Patent Publication Number: US-2004053938-A1

Title: Novel method and device for treatment of exercise induced pulmonary hemorrhage in horses

Description:
[0001] This application claims the benefit of priority in U.S. Provisional Application Serial No. 60/309389 filed on Aug. 1, 2001. 
    
    
     
       FIELD OF THE INVENTION  
       [0002] The present invention generally relates to methods and devices for inhalation therapy in horses. In particular, the invention relates to methods and devices for nebulization therapy in horses for the treatment and prevention of respiratory conditions including Exercise-Induced Pulmonary Hemorrhage (EIPH) and related pulmonary sequella in the horse.  
       BACKGROUND OF THE INVENTION  
       [0003] Exercise Induced Pulmonary Hemorrhage (EIPH) is an endemic production disease of racing and other high-intensity exercise horses. EIPH or “bleeding” has been a recognized condition in racing horses for at least three hundred years. Virtually all horses that are subjected to intense exercise bleed into the lungs, and these episodes of bleeding often commence as soon as these horses enter training. Healing occurs, but complete restoration of pulmonary function in the affected area often does not occur. Repeated episodes of intense exercise can result in repeated episodes of pulmonary hemorrhage, and cumulative damage to the affected lung tissue can occur such as e.g., fibrosis and/or scaring and consolidation of alveoli. These chronic changes occur, particularly in the dorso-caudal lobes of the lung, and such changes can eventually curtail the performance of the horse.  
       [0004] Preventative/ameliorative/curative/restorative measures for EIPH affected horses have also been sought for several hundred years. For many years, the treatment of choice for prevention of EIPH in the race horse has been pre-race treatment with the diuretic furosamide (Lasix®). The exact mechanism of action of furosamide in prevention of EIPH is unknown, although many theories have been postulated over the years. The treatment of choice for EIPH, after the fact, is usually rest (mandatory in many racing jurisdictions) and often in conjunction with antibiotics to prevent secondary bacterial infection and/or the use of anti-inflammatory medication.  
       [0005] More recently, (following the research of West et al. J. Appl. Physiol. 1993, 75: 1097-1109 related to the relationship of EIPH and increased pulmonary artery pressure) attempts at treating EIPH via nitric oxide administration have been tried, e.g., by Perry (U.S. Pat. No. 5,765,548). Perry describes administration of nitric oxide through continuous insufflation of the nitric oxide to the horse during the exercise period. Alternatively, the horse is treated with insufflation of nitric oxide prior to the exercise event and then is given an intramuscular injection of a phosphodiesterase inhibitor, e.g., ZAPRINAST. The treatment during exercise as described by Perry is both cumbersome and problematic for the racing animal and has never gained widespread acceptance. Likewise, systemic treatment of the racing animal with phosphodiesterase inhibitors opens the door for unwanted side effects and requires regulatory scrutiny.  
       [0006] Thus, prior to the present invention, there has not been a safe and effective method to prevent and/or treat EIPH in the racing animal. Accordingly, there still exists a need in the art for such methods.  
       OBJECTS OF THE INVENTION  
       [0007] It is an object of the invention to provide an inhalation therapy regimen and system for the treatment and/or prevention of EIPH comprising the inhalation of a therapeutic amount of sildenafil citrate and/or the metabolites of sildenafil citrate alone or in combination with other compounds.  
       [0008] It is a further object of the invention to provide a device suitable for inhalation delivery of a pulmonary therapeutic agent, e.g., delivery through an equine nasal cannula into the nasal passages of an equine.  
       [0009] Another object of the invention is to provide a device comprised of an equine nasal cannula designed to place the therapeutic inhalant directly into the nasal passages without covering the nasal openings of the subject equine thereby allowing reasonable mobility and reducing patient discomfort while undergoing therapy and thereby improve patient acceptance.  
       [0010] Thus, a primary object of the invention is to provide an improved apparatus or device for delivery of an inhaled therapeutic regimen into the nasal passages of an equine wherein said device is comfortable for the equine and is also easy to visually inspect and maintain when in use.  
       [0011] Still another object of the invention is to provide prophylactic and therapeutic benefits of sildenafil citrate, or the metabolites of sildenafil citrate, as a nebulized inhalant inducing the local release of nitric oxide or precursors or donors. Sildenafil citrate and/or its metabolites, salts, isomers and/or derivatives thereof, used according to the invention may be administered alone or in combination with other agents, in the prophylaxis, treatment, and resolution of the pathological changes associated with Exercise Induced Pulmonary Hemorrhage (EIPH) in horses.  
