described during heat waves in urban areas (Ferguson, M., and M.M. O'Bri [1960] Ηeat Stroke in New York City: Experience with 25 Cases," NY State Med. 60:2531-2538).

The "dehydration syndrome" is characterized by loss of appetite a limited capacity for work. Evidence of heat exhaustion becomes apparent wit losses of 5% of the body water, and at 7% disorientation and hallucinatio occur. Losses of body water of 10% or greater are extremely hazardous a lead to heat stroke and death if not treated immediately. Heat stroke accompanied by high body temperature (106-1 0°F)_; deep coma, and in mo cases there is complete absence of sweating, and failure of the major orga systems.

Three factors determine the thermal balance of the body: metabolic he production, heat exchange between the organism and its surroundings, and he loss by the evaporation of sweat (Knochel, J.P. [1980] "Clinical physiology of he EET exposure," In Clinical Disorders of Fluid and Electrolyte Metabolism, M. Maxwell and C.R. Kleeman, eds., McGraw-Hill, New York). For the subj exercising or working, particularly in a hot environment, the capacity to dissip metabolically produced heat depends for the most part on the subject's abil to form and vaporize sweat (Costal, D.L. and K.E. Sparks [1973] "Rapid fl replacement following thermal dehydration," J. Appl. Physiol. 34(3):299-3 Greenleaf, J.E. [1979] 'Ηyperthermia and exercise," Int. Rev. Physiol. 20:15 208).

During exercise in a hot environment, serious deficits in effecti circulating volume may occur. Muscular work, independent of environme results in massive shunting of blood to skeletal muscle, along with a substanti loss of plasma volume into the working muscle. Moreover, effective circulati volume is also diminished by losses of sweat (Knochel [1980] supra). The defic in intravascular volume impedes the delivery of heated blood to the periphe for evaporative cooling. Thus, in the dehydrated exercising subject, there is progressive increase in the core body temperature as sweat losses accumulat Indeed, salt and water depletion are important predisposing factors to th development of heat-related illnesses.

Exercise is characterized by a marked increase in glucose utilization. Th exercising muscle has a greatly increased need for energy. Some of the glucos needed for energy comes from liver glycogen stores. With prolonged exercis liver glycogen stores are depleted and the rate of glucose production fails t keep pace with glucose utilization, resulting in a fall in the blood glucos concentration. The development of frank hypoglycemia has been described i marathon runners (Felig, P., A. Cherif, A. Minagawa et al. [1982] 'Hypoglycemi during prolonged exercise in normal men," N. Engl. J. Med. 306(15):895-900). Notable among the many physiological responses to physical exertion ar increased body temperature, perspiration and pulse rate, a decrease in the bloo volume, and biochemical changes associated with the metabolism of compound to produce energy.

One metabolic change which is associated with continued physica exertion is a shifting of the type of compound used as the primary energy source. In the absence of physical exertion, the metabolism of fat is a primary energ source for the body. During times of exertion, carbohydrates are increasingly used as a source of readily available energy. The body continues to utili carbohydrates as a major source of energy during prolonged periods of exercis If, however, the exercise is particularly strenuous or long in duration, th supply of readily available carbohydrates may become depleted and the body forced to utilize another source of energy. The metabolism of proteins fills th energy void caused by the depletion of carbohydrates. Unfortunately, th metabolism of protein is not an efficient source of energy for the exercisin individual. Protein metabolism results in the utilization of amino acids. Thi amino acid utilization can result in the depletion of essential amino acids in th plasma. The loss of amino acids can detrimentally affect the person or anim in many ways. One detrimental effect of the depletion of amino acids is reduction on the body's ability to repair tissue which is damaged in the cours of the strenuous exercise.

Attempts have been made to counteract the adverse effects of strenuou exertion. For example, the consumption of water helps to maintain bod temperature and blood volume. This technique has met with very limite success, however. Also, products have been developed recently which combin sugar and electrolytes with water. One well known example of this type o product is GATORADE* which contains 21 millequivalents per liter (21 meq 1 of sodium, 2 meq/I potassium, and 6% sucrose. The GATORADE^® compositio is described in British Patent No. 1,252,781, which issued to Bradley et al. Othe such compositions are known and are described, for example, in U.S. Paten Nos. 4,042,684 and 4,322,407.

