A weanling AQHA filly suffered from protein-losing enteropathy due to Bute (phenylbutazone) toxicosis. She had been administered the Bute following an adverse reaction to her routine vaccinations. She was treated by several different veterinarians, and hospitalized two times. She underwent various different treatments including plasma transfusions, hetestarch transfusions, antibiotics (Naxcel, penicillin, and SMZ's), and pink bismuth. She suffered from chronic diarrhea, dehydration, anorexia, severe colic episodes, weight loss, high fevers and intermittent facial swelling. In addition to these she also suffered from chronic upper respiratory disease.

After 5 months of illness, numerous vet bills, and various treatment regimens, a new veterinarian was introduced to the case. After numerous diagnostic tests, the diagnosis was protein-losing enteropathy. This filly began treatment with GastroPLUS™ and Pulmon-EZ™. After 5 days treatment with GastroPLUS™, this filly finally had a normal day and her progress continued from that point on. 5 weeks later, Pulmon-EZ™ was added to the treatment regime for the respiratory illness she had suffered from for months. Within 24 hours after beginning Pulmon-EZ™, her cough and snotty nose cleared up. She continued treatment with Pulmon-EZ™ for approximately 10 days. Treatment with a total of 4 bottles of GastroPLUS™ were used intermittently over a period of 7 months and completed by September 24, 2003. As of March 14, 2004, she still healthy and has begun ground training.
 

On September 5, 2002, April, a weanling 5-month-old AQHA show filly was vaccinated with 4 ways, flu/rhino, rabies, and West Nile Virus (WNV). The filly had been vaccinated at birth, 3, and 4 months of age for all of the above except WNV, without any adverse reactions. This was her first and only WNV vaccine. The day following the vaccinations the filly's head, vaccination area, chest and legs were significantly swollen. She had developed edema from her chest to along her ventral line. She was unable to walk without pain, was off her feed, stopped drinking, and had diarrhea. The treating veterinarian recommended 1 gm Bute 2x per day. On September 7, 2002, while administering the Bute via paste form, the ring slipped and an overdose of 6-7 grams was administered. The filly developed diarrhea and stopped eating and drinking. Pedialyte, salt water and Red Cell were given by the owner to avoid dehydration and help stimulate her. On September 9, 2002, the veterinarian examined the filly and in his opinion she was not dehydrated, but prescribed probios paste to help stop the diarrhea. GastroGuard was also prescribed but declined due to the high cost.

September 12, 2002, April was examined by another veterinarian who diagnosed "Bute toxicity" and referred her to an equine hospital where she was placed in ICU. Blood work determined that she was losing proteins rapidly, they were at 3.4. (Normal is 5.2-7.9 g/dL). The WBC was also low. A small ulceration was detected in the intestine but with no signs of perforation. She was treated with IV fluids, 2-3 liters plasma and also hetastarch transfusions, antibiotic therapy with Naxcel, and pink bismuth for the diarrhea. Hetestarch is a commonly used colloid. It is produced by chemical modification of the starch amylopectin, through hydrolysis and hydroxyethyl substitution, and is a modified branched chain glucose polymer.

April was given only a 20% chance of survival. Between September 15 and September 22, 2002 Aprils condition was up and down. The edema continued on her legs, chest and neck areas. Euthanasia was mentioned at one point. By September 23, 2002 she was eating and drinking well on her own. Protein was up to 4.0, and sodium up to 137 (normal is 136-142 mEq/L). The following day September 24, 2002, the filly had begun to develop pneumonia. Her protein dropped to 3.6 and her WBC also dropped. More plasma and hetastarch transfusions were administered and antibiotics were increased. By September 27, 2002, her blood work was normal and the following day she was released to go home.

By 6 P.M. on Aprils first day home, she became uncomfortable, bloated and gassy. Owner administered Banamine and whisky and hand walking was done with some improvement, but by 5 A.M. she began thrashing and threw herself down, and was taken back to the ICU. IV's were again administered, and numerous diagnostic tests were run. Her temperature was 104 F and her proteins and WBC were way down. Surgery was contemplated, but due to her extreme weakness was decided against. If she continued to worsen, euthanasia was again to be considered. She received another plasma transfusion, continued to improve and was discharged on October 5, 2002.