       SUMMARY OF THE INVENTION  
       [0012] In the field of veterinary medicine, the equine athlete and particularly the racing equine, may, and many indeed will, develop Exercise Induced Pulmonary Hemorrhage (EIPH) due to the training and exercise requirements needed to effectively compete in athletic events. The current invention provides a method and device for the administration of single or combined therapeutic elements, e.g., comprised of sildenafil citrate and other components, to provide an effective remedy for EIPH.  
       [0013] The device of the invention allows for the uninterrupted administration of a specified therapeutic regimen in such a manner that the subject equine is able to maintain adequate mobility during therapy, e.g., to move about a stall or to allow access to food and water while continuously receiving therapy. Therapy may generally be administered before and/or after exercise, training or exertion. The concentration of the active comprising the therapeutic mixture and the rate of delivery can, of course, vary according to the apparent physical condition (e.g., size of the animal and severity of EIPH) and specific needs of each individual equine.  
       [0014] Thus, the present invention provides an inhalation therapy regimen administered through, e.g., a non-invasive equine nasal cannula device as also provided by the invention. In one embodiment, the therapy regimen includes the introduction of a composition comprised of sildenafil citrate or congeners of sildenafil citrate with or without potentiating agents delivered to the subject equine via the attendant inhalation therapy system in a non-invasive manner that is conducive to the care and comfort of the equine mammal under treatment. In one embodiment the composition comprised of sildenafil citrate is nebulized for delivery as an inhalant into the pulmonary system of the subject equine. 
     
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
     [0015]FIG. 1 is a schematic representation of the device of the invention in use on a horse. Bilateral nasal cannulas can be seen in a desired position adjacent the horse&#39;s nostrils for delivery of a therapeutic inhalant agent.  
     [0016]FIG. 2 is a top plan view of one embodiment of the device of the invention.  
     [0017]FIG. 3 is a perspective view of one embodiment of the nasal cannula portion of the device of the invention.  
     [0018]FIG. 4 is a perspective view of one embodiment of the inhalator manifold of the device of the invention.  
     [0019]FIG. 5 is a perspective view of one embodiment of the nebulization apparatus and air supply for delivery of a desired therapeutic agent via the device of FIGS.  1 - 2 .  
     [0020]FIG. 6 is a color digital photograph showing a left elevational view of one embodiment of the device of the invention.  
     [0021]FIG. 7 is a color digital photograph showing a left frontal view of one embodiment of the device of the invention.  
     [0022]FIG. 8 is a color digital photograph showing a top plan view of one embodiment of the device of the invention.  
     [0023]FIG. 9 is a perspective view of an alternate embodiment of the inhalator manifold shown in FIG. 4. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
     [0024] The foregoing and other objects, features and advantages of the present invention should become apparent to those of skill in the art in the following description when taken in conjunction with the accompanying drawings and through practice of the invention.  
     [0025] The present invention provides a device and method for convenient, patient compliant inhalation therapy of equine species. The device of the invention can be used to deliver any agent to the nostrils or nasal passages of a horse for inhalation therapy and can be used to treat any of a number of conditions including, but not limited to e.g., pneumonia (bacterial and viral mediated), asthma or heaves and the like. However, a preferred utilization of the device as set forth herein is in the treatment and/or prevention of EIPH and related pulmonary conditions in horses.  
     [0026] The inhalation therapy device and regimen provided herein comprises a non-invasive equine nasal cannula developed exclusively to deliver an inhalant therapy mixture primarily for use in the treatment of equine exercise induced pulmonary hemorrhage (EIPH) and related ailments. As can be appreciated by one of skill in the art, the equine nasal cannula (the device) of the invention can also be used for delivery of any mendicant suitable for or adapted for inhalant delivery including, but not limited to the simple placement of oxygen into the nasal passages of equine mammals or any of a number of inhalant delivery forms known in the art, e.g., via nebulization of the active.  
     [0027] The Equine Nasal Cannula  
     [0028] As shown in FIG. 1, one embodiment of the device  10  of the invention is an equine nasal cannula that is designed with means  20  for removable attachment to the head  30  of the subject equine. In the embodiment shown, in FIG. 1, the device  10  and attachment means  20  are shown attached to the head  30  of the subject equine and lying beneath a standard equine halter  60 . Thus, one of skill in the art can appreciate that the device  10  and attachment means  20  can be attached and used independent of but in conjunction with halters, bridles or other equine head gear. Alternatively, the attachment means  20  can be connected directly to or integral with (incorporated into, e.g., a halter of the type shown in FIG. 1 (halter  60 ) or as shown in FIG. 2.  