It is well known that glyceroi (glycerin) can be ingested safely. Limite clinical studies have suggested that glyceroi, in solution with water, may be use to induce hyperhydration (Riedesel, M.L., D.Y. Allen, G.T. Peake, and K. Al Quattan [1987] "Hyperhydration with glyceroi solutions," J. Appl. Physiol 63(6):2262-2268). The work of the Riedesel group which was described in th 1987 publication has also been described, in part, in other places. In a 198 abstract and in a 1987 abstract, Riedesel and coworkers reported that ingestio of an approximately 23% glyceroi solution in saline resulted in overhydration o the subjects. The two abstracts had conflicting results regarding whether swea rates were increased (Lyons et al. [1987] "Physiological Costs of Exercis Following Hyperhydration with Glyceroi," Temperature Regulation I (35-40), p. 323 [abstract]; Allen et al. [1985] Environ. Physiol. II [3713-3720] p. 1 [abstract]). In a 1987 report to the Air Force, Riedesel reported overhydrat of rats which were fed glyceroi (Riedesel [1987] "Oral Glyceroi Solutions a Deterrent to Dehydration During Heat Exposure," Department of the Air Fo Report. AD-A118746). In a 1988 abstract Riedesel et al. again report hyperhydration and decreased urine output after glyceroi ingestion (Meuli et [1988] Exercise π [1309-1314] p. a521).

Other researchers have also examined the effects of glyceroi ingesti Maughan and Gleeson found that ingestion of large amounts of glyceroi afte 36 hour fast did not significantly improve performance of exercising subje

(Maughan et al. [1988] The Eur. J. Appl. Physiol. 57:570-576). In fact, for o of the control groups, exercise duration after glyceroi ingestion was lower th after water ingestion alone. This 1988 article confirms earlier work by Glees and Maughan which found that ingestion of large amounts of glyceroi did n enhance exercise performance (Gleeson et al. [1986] The Eur. J. Appl. Physi

55:645-653).

Researchers at Washington University School of Medicine have al examined the effects of glyceroi ingestion. In 1981 the Washington Universi group reported that glycerol-fed rats had increased endurance, apparent because glyceroi protected against hypoglycemia (Terblanche et al. [1981]

Appl. Physiol 50(1):94-101). Significantly, however, two years later t Washington group found that glyceroi did not increase endurance in man whe administered according to their protocol (Miller et al. [1983] Medicine an Science in Sports and Exercise 15(3):237-242). These published reports on th effects of glyceroi have revealed that ingestion of large amounts of glyceroi ca result in decreased urine output and hyperhydration. Several studies hav specifically looked at the effect of glyceroi on endurance, and each of thes studies has found that glyceroi in large doses does not appear to increas endurance in man. Much of the previous research has focused on the ability of glyceroi t cause water retention. However, water retention alone has little or n correlation with enhanced endurance or physiological performance. In order t have a beneficial effect on endurance and performance, the water must b appropriately allocated throughout the body. It is not enough to simply reduc urine output. Water must be available for sweating, cells cannot be dehydrat and plasma volume must be maintained. Only if these physiological objectiv are met can endurance and performance be enhanced. This enhancement of t physiological response to exercise and heat can be largely attributed to efficie cooling of the body.

Osmotic pressure is primarily responsible for the direction and rate movement of water across membranes in the body. The general concepts osmosis and osmotic pressure are very well known chemical phenomena where water moves across a semipermeable membrane in such a way as to make thermodynamic activity uniform across the entire system. Thus, water will mo across a semipermeable membrane such that the net flow of water will be acro the membrane into the fluid which initially had the highest concentration solutes. The allocation of water between digestive organs, blood plasma, a cells depends upon the relative osmotic pressures between these sites. Althou it has been established that the ingestion of massive amounts of glyceroi resul in the retention of water within the body, i.e., the rate of urine flow is decrease this observation alone produces no information as to whether the bod physiological responses to heat or physical exertion have been enhanced. F example, a large concentration of glyceroi in the stomach or intestine can cau water to move across the gastrointestinal membranes into the digestive tra

This might cause detrimental responses to physical exertion and heat exposur Also, high concentrations of glyceroi in the blood plasma can cause water leave the cells and enter the plasma. Again, the resulting dehydration of t cells could have detrimental effects on the person or animal. Studies where large amounts of glyceroi have been administered in sho time periods have not shown beneficial physiological effects. The researche have observed water retention, but none have demonstrated any effect whic would enhance endurance or lessen a person's discomfort. These studies do n establish any relationship between the administration of glyceroi and actu physiological responses to exercise or heat exposure. Also, no studies hav examined the physiological effects of glyceroi or related compounds in solutio with compounds other than water or saline.

