TREATMENT OF EXERCISE-INDUCED PULMONARY HEMORRHAGE IN ANIMALS

Abstract: A method and composition for the preventive and curative treatment of exercise-induced pulmonary hemorrhage in animals. The method comprises administration to the animal of a mixture of urea, alkaline potassium salts and magnesium salts. The composition comprises a mixture of urea, alkaline potassium salts, and magnesium salts, and if required, a pharmaceutically acceptable carrier.

Description: TREATMENT OF EXERCISE-INDUCED PULMONARY HEMORRHAGE IN ANIMALS FIELD OF THE INVENTION This invention is directed to a method and composition useful for the preventative and curative treatment of exercise-induced pulmonary hemorrhage in animals. BACKGROUND OF THE INVENTION Blood flowing from the nostrils of competitive thoroughbred horses has been observed as far back as the sixteenth century. And despite over three hundred years of recognition, the condition has remained an enigma and until recently little has been attempted or achieved to uncover the underlying etiology and pathogenesis of this condition. A recent retrospective survey of post-exercising horses with clinical evidence of blood at the nostrils positively identified the source of blood to have orig- inated from the lungs. And repeated occurrences of pulmon¬ ary hemorrhage were precipitated by competitive exercise only. Further support of the hypothesis of the lung being the source of the blood was determined in horses with indwelling tracheostomy tubes that bled while being raced, the blood exiting the respiratory tract via the trache¬ ostomy. By temporarily closing the tracheostomy, the blood flowed from the nostrils. The appearance of blood at the nostrils in exercising horses ranges from less than 1 to as high as 12 percent, but is generally about 0.5 to 2.5 percent. However, endoscopic surveys worldwide indicate that the actual prevalence of pulmonary hemorrhage is significantly higher than previously thought, with a range of 45 to 86 percent of racing or near maximal exercising horses. The incidence of pulmonary hemorrhage increases in direct proportion to the length of, and number of times, the endoscope is used on the individual animal. Histological examination of the caudal portion of the lung lobes re- vealed that 96 percent of horses that have raced had evidence of old alveolar hemorrhage. The term used to describe the condition of pulmonary hemorrhage in horses without blood at the nos- trils is exercise-induced pulmonary hemorrhage (EIPH) . EIPH is a more accurate description of bleeding in the racing horse than "bleeder". Multiple endoscopic surveys indicate that although pulmonary hemorrhage is experienced by a large number of racing or maximally exercising horses, epistaxis is a relatively infrequent manifestation of this phenomena. The frequency of occurrence of EIPH shows no relationship between the horse's sex, finishing position in the race, increasing age or distance raced. However, increased speed of exercise is directly associated with, and the common factor in, a higher incidence of EIPH in racing or maximally exercising horses. To determine the incidence of EIPH in post- racing horses, the animal was examined within 90 minutes of the completion of racing using a flexible fibreoptic endoscope. Both nostrils were examined for signs of hemorrhage. Other than the endoscopic observation of blood in the airways, a clear definitive set of clinical signs on which to establish a diagnosis of EIPH has not been docu¬ mented. Astute horsemen report that horses with EIPH often have a distressed or anxious expression, "cool-out" slowly, cough occasionally and swallow frequently. Coughing is not a consistent sign. Swallowing is a more consistent sign and is often the first indication of EIPH post-race. As the mucociliary blanket of the trachea clears the blood carried from the original source in the lungs, the blood pools on the floor of the larynx, flows onto the epiglot¬ tis, and then initiates the swallowing reflex. The major lesions of EIPH are multiple, separate and coalescing foci of moderately proliferative small airway disease accompanied by intense neo-vascularization of the bronchial circulation. These lesions are bilateral¬ ly symmetrical and confined to the dorsal angle of the lungs. Lesion extension occurs only along the dorsum of the lungs. Microscopic examination of the lungs of horses dying of EIPH has revealed engorgement of the pulmonary arteries, veins and capillaries, and rupture of the capil- laries with hemorrhage into alveoli, bronchioles, bronchi, interstitium and subpleural tissue. The severity of engorgement and hemorrhage varied from almost nonexistent to massive in various areas of the lung, but the caudal portion of the lung lobes was the site of the most severe hemorrhage. Focally extensive pleural and interstitium fibrosis, and bronchiolitis were often accompanied by severe hemorrhage around large vessels and airways. Hemosiderophages also were present within this fibrous tissue, particularly at the junction of the pulmonary parenchyma and the deep layers of the pleura. Latterly, numerous procedures have been performed in an attempt to prevent EIPH, with or without epistaxis, such as change of feed, bedding or ventilation, application of external or cold compresses to the nasal turbinate area, intermittent application of cold water over the thorax, and tying up the tail. More recently, various parenteral agents have been utilized in an effort to diminish the magnitude of EIPH in racing or near maximally exercising horses, namely atropine, estrogens, coagulants, clenbuterol (Ventipulmin™) , ipratropium (Atrovent™) , cromolyn (Intal™) , intravenous saline infusion and steam inhalation. Hesperidin-citrus bioflavinoids administered orally do not alter the prevalence of the pulmonary hemorrhage. Enforced rest, with a convalescence length much longer than three months duration, does not change the repeatability of the EIPH episodes which recur, with or without epistaxis, upon resumption of training and upon attaining maximal exercise form. But most of these techniques and treatments are now rarely utilized. Currently, the sulfamoyl-anthranilic acid deriva¬ tives, for example, furosemide (Lasix™) and ethacrynic acid, are parenterally administered to horses prior to racing in an attempt to control EIPH. Both of these drugs are potent diuretics which cause marked circulatory volume contraction in horses. The efficacy of these drugs in preventing EIPH has been extensively evaluated with widely variable results - sometimes stopping the hemorrhage, other times not stopping the hemorrhage, and yet at other times reducing the severity of the hemorrhage but not stopping the hemorrhage. Administration of these diuretics to horses having EIPH did not influence either the racing time or the systemic circulation physiology. However, adminis¬ tration of furosemide to horses negative for EIPH enhanced racing performance. All the aforementioned procedures and drugs have been used in an attempt to prevent EIPH in exercising horses without fully understanding the underlying patho- physiology. EIPH, with or without epistaxis, in racing or maximally exercising Thoroughbred or Standardbred horses, causes greater financial losses than is encountered in other breeds of horses. Monetary loss following an EIPH episode ranges from slight to severe. EIPH occasionally can be fatal with affected horses dying almost instan¬ taneously, this fatality often occurring during the latter portion of a race. But all affected EIPH horses are subject to an economic loss of some degree. In spite of a multiplicity of endeavours used to minimize EIPH in racing or maximally exercising horses, it remains today a major worldwide problem in the horse racing industry. SUMMARY OF THE INVENTION This invention relates to the discovery that a mixture of urea, alkaline potassium salts and magnesium salts exhibits surprisingly effective activity against EIPH, and, in particular, is useful in the treatment of EIPH. Specific compositions and methods of application of urea, alkaline potassium salts and optional magnesium salts mixtures have now been discovered. Use of such compositions and methods relate to the prophylactic and curative treatment of EIPH in animals, and in particular, in animals of the equine species, notably horses. These new methods comprise administration to animals of an effective amount of a mixture of urea, alkaline potassium salts and, if