     [0029] In the embodiment shown in FIG. 1, the attachment means  20  itself is a halter-type or halter-like apparatus constructed of nylon or leather with adjustable straps for securing to the head  30  of the subject equine and is separate from halter  60 . As set forth more filly below, the attachment means  20  for the device  10  can be separate from halter  60  or integrated therein. As can be appreciated by one of skill int the art, the attachment means can be constructed from other suitable materials including, but not limited to plastic, rope and the like.  
     [0030] The device  10  is held in position by attachment means  20  such that the distal ends  16 ,  18  of elongated delivery tubes  12 ,  14  (cannulas) are placed adjacent the external openings  32 ,  34  of the subject equine&#39;s nasal cavity (adjacent the nares) so as to effectively deliver the composition selected for inhalation at the appropriate site. In a preferred embodiment, the methods of the invention provide for delivery of a preselected active ingredient via device  10  in an inhaled therapeutic regimen comprised of at least one active delivered directly into the apertures of the equine&#39;s nasal passages in such a manner as to allow the inhalation of substantially the entire volume of the therapeutic composition delivered to the equine&#39;s nasal passages.  
     [0031] In the presently preferred embodiment, the device  10  of the invention (the equine nasal cannula) is comprised of a nylon attachment means  20  (similar to a halter) that is configured to adapt to the contours of the equine skull  30  in such a manner as to effectively place and hold the distal ends  16 ,  18  of the elongated delivery tubes  12 ,  14  in a desired position for the administration of a therapeutic inhalant while minimizing the requirements for specialized animal restraint and/or restriction of movement.  
     [0032] This device  10  (equine nasal cannula) is designed in such a way as to place the inhalation therapy stream, e.g., a nebulized composition or simply oxygen directly into the nasal apertures  32 ,  34  (adjacent the mucocutaneous junction of the nares) without entering or occluding or otherwise covering the nasal passages. This device and protocol also has the advantage of reducing the tendency for the nasal passages to become dry and irritated during therapy.  
     [0033] In one embodiment, padded extrusions (not shown) are provided at the distal ends  16 ,  18  (nasal end) of the elongated tubes  12 ,  14  (cannulas) to prevent injury or irritation that may occur from rubbing the nostrils or the inner linings (mucosa) of the nostrils. The padded extrusions can be designed with slots on the sides or holes or other such configurations to enable the flow of the therapy stream to continue in the event a portion of the cannula outlet becomes blocked or clogged with mucus or from exhaled environmental contaminates.  
     [0034] The device  10  or equine nasal cannula can be designed to conform to or become an integral part of harness and/or bridle or other halter-type equipment normally associated with the training and racing of equine athletes. The device  10  or equine nasal cannula is user friendly in that it closely resembles equipment that racing animals are familiar with. Further, the device  10  or equine nasal cannula is easy to position on the equine animal&#39;s head  30  and is easily adjustable to fit nearly any equine. When constructed of a suitable material such as nylon, plastic or leather, it is also easy to care for and clean.  
     [0035]FIG. 1 is a perspective view of an equine head  30  fitted with the device  10  (equine nasal cannula) (showing the device in use) e.g., preparatory to receiving a composition comprised of sildenafil citrate and/or its congeners, potentiating agents, complementing agents and carrier gases for the treatment or prevention of EIPH.  
     [0036] While the device  10  (equine nasal cannula) in the illustrations contained herein has specific dimensional and other characteristics (see, FIGS.  2 - 5 .), one of skill in the art will appreciate that other variations are possible and are within the scope of the invention. Thus, the dimensional and other characteristics shown in FIGS.  2 - 5  are in no way intended as limitations and are only illustrative of one embodiment of the present invention.  