Thus, the focus of glyceroi research in the past has been primarily t achieve random generalized water retention. By contrast, the research which h led to the subject invention concentrated on achieving appropriate wa distribution within the body. This has led to the formulation of a no composition which greatly enhances the physiological response to physi exertion and heat exposure. Although GATORADE^® does help to combat some of the negat effects resulting from physical exertion, long distance runners and other athle who must endure long periods of strenuous exercise still suffer the effects decreased blood volume and a loss of energy-providing carbohydrates.

The invention described here is a novel fluid composition whi surprisingly and advantageously maintains blood volume at levels well abo those observed in the absence of fluids or even with GATORADE^®. The no product has the additional advantage of providing an energy source. Furth users of the product report lower levels of perceived difficulty of exercise wh the novel fluid composition is used.

Brief Summary of the Invention The subject invention relates to novel compositions and methods f ameliorating the adverse physiological effects which can result from physic exertion and heat exposure. The subject invention can be used with humans an other animals. Described here is a novel fluid composition comprising

(a) water;

(b) electrolytic compound(s);

(c) sugar; and

(d) an additional compound which is characterized by: (i) non-toxic to man or animals;

(ϋ) is rapidly absorbed through the gastrointestinal tract; (in prevents the decrease of blood volume; and (rv) is an energy source wherein the concentration of said additional compound(s) is from about 0.5 to about 10%. More preferably, the concentration of said additional compoun may be from about 0.5% to about 5%.

One example of said additional compound is glyceroi. Other compound which may be used according to the subject invention include pyruvate, alanine and/or lactate, which are particularly useful because they function to enhance th energy available for working muscles. The presence of pyruvate or lact improves performance and helps to prevent the detrimental breaking down protein as an energy source. The compounds added to the electrolyte/gluc solution may be used in the solution individually or in combination. Also described here are unique methods, involving the use of the no fluid composition, for ameliorating the adverse effects which can result fr physical exertion, heat exposure, exposure to cold, and blood loss.

Brief Description of the Drawings The invention can be better understood with reference to the followi drawings in which:

Figure 1 shows the changes in blood volume of three trials of hum subjects working at 75-80% of their maximal rate of oxygen uptake on a bicy ergometer. The trials are designated in the figure. One standard error is set at each mean. This figure shows that only the group which was given TQ₂ ( minutes before initiation of exercise [200 ml], at 15 min, 45 min, and every h hour thereafter) was able to maintain their blood volume during the period exercise.

Figure 2 shows that the pulse rate of the group receiving TQ₂ w maintained at a lower value than the other two trials during the course exercise. The trials are the same as those shown in Figure 1. One standa error is set off at each mean.

Figure 3 shows the high level of cardiac output achieved in connecti with the administration of TQ₂. Figure 4 shows the time required to reach a rectal temperature of 38° by the three trials shown in Figure 1, as well as an additional group receivi nothing per os (NPO) prior to the exercise.

Figure 5 shows the mean rates of sweating of the same four trials as Figure 3. Figure 6 shows the respiratory quotient ([OC /JOJ) as a function exercise time. Respiratory quotient is an indication of the metabolic ener source being utilized.