required, magnesium salts. More specifi¬ cally, it is found that when urea-alkaline potassium salts and, optionally, magnesium salts compositions are adminis¬ tered orally to said animals, daily water intake increases, urine excretion increases by an increased glomerular filtration rate and the urine flow rate increases by an osmotic diuretic effect. Magnesium salts are required if the total daily feed consumed by the horse provides insuf¬ ficient magnesium salts. The following alkaline potassium salts are all well known and available commercially and have been found to be effective in treating horses in accordance with the present invention: potassium chloride, potassium citrate, potassium phosphate, potassium nitrate, potassium sulfate, potassium acetate, potassium gluconate, potassium silicate. Of the foregoing, potassium chloride appears to possess the most desirable therapeutic characteristics. Potassium chloride is advantageous because it is a non-toxic, non-corrosive, readily available, chemically stable compound. The following magnesium salts are all well known and available commercially, and have been found to be effective in treating horses in accordance with the present invention: magnesium oxide, magnesium hydroxide, magnesium phosphate, magnesium sulfate, magnesium acetate, magnesium chloride, magnesium adipate, magnesium lactate, magnesium gluconate, magnesium carbonate. Of the foregoing, magnesium oxide appears to possess the most desirable therapeutic characteristics. Magnesium oxide is advantageous because it is a non-toxic, readily available, chemically stable compound. In a particular embodiment, the urea can be in the free base form, the alkaline potassium salt can be potassium chloride and the magnesium salt can be magnesium oxide. The mixture can comprise about 1 to about 65 percent by weight urea, about 0.05 to about 50 percent by weight alkaline potassium salts and about 0.25 to about 25 percent by weight magnesium salts. The alkaline potassium salt can be present in an amount ranging from about 0.05 to about 45 percent by weight, or more specifically from about 0.05 to about 35 percent by weight. Alternatively, the alkaline potassium salt can be present from about 0.25 to about 0.8 parts by weight per 1 part by weight of urea, or more specifically rom about 0.6 parts by weight per 1 part by weight of urea. The magnesium salt can be present in an amount ranging from about 1 percent to about 25 percent by weight. Alternatively, the magnesium salt can be present from about 0.05 to about 0.25 parts by weight of urea. The mixture can be incorporated into a feed or liquid composition and fed to the animal on a daily basis. The mixture can be included in the daily diet of the animal in an amount between about 10 to about 1,000 g. The animal treated with the mixture can be a member of the equine species, and specifically a horse. The invention is also directed to a composition for the prophylactic and curative treatment of exercise- induced pulmonary hemorrhage in an animal comprising: (a) urea or a pharmaceutically acceptable salt thereof; (b) an alkaline potassium salt selected from the group consisting of potassium chloride, potassium citrate, potassium phos¬ phate, potassium nitrate, potassium sulfate, potassium acetate, potassium gluconate, potassium silicate; and (c) a magnesium salt designated from the group consisting of magnesium oxide, magnesium hydroxide, magnesium phosphate, magnesium sulfate, magnesium acetate, magnesium adipate, magnesium lactate and magnesium gluconate. The urea can make up about 1 to about 65 percent by weight of the composition, the alkaline potassium salt can make up about 0.05 to about 45 percent by weight of the composition and the magnesium salt can make up about 1 to about 25 percent by weight of the composition. The alka¬ line potassium salt can be potassium chloride and can be present in the composition in an amount ranging from about 0.05 to about 35 percent by weight of the composition. The ratio of urea to potassium chloride can be about 1 part by weight urea to about 0.6 parts by weight potassium chlor¬ ide. Urea and the potassium chloride can be mixed with a pharmaceutically acceptable carrier. The magnesium salt can be magnesium oxide and can be present in the composi¬ tion in an amount ranging from about 1 to 10 percent by weight of the composition. The ratio of urea to magnesium oxide can be about 1 part by weight urea to about 0.16 parts by weight magnesium oxide. Urea and magnesium oxide can be mixed with a pharmaceutically acceptable carrier. Urea, potassium chloride and magnesium oxide can be mixed with a pharmaceutically acceptable carrier. DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION The urea used in the practice of this invention can be in the free base form or in the form of a pharma¬ ceutically acceptable salt. For example, urea may be readily converted to one of its nontoxic acid addition salts by customary methods used in the chemical art. Nontoxic salts of this invention can be formed from free base urea and an acid which is pharmaceutically acceptable in the intended dosages. Such salts include those prepared from inorganic acids, organic acids, higher fatty acids, higher molecular weight acids, and the like. Exemplary acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methane sulfonic acid, benzene sulfonic acid, acetic acid, propionic acid, malic acid, succinic acid, glycolic acid, lactic acid, salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid, abietic acid, and the like. The amount of urea in such preparations may be as little as 1 percent by weight or as high as about 50 percent by weight. Below 1 percent by weight, the urea is generally too low to be therapeutically useful. The upper limit of about 50 percent by weight is based on the solu¬ bility limit of urea in water. The amount of alkaline potassium salts added to the preparation should be in the range of about 0.05 to 50 percent by weight. Below about 0.05 percent by weight, the alkaline potassium salts are generally ineffective. Amounts of alkaline potassium salts in excess of about 50 percent by weight have been found to be unnecessary and wasteful. Generally no more than about 45 percent by weight, and preferably, no more than about 42 percent by weight of alkaline potassium salts are used. As a general rule, the amount of alkaline potassium salts used is based on the amount of urea used. Good results are obtained when the amount of alkaline potassium salt is about 25 to 80 percent by weight of the weight of urea in the prepara¬ tion, with alkaline potassium salts at about 35 percent by weight of urea providing particularly good results. The following alkaline potassium salts are generally effective in the prophylactic and curative treatment of EIPH in horses: potassium chloride, potassium citrate, potassium phosphate, potassium nitrate, potassium sulfate, potassium acetate, potassium gluconate, otassium silicate. Of these, potassium chloride, hereinafter re¬ ferred to simply as KC1, is usually the most suitable for use in pharmaceutical compositions, feed mixtures, feed and liquid supplements for the prophylactic and curative treatment of EIPH in the equine species, including horses. The amount of magnesium salts added to the preparation should be in the range of about 1 to about 25 percent by weight. Below about 1 percent by weight, the magnesium salts are ineffective. Amounts of magnesium salts above 25 percent are wasteful and unnecessary. Generally, no more than about 20 percent by weight, and preferably, no more than about 15 percent by weight of magnesium salts are used. Good results are obtained when the amount of magnesium salt is about 5 to about 25 percent by weight of the urea in the preparation, with magnesium salts at about 10 percent by weight of urea providing particularly good results. The following magnesium salts are generally effective in the prophylactic and curative treatment of EIPH in horses: magnesium oxide, magnesium hydroxide, magnesium phosphate, magnesium sulfate, magnesium acetate, magnesium chloride, magnesium adipate, magnesium lactate, magnesium gluconate, magnesium carbonate. Of these, magnesium oxide, hereinafter referred to simply as MgO, is usually the most suitable for use in pharmaceutical compositions, feed mixtures, feed and liquid supplements for the prophylactic and curative treatment of EIPH in the equine species, including horses. The compounds defined above are readily