The disease complex that precipitates ulceration of the esophageal, gastric, or duodenal mucosa in the horse is referred to as Equine Gastric Ulcer Syndrome (EGUS). It includes both asymptomatic and symptomatic cases; focal or multifocal ulceration of squamous mucosa, glandular mucosa, or both; and gastritis and complications of these disorders.³

EGUS spans a spectrum of severity, ranging from inflamed but intact epithelium to single, superficial erosions of the mucosal surface, and from there to multiple actively hemorrhaging hyperemic and/or necrotic craters extending beneath the mucosal surface.⁴ Perforation may occur, and when it does it is usually fatal.⁵

Endoscopy provides a definitive diagnosis, but it requires endoscopes of 3 meters (9.8 feet), which may not be available in many localities. However, a variety of clinical signs, such as reduced appetite, poor body condition, poor performance, diarrhea, and colic, may be highly suggestive of gastric ulceration. Response to empirical antiulcer therapy may help establish the diagnosis in the absence of endoscopy.

In addition to intensive training, other risk factors that may predispose horses to gastric ulceration include intermittent feeding, reduced hay intake, physical stress (such as injury, illness, and hospitalization), other stressors (such as shipping, relocation, and resocialization), and, possibly, high doses of some medications. Helicobacter pylori , a bacterium that is a major factor in the development of human ulcers, has not been isolated from horse stomachs and is not currently considered to be a cause of horse ulcers.³

EGUS is increasingly recognized as a major problem affecting the well-being and performance of horses. Antacids, histamine H2 antagonists, ulcer-coating agents such as sucralfate, synthetic prostaglandins, and anticholinergics have been used to treat gastric ulcers in horses. None of these products is approved by the FDA for use in horses, and their effectiveness and safety have not been assessed in large-scale, placebo-controlled trials. Limited reports of the use of these agents show variable results, and there is no recommended dose or administration schedule. Importantly, horses must be removed from training to achieve healing of stomach ulcers if these agents are used.³ Omeprazole, an acid pump inhibitor, is the most widely prescribed antisecretory ulcer medication in humans and the number one selling prescription drug in the world. A potent suppressor of gastric acid secretion, omeprazole is inherently long-acting and generally well-tolerated. These are desirable characteristics in an equine medication, and formed the initial basis of developing an omeprazole-based product for equine use.

GASTROGARD® (omeprazole) Oral Paste for Equine Ulcers has been developed specifically for horses. GASTROGARD is administered orally by syringe. A dose of 4 mg omeprazole/kg/day has been shown to produce maximal suppression of gastric acid secretion. Each syringe has sufficient omeprazole paste to treat a 1250-lb horse.

Omeprazole, the active ingredient in GASTROGARD, belongs to a novel class of antisecretory compounds, the substituted benzimidazoles. Omeprazole is 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl]sulfinyl]-1-H-benzimidazole. Its empirical formula is C₁₇H₁₉N₃S, and its molecular weight is 345.42. The structural formula is:

GASTROGARD, a flavored paste, contains 37% w/w omeprazole and is available in an adjustable-dose syringe. Each syringe contains 2.28 g of omeprazole.

Omeprazole provides superior acid suppression because it most effectively shuts down acid production in the stomach, giving the ulcer time to heal. The cells of the stomach mucosa contain several acid-stimulating receptors, and when these receptors are activated they switch on the H+,K+ ATPase acid pump (an enzyme system) to secrete acid into the stomach. Omeprazole inhibits the acid pump, so when receptors are activated the acid pump does not initiate acid secretion. Omeprazole is the only medication approved for use in horses that acts directly on the acid pump, preventing acid secretion no matter what receptor is activated.⁶

Omeprazole was the first acid pump inhibitor to be approved for use in humans, and is now the first and only acid pump inhibitor approved for the treatment of stomach ulcers in horses.⁶ In a pharmacokinetic study involving thirteen healthy, mixed-breed horses (8 female, 5 male) receiving multiple doses of omeprazole paste (1.8 mg/lb once daily for 15 days) in either a fed or fasted state, there was no evidence of drug accumulation in the plasma when comparing the extent of systemic exposure (AUC-0-infinity). When comparing the individual bioavailability data (AUC-0-infinity, Cmax, and Tmax measurements) across the study days (doses 1 and 15 in fed animals), there was great inter- and intrasubject variability in the rate and extent of product absorption.