Figure 7 shows the perceived difficulty (in arbitrary rating units) of t exercise as scored by observers during the exercise. Detailed Description of the Invention The invention described here is a novel composition which has be shown to improve the physiological response in animals, including humans, physical exercise and environmental exposure. Specifically, the inventi comprises a fluid which contains, as one of the ingredients, glyceroi or an est of glyceroi, or any other analog or derivative of glyceroi which is non-toxic animals, can be rapidly absorbed through the gastrointestinal tract, distribut into plasma and extracellular fluid, but is not transferred, or is transferr poorly, into the brain. As used hereinafter, the term glyceroi refers to glycer itself and any ester, analog, or derivative which has the same function as glycer in the composition described here. Instead of glyceroi, or in addition glyceroi, the composition may contain pyruvate. Other compounds satisfying t aforementioned characteristics can be found in standard medical pharmacology reference books. The novel fluid's surprising and beneficial physiological effects on t body during exercise or environmental exposure include maintenance of bloo volume and cardiac output, readily available energy source, improved skin bloo flow, prevention or delay of onset of hyperthermia, increased rate of moveme of electrolytes across the gastrointestinal wall, reduction in the breakdown proteins and associated metabolism of essential amino acids, and decreased tim needed for repair of body tissue following strenuous exercise.

When the fluid of the subject invention is administered, the body' physiological response to exercise or environmental exposure is greatly enhance compared to the response when the body receives no fluids, receives only wate or receives fluids such as GATORADE^® which contain electrolytes and a suga source in addition to water. Thus, the novel composition described here can b used to ameliorate the adverse effects of physical exertion or environmenta exposure. As used herein, the term "ameliorating the adverse effects of physica exertion or environmental exposure" refers to the achievement of one or mor of the following: prevention of plasma volume decrease, increased respirator quotient, reduced rate of increase of rectal temperature, reduced pulse rate, o increased cardiac output; combined with either enhanced endurance o performance, lower perceived difficulty of a physical task, or an enhanced abili to withstand heat exposure or chronic exposure to cold. The many advantages of the novel fluid composition (designated TQ^ described here are clearly sho in Figures 1 through 7. The TQ₂ which was administered to exercis individuals in order to achieve the results discussed below was primarily wat In addition to the water, the composition comprised glucose (4%), potassium meq/I), sodium (26 meq/l), phosphate (4 meq/1), and glyceroi (3%).

One important advantage of TQ₂ is that it allows the body to maintain volume of blood at levels close to the pre-exercise volume. Even where wa or GATORADE^® are given to the exercising person, significant decreases blood volume are observed. The blood volume comparisons are shown in Fig 1. Figure 2 illustrates the ability of the novel fluid composition to prevent t elevation of heart rate to the level of that observed for subjects receiving eit water or GATORADE^®.

When the novel fluid composition is administered, cardiac output advantageously sustained at a high level, even over extended periods of exerti Figure 3 illustrates this effect. Increases in body temperature during exerc occur much more slowly when the novel fluid composition is given than when fluids are administered or when either water or traditional GATORADE^® a administered. Figure 4 shows that, on the average, it takes more than 30 longer for rectal temperature to reach 38°C when TQ₂ is used than wh GATORADE^® is used. It is possible to exercise for well over 1 hour at 75-80 of maximal rate of oxygen consumption without reaching a body temperature 38°C when TQ₂ is administered. Also, a marked decrease in the rate sweating is observed for individuals given the novel fluid composition of t subject invention. This decrease in sweat rate is shown in Figure 5. T decrease in sweat rate is significant because this suggests that the body is bei cooled more efficiently. This can be attributed to increased blood volume whi results in improved peripheral circulation and movement of blood near the sk surface. This surface circulation is very important in the effective dissipation body heat. Further evidence suggests that the use of TQ₂ results in an increase in t proportion of energy derived from carbohydrates as opposed to energy deriv from the metabolism of fat or protein. This unexpected and advantageous res can be seen from Figure 6 which shows the respiratory quotient as a function time. Respiratory quotient, which is defined as the ratio of carbon dioxi output to oxygen input, is an indication of the type of compounds which being metabolized as an energy source for the exercising person or animal. metabolism of carbohydrates, the respiratory quotient is 1.0. The respirat quotient for metabolism of fats or proteins is less than 1.0. If fat is the prim source of energy, then the respiratory quotient is approximately 0.6. respiratory quotient of approximately 0.8 can be expected if the cells are burni half fat and half carbohydrates. Thus, the higher respiratory quotients shown Figure 6 for TQ₂ indicate that these individuals are utilizing a greater proporti of carbohydrates as their energy source. The increased use of carbohydrates c have important physiological advantages, especially when strenuous exercise maintained over a long period of time. For example, carbohydrate metabolis is preferable to fat metabolism because it is a quicker and more efficient sour of immediate energy. Further, carbohydrates are preferred as an energy sour over proteins because protein metabolism can cause the depletion of essenti amino acids. The depletion of amino acids can have adverse physiologic effects including a reduction in the body's ability to repair muscle which damaged in the course of exercise.