absorbed into the blood stream from the stomach and intestinal tract of the treated animal when taken orally, and therefore the preferred method of treatment is to administer the compound orally to the animal. This is also the safest, simplest and most practical route of administration. Optional modes can be used where, for example, the animal is not eating or cannot swallow or has difficulty in swallowing. Other acceptable methods of administration which permit the compound to be absorbed in the gastrointestinal tract or which deliver a solution of the compound directly to the bloodstream (intravenous injection) can then be employed. The method of administration may also vary depending on the purpose of administration. For example, use as a prophylaxis or preventative treatment or as a treatment of affected animals can require different methods of treatment and dosage forms easily formulated by those skilled in the art. The dosage regimen in carrying out this invention utilizing the urea - KCl-MgO mixture for treatment of EIPH of horses are those which insure maximum therapeutic response. The average effective daily dose of the urea - KCl-MgO mixture is between about 100 mg/kg to about 2000 mg/kg of body weight, with about 600 to about 1250 mg/kg of body weight being preferred. The treatment of animals can normally be accom¬ plished by incorporating an effective amount of the com¬ pound in the animal's diet as a solid or liquid feed supplement, or dissolved in the animal's liquid intake. The urea-KCl-MgO mixture for use in the practice of the present invention includes compounds which are non-toxic to the animals, including horses, when administered daily to the animal in the animal's feed diet in concentrations of about 10 to about 1,000 g. Anti-EIPH effects can be realized also for the various urea, alkaline potassium salts and magnesium salts when administered daily in the animal*s feed diet in concentrations of about 10 to about 1,000 g. Compositions useful in the practice of the present invention can be prepared in forms suitable for administration by compounding an effective single dose amount of the compound with known pharmaceutically accept¬ able carrier ingredients generally employed in the prepara¬ tion of theurapeutic compositions of the type which are provided as tablets, hard capsules, powders, granules and aqueous suspensions. Compositions intended for oral use may be pre¬ pared according to methods known generally in the art. Such compositions may contain one or more pharmaceutically acceptable carrier agents selected from the group consist- ing of sweetening agents, flavoring agents, coloring agents and preserving agents. In general, the composition will contain a mixture of urea, alkaline potassium salts and magnesium salts in admixture with non-toxic pharmaceuti¬ cally acceptable excipients. Exemplary excipients are: interdilutants such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulat- ing or disintegrating agents, for example, maize, starch, and algenic acid; binding agents, for example, starch, gelatin and acacia; and lubricating agents, for example magnesium stearate, stearic acid, and talc. Tablets may be uncoated or they may be coated by known techniques to make them more therapeutically effective, for example, to delay disintegration or absorption, or to make them more palat¬ able, or for other reasons for which orally administered mixtures of urea, alkaline potassium salts and magnesium salts have been previously provided in coated form. Formulations for oral use may also be presented as hard gelatin capsules wherein the mixture of urea, alkaline potassium salts and magnesium salts is admixed with an inert solid diluent, for example, calcium carbon¬ ate, calcium phosphate and kaolin. Aqueous solutions containing a mixture of urea, alkaline potassium salts and magnesium salts can also be utilized, when desirable. Excipients suitable for aqueous suspensions may be employed, if desired. Such excipients include: suspending agents, for example, sodium carboxmethyl- cellulose, methylcellulose, hydroxypropyl- methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide, for example, lecithin, condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadeca- ethyleneoxy-cetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example polyoxyethylene sorbitol monoleate, and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan monoleate. The said aqueous suspensions may also contain one or more preserv¬ atives, for example, ethyl, or n-propyl-p-hydroxy benzoate, one or more coloring agents, one or more flavouring agents, and one or more sweetening agents such as sucrose. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the mixture of urea, alkaline potassium salts and magnesium salts in admixture with dispersing, suspend- ing or wetting agent. Additional excipients, for example, sweetening, flavoring and coloring agents may also be present. The pharmaceutical compositions may be in the form of a sterile injectionable preparation, for example, as a sterile injectable aqueous suspension. This suspen¬ sion may be formulated according to available art methods using suitable dispersing or wetting agents and suspending agents such as those which have been mentioned above, or others. This sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as an aqueous solution buffered to a pH of about 4.0 to 7.0 and made isotonic with sodium chloride. Further, the mixture of urea, a single alkaline potassium salt and a single magnesium salt may be adminis¬ tered alone or in admixture with a mixture of urea, other alkaline potassium salts and other magnesium salts, or with other agents having the same, similar or different pharma¬ cological properties. The following examples of preferred embodiments of this invention, showing veterinary and pharmaceutical compositions, were all prepared using urea, KC1 and MgO. Similar granules, capsules, tablets, feed and liquid supplements can be prepared containing other of the desig- nated alkaline potassium salts and magnesium salts. Description of Preferred Embodiments Compositions containing urea-KCl-MgO mixtures in dry powder or granular form should generally contain only about 65 weight percent of urea and preferably no more than about 58 weight percent; and should generally contain only about 50 weight percent of KC1 and preferably no more than about 35 weight percent, and should generally contain only about 25 weight percent of MgO and preferably no more than about 10 weight percent. Formulations containing urea-KCl-MgO preparations in aqueous solution should generally contain only about 50 weight percent of urea and preferably no more than about 35 weight percent, and should generally contain only about 25 weight percent of KC1 and preferably no more than about 20 weight percent and should generally contain only about 20 weight percent of MgO and preferably no more than about 10 weight percent. The following examples are provided to illustrate the activity of various urea-KCl-MgO formulations in the prophylactic and curative treatment of EIPH in racing or maximally exercising horses. The examples are not to be taken as an exhaustive list of the possible methods and compositions for using the urea-KCl-MgO formulations and the benefits resulting from their use. The examples do, however, give some indication of the broad scope of this invention, specifically, the suitability of urea-KCl-MgO preparations for a variety of situations. Example 1 A series of blood samples were collected from various horses to demonstrate that in the Thoroughbred and Standardbred breeds of racing horses elucidation of the etiopathogenesis and verification of EIPH through implemen¬ tation of hematology and biochemical screening procedures are uninformative and valueless. Even though both breeds are exposed to a wide variety of environmental conditions throughout the world the incidence of bleeding from the nostrils, ie. epistaxis, is greater in the Thoroughbred than the Standardbred breed. It is thought that the occurrence of bleeding in racing or maximally exercising horses may be caused by an inherited genetic factor which is expressed more often in Thoroughbreds than Standardbreds. However, the incidence of EIPH in both breeds of horses varies similarly statisti¬ cally (between 45 to 86 percent) and anatomically (caudal diaphragmatic lung lobes) , whereas the incidence of bleed- ing in Thoroughbreds varies from less than 1 up to 12 percent