     [0037] In a preferred embodiment shown in FIG. 3, the elongated tubes (shown as  12 ,  14  in FIG. 1) are adjustable and may be adapted for use with different size horses i.e., for lengthening or shortening the tube length so as to provide the proper distance or length of tube such that distal ends  16 ,  18  are properly positioned at the external opening of the equine&#39;s nose  32 ,  34  thereby directing a fluid flowing there through directly into the equine nasal openings. In the embodiment shown in FIG. 3, the adjustment means for elongated tubes  12 ,  14  comprises a first segment or tube  13  having a distal end  15  with an inside diameter that is sized complimentary to the outside diameter of the proximal end  17  of a second segment or tube  19  such that the proximal end  17  of the second segment  19  is slidably and sealingly engaged with the distal end  15  of the first segment  13 .  
     [0038] As illustrated in FIG. 3 and by way of example, one embodiment of the invention comprises two segments of clear plastic or neoprene elongated tubing  13 , 19  wherein the first segment  13  is comprised of a ¼ inch inside diameter (I.D.) and the second segment  19  comprises a ¼ inch outside diameter (O.D.) whereby proximal end  17  of the second segment  19  is slidably and sealingly engaged within the distal end  15  of first segment  13 . A presently preferred embodiment of the invention however, comprises two segments of clear plastic or neoprene elongated tubing  13 , 19  as shown in FIG. 3 wherein the first segment  13  is comprised of a {fraction (5/16)}th inch inside diameter (I.D.) and the second segment  19  comprises a {fraction (5/16)}th inch outside diameter (O.D.) whereby proximal end  17  of the second segment  19  is slidably and sealingly engaged within the distal end  15  of first segment  13 . Of course, one of skill in the art can appreciate that other configurations, sizes of tubing and choice of materials are possible and are within the scope of the invention.  
     [0039] Referring now to the attachment means  20 , shown in the embodiment set forth in FIGS.  1 - 2 , another embodiment contemplated by the invention is to have the attachment means  20  incorporated into or integral with halter  60 . In this alternate embodiment, the upper portion of the halter-like structure can have an elastic or other adjustable band, the crown strap  22  which is attached to buckles  40  at distal ends  23  and designed so as to fit the subject equine&#39;s head  30  behind the ears  36 . Crown strap  22  can further comprise adjustable fasteners (not shown) at for attaching to buckles  40  for adjustment of crown strap  22  to fit different sized heads  30 .  
     [0040] Forehead strap  24  can slidably attach to crown strap  22  adjacent to or confluent with adjustable throat latch  26  which works in conjunction with the crown strap  22  to secure the upper portion of attachment means  20  to the head  30 . Optionally, the forehead strap  24  can attach to buckles  40  depending upon the desired length of crown strap  22 . Cheek straps  25  are connected to buckles  40  at the proximal ends  27 ,  28  thereof and can be connected to the nose band assembly  42  at the distal ends of cheek strap  25 .  
     [0041] Still referring to FIGS.  1 - 5 , the lower portion of the halter-like configuration of attachment means  20  of device  10  can be configured to surround the mandibles  33  of the head  30  to hold the elongated delivery tubes  12 ,  14  firmly in place on the bridge of the equine&#39;s nose. For example, a portion of the lower section may contain an elastic nose band assembly  42  (with/or without adjustable fasteners) designed in a “figure 8” arrangement so as to fit firmly under the throat latch, over the bridge of the nose and under the chin such that the strap of the figure-8 loop crosses over the bridge of the nose thereby enabling elongated tubes  12 ,  14  of the cannula device cannula to be held in place throughout the therapy regimen. Nose band assembly  42  which comprises the lower portion of attachment means  20  can be connected to the upper portion of attachment means  20  by nose bridge strap  49 . The proximal end of nose bridge strap  49  attaches to forehead strap  24  and attaches at its distal end to nose band  42 .  
     [0042] In the embodiment shown in FIGS.  1 - 2 , the nose band assembly  42  can optionally further comprise a bridge band  44  having distal ends  45 ,  47  designed to fit over the bridge of the equine&#39;s nose and attach to a triple loop buckle assembly (such as is shown in FIG. 1 at  50 ) at proximal and distal ends  45 ,  47  of bridge band  44 . Adjustable chin strap  48  may also be connected to triple loop buckle assembly  50  to give additional support and security to the attachment means  20 . It can be appreciated that buckle the triple loop buckle assembly  50  can have a variety of configurations varying from the ring like structures shown in FIG. 1 to other configurations known in the art.  