To further enhance the energy sources available to cells, pyruvate may b added to the novel composition. It has also been found that by administerin pyruvate, it is possible to maintain a relatively steady concentration of pyruvat for use by cells as an energy source. Addition of a small amount of pyruvat given at frequent intervals, improves performance and endurance, apparentl because it enhances entrance of acetyl CoA into the Krebs cycle. The Kreb cycle is a well known, but very complicated, biochemical pathway which provide a working muscle with its energy source. A detailed description of the Kreb cycle can be found in most biochemistry textbooks, including Lehninge

(Lehninger, A.J. Biochemistry: The Molecular Basis of Cell Structure an

Function. 2ed., Worth Publishers, Inc.: New York, pp. 444-449, 1975).

Pyruvate normally is formed from glucose but, during vigorous exercise pyruvate may not be formed fast enough to keep up with cellular demand

Thus, the concentration of pyruvate drops markedly. This loss of availabl pyruvate not only deprives cells of their primary carbohydrate energy source, bu also inhibits the metabolism of fats as an energy source. Fats enter the Kreb cycle as acetyl CoA. Acetyl CoA, which is formed as a result of the breakdown of long chain fatty acids, apparently does not enter in the Krebs cycle prope if pyruvate is not present. When acetyl CoA is not metabolized in the Kre cycle, it is converted to aceto-acetic acid, which does not act as a ready ener source. Therefore, when pyruvate is available in short supply, the cells a deprived of their primary carbohydrate source, and they cannot effectiv metabolize fats either. Thus, the cells can be forced to depend upon amino ac metabolism in order to derive energy. If the concentration of pyruvate fa during vigorous exercise, no fuel can enter the Krebs cycle, and the cell, effect, starves. By administering the novel composition described here, blo pyruvate is stabilized at a level sufficient to assure adequate energy suppli

Lactate may be used instead of, or in addition to, pyruvate in the curre invention. Alanine may also be used instead of, or in addition to, lactate pyruvate in the current invention.

An additional important indicator of the novel fluid composition effectiveness is illustrated in Figure 7. This figure shows a significant loweri of the perceived difficulty of long term exercise among individuals to whom T is administered. .Although all individuals naturally perceive an increase difficulty of exercise as the exercise is maintained for long periods of tim individuals who were given TQ₂ showed a significantly reduced rate of increa in the perceived difficulty of the exercise. The trial ingesting water showed t normal perceived difficulty within 90 minutes of beginning exercise while in t trial receiving GATORADE^® reached the same level of perceived difficulty aft 150 minutes of exercise. The trial receiving TQ₂ reached this level after 1 minutes. The lower difficulty perceived by individuals receiving TQ₂ could lea to enhanced physical performance, especially when long term exercise, such marathons, are involved.

The novel fluid composition of the subject invention can be used t improve the physiologic response of any animal undergoing exercise or bein subjected to high temperature conditions. For example, humans, horses, dog mules, oxen, camels, elephants, sheep, cows, and pigs are a few of the anima which can benefit from the administration of the novel fluid compositio described here. The fluid of the subject invention can also be used to alleviat or prevent dehydration which is known to result from chronic exposure to col temperatures. The fluid of the subject invention can be administered to an animal orall intravenously, or by any other means of conveying said fluid into the tissues the animal.

Following are examples which illustrate materials, methods an procedures, including the best mode, for practicing the invention. Thes examples are illustrative and should not be construed as limiting. Wher concentrations are expressed as percentages, these percentages refer to weigh ratios.

Example 1

For use in humans or other animals which are about to undergo, ar undergoing, or have recently undergone physical exercise, a novel flui composition comprising water, a sugar source, electrolytes, and glyceroi can b administered orally.