but occurs only rarely in Standardbreds. Thus the disparity in the incidence of bleeding between these two breeds of racing horses may be due to either: (1) genetic differences between the hematology and biochemical values, or (2) the speed of racing or maximally exercising. To examine the possibility of a heritable genetic difference occurring between the hematological and bio¬ chemical levels of racing Thoroughbred and Standardbred horses a series of blood samples were collected from eight racing Thoroughbreds and eight racing Standardbreds for laboratory analysis and the results recorded. The age of the eight racing Thoroughbreds in this test ranged between 3 to 7 years with an average age of 4.2 years, body weight ranged between 420 and 468 kg. with an average of 444 kg. The eight racing Standardbred horses ranged in age between 2 to 9 years with an average of 3.5 years, body weight ranged between 397 and 470 kg. with an average of 439 kg. The average hematological and biochemical levels of the said test horses are listed below: Hematology and Biochemistry White cell count Red cell count Hemoglobin Hematocrit Platelet count Glucose Blood urea nitrogen Creatinine Sodium Potassium Calcium Phosphorus Total protein Albumin Globulin Bilirubin total Albumin/Globulin ratio Calculated Osmolality Chloride Carbon dioxide Anion gap Cholesterol *L - Lower than normal value H - Higher than normal value Comparison of the measured hematological and bio¬ chemical parameters between the two breeds of racing horses indicates that there is a striking similarity between the two sets of hematological and biochemical values for Thoroughbred and Standardbred horses rather than a distinct demonstrable difference. Since the incidence of EIPH in Thoroughbreds and Standardbreds is similar, it appears from these examples that the difference in the incidence of EIPH with epistaxis between racing Thoroughbreds and Standard- breds must be directly related to the speed of racing and is not a visible expression of a heritable genetic factor. The probability of speed being a factor in having EIPH, with or without epistaxis, has credence since it has been found that a speed greater than 240 meters per minute is necessary to produce EIPH and that the average speed of racing Thoroughbreds is about 1050 meters per minute, whereas the world record speed of a Standardbred pacer is about 885 meters per minute. Example 2 This example illustrates the effect of daily oral feeding in the grain ration of a dry urea-KCl-MgO composi¬ tion to eliminate or prevent EIPH in a 5 year old Standard¬ bred mare, 440 kg. body weight, with a long history of EIPH episodes occurring during racing. The mare is currently racing with a pre-race intravenous bleeder injection to prevent EIPH during the race. A dry feed supplement intended as a feed for racing and maximally exercising horses was prepared by blending about 4 percent weight of urea, about 3 percent weight of KCl and about 0.2 percent weight of MgO in a basic performance-type horse ration containing: Ingredient Amount The total daily feed intake consisted of about 13 pounds (5.9 kg) of timothy hay, about 3.3 pounds (1.5 kg) of alfalfa cubes, about 11.25 pounds (5.1 kg) of whole oats and about 3.75 pounds (1.8 kg) of commercially mixed grain to which was added the dry urea-KCl-MgO com¬ position at a level of about 4 percent weight of urea, about 3 percent weight of KCl and about 0.2 weight per¬ cent of MgO. Salt (NaCl) was added at a level of sup- plementation to provide the test animal a total daily intake of about 1600 mEq Na + . Supplementation of the daily grain ration with about 4 weight percent of urea, about 3 weight percent of KC1 and about 0.2 weight per¬ cent of MgO provided the test animal a total daily intake of about 4200 mEq of urea, about 6200 mEq of K + and about 3000 mEq of Mg 2+ . The dosage regimen in carrying out this test, where the said composition was used for the prophylactic or curative therapy of EIPH during racing or maximal exercise in horses, was used to insure maximum thera¬ peutic response. The effective daily dosage attained by the animal for the active ingredient urea of this invention was between about 475 mg/kg body weight to about 550 mg/kg body weight, and for KCl was between about 335 mg/kg to about 375 mg/kg body weight, and for MgO was between about 70 mg/kg body weight to about 80 mg/kg body weight. Demonstrable effectiveness for this route of administration of this invention in preventing or elimin¬ ating EIPH during racing or maximal exercise in a horse is illustrated by the race results produced by this 5 year old Standardbred mare in a total of thirteen con¬ secutive officially sanctioned harness races. The thirteen races which were run during the spring and summer racing season by the 5 year old Standardbred mare were all performed within a single class of competition. The first three races of this series were run with the usual pre-race intravenous bleeder injection. The next seven races were performed without a pre-race intravenous bleeder injection but with the said composition supplemented at maximum therapeutic level in the daily grain ration. The final three races of this series again were run with only a pre-race intra¬ venous bleeder injection and without the supplementation of the said composition. The economic placement, total monetary winnings and winnings per start for the thirteen races are listed below: Economic Placement Total Monetary Monetary Returns Races 2 3 4 5 No. (%) Earnings ($) Per Start ($) Six races - pre-race intravenous bleeder injection 3/6 50 1,656 276 Seven races - daily urea-KCl-MgO compositon 5/7 71 3,140 448 Winnings per start in this series of thirteen races increased by more than 62 percent with the addition of the said composition to the daily grain ration over the use of a pre-race intravenous bleeder injection for prevention of EIPH during the race. No evidence of EIPH was observed in this horse while racing, or after racing, or during the entire seven races while consuming the dry urea-KCl-MgO formulation at maximum therapeutic level in the daily grain ration. Urine samples, collected from the first and second place winners by authority of the Federal Racing Commission, were laboratory tested for the presence of illegal performance enhancing drugs and were always cer¬ tified negative and the tests were never masked or com- promised by the oral use of this invention. During the time the said preparation was sup¬ plemented in the daily grain ration there was a notice¬ able improvement in the horse's demeanor, power, endur¬ ance and speed during training which carried over to surprisingly influence the official race results. Upon cessation of daily intake of this invention, the horse rapidly reverted to the previous level of performance. Use of dry urea-KCl-MgO composition added to the daily grain ration at a sufficient level to ensure maximum therapeutic response eliminated or prevented EIPH in a horse with a long standing history of EIPH occurring during racing. Example 3 The effectiveness of dry urea-KCl-MgO composi¬ tion in treating and preventing EIPH in a 4 year old Standardbred mare, 428 kg body weight, with a long his¬ tory of EIPH occurring during racing was determined. The mare was currently utilizing a pre-race intravenous bleeder injection for the prevention of EIPH during rac¬ ing. The dry urea-KCl-MgO composition, as well as supplemental NaCl, were admixed into the daily grain ration so that about 4 weight percent of urea, about 3 weight percent of KCl and about 0.2 weight percent of MgO were consumed by the test animal. In addition, about 3.3 pounds (1.4 kg) of alfalfa cubes and about 12 pounds (5.5 kg) of alfalfa-timothy mixed hay were the daily roughage intake of the daily ration. The effective dosage of the composition con- sumed daily by the test animal was between about 500 mg/kg body weight to about 585 mg/kg body weight for urea, was between about 200 mg/kg body weight to about 375 mg/kg body weight for KCl and was between about 50 mg/kg to about 60 mg/kg for MgO. The dosage was prefer- ably no more than about 575 mg/kg body weight of urea, about 350 mg/kg body weight of KCl and about 55 mg/kg body weight of MgO. The daily ration supplemented with this invention provided a daily intake of about 4200 mEq of urea, about 6000 mEq of K + and about 2400 mEq of Mg 2+ . The supplemental NaCl provided the test animal a total daily intake of about 1500 mEq Na + . The dosage