     [0043]FIG. 4 is an isolated view of an inhalator manifold  70  which can be used to connect the remote drug supply means, e.g., the nebulizers  80  and pressurized air supply  90  shown in FIG. 5 and facilitate delivery of the active agent to the desired site. The inhalator manifold  70  can be constructed of any suitable material including metals such as aluminum, stainless steel, plastics and the like. The proximal end  72  of inhalator manifold  70  is adapted for a removable connection to air supply tube  74  at its distal end  76 . Preferably, the air supply tube  74  is flexible, elastic and constructed of a reinforced material such as rubber or plastic. In one embodiment, the air supply tube  74  is a ¼ inch flexible wire reinforced clear plastic tubing. The proximal end (not shown) of flexible tube  74  connects to the air supply and drug source. The distal end  77  of inhalator manifold  70  contains a means for sealing yet removable connection to elongated tubes  12 ,  14  as shown in FIGS.  1 - 2  and FIGS.  6 - 8 .  
     [0044] A presently preferred embodiment of the inhalator manifold is shown in FIG. 9. FIG. 9 is an isolated perspective view of inhalator manifold  970  and is an alternate embodiment of the inhalator manifold  70  shown in FIGS. 1&amp; 4. Inhalator manifold  970  can be used to connect the remote drug supply means, e.g., the nebulizers  80  and pressurized air supply  90  shown in FIG. 5 to elongated tubes  12 ,  14  as shown in FIGS.  1 - 2  and FIGS.  6 - 8 . The inhalator manifold  970  can be constructed of any suitable material including metals such as aluminum, stainless steel, plastics and the like. The proximal end  972  of inhalator manifold  970  is adapted for a removable connection to the air supply tube (e.g., air supply tube  74  shown in FIG. 4). The proximal end (not shown) of the flexible air supply tube  74  in turn connects to the air supply and drug source (not shown). The distal end  977  of inhalator manifold  970  contains a means for sealing yet removable connection to elongated tubes or nasal cannulas of the type shown as elongated tubes  12 ,  14  in FIGS.  1 - 2  and FIGS.  6 - 8 .  
     [0045] In the embodiment shown in FIG. 9, distal end  977  of inhalator manifold  970  forms a “Y” bifurcation terminating in distal connecting ends  978 , 979  which are adapted for removable connection to the proximal ends of elongated tubes  12 , 14  shown in FIG. 1. Thus, fluid flow through the device will originate from an outside air supply (e.g., air supply  90  as shown in FIG. 5) and may pass through a nebulizer  80  for addition of an active agent or drug and into air supply tube  74 . The fluid composition containing the nebulized active then passes through air supply tube  74  into the proximal end  972  of the inhalator manifold  970 , through the “Y” bifurcation and distal connecting ends  978 , 979  and into elongated tubes (nasal cannulas)  12 , 14  for delivery into the equine nasal passages. The improved airflow properties of the “Y” bifurcation design of inhalator manifold  970  acts to lessen or reduce any tendency for the nebulized or atomized active agent to accumulate within the manifold. The inhalator manifold  970  also aids in providing the necessary airflow volume for delivery of various active agents, e.g., airflow volumes of between about 2-2.5 liters of air per minute. In one embodiment, the inside diameter of inhalator manifold  970  is about ⅝th of an inch to accommodate the desired airflow volumes.  
     [0046] In general, the dorsal portion of the lower section of the attachment means of the device (the equine nasal cannula) is designed to provide for the placement of the distal ends of two elongated plastic tubes into or adjacent to the nasal apertures (openings) of the equine mammal nasal passages.  
     [0047] The elongated plastic tubes are attached to the dorsal portion of the lower section of the attachment means in a manner allowing for movement of the tubes in two directions to enable the nasal portions of the tubes to be adjusted to fit the majority of equine mammals.  
     [0048] The elongated plastic tubes are connected to flexible plastic tubing via a manifold in such a manner as to provide firm but removable attachment to the thereto. This flexible plastic tubing connects the equine nasal cannula to the therapy supply at the source of the therapeutic inhalant or oxygen outside the confinement area of the equine.  
     [0049] The portion of flexible tubing extending from the cannula connection to the therapy supply can be wire spring reinforced to prevent collapse or the disruption of the therapy supply to the cannula.  
     [0050] In the embodiment shown in FIGS.  6 - 8 , the device  110  of the invention is designed such that attachment means  120  is a stand alone unit such that the device  110  and attachment means  120  can be attached to the subject equine with or without a halter, bridle or other related device. The device  110  and its adjustable attachment means  120  can be worn either under or over a halter, bridle, harness or the like.  