The composition, which is predominantly water, may contain between about 0.5% to about 5% glyceroi. Preferably, the composition may contain about 1% to about 1.5% glyceroi. The sugar of the composition may be sucrose, glucose or other appropriate sugar compound. Specifically, the composition may have a glucose concentration of from about 2% to about 8%. Preferably, the glucose concentration may be about 4%.

The electrolytes of the composition can be selected, for example, from the group consisting of sodium, potassium, phosphate, bicarbonate, sulfate, chloride, calcium, and magnesium. For example, the fluid may contain from about 1 meq/t to about 5 meq/1 potassium and from about 15 meq/1 to about 30 meq/1 sodium. Preferably, the composition may contain about 2 meq/I potassium and about 26 meqf sodium. Also, the composition may contain phosphate in concentrations varying from about 2 meq/1 to about 8 meq/1. Specifically, the phosphate concentration may be about 4 meq/l. The novel fluid may also contain citric acid, citrate, preservatives, flavorings, artificial sweeteners, vitamins, minerals, and other compounds appropriate in a beverage of this type. The novel fluid may also be carbonated. Example 2

In order to provide a readily available source of energy for cells, composition of the subject invention can contain pyruvate, lactate, o combination of the two. It has been found that sufficient concentrations pyruvate are necessary for the proper entrance of carbohydrates and fats i the Krebs cycle. During the course of strenuous exercise, the concentration pyruvate available to cells can decrease markedly. By ingesting pyruvate, i possible to maintain sufficient plasma concentrations so that the cells are a to utilize pyruvate as an energy source and so that fats can be effectiv metabolized. According to the subject invention, lactate may be used instead or in addition to, pyruvate. Alanine may also be used instead of, or in additi to, either lactate or pyruvate, or both.

The concentration of pyruvate, lactate, alanine, or any combinati thereof, may be from about 0.5% to about 10%. Preferably, the concentrati of pyruvate, lactate, alanine, or any combination thereof is between about and about 1.5%. When glyceroi at about 1% and pyruvate at about 1% are b added to an appropriate glucose-electrolyte solution so that the osmotic press of the solution does not exceed 400 milliosmol, performance and endurance enhanced. The level of enhancement achieved by the composition containi glucose, electrolytes, glyceroi, and pyruvate is beyond the effect of the gluco electrolyte solution alone, the glucose-electrolyte solution plus glyceroi, or t glucose-electrolyte solution plus pyruvate. Best performance is achieved if t solution is kept between 300 and 350 milliosmol.

Example 3

The composition of the subject invention may be designed for intraveno use. Intravenous use may have application in humans and in other animals. the case of humans, intravenous use may be necessary when, for example, person has fainted or otherwise become unconscious as a result of, for examp over-exertion and/or overexposure to sunlight, heat, or hemorrhage and loss blood.

For intravenous application, no flavoring compounds would be prese Also, a neutral pH would be needed, therefore, no acidic compounds would present in concentrations sufficient to significantly alter the pH of the sali solution.

The composition of the subject invention can also be used as a tempor substitute for blood. For example, in trauma cases where there has been a lar loss of blood, this fluid can be given to replenish the blood volume. .Also, duri heart surgery or other surgical procedures where a heart-lung machine is use the novel composition can be used to prime the heart-lung machine, there helping the patient to maintain plasma volume and to provide energy to he ameliorate the physiological trauma of surgery. .Also, by maintaining vascul volume, complications such as post-surgical acute renal failure can be minimize

For use as a blood substitute, the composition will comprise, preferabl water, electrolytes, glucose, and glyceroi. Sucrose and citric acid are to avoided when the composition is given intravenously. When used as a bloo substitute, the composition of the subject invention may also comprise pyruvat lactate, alanine, or any combination thereof.

An experiment has been conducted on rats to assess the effects of th administration of TQ₂ after blood loss. A total of nine male rats were used i this experiment. They varied in body weight from 280 to 350 g. Prior to th experiment, all rats were maintained in a temperature controlled room at 25 2°C, which was illuminated from 7:00 am to 7:00 pm. The mean blood pressur of the rats prior to the experiment was in the range of around 90 mm Hg to 12 mm Hg. All animals were allowed tap water and food (Purina Laboratory Cho #5001) ad libitum.