The antisecretory effects of omeprazole persist far longer than the drug's serum level, because omeprazole becomes bound to the H+,K+ ATPase of the parietal cell, allowing it to exert its effect for 24 hours after a single dose.⁷ This prolonged duration of action enables once-daily dosing. Omeprazole, the active ingredient in GASTROGARD, is a potent inhibitor of gastric acid secretion. Inhibition of the acid pump by omeprazole results in near-complete suppression of acid secretion, regardless of stimulus, for a long period of time.⁶ In a study of pharmacodynamic effects using horses with gastric cannulae, secretion of gastric acid was inhibited in horses given 4 mg omeprazole/kg/day (1.8 mg omeprazole/lb/day). After the expected maximum suppression of gastric acid secretion was reached (5 days), the actual secretion of gastric acid was reduced by 99%, 95%, and 90% at 8, 16, and 24 hours, respectively.⁶

GASTROGARD is indicated for treatment and prevention of recurrence of gastric ulcers in horses and foals 4 weeks of age and older.⁶

A series of four dose-confirmation trials, six field trials, two acceptability trials, and four safety trials was conducted to establish the clinical utility of GASTROGARD.⁶

Ulcers vary in their location, size, depth, and other characteristics. A standardized scoring system is therefore necessary to evaluate healing and to compare severity of lesions among trial subjects. Investigators in both the dose-confirmation trials and the field trials were trained to use a four-point scoring method.⁶ The higher the score, the more severe the lesion.

The benefit of GASTROGARD for the treatment of ulcers is based upon the capacity of its active ingredient, omeprazole, to almost completely inhibit acid secretion.⁶ Initially, pharmacodynamic experiments and field trials were conducted to assess the efficacy of various omeprazole pastes in inhibiting gastric acid secretion using several doses. There was a clear indication that at 3 mg/kg/day, ulcer healing and improvement were considerably less than maximum. Further studies led to the conclusion that treatment with GASTROGARD given at 4 mg/kg once daily is the most effective dose for optimal acid suppression in the horse.⁶

Four trials were conducted to evaluate the efficacy of daily doses of 4 mg/kg of GASTROGARD in treating existing ulcers in horses and preventing their recurrence.⁶ The results of these trials were pooled for statistical analysis.

Subjects.

Thoroughbred horses at least 2 years old and healthy other than the presence of gastric ulcers were included in trials at sites in Texas, Florida, and Kentucky. When horses followed a typical exercise schedule used by many race-training facilities, ulcers were consistently present over a 56-day period. Exercise consisted of galloping or running at the training track, with distance varied according to the horse's level of training and conditioning. As each horse's condition improved, the length of its runs was increased. Horses were galloped for the required distance 5 days per week, and breezed (run hard for distance) 1 day a week. Day 7 was reserved for rest.⁶

Horses were housed in individual stalls throughout the trial, with feeding that met National Research Council requirements for adult horses in training. Animals were handled in compliance with all applicable local regulations and with due regard for their welfare.⁶

Methods. The dose-confirmation trials were divided into two parts to evaluate both efficacy of treatment as well as prevention of recurrence. In Part 1, involving 100 horses, horses within each trial were grouped into replicates comprising four animals with similar pretrial gastric lesion scores and gender. One randomly selected animal in each replicate was sham dosed using an empty syringe, while the other three received omeprazole 4 mg/kg/day. Dosing was continued for 4 weeks, with endoscopic examination and gastric lesion scoring after 2, 3, and 4 weeks of dosing.⁶

In Part 2, the objective was to determine the omeprazole dosage needed to prevent or reduce ulcer recurrence. The animals that had received omeprazole were regrouped into new replicates of three based on their final gastric lesion scores at the end of Part 1. Treatments at two daily dosages (2 mg/kg/day and 4 mg/kg/day) were randomly allocated to horses within each replicate, with the remaining horse sham dosed. This part of the trial continued for 30 days.⁶ Investigators, including the endoscopist, in these trials were kept unaware of which animals received omeprazole and of the dosages used.⁶

Statistical Analysis. Changes in ulcer score from baseline were analyzed nonparametrically using a modified Friedman's test (Cochran-Mantel-Haenszel procedure) to assess differences between omeprazole and control after 2, 3, and 4 weeks. Change in ulcer score over the next 30 days was also analyzed using a modified Friedman's test, with contrasts tested using Dunn's procedure to assess differences among omeprazole dosing regimens. The two-sided significance level for all testing was 0.05.⁶