regimen of the said composition was such as to ensure maximum thera¬ peutic response in treating and preventing the occurrence of EIPH in a 4 year old Standardbred mare with a long standing history of EIPH occurring while racing. The effectiveness of this invention in prevent¬ ing and treating an EIPH prone animal and the competi¬ tive racing results resulting therefrom are documented below. Initially, four races at the start of the au¬ tumn racing meet were completed with a pre-race intra¬ venous bleeder injection which resulted in no EIPH epi¬ sodes and a single economic placement (5th) . Subse¬ quently, a two month rehabilitation period away from the racetrack environment intervened. Upon return to racing, a series of nine consecutive races were run in a single competitive class. The first six races were performed using a pre-race intravenous bleeder injection as a pro¬ tective measure against EIPH whereas the inal three races were performed without a pre-race intravenous bleeder injection but with the maximum therapeutic dosage of dry urea-KCl-MgO composition being consumed daily in the grain ration to prevent or eliminate EIPH during racing. The dry urea-KCl-MgO composition was slowly introduced into the daily grain ration and maximum thera- peutic dosage was reached only after the eighth day. Full dosage was reached twelve days before the sixth race and was maintained at that dosage level until completion of the test. No gastrointestinal upset or colic occurred during the test and daily grain consumption and palatability were unaffected with admixture of this in¬ vention. A noticeable increase in water intake and in¬ creased urine excretion were obvious before the third day of supplementing the daily grain ration with this inven- tion. Both of the aforementioned physiological parame¬ ters increased in quantity until full daily dosage was reached and remained at that elevated level until cessa¬ tion of the test. Before the second day after the end of the test both the quantities of water consumed and urine produced noticeably decreased and returned to more normal amounts for a racing horse not fed the composition of this invention. Two blood samples were collected for determina¬ tion of hematological and biochemical parameters. The first blood sample was obtained after the sixth race and before the start of feeding the said composition in the daily grain ration, and the second blood sample was col¬ lected after the ninth race and the completion of the test. The laboratory values obtained for hematology and biochemistry of the two blood samples are listed below. *L - Lower than normal value H - Higher than normal value The economic placement, monetary winnings and monetary returns per start for the entire nine races, the six races run with a pre-race intravenous bleeder injec¬ tion and the three races competed with only this inven- tion supplemented into the daily grain ration are listed below: Economic Placement Total Monetary Monetary Returns Races 1 2 3 4 5 No. (%) Earnings ($) Per Start ($) Nine - total 6/9 66 1,931 214 Six - pre-race intravenous bleeder injection 3/6 50 1,195 199 Three - daily urea -KCl-MgO composition 3/3 100 736 245 It specifically appears from the race results - that with no change in management procedures other than the supplementation of the daily grain ration with this invention, the monetary return per start increased more than 23 percent over that attained with a pre-race intra¬ venous bleeder injection. It is logical to conclude that the increased economic returns and absence of EIPH occur¬ ring during racing are directly related to the daily intake of this invention in the animal's daily grain ration. Observable clinical manifestations of colic, gastrointestinal and endocrinological abnormalities were not apparent from close observation of the test animal during the test period. Throughout the twenty-nine day test period, with supplementation of the daily grain ration with the dry urea-KCl-MgO composition, and during or after many training sessions and during or after competing in three officially sanctioned races, no characteristic clinical signs of, or endoscopic evidence of EIPH, developed in this 4 year old Standardbred mare, which previously had a long history of EIPH occurring while racing. As this example illustrates, not only is EIPH eliminated or reduced in a 4 year old racing Standardbred mare with a long history of EIPH episodes occurring while racing, but specifically also demonstrates the suitabil¬ ity of this invention to enhance an animal's racing or maximal exercising performance up to its genetic poten¬ tial. Example 4 The safety of long-term administration and possible cumulative effects of the urea-KCl-MgO composi¬ tion in aqueous solution when given daily and orally for a 282 day period at maximum therapeutic dosage for the prevention or elimination of EIPH in a 4 year old Standardbred gelding, 450 kg body weight, during the pre- race training period and official harness race meet was investigated. Hematological and biochemical values ob¬ tained from four blood samples were compared to determine if the measured parameters were pathophysiologically altered by the long-term daily consumption of the said composition admixed into the daily grain ration. The animal's daily feed intake consisted of about 3.3 pounds (1.4 kg) of alfalfa cubes and about 10 pounds (4.5 kg) of alfalfa hay for roughage and grain, about 11 pounds (5 kg) of whole oats and about 3.5 pounds (1.5 kg) of commercial mixed grain (see Example 2). The daily dosage of the said composition in aqueous solution provided the test animal with between about 485 mg/kg body weight and about 550 mg/kg body weight of urea and for KCl between about 260 mg/kg body weight and about 350 mg/kg body weight. Thus, the test animal was provided with a total daily intake of about 4200 mEq of urea and about 6400 mEq of K + . NaCl was supplemented daily to the test animal to provide a total daily intake of about 1500 mEq Na + . MgO was supplemented daily to the test animal to provide a total daily intake of about 3300 mEq of Mg 2+ . At various times during the 282 day test period, the aqueous solution was supplied to the test animal in the drinking water, admixed into the oats and mixed grain or poured onto the alfalfa hay or cubes. Palatability of this composition was unaffected regard¬ less of the route of administration. The test animal did not react adversely to the various oral routes of intake nor at any time throughout this test period show any physical discomfort or clinical evidence of gastroin¬ testinal upset or colic. The hematological and biochemical levels ob¬ tained from blood samples collected: (1) immediately prior to the start of the long-term feeding test of the said composition in aqueous solution (Day 0) ; (2) midway during the training period (Day 168) ; (3) immediately prior to the start of the race meet (Day 203) ; (4) sev- • eral days after the eighth race of the race meet (Day 245) ; and, (5) two days after the eleventh race of the race meet (Day 282) , are listed below: Blood Sample 1 2 3 4 5 Protein Electrophoresis Day 0 Day 168 Day 203 Day 245 Day 282 Units Albumin Alpha-1 Globulin Alpha-2 Globulin Beta-1 Globulin Beta-2 Globulin Gamma Globulin *L - Lower than normal value H - Higher than normal value These results demonstrate the safety of long- term administration of this invention at a dosage regimen to produce maximum therapeutic effect. It is also evi¬ dent that the hematological and biochemical levels ob- tained prior to the administration of this invention progressively increase with continuous feeding into a normal equine hematological and biochemical profile, even though some of the initial values are outside the normal physiological range. From this sampling, it is logical to conclude that cumulative toxic effects attributable to the long-term daily intake of the above defined composi¬ tion, and consumed at the indicated dosage regimen, are non-existent and physiologically unapparent. The protein electrophoretic values in the plasma from the serial blood samples illustrate that the albumin level markedly increases with the start of com¬ petitive racing. With the start of daily feeding of this invention, both the alpha-1 and beta-1 globulin fractions are increased to normal physiological values. Long-term feeding of this invention substantially increases the alpha-1 globulin fraction while the alpha-2 globulin fraction at first declines to a