AN ORAL ENERGY-RICH COMPOSITION AND SOLUTION FOR COMBATTING DIARRHEA IN MAMMALS

Abstract: A hyperosmotic oral veterinary composition in liquid form that provides easily absorbed and metabolized energy sub­ strates comprises 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 and 4 to 12 percent of a non-toxic alkali metal salt of acetic acid. When diluted with water for administration the mono­ saccharide is suitably present in a concentration of 30-90 grams per liter. The composition is especially useful for the treatment of diarrhea in animals such as calves.

Description: An oral energy-rich composition and solution for combatting diarrhea in mammals Field of the Invention Diarrheal diseases in mammals cause severe dehydration and electrolyte-energy imbalances. The present invention provides a composition which is able to restore 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 towards solving the problem of dehydration and, in some cases, towards providing electrolytes and a minimal amount of energy sources such as glucose. However, the principal 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 most". 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. US-A-3,898,328 describes a dry stable composition for the treatment of scours and dehydration, and US-A4,164,568 describes an oral scour formulation comprising 40-80% of actively absorbed monosaccharide, 7.5-30% of actively absorbed naturally occurring amino acid and 0.5 to 10% of citric acid or a citrate. These oral products are intended to 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 our earlier US-A-3,928,574, a method and composition for treating diarrhea in bovine animals are disclosed. 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, anaerobic 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 to 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: 1 citric acid on oxidation EMI3.1 6 CO2 1 acetic acid on oxidation EMI3.2 2 CO2 1 sodium acetate on oxidation EMI3.3 1 C02 + 1 sodium bicarbonate (NaHCO3) Summary of the Invention It has now been found that, contrary to the teaching of the prior investigators, when dealing with oral therapy,a formulation comprising an actively absorbed monosaccharide, an actively absorbed naturally occurring amino acid, citric acid, and a non-toxic alkali metal salt of acetic acid, optionally together with one or more 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, preferably of from 600 to 1200 mOsm/l or 2 to 4 times normal body osmolality. The formulation provides an adequate easily absorbed metabolized substrate and is intended to be administered at a rate such that the energy substrates it contains provide 50 to 110% of a calf's (or other mammal'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. The bicarbonate formed and retained results from the provision of an equivalent amount of a cation with an organic metabolizable anion such as acetate. Description of the Drawings Figure 1 of the accompanying drawings shows the therapy response based on recital temperature and fetlock surface temperature as a function of time and plasma glucose concentration; Figure 2 is a graph of the glucose blood level relating to time after dose and compares the formulation of the current invention with the formulation of the prior art as set forth in US-A-4,164,568; and Figure 3 is a graph of the changes in blood urea nitrogen during the course of therapy and compares formulation of the current invention with the formulation set forth in US-A-4,164,568. Figure 4 is a graph showing changes in glucose concentration during 3 hours following therapy. Detailed Description of the Invention The easily absorbed and metabolized composition according to the present invention which is useful in treatment of diarrhea in animals comprises 70 to 90 (more preferably 81 to 85) weight percent of an actively absorbed monosaccharide, 1 to 7.5 (more preferably 2 to 6) weight per cent of an actively absorbed naturally occurring amino acid, 0.1 to 5 (more preferably 0.2 to 0.45) weight percent of citric acid, and 4 to 12 weight percent of a non-toxic alkali metal salt of acetic acid. The concentrations of the first-mentioned and lastmentioned ingredients are preferably such that when the composition is diluted with water for administration, they are present in the resulting aqueous mixture at concentrations of 30 to 90 grams per liter and 3 to 12 grams per liter, respectively. Preferably, the composition also contains 3 to 8 weight percent of inorganic salts such as sodium chloride and potassium chloride. The invention also provides an aqueous solution for use in the treatment of diarrhea in bovine animals and comprising an actively absorbed monosaccharide such as glucose, an actively absorbed naturally occurring amino acid such as glycine, citric acid and a non-toxic alkali metal salt of acetic acid, for example a solution obtained by diluting a composition according to the invention with water to the concentrations specified above, the solution being one which will have an osmolality of 50 to 100 mOs as oxidised. Examples of suitable actively absorbed monosaccharides include dextrose and galactose. The actively absorbed naturally occurring amino acid may for example be glycine or a related compound. Examples of non-toxic alkali metal salts 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 signiflcantly 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 glycine, acetate and citric acid together with any electrolytes enhance the absorption of all ingredients because they are absorbed by different mechanisms. 