On October 22, 2002, April began swelling around her jowls, cheeks and chin. Hot packs would reduce the swelling and the veterinarian suspected that her teeth were bothering her and placed her on SMZ antibiotics. She developed a fever of 102 F, her diarrhea resumed, and she became gassy again. She had tremors and chills, was blanketed with 2 blankets and put under heat lamps. Banamine and whisky were again administered. Her swelling and fever continued and the treating veterinarian thought she may have a tooth abscess and wanted her to continue antibiotics. Another veterinarian felt she was too young for teething problems and felt she had developed the flu, he recommended penicillin. The swelling, low-grade fevers, diarrhea and gassy spells were intermittent through the month of November. By December, the fevers had subsided, but the chronic swelling of her face, cheeks, throat and jowls, and the soft stool continued through December and into the middle of January 2003.

January 9, 2003, when April tried to exercise herself, she developed a cough and snotty nose. January 19, 2003, the fillies snotty nose worsened and she began to have the chills again. A new veterinarian was called in. He suggested the following tests: Glucose absorption test to test for juvenile diabetes; malabsorption tests; anti-nuclear work up; CBC, and an intestinal biopsy (not feasible due to cost). He also wanted to test proteins and Albumin levels. The above tests were performed and the diagnosis was Protein Losing Enteropathy. He recommended ulcer medication, and in 4-6 months re-run CBC and ANA tests.

On January 26, 2003, Aprils' owner ordered GastroPLUS™ for the treatment of gastric ulcers.

On February 4, 2003, her snotty nose was still present and she began treatment with Naxcel 12cc 2x per day, to aggressively combat the respiratory infection.

February 5, 2003, April began treatment with GastroPLUS™, at 45cc oral 2x per day. That evening before the initial dosing, the filly's symptoms were still the same, snotty nose and chin swollen. The following morning no swelling was present, and she was dosed again. But by evening her jowl and chin were swollen again. After dosing with GastroPLUS™ in the evening, the swelling was down within 2 hours.

February 6, 2003, her swelling episodes were reduced and after dosing with GastroPLUS™ the swelling would be eliminated. On February 8, 2003, AM, her head was completely swollen. After dosing with GastroPLUS™ the swelling was down within an hour. That evening she was found down, suffering from chills and tremors, swelling was back and she was not eating. Again she was dosed with GastroPLUS™ and by 9 P.M. she no longer had the chills, and her swelling was gone. She had some swelling around her chin and jowls and again after dosing with GastroPLUS™ the swelling was gone.

February 9, 2003, was the last day of treatment with the antibiotic Naxcel.

February 10, 2003, her fifth day on GastroPLUS™, was her first completely normal day. The following day she finally had normal stool for the first time since Sept. 6, 2002. While April was responding favorably to the GastroPLUS™, and showing signs of recovering, she still had a way to go. When the dosages of the GastroPLUS™ were reduced from 45cc powder to 30cc powder on February 13, 2003, she began to show some slight swelling again, and also began a golf ball size lump in her throat. Her respiratory illness continued to be a problem in spite of the Naxcel she had received for 6 days.

Even though she still had the snotty nose, by February 15, 2003, she was very bright and beginning to show an attitude. April started getting some exercise and turn out time. April was improving very well, and had more normal days than not, with her energy level increasing. Swelling was infrequent now, but the snotty nose would keep reappearing.

By February 27, 2003 she appeared normal, attitude was good, swelling diminished, stools normal, but she had started to develop a cough. It worsened and her snotty nose continued.

On March 15, 2003, Pulmon-EZ™, another nitric oxide delivering product was added to her treatment regime. Pulmon-EZ™ uses nitric oxide precursors to support lung function and to help combat chronic respiratory disease. April had not been able to shake this respiratory illness that began on January 9, 2003, even though she had been on Naxcel and penicillin several times over the previous months. 