     [0051] The upper portion of attachment means  120  comprises an adjustable crown strap  122  which can be slidably attached at distal ends  123  to the lower portion of attachment means  120 . The lower portion of attachment means  120  is comprised of an adjustable “figure-8” nose band assembly  145 . The nose band assembly  145  is further comprised of a continuous strap  146  having two portions, an adjustable throat latch loop  148  and a chin strap portion  147 . The nose band assembly  145  is designed to fit around the equine muzzle such that an “X” is formed on the bridge of the nose of the subject horse as the continuous strap  146  loops under the chin of the horse and over the nose and under the throat latch. At the point where continuous strap  146  crosses itself (on the bridge of the nose) the device  110  and especially elongated tubes  112 ,  114  are attached or fastened to attachment means  120  via cannula attachment straps  149  as shown best in the top plan view of FIG. 8.  
     [0052] In the embodiment shown in FIG. 8, a first attachment strap  149   a  crosses over and around elongated tubes  112 , 114  substantially perpendicular to the long axis thereof and a second attachment strap  149   b  is located between elongated tubes  112 , 114  crossing over elongated strap  149   a  and under the point at which continuous strap  146  crosses (forms an “X” in the “figure-8” configuration as set forth above) on the bridge of the nose. Optionally, a nose bridge pad  190  may be incorporated into the above-arrangement to provide additional stability and support for the attachment of the device  110  as well as to add comfort to the subject equine.  
     [0053] A second nose bridge band  192  may optionally be incorporated into the distal loop (chin strap portion  147 ) of continuous strap  146  of nose band assembly  145  for additional support of device  110  and especially to aid in securing elongated tubes  112 , 114  in their proper positions. As shown best in FIG. 7, nose bridge band  182  can be slidably connected to the chin strap portion  147  of continuous strap  146 . In addition, velcro fasteners  184  or other type of fasteners known in the art may be added to nose bridge band  182  to hold elongated tubes  112 , 114  firmly into their desired position.  
     [0054] In another embodiment, the invention provides a method for providing inhalation therapy in an equine. As set forth above, the methods and device of the invention can be used to deliver to an equine subject any drug or other pharmaceutical agent which can be adapted for inhalation into the lungs of the subject animal. In a presently preferred embodiment, the invention provides a method for the treatment or prevention of EIPH, wherein the composition for inhalant therapy is a mixture comprised of sildenafil citrate or its congeners (e.g., metabolites, isomers, salts or other active derivatives of sildenafil citrate) using air as the delivery vehicle to carry the inhalant into the equine mammal. The sildenafil citrate or its metabolites in conjunction with the other specified elements can be nebulized into the inhalant stream at flow rates and drug delivery rates that will vary depending upon many factors, including but not limited to the relative severity of the EIPH coupled with the age, weight and gender of the equine being treated. It can be appreciated that the inhalant therapy may be administered as a pre-exercise or pre-activity treatment to lessen or eliminate the effects of exercise-induced pulmonary hemorrhage (EIPH). The inhalant therapy may also be administered post-exercise or post-activity to treat or aid in the recovery of the lung from the damage induced by EIPH in the equine athlete.  
     [0055] Although the presently preferred embodiment of the invention contemplates the use of the phosphodiesterase inhibitor sildenafil citrate as the preferred active for the methods set forth herein in the treatment and/or prevention of EIPH, it is specifically contemplated that other phosphodiesterase inhibitors are within the scope of the invention. Other phosphodiesterase inhibitors, including but not limited to e.g., ZAPRINAST, may be administered to the animal as an inhalant therapy, e.g., via nebulization, for the treatment of EIPH or pulmonary hypertension.  
     [0056] Elevations of the levels of nitric oxide created by the administration of compositions according to the methods of the invention e.g., administration of a nebulized sildenafil citrate into the pulmonary airways of horses prior to exercise, reduce the incidence of EIPH because of the effect of the released nitric oxide within the lung tissue. Since EIPH is believed to be caused by the very high blood pressures occurring in the lungs of intensely exercising horses, sildenafil citrate (or other phosphodiesterase inhibitors) induced nitric oxide dependent vasodilation acts directly to reduce the incidence and intensity of EIPH. The administration of nebulized sildenafil citrate into the airways of horses following exercise accelerates the resolution of the pathological changes in the lungs of horses because of its potent vasodilator properties.  