lower than normal physio¬ logical value and then rises to a normal physiological level. The beta-1, beta-2 and gamma fractions remain within their respective normal physiological range throughout the 282 day test even though the animal was continuously raced during this test. The obvious visible signs of EIPH have not occurred in the test animal during either the many train- ing sessions or the official races run in the current race meet while ingesting this invention admixed into the daily feed ration. An unexpected discovery has been made from these results. It specifically appears that even with the relatively high levels of dietary crude protein (12 to 14 percent) present in the ration of racing horses, the level of nitrogen retention is significantly enhanced by gut microflora utilizing the NPN contained in this invention. Urea is largely excreted by the kidney into the urine before any recycling can occur. However, some urea recycling occurs into the large intestine and cecum where it is hydrolyzed into ammonia (NH 3 ) and carbon dioxide (C0 2 ) by urease enzyme, a product of plant and bacterial origin. The NH 3 is then utilized by the intes¬ tinal and cecal microflora for the synthesis of protein. Cecal microbial protein is hydrolyzed to yield amino acids (both essential and non-essential amino acids which may be lacking in the diet) which are then absorbed into the blood plasma where they can be utilized by the liver for synthesis of protein. This specifically appears to be what is occurring when the abnormal hematological and biochemical values of this test animal are normalized and improved with the daily intake of this invention even while continuously racing. The invention is therefore not only useful in the prevention or elimination of EIPH. But when this invention is fed daily to racing or maximally exercising horses, there is a simultaneous normalization of hema¬ tological and biochemistry values and a substantially marked improvement in the speed, stamina and performance of the animal. Another unexpected discovery following from the results obtained above was that since proteins are the only dissolved substances in the plasma that do not read¬ ily diffuse into the interstitial fluid, and only those substances that fail to pass through the pores of a semi- permeable membrane exert osmotic pressure, it is the dissolved proteins of the plasma and interstitial fluids that are responsible for the osmotic pressure at the capillary membrane. Thus colloid osmotic pressure of the plasma is caused by the dissolved proteins and since the concentration of dissolved plasma proteins substantially increases with the daily consumption of this invention, there develops simultaneously a significantly effective physiological elevation of the plasma colloid osmotic pressure. The Donnan effect of the plasma proteins causes the osmotic pressure to be about 50 percent greater than that caused by proteins alone. This results from the fact that the protein molecules themselves cannot readily diffuse through the semi-permeable capillary membrane and the electronegative charges on the proteins, which are negative ions, attract positive ions (cations) , mostly sodium ions but also include all the other cations in the extracellular fluid, and thus balance those charges. Osmotic pressure is determined by the numbers of particles per unit volume of fluid, not the weight of the particles. Those extra cations increase the number of osmotically active substances wherever the dissolved proteins occur and thus increase the total colloid osmot¬ ic pressure. Thus the Donnan equilibrium effect becomes more significant the higher the concentration of proteins, therefore justifying the requisite daily intake of NaCl to provide a racing or near maximally exercising horse about 1500 mEq Na + , and the daily intake of KCl to provide about 6400 mEq of K + and MgO to provide about 3300 mEq Mg 2+ and about 4200 mEq urea when this invention is consumed daily at a dosage regimen sufficient to produce maximum therapeutic effect and thus effectively provi¬ sion for the prevention or elimination of EIPH. Example 5 This example illustrates the effectiveness of the daily oral administration of powdered urea-KCl-MgO formulation to a 9 year old Standardbred gelding, 480 kg body weight, with a long documented history of EIPH oc¬ curring during racing. Prior to each race, an intravenous bleeder injection was administered and no evidence of EIPH occurred until what was the animal's last race of the spring race meet. During that last race, an obvious aberration of the animal's usual per- formance became evident. Between 45 and 60 minutes post- race, an endoscopic examination was performed and a posi¬ tive diagnosis made of EIPH with the presence of copious amounts of free-flowing blood in the bronchi and trachea. Further verification of the EIPH episode was documented several days later by a tracheobronchial wash which was cytologically examined and the presence observed of a predominance of macrophages which often contain hemo- siderin, ie. siderophages, hemosiderophages, thus con- firming with absolute certainty the presence of a previ¬ ous EIPH episode in this animal which occurred during racing. Subsequently, the animal was removed from the race track and rested for five months. Upon returning to training, in anticipation of racing, the daily feed in- take consisted of about 14 pounds (6.4 kg) of alfalfa hay, about 8 pounds (3.6 kg) of whole oats and about 8 pounds (3.6 kg) of commercial mixed grain plus supple¬ mental NaCl and a mineral-vitamin mixture. The powdered preparation of urea-KCl-MgO was added to the daily grain ration at a level of about 2.5 weight percent of urea, about 1.5 weight percent of KCl and about 0.1 weight percent of MgO. At this level of feed intake, the test animal was provided with a total daily intake of about 3,000 mEq of urea and about 6400 mEq K + . NaCl was supple- mented to provide the test animal with a total daily intake of about 1550 mEq Na + . The effective daily dosage administered of this invention was between about 320 mg/kg body weight and about 380 mg/kg body weight for urea, for KCl was between about 185 mg/kg body weight and about 250 mg/kg body weight and for MgO was between about 6 mg/kg body weight and about 7 mg/kg body weight. The dosage regimen em¬ ployed during this test was sufficient to ensure maximum therapeutic response for the prevention or elimination of EIPH in racing or maximally exercising horses. To ascertain if any pathophysiological alter¬ ations occurred during the test and became apparent in the hemogram and biochemical profile of the test animal, a series of blood samples were collected: (1) post- rest/pre-training (Day 0) ; (2) mid-training (Day 49) ; (3) post qualification race (Day 137) ; (4) training following qualification race (Day 178) . The results are listed below. o. Blood Sam le Protein Electrophoresis Albumin Alpha-1 Globulin Alpha-2 Globulin Beta-1 Globulin Beta-2 Globulin ι_> Gamma Globulin *L - Lower than normal value H - Higher than normal value On Day 0, the hemogram and biochemistry values obtained were essentially normal for a rested horse en¬ tering race training. The exception to the essentially normal profile was the markedly elevated globulin portion of the total protein. Plasma protein electrophoresis revealed, surprisingly, even after five months of pasture rest, that the alpha-1 globulin fraction was of a lower than normal value which was comparable to the value found in some horses at the finish of a multi-race meet. Even more surprising was the obvious grossly above normal elevation of the gamma globulin fraction of the pla a protein with a complete absence of any abnormal clinical or physical signs. Upon reviewing these electrophoretic results, the clinical pathological diagnosis of this data was polyclonal gammopathy. Midway through the race training period (Day 49) , the hematological and biochemical values were deter¬ mined from the second blood sample. The values obtained were slightly lower than found in the first blood sample (Day 0) but were essentially normal except for the still large above normal elevation of the globulin portion of the plasma protein. Electrophoretic fractionation of the plasma protein of this blood sample revealed an elevated and a diminished concentration of the alpha-1 and alpha- 2 globulin fractions, respectively. This phenomena has previously been observed to occur when this invention was