April began Pulmon-EZ™ in addition to GastroPLUS™ on March 15, 2003, and her respiratory illness, snotty nose and chronic coughing ceased by the next day. April remained on Pulmon-EZ™ for less than 2 weeks, as her symptoms were relieved immediately. She remained on GastroPLUS™ and was gradually weaned off of that product. First by lowering the dosages, then decreasing the frequency of doses. By May 18, 2003, she was dosed with GastroPLUS™ every other day and then only twice a week. She has not had any GastroPLUS™ since September 24, 2003.  Every so often she will have a little swelling in her jowls, or some softer stool. Overall April is now in very good health. With everything the owner has been through she found that in addition to successfully treating her internally with GastroPLUS™ and Pulmon-EZ™, that her feeding has also been a factor in Aprils condition. Coarse hay is not well tolerated, so only fine stem hay is fed to April. April and all the others at this facility owned by Vicki Spina- Maraugha are very well cared for, and follow a strict de-worming and vaccination program.

Protein losing enteropathy is a disease affecting the gastro intestinal system resulting in protein loss when the epithelial cell barrier is lost due to mucosal ulceration, or when interstitial edema disrupts the tight junctions between epithelial cells. Protein-losing enteropathy has most commonly been associated with mucosal absorptive defects such as granulomatous enteritis, eosinophilic gastroenteritis, gastrointestinal neoplasia (lymphosarcoma, and squamous cell carcinoma), intestinal parasitism, acute salmonellosis, congestive heart failure and NSAID toxicity.

Aprils' Protein-losing enteropathy is thought to have been caused from NSAID toxicity, the Bute overdose she received when the plastic ring slipped on the paste Bute she had been administered. Bute was prescribed to try and relieve the pain and swelling caused by the reaction to her vaccines. According to research, severe intestinal protein loss from mucosal ulceration resulting from NSAID toxicity is caused from high doses of phenylbutazone (Bute) or other NSAIDs given over a period of several days. Experimentally, hypoproteinemia has developed in horses even when a standard dosage of NSAIDs has been administered. The implication is that stress and dehydration increases the susceptibility of the horse to the adverse affects of NSAIDs. April was already experiencing diarrhea, and was quite possibly dehydrated before the Bute was administered.

Experimentally induced Bute toxicosis in ponies produces ulcerations in the mucosa of the tongue, gingiva, hard palate, stomach, small intestine and the colon. Gastric ulceration induced by NSAIDs involves increased gastric mucosal permeability to hydrogen ions, inhibition of mucus synthesis, and decreased gastric mucosal blood flow. There is growing evidence in humans that NSAID toxicity (example: ibuprofen) increases permeability of the small and large intestinal mucosa by damaging the intercellular junctions.

Bacterial invasion of the submucosa after damage to the mucosal barrier appears to be important in the pathogenesis of the ulcerative lesions.

Phenylbutazone (Bute) toxicity has been thought to be a cause of protein-losing enteropathy attributable to extensive ulceration of the right dorsal colon. Gross examination has revealed severe diffuse ulceration and congestion of the tunica muscuilaris. Fibrinonecrotic debris partially covers the ulcerated mucosa. Microscopic examination reveals a mixed population of inflammatory cells and fibroblast proliferation. It is postulated (a set of criteria for judging whether a given bacterium is the cause of a given disease) that small ulcers form initially and are then invaded by colonic bacteria. Mucosal regeneration is impaired and a chronic active disease results.

Clinical signs usually associated with protein-losing enteropathy include: lethargy, exercise intolerance, weight loss, diarrhea, intermittent colic and dependent edema. The edema is secondary to low plasma oncotic pressure caused by hypoalbuminemia. Anorexia, depression and weight loss are the most common clinical signs when gastric sguamous cell carcinoma is present. Acute colic and clinical signs of endotoxemia sometimes occurs in protein-losing enteropathy caused by NSAID toxicity or severe intestinal parasitism.

Laboratory findings: Hypoalbuminemia with decreased, increased or normal plasma globulin concentrations characterizes the plasma protein changes in protein-losing enteropathy. Because hyperglobulinemia occurs in many different gastrointestinal diseases, total plasma protein concentrations are often normal. Quantitation of protein fractions is an important laboratory evaluation when protein-losing enteropathy is suspected. With horses suffering from granulomatous enteritis, early intestinal protein loss involves relatively greater quantities of albumin than globulins, whereas all protein fractions may be lost in the later stages of disease.