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 wt% Grams 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 0.44 0.7 3 2 NaCl 4.42 7.02 - 120 -CC1 2.43 3.72 - 50 Water 2 liters 564 703 The composition of the residual replacement fluid after metabolism of the organic constituents is set out in the Table below. Table II mEq/liter Electrolytes Fluid from Diarrheic Invention Normal Plasma Plasma 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/1 138.9 + 0.3 140.3 + 1.0. 140.5 i 0.6 139.9 + 1.0 Plasma Potassium mEq/l 5.21 -+ 0.20 4.59 + 0.4 4.65 + 1.0 4.56 + 1.2 Hematocrit % 58.7 + 1.3 51.2 -+ 2.4 48.9 -+ 0.4 50.7 t 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. Figure 1 of the drawings 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 effe'i3ts of the formulation set out in Table I with the formulation set out US-A-4,164,568 consisting of the following composition: Table IV Formulation from US-A-4,164,568 wt% Grams Kcal/2 liters mOsm/l Glucose 69.9% 44.6 178 124 Glycine 9.7% 6.2 19 41 Citric A 0.8% 0.5 3 1 K3 Citrate 0.2% 0.1 - 4 1 NaCl 13.3% 8.5 - 145 KH2PO4 6.4% 4.1 - 30 2 liters H20 200 342 The composition of the residual replacement fluid after metabolism of the organic constituents is set out in the table below. Table V m/Eq/liter Fluid from Diarrheic US-A- Normal Plasma 4,164,568 Plasma Sodium 72 135 135 Potassium 15 5 8 Chloride 72 100 100 Bicarbonate < 1 25 15 (from K3 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 formulation set out in Table I and the formulation covered in US-A-4,164,568 were administered as two quart (1.9 liter) doses to neonatal diarrheic calves less than 75 lbs (34 kg) weight and 3 quart (2.85 liter) doses to neonatal calves greater than 75 lbs (34 kg) weight 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. These data are set out in Table VI. Table VI Changes in plasma protein concentration one hour following therapy. pretherapy ¯ 1 hour post decrease Formulation of -+ + 0.3 4.6 + 0.4 - 0.3 Table I Formulation of 4.8 -+ 0.3 4.6 f 0.2 - 0.2 Table IV If the formulation of the present invention causes proteins to become more concentrated, then net secretion, not net absorption, has occurred. However, the formulation of the present invention, on the average, caused more dilution of plasma proteins in the first hour after administration than the formulation covered in US-A4,164,568. 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 present invention was 104 mg/dl. In contrast, the calves receiving the formulation covered by US-A4,164,568 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 present invention was 70 mg/dl versus only 20 mg/dl for the therapy using the formulation described in US-A-4,164,568. This is shown graphically in Figure 2 of the drawings. This continuing three-fold elevation emphasizes the sustaining longer term benefits of the formulation of the present 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 US 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/D Formulation of 5.3 i 0.6 -1.1 i 0.5 Table I 5.3 i Formulation of 5.0 + 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 present invention and all were within the normal range. In contrast, the calves receiving the therapy covered in the US 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 present 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 1i days prior to the 4th therapy. This information is shown in Figure 3 of the drawings. 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 present invention had blood urea nitrogen levels in a normal range in the last one-half of the experiment. Figure 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 US-A-4,164,568. One of the best indications of the long-term benefit of the therapeutic approach of the present invention is the maintenance of body weight during therapy. These data are set out in Table VIII. Table VIII Change in body weight (kg) following therapy: Formulation of Formulation of Table I Table IV 2 days * +0.68 0 4 days ** +2.04 -0.45 * 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 present 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 obtained are set out in Table IX below. Table IX Potassium concentration (mEq/l) changes due to therapy. Mean Pretherapy 1 Hour Post Change Invention 5.1 i 0.1 4.5 i 0.1 -0.6 Prior Art US-A- 5.0 + 0.1 4.8 + 0.1 -0.2 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 present invention. 