All rats had arterial and venous cannula placed in the right femoral arter and vein, respectively, two weeks prior to the experiment When the experimen began, each unanesthetized rat was placed alone in a stainless steel cage, and th arterial cannula was coupled to a pressure transducer which was coupled to previously calibrated NarcoBio Instruments Company polygraph. After a contro period of 30 minutes, during which mean blood pressure was recorded for each rat, blood was removed slowly during a 30 minute period until mean bloo pressure was 60 mm Hg. Blood pressure was maintained at this level for 20 minutes, after which 3 rats received warm (37°C) isotonic NaCl solution intravenously at a volume equivalent to the amount of blood removed. An additional 4 rats received warm TQ₂ at a volume equivalent to the amount of blood removed. The TQ₂ composition used in this experiment consisted water, electrolytes, 3% glucose, about 2% glyceroi, and about 2% pyruvate. T pH of the solution was about 7.0, and the osmotic pressure was about 2 milliosmol. A pH of approximately 7.0 can be maintained by use of appropriate buffer system such as NaH₂P0₄:Na₂HP0₄ in a ratio of 1:4. O additional rat received nothing after its mean blood pressure had been reduc to 60 mm Hg for 20 minutes.

The results of this study are shown in Table 1. Of the three rats th received saline, mean blood pressure had increased 10 mm Hg 30 minutes late Of the four rats that received TQ-^ mean blood pressure also increased 10 m Hg 30 minutes later. The striking difference occurred in survival 24 hours late Of the 3 saline-treated rats, only 1 survived; of the 4 TQ₂-treated rats, survived. The rat that received nothing did not survive for 24 hours. Thu there was enhanced survival in rats treated with TQ₂ compared with thos treated with saline, demonstrating the efficacious effect of TQ₂.

Table 1. Effect of hemorrhage on survival of rats receiving either saline, TQ or nothing.

Group Number of Change in Mean Blood Number Rats Pressure at 30 min. Surviving (mm Hg) at 24 hours

Saline

TQ₂

Nothing

Example 4

A fluid composition similar to that described in Example 1 may b administered to animals which are subject to strenuous exercise such as race uHiα ug.t.x miXm. xi mm.1 WOΓΛ.. J.11C cλαu »-.ujχι uaιι.njιι ui uie iiuiu aa vcι as m concentrations of its components may depend upon what type of animal i receiving the treatment. The teachings of this document combined with th expertise of one skilled in the biological and medical sciences would enable th

SUBSTITUTE SHEET practitioner to adjust the composition of the fluid in order to accommodate th needs of a particular animal.

The administration of the novel fluid could be orally, intravenously, or by other means capable of delivering the fluid to the tissues of the recipient animal. If the fluid is to be delivered orally, such a composition could contain flavoring which would make the fluid attractive to the animal. For example, for horses, the fluid could be flavored with an oat extract.

Example 5 To enhance the beneficial effects of the novel fluid composition described here, caffeine may be added. The concentration of caffeine may range from about 50 mgfl to about 5000 mg 1.

Example 6 The novel fluid composition described here may also be used to help maintain the weight and health of agricultural animals subjected to heat stress.

Heat stress may occur, for example, on the open range, in zoos, and during the transportation of animals.

The fluid may be administered in any of the ways previously described. If administered orally, the fluid may be combined with appropriate flavorings to make it attractive to the animals.

Example 7

The novel fluid composition described here may also be used to alleviate the effects of volume depletion which is a problem which has been observed in astronauts.

Example 8

The use of glyceroi in a heverage could also be used in areas of cold environment where it would reduce tissue damage due to frostbite and extreme cold. Such a glyceroi beverage would allow distribution of the glyceroi into the tissues, particularly in the extremities, fingers and toes, which are affected most by crystallization in the tissues and by diminished blood flow. Glyceroi has been found to be distributed throughout the body in ten minutes after ingestion; thus, it could be used to rapidly provide protection from extreme cold. This could be especially useful, for example, for football players who must play in cold climates, but who cannot or do not wish to wear gloves or other protective covering. .Also, it is well established that dehydration can be a serious problem which accompanies prolonged exposure to cold temperatures. Because the subject composition can be utilized to achieve proper water allocation and prevent blood plasma volume depletion, it can be used to ameliorate the effects of dehydration caused by exposure to cold temperatures. Thus, the novel composition can be used advantageously by skiers or by army personnel in cold climates.