Recommended treatments for protein-losing enteropathy involve managing the primary disease and/or treatment of hypoproteinemia. Plasma transfusions are necessary when total protein concentration decreases below 4g/dL. It must be realized that continued protein losses tend to decrease the efficacy of the plasma transfusion. NSAID therapy should be discontinued if hypoproteinemia or signs of gastrointestinal disease are noted. For NSAID toxicity, broad-spectrum antimicrobial drugs can help. Cimetadine (Tagamet) and other histaminergic receptor antagonists allow the body's own healing process of the gastric ulcers, but do not treat protein-losing enteropathy. It is advisable for horses receiving Cimetidine to be monitored for kidney and liver functions.

In rare cases in humans receiving this drug, decreased white blood cell or platelet counts were also reported. Sucralfate (Carafate) will also help promote the body's own healing process of the gastric ulcers, and may increase production of prostaglandin E. Sucralfate is poorly absorbed, and also binds to and partially prevents absorption of some drugs like ranitidine and cimetidine, some oral antibiotics, phenytoin, and digoxin. Surgical resection of the affected portion of the right dorsal colon for ulcerative colitis has been recommended in some cases. The prognosis for horses with severe NSAID toxicity and right dorsal ulcerative colitis is guarded whether or not surgery is performed. Dietary management consisting of feeding pellets and restricting roughage may benefit some horses suffering from protein-losing enteropathy. Treatment of granulotamous enteritis with corticosteroids, salicylazosulfapyridine, azathioprine, and isoniazid has been attempted without success, and the prognosis for recovery is poor.

GastroPLUS™ was not only created to help increase necessary mucus to line and coat the stomach and intestinal linings to allow the body's own healing process. More importantly GastroPLUS™ helps provide crucial nitric oxide formation. Studies have shown that insufficient amounts of nitric oxide will allow the intestinal walls to become damaged, and to possibly perforate. These same studies have also shown that by increasing nitric oxide that the intestinal walls not only heal, but also become resistant to damage.

One study done at the University of Calgary in 1995 states that with sufficient nitric oxide, they were unable to damage the intestine. This same study also addressed the question of possibly dosing with too much nitric oxide, and would it be harmful? This study concluded that nitric oxide is necessary, and excessive amounts of nitric oxide are not considered harmful, but instead are beneficial.

The researcher who headed these studies was Paul Kubes Ph.D. Dr. Kubes was awarded the 1995 Gastroenterology Young Investigator Award from the American Gastroenterology Association for this CCFC funded work. The University of Calgary and Assistant Professor Paul Kubes PhD also received new funding from the CCFC to continue this work for 1996-1999 for the role of iNOS in models of Inflammatory Bowel Disease.

Testimonial from Vicki Spina-Maraugha, owner of April:

"In August 2002, our filly April was given the West Nile Virus shot to comply with our 4-H State show rules. Within hours of receiving the shot, she began to swell throughout her head. By the next morning, her entire head was swollen, along with her legs and the underline of her belly, plus a large lump in her chest. Upon the next call to our vet, she was given a regimen of Bute, which happened to be a toxic dose for a filly of this age (6 months).

April was rushed to the nearest equine ICU and given a 20/80 shot of survival, not in her favor. After tons of medications, tests and an extraordinary amount of money were expended, the vet suggested putting her down or placing her on Gastro Guard for her ulcerated intestines, which happened to be $975 per month. I couldn't see spending the money that I didn't have on a 20/80 shot, nor did I want to put her down, so she was brought home. I used home remedies such as Pepto Bismol to coat her stomach while I searched the Internet for solutions.

I then found the web site for GastroPLUS, and began to email my story and shortcomings to its owner. At that time, GastroPLUS™ was suggested, which was more cost efficient and offered money back guarantee, so I couldn't really lose anything. After 2 weeks on this product, April began to eat a whole portion of her feed and finish it, along with improving in brightness and had limited swelling. I used this product for approximately 7 months and now April is living a healthy, normal life, with very few problems. With a corrected high fiber diet and an occasional dose of GastroPLUS™ to keep her levels up, she is now being started into training."