consumed daily at a level sufficient to produce maximum therapeutic response for the prevention or elimination of EIPH in racing or maximally exercising horses. The gamma globulin fraction of the plasma protein was still grossly elevated, and thus the clinicopathological diagnosis was made again of polyclonal gammopathy. Two days after an attempted qualifying race, when an unacceptable time of 2:13 for the mile was at¬ tained, a third blood sample (Day 137) was collected for hematological and biochemistry analysis. Again, with the exception of the globulin fraction of the plasma protein, the hemogram and remaining biochemical values were within normal limits. Electrophoretic analysis revealed the usual increase in albumin concentration which occurs after the initiation of competitive racing. The alpha-1 globulin fraction, although decreased in concentration from sample two (Day 49) , was still elevated above normal level, but the concentration recorded was comparable to that occurring in the long-term daily feeding of a racing test animal. The alpha-2 globulin level, previously a lower than normal value, had now increased to a concen¬ tration within the normal range. The gamma globulin fraction was still elevated prominently to a higher than normal value, thus eliciting the continual clinicopatho- logical diagnosis of polyclonal gammopathy. The fourth blood sample (Day 178) was collected 41 days after the unsuccessful qualifying race and after much more endurance training and eight race-works. With the exception of the increased globulin concentration of the plasma protein, the remainder of the hemogram and biochemical values in this blood sample were within the normal range. Plasma protein electrophoresis revealed, as previously recorded in sample 3 (Day 137) , an increased alpha-1 globulin, a normal concentration of alpha-2, beta-1 and beta-2 globulin fractions and still a markedly increased gamma globulin fraction, thus result¬ ing in the repetitive clinicopathological diagnosis of polyclonal gammopathy. At no time during the entire 187 day test period did the test animal show any hesitation or refusal to consume this invention when it was admixed into the daily grain ration. Nor was there ever any clinical indication evident of gastrointestinal upset or symptoms of physical discomfort or colic that could be attributed to the daily consumption of this invention. About 45 minutes after completion of the unsuc¬ cessful qualifying race, which the test animal completed with a speed of about 726 meters per minute, an endoscop¬ ic examination of the lungs was performed by the official racetrack veterinarian to determine if the presence of EIPH was the primary factor influencing the slow racing time attained. The numerical classification of the per¬ formed endoscopic examination was Grade 0 - no blood present. The test animal avidly consumed water when it was offered after completion of the qualifying race. As this example particularly illustrates, especially with the absence of endoscopic documentation of the most com¬ mon presenting signs of EIPH, it is manifestly logical to conclude that other abnormal physiological factors are primarily responsible for causally influencing the re¬ sulting slow race time performed by the test animal. Following the unsuccessful qualifying race, in which the test animal failed to reach a minimum speed of 754 meters per minute, the said animal was further endur¬ ance trained and race-worked eight times in the following 41 days. A race-work consists of a warm-up mile at a speed of about 644 meters per minute, followed by a 30 minute rest and then an all-out-speed mile. In all eight of the all-out-speed miles, the minimum qualifying speed for racing of about 754 meters per minute was not reached, the speed produced ranged between about 695 meters per minute and about 721 meters per minute. How¬ ever, at no time during or following these eight all- out-speed miles did the test animal show any characteris¬ tic symptoms of EIPH, ie. swallowing, coughing or dyspnea, and it always readily consumed water when of- fered after these race-works. From these results, it specifically appears and is logical to conclude that the daily oral administration of this invention at the aforementioned dosage regimen to a 9 year old Standardbred gelding, having a long docu- mented history of EIPH occurring while racing and a cur¬ rently ongoing clinical pathological diagnosis of polyclonal gammopathy, produces the anticipated maximum therapeutic response which is to effectively prevent or eliminate EIPH in racing or maximally exercising horses. Example 6 Racing or maximally exercising horses generally consume a total daily feed ration comprised of about 12 to 14 percent crude protein which is acknowledged as being an adequate and acceptable level of protein intake. Even with this level of protein in the ration the globu- lin fraction of the plasma proteins is surely and irrevo¬ cably reduced with continuous racing of the said animals during the course of a long multi-race meet. A surprising discovery is that the levels of both the albumin and globulin fractions of the plasma protein are substantially increased when this invention is administered daily to racing horses at a dosage regi¬ men sufficient to produce maximum therapeutic response for the prevention or elimination of EIPH. The quantity of feed nitrogen utilization and retention is signifi- cantly enhanced by intestinal microflora utilizing the NPN, ie. urea, present in this invention. The albumin and globulin fractions of plasma protein were determined through the laboratory technique of protein electrophoresis and the results listed below for each blood sample collected. Single blood samples were obtained from a 4 year old Standardbred and an 8 year old Thoroughbred following completion of their re¬ spective six-months long race meets and consuming the usual type of diet fed to racing horses. For comparison, a series of blood samples were procured from a 3 year old Standardbred at various times during an ongoing multi- race meet while consuming this invention supplemented into the usual type of ration fed to a racing horse: (1) post-training and pre-racing (Day 0) ; (2) early racing (Day 30) ; (3) mid-racing (Day 72) ; and, (4) late mid- racing (Day 107) . Standardbred-Racinq Late Protein Standardbred Thoroughbred Pre-Race Early Race Mid-race Mid-Race Electrophoresis Post-race Meet Post-race Meet Day 0 Day 30 Day 72 Day 107 Units Albumin Alpha-1 Globulin Alpha-2 Globulin Beta-1 Globulin Beta-2 Globulin Gamma Globulin *L - Lower than normal value H - Higher than normal value The rate of synthesis of plasma protein by the liver depends on the concentration of amino acid in the blood. Consequently, the concentration of proteins be¬ comes reduced whenever an appropriate supply of amino acid is not available. Conversely, when excess proteins are available in the plasma but insufficient proteins are available in the cells, the plasma proteins are used to form tissue cells. Undoubtedly, this is the sequence that is occurring when the plasma protein level is measured in horses that are continuously raced and con¬ sume a normal performance-type feed ration. Essentially, all the albumin of the plasma proteins, as well as 60 to 80 percent of the globulins, are formed in the liver. The remainder of the globulins, mainly the gamma globu- lins which constitute the antibodies, are formed in the lymphoid tissue and other cells of the reticuloendo- thelial system. The principal function of albumin is to provide colloid osmotic pressure which prevents plasma loss from capillaries. The globulins also perform a number of enzymatic functions in the plasma but princi¬ pally they are responsible for the natural and acquired immunity against invading organisms. Regardless of the diet available, the albumin content of plasma protein is firstly and sizeably increased when a horse begins continuous racing. Unless excess amino acids become available from the diet, the globulin fraction of plasma protein, with the exception of the immunogenic gamma globulin fraction, found in racing horses is substantially reduced with continuous racing. Even though the colloid osmotic pressure of the plasma is a weak osmotic force, it plays an exceedingly important role in the maintenance of normal blood and interstitial fluid volumes. Since 1 gram of albumin contains twice as many molecules as 1 gram of globulin, each gram of albumin exerts twice as