     [0057] Therefore, one method of prevention of EIPH comprises the use low levels sildenafil citrate administered as an inhalant directly into the lungs to locally elevate nitric oxide concentrations in the lungs of horses that are about to perform intense exercise and thereby avoid the potential side effects of systemic administration. This therapy regimen will allow horses to benefit from the preventive or prophylactic effects of sildenafil citrate released nitric oxide and its action against EIPH. This treatment regimen can also be provided as a therapeutic regimen following intense exercise to produce sildenafil citrate induced nitric oxide dependent vasodilation, thereby accelerating resolution of the pulmonary lesions associated with EIPH.  
     [0058] In one embodiment the methods of invention for the treatment and/or prevention of EIPH can comprise administration of between about 0.01 mg/kg and about 10 mg/kg of sildenafil citrate. A presently preferred embodiment, comprises administration of about 2.0 mg/kg of sildenafil citrate.  
     [0059] In one embodiment, the anticipated typical dosage would be based on a composition comprised of about 2.0 mg/kg combined sildenafil citrate admixed with about 500 cc sterile water and nebulized into the air flow at a rate of between about 50-200 parts per million (ppm) but especially between about 80-100 ppm for a specified period of time, e.g., for a minimum of about 2 hours per day per treatment to a maximum of about 6 hours per day depending upon the severity of the EIPH. The sterile water and sildenafil citrate represents an aqueous solution to transport the active, sildenafil citrate, and any other desired components into the horse.  
     [0060] Another embodiment of the methods of treatment of EIPH provided by the present invention comprises administration of compositions comprised of 1-arginine with or without sildenafil citrate. As provided by the invention, it has been found that nebulization of and administration of 1-arginine or 1-arginine precursors or analogs of 1-arginine act as an accelerant in the formation of nitric oxide in the lungs of sildenafil citrate treated horses. Additionally, it is contemplated by the invention that the methods of treatment of EIPH can further comprise nebulization of and administration of nitroglycerin and other nitric oxide donors into the lungs of horses as a means of potentiating the benefits of nitric oxide releasing compounds such as, e.g., sildenafil citrate.  
     [0061] Further provided by the methods of the invention are administration of a composition comprised of an iron chelating agent to reduce the pathological damage in EIPH caused the presence of free iron, released from hemoglobin in the pulmonary tissues. As part of the prophylactic and or therapeutic regimen, the methods of treatment of EIPH can comprise a composition for nebulization and administration comprised of des-ferox amine in either a prophylactic or therapeutic approach to EIPH. Des-ferox amine, by chelating iron, reduces its chemical reactivity, and thereby its ability to generate reactive oxygen species and produce the typical cumulative pathological changes associated with EIPH.  
     [0062] In particular, it is contemplated that the following compounds can be used either individually or in various combinations for the prophylaxis and treatment of EIPH as provided by the invention: sildenafil citrate, or a pharmaceutically acceptable derivative thereof, e.g., an isomer, a metabolite, analog or a salt, zapranist, MY5445, dipryidamole; cyclic nucleotides and their derivatives or analogs; Type V phosphodiesterase inhibitors that include but are not limited to zapranist, MY5445, dipryidamole; nitric oxide precursors including L-arginine; nitric oxide donors that include nitroglycerin, isosorbide dinitrate, erythrityl tetranitrate, amyl nitrate, sodium nitroprusside, molsidomine, linsidomine chlorhydrate, S-nitro-N-acetyl-d, 1-penicillamine, S-nitroso-N-cysteine, S-nitro-N-glutathine, diazenium diolates, and combinations thereof; nitric oxide analogs and derivatives that include nitroglycerin, nitroprusside, and Sin-1. It is also contemplated that a permeabilizing agent may be administered concurrently with the afore-mentioned therapeutic agents to facilitate the passage of the compounds through cell membranes, particularly when the compound, drug, analog, or drug derivative is a cyclic nucleotide. A preferred embodiment of the permeabilizing agent is dimethlysulfoxide (DMSO) or its derivatives or analogs. Nebulization of and administration of the afore-mentioned compounds via the devices of the invention provide multiple alternatives for effective treatment and/or prevention of EIPH in horses.  
     [0063] The foregoing description of a preferred embodiment of the invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed. Obvious modifications or variations are possible in light of the above teachings. The embodiment was chosen and described to provide the best illustration of the principles of the invention and its practical application to thereby enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such modifications and variations are within the scope of the invention as determined by the appended claims when interpreted in accordance with the breadth to which they are fairly, legally and equitably entitled.