Example 9

The optimal rate of administration of the novel composition described here can depend upon the physiological characteristics of the individual receiving the fluid, the nature of the physical exertion or exposure, and the environmental conditions. However, a standard rate of application would be approximately 170 to 260 ml of fluid every 15 to 20 minutes, starting approximately 15 minutes before the exercise or exposure is commenced. If significant sweating is occurring, as would be expected in hot environments or with physical exertion, the intake of fluid should be adjusted so that the volume ingested approximates the amount of fluid lost through sweating. When the fluid is ingested to alleviate the dehydration accompanying prolonged exposure to cold temperature, the quantity of fluid ingested may be less than that which is necessary to achieve the desired effects in hot climates.

The ratio of ingredients in the composition may also be adjusted for changing environmental or physiological conditions. For example, in cold weather, the composition may contain a greater concentration of glyceroi and a reduced concentration of electrolytes. Also, for individuals who desire a lower calorie drink, the sugar may be replaced with an artificial sweetener such as aspartame. For individuals who are concerned about high blood pressure, the drink can contain reduced concentrations of sodium. Example 10

The composition of the subject invention may also be prepared in a dehydrated, powder, or concentrate form for convenience of sale or shipment When formulated in this way, the product could be reconstituted by the addition of water. The preparation of such a product in the dehydrated, powder, or concentrate form is well known to those skilled in the art. See for example, U.S. Patent Nos. 4,042,684 and 4,322,407. .Although glyceroi cannot be provided in powder form, it can be provided separately or in a mixture of the other ingredients in a reduced water volume to facilitate bulk shipping.

SUBSTITUTE SHEET

Claims

1. A fluid composition comprising: (a) water; (b) electrolytes; (c) at least one sugar compound selected from the group consisting o glucose, fructose, and sucrose; (d) glyceroi in a concentration of from about 0.5% to about 5.0%; an (e) lactate.

2. The fluid composition, according to claim 1, wherein the concentratio of lactate is between about 0.5% and about 10%.

3. The fluid composition, according to claim 2, further comprisin pyruvate, wherein the total concentration of pyruvate and lactate is betwee about 0.5% and about 10%.

4. The fluid composition, according to claim 3, comprising the followin ingredients: Ingredient Approximate Concentration Potassium 2 meq/L Sodium 26 meq/L Glucose 4% Glyceroi 1% Pyruvate 0.5% Lactate 0.5% Caffeine 150 mg/L Water balance.

5. A dehydrated, powder, or concentrate composition which, when reconstituted with water, forms a composition comprising water, electrolytes, glyceroi, and at least one compound from the group consisting of pyruvate and lactate, wherein the combined concentration of said pyruvate and lactate is between about 0.5% and about 10%.

6. In a beverage comprising water and electrolytes, an improvement wherein said beverage further comprises alanine in a concentration of from about 0.5% to about 10%.

7. The beverage, according to claim 6, further comprising at least one sugar compound selected from the group consisting of glucose, fructose, and sucrose.

8. The beverage, according to claim 6, wherein said beverage further comprises at least one compound selected from the group consisting of pyruvate and lactate, and the total concentration of pyruvate, lactate, and alanine is between about 0.5% and about 10%.

9. The beverage, according to claim 6, wherein said beverage further comprises glyceroi in a concentration from about 0.5% to about 5%.

10. A dehydrated, powder, or concentrate composition which, when reconstituted with water, forms a composition comprising water, electrolytes, and at least one compound selected from pyruvate, lactate, and alanine wherein the combined concentration of said pyruvate, lactate, and alanine is between about 0.5% and about 10%.

11. A method for ameliorating the effects of physical exertion, said method comprising the administration to a person in need of such amelioration the composition of claim 6.

12. A method for ameliorating adverse effects associated with blood loss, comprising the step of administering parenterally to a human or other animal an effective amount of the composition of claim 1.

13. A method for ameliorating adverse effects associated with blood loss, comprising the step of administering parenterally to a human or other animal an effective amount of the composition of claim 6.

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