much osmotic pres¬ sure as each gram of globulin. Since there is almost 50 percent more albumin than globulin, about 60 percent of the total osmotic pressure of the plasma in racing horses results from the albumin fraction and about 40 percent from the globulins. Capillary hemodynamics in non-racing horses are mainly influenced by albumin. However, a further discovery is that in racing horses the globulins, and primarily the alpha-1 globulin fraction, sub¬ stantially effect the total colloid osmotic pressure of the plasma. The alpha-1 globulin level is increased between about 3 to about 10 times more in continuously racing horses consuming this invention daily than the level found in continuously racing horses not consuming this invention. With the daily intake of this invention admin- istered at maximum therapeutic dosage to prevent or elim¬ inate EIPH the globulin fraction of the plasma proteins becomes substantially increased in racing horses. The concentration of the alpha-1 globulin fraction especially becomes increased many times more than the other globulin fractions. The colloid osmotic pressure exerted by al- pha-1 globulin at every plasma protein concentration is more than twice that produced by the same plasma protein concentration of albumin, thus positively influencing the non-appearance of EIPH and the markedly improved perform- ance of racing or maximally exercising horses sup¬ plemented daily with this invention. Example 7 This example illustrates the preparation and utilization of specialized forms of this invention that can be alternately and adjunctly used for the prevention or elimination of EIPH in racing or maximally exercising horses. The test was conducted to demonstrate that vari¬ ous physical forms of this invention produce identical observable physiological effects, ie. increased water intake and increased urine excretion, as observed in the safest and most practical methods of administration, namely, as dry formulations or aqueous solutions added to the daily feed ration and voluntarily consumed by the horse. Hard capsules were prepared from the following formulation: 225 g of urea 160 g of potassium chloride The above ingredients were thoroughly mixed with each other and the mixture was filled into gelatin capsules. Each capsule contained about 28.6 g of the composition and thus about 16.6 g of urea, about 11.8 g of KCl and about 800 mEq Mg 2+ . The capsules were adminis¬ tered on a daily basis to horses. Tablets were prepared from the following formu- lation: 225 g of urea 160 g of potassium chloride 5 g of magnesium stearate The active ingredients were thorougly mixed with magnesium stearate and compressed into tablets, each weighing about 100 g and containing about 58 g of urea and about 41 g of KCl. The tablets were considered suit¬ able for administration to horses. Compositions defined above are readily absorbed into the bloodstream after reaching the stomach and in¬ testine when given orally. The oblets provide an alter¬ nate or adjunct method of prophylactic or curative treat¬ ment of EIPH in racing or maximally exercising horses. A series of tests were performed on each of two horses, one a 4 year old Thoroughbred gelding, 431 kg body weight, the other a 4 year old Standardbred gelding, 428 kg body weight, using the above formulations and documenting the resulting observable physiological ef¬ fects. Each test period duration was seven days with a recovery period of the same length of time. During the two tests, the Thoroughbred animal received an effective daily dosage of urea of between about 475 mg/kg body weight to about 535 mg/kg body weight and between about 225 mg/kg body weight and about 380 mg/kg body weight of KCl, while the Standardbred was given about 485 mg/kg body weight and about 540 mg/kg body weight of urea and between about 230 mg/kg body weight and about 385 mg/kg body weight of KCl. Each test animal received supplemental NaCl to provide a total daily intake of about 1400 mEq Na + . The total daily feed intake along with the administration of the specialized forms of this invention provided each test animal with a daily intake of about 3800 mEq of urea and about 6300 mEq of K + . The animal's daily feed provided a total daily intake of about 900 mEq of Mg 2+ . In both test animals, during these tests, no- ticeable physiological effects, ie. increased water in¬ take and increased urine excretion, occurred when the tablets and hard capsules were given orally. By the second day after the start of oral administration of these formulations, the physiological effects became noticeably elevated and remained at that level until the third day after completion of the tests, at which time, both water intake and urine excretion decreased to pre¬ test levels. The two test horses did not react adversely to the oral administration of the specialized forms of this invention. No evidence of colic or gastrointestinal upset occurred in these horses during these tests. It is evident from this example that regardless of the physical form of this invention, the occurrence of noticeable physiological effects, after oral administra¬ tion, were identical whether the horse was racing, maxi¬ mally exercising or in a maintenance condition. It thus follows that the etiopathogenesis of EIPH in racing or maximally exercising horses could also be prophylac- tically or curatively treated by oral administration of specialized forms of this invention. While I have described and given examples of preferred embodiments of my invention, it will be appar¬ ent to those skilled in the art that changes and modifi¬ cations may be made without departing from from my inven- tion in its broader aspects. I therefore intend the ap¬ pended claims to cover all such changes and modifications as fall within the true spirit and scope of my invention.

Claims: CLAIMS 1. A method for treating or preventing exercise- induced pulmonary hemorrhage in an animal characterized by administering to the animal a mixture of urea, and pharmaceutically acceptable salts thereof, and an alka¬ line potassium salt. 2. A method according to claim 1 wherein the alka- line potassium salt is potassium chloride, potassium citrate, potassium phosphate, potassium nitrate, potas¬ sium sulfate, potassium acetate, or potassium gluconate. 3. A method according to claim 2 including a third chemical additive containing a magnesium salt. 4. A method according to claim 3 wherein the mag¬ nesium salt is magnesium oxide, magnesium hydroxide, mag¬ nesium phosphate, magnesium sulfate, magnesium acetate, magnesium chloride, magnesium adipate, magnesium lactate, magnesium gluconate or magnesium carbonate. 5. A method according to claim 1, wherein the mixture comprises about 1 to about 65 percent by weight urea, and about 0.05 to about 50 percent by weight alka¬ line potassium salt. 6. A method according to claim 5 including about 0.25 to about 25 percent by weight of magnesium salt. 7. A method according to claim 4 wherein the ani¬ mal is a horse and the mixture is included in the daily diet of the animal in an amount between about 100 to about 1250 mg/kg body weight of the animal. 8. A composition for prophylactic and curative treatment of exercise-induced pulmonary hemorrhage in an animal characterized by: (a) urea and pharmaceutically acceptable salts thereof; and (b) an alkaline potassium salt. 9. A composition according to claim 8 wherein the alkaline metal salt is potassium chloride, potassium citrate, potassium phosphate, potassium nitrate, potas¬ sium sulfate, potassium acetate, potassium gluconate or potassium silicate. 10. A composition according to claim 8 including a magnesium salt. 11. A composition according to claim 10 wherein the magnesium salt is magnesium oxide, magnesium hydroxide, magnesium phosphate, magnesium sulfate, magnesium acet- ate, magnesium chloride, magnesium adipate, magnesium lactate, magnesium gluconate or magnesium carbonate. 12. A composition according to claim 8 wherein the urea makes up about 1 to about 65 percent by weight of the composition. 13. A composition according to claim 12 wherein the alkaline potassium salt makes up about 0.05 to about 50 percent by weight of the composition. 14. A composition according to claim 13 wherein the magnesium salt makes up about 0.25 to about 25 percent by weight of the composition.

Inventors: MILLS JOHN A, MILLS, JOHN, A.
Applicants: MILLS JOHN A, MILLS, JOHN, A.
Application year: 1991
Main classification: A61K33
IPC codes: A61K33