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 Figure 4 of the drawings, changes in glucose concentration during the three hours following therapy have been plotted for calves treated with the formulation of the present 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 present invention became slightly hypoglycemic between therapies, 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 present 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 present invention had high normal glucose concentration three hours following therapy while the prior art calves had already become hypoglycemic again (Figure 1). Example VI Further evidence substantiating the claim that the hyperosmotic nature of the formulation of the present invention does not cause hemoconcentration can be gleaned from Table X below 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 present invention. On the average, the therapy elicited a minor hemodilution as evidenced by a decrease in both hematocrit 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 present 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 present 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 Therapy &num;Calves Pre-Therapy 1 Hr.Post Pre-Therapy 1 Hr.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* pH US-A-4,164,568 Invention Prior Art Therapy Pre Therapy 7.461 -+ 0.007 7.470 t 0.008 Post Therapy (1 hour) 7.484 + 0.012 7.465 -+ 0.005 Change in pH +0.023 -0.005 Total Bicarbonate Invention Prior Art Therapy Pre Therapy 24.9 -+ 0.5 21.8 t 0.5 Post Therapy (1 hour) 26.0 of 0.5 21.1 -+ 0.4 Change in HC03 +1.1 -0.7 Base Excess** Invention Prior Art Therapy Changes in Base Excess 1 Hour +1.5 + 0.3 +0.1 + 0.1 after Therapy * Values shown are mean + S.E. ** Base excess is a measure of total acidity and alkalinity. An increase in base excess indicates correction of acidosis.

Claims: CLAIMS 1. An easily absorbed and metabolized veterinary composition useful for the treatment of diarrhea in mammals and containing a major proportion of an actively absorbed monosaccharide and minor proportions of an actively absorbed naturally occurring amino acid and of citric acid, characterized in that the composition additionally contains 4 to 12 weight percent of non-toxic alkali metal salt of acetic acid, the monosaccharide concentration being 70 to 90 weight percent, the amino acid concentration being 1 to 7.5 weight percent and the citric acid concentration being 0.1 to 5 weight percent, all based on dry weight. 2. A veterinary composition according to claim 1, characterized in that it is dissolved in an aqueous carrier suitable for veterinary administration such that the monosaccharide is present in a concentration of 30 to 90 grams per liter. 3. A veterinary composition according to claim 2, characterized in that the osmolality of the fluid is from 600 to 1,200 mOsm per liter. 4. A veterinary composition according to claim 2 or 3, characterized in that the non-toxic alkali metal salt of acetic acid is provided in an amount such that the bicarbonate formed from the acetate as it is oxidized will be from 40 to 120 mOsm per liter. 5. A veterinary composition according to any of claims 1 to 4, characterized in that the alkali metal salt of acetic acid is sodium acetate. 6. A veterinary composition according to any of claims 1 to 5, characterized in that sodium and potassium ions are present, the sum of the sodium and potassium present is 120 to 160 mOsm/l with the potassium being present at 10 to 30 mOsm/1 and the sodium at 110 to 150 mOsm/l. 7. A veterinary composition according to any of claims 1 to 6, characterized in that the energy substrates consisting of the monosaccharide, the amino acid, the citric acid and the acetate present provide 50 to 100 percent of the animal's energy requirements as they are metabolized. 8. A veterinary composition according to claim 7, characterized in that as the energy substrates are metabolized the remaining ions approximate an isoosmotic extracellular fluid. 9. A veterinary composition useful for treating diarrhea in bovine animals and comprising an aqueous solution of an actively absorbed monosaccharide, an actively absorbed naturally occurring amino acid and citric acid, characterized in that it additionally contains a non-toxic alkali metal salt of acetic acid and will have an osmolÅal- ity of 50 to 100 mOs as oxidized. 10. A veterinary composition according to any of claims 1 to 9, characterized in that the monosaccharide is glucose and the amino acid is glycine.

Inventors: PHILLIPS, ROBERT W.
Applicants: COLORADO STATE UNIVERSITY RESEARCH FOUNDATION, INC.
Application year: 1984
Main classification: A61K31
IPC codes: A61K31