Results: Part 1. GASTROGARD, administered to provide omeprazole at 4 mg/kg (1.8 mg/lb) daily for 4 weeks, effectively healed or reduced the severity of gastric ulcers in 92% of treated horses. In comparison, 32% of sham-dosed horses exhibited healed or less severe ulcers. All horses began the trial with gastric lesion scores >1, and the average pretreatment lesion score was 2.2. More than 44% of the horses had extensive, often coalescing lesions with apparent areas of deep ulceration that resulted in a score of 3. The reduced severity of gastric ulcers compared to baseline was significantly (P<0.01) greater for omeprazole-treated horses than for controls at each endoscopic examination. Ulcers were healed or improved after 4 weeks in horses treated with GASTROGARD.⁶

Prevention of Recurrence: Part 2. In the second part of the study, GASTROGARD at either full or half doses prevented recurrence of gastric ulcers. GASTROGARD (given to provide omeprazole at 4 mg/kg/day or 2 mg/kg/day) or sham dosing was given for 30 days to treated horses that had completed the first part of the study. There was no recurrence of ulcers among 84% of horses receiving prevention with GASTROGARD at either dose, whereas ulcers persisted, recurred, or became more severe in 92% of sham-dosed horses (the proportion of horses with healed ulcers or reduced severity of ulcers was significantly higher for horses continued on omeprazole compared to sham-dosed controls).⁶

The two dosages of omeprazole did not significantly differ in their efficacy at preventing recurrence of ulcers, with 88% and 84% of horses having healed or reduced severity of ulcers at 4 mg/kg/day and 2 mg/kg/day omeprazole, respectively.⁶

When omeprazole treatment stopped, ulcers recurred. At the end of 30 days, 92% of horses that stopped omeprazole treatment had ulcers.⁶

An additional six studies were conducted to assess the efficacy of omeprazole paste under field conditions.⁶

Subjects. The horses ranged in age from 4 weeks to more than 15 years, and represented a wide variety of breeds, including Standardbreds, Thoroughbreds, Quarter Horses, Appaloosas, Paints, Tennessee Walking Horses, ponies, warmbloods, and crossbreds. Horses enrolled in these trials were otherwise healthy horses confirmed by gastroscopy to have gastric ulcers. The severity of gastric ulcers was scored using the method described in the dose-confirmation trials. Gastric ulcers were not induced specifically, but occurred within the routine management of each facility. Racing, other performance, and non-performance horses were included.⁶ Animals were maintained on their usual diets, housing, and exercise, which varied among sites and according to the age, condition, and occupation of the horses. Trial sites were located in Indiana, Oklahoma, California, Illinois, Missouri, and Tennessee.⁶

Methods. At each trial facility, horses were grouped into replicates of four, based on type of activity or location. Within each replicate, three horses were randomly selected to receive omeprazole while the remaining horse was sham dosed. Each horse was examined endoscopically prior to the first dose and after week 4, and gastric lesion scores were determined. Each animal was also observed twice daily for changes in condition and health during each trial.⁶

Statistical Analysis. Data including change in gastric ulcer score, body weight, and incidence of health problems were pooled from the six trials. Change in gastric lesion score from baseline to week 4 were analyzed nonparametrically using a modified Friedman's test (Cochran-Mantel-Haenszel procedure). Baseline body weight and weight gain to weeks 2 and 4 were analyzed using mixed-model analysis of variance. In addition, incidence of one or more health problems was also analyzed using the Mantel-Haenszel test. The two-sided significance level for all testing was 0.05.⁶

Results. GASTROGARD administered at 4 mg/kg (1.8 mg/lb) daily for 28 days healed or reduced severity of gastric ulcer lesion severity scores in 99% of omeprazole-treated horses. Among treated animals, none had a lesion score that increased, and only one animal had an unchanged score. In comparison, only 32% of sham-dosed horses had healed ulcers or ulcers that were reduced in severity. Two thirds of the control animals had lesion scores that remained the same or increased during the trial. There were no adverse health effects related to medication.⁶

In the field trials, horses readily accepted GASTROGARD, with >99% of the nearly 3000 doses administered with no loss of paste.⁶ Two additional field trials were conducted in horses without ulcers to further assess the acceptability of the paste. Each followed the protocols outlined for the previously described field trials, with the omission of the requirement for preexisting ulcers. Subjects included 20 healthy Thoroughbred foals aged 11 to 16 weeks and 20 Thoroughbred yearlings at a facility in Virginia.⁶

The horses readily accepted the paste. No paste was rejected by any of the horses.6

GASTROGARD was well tolerated in controlled efficacy and safety studies.

In the previously described dose-confirmation and field trials, no adverse effects attributable to omeprazole treatment were noted.⁶

Additional safety studies were conducted in which clinical chemistry, hematology, and physical examinations were performed, and tissues and organs were examined at necropsy for gross lesions. Tissue samples were also taken for histopathologic examination.⁶

In the first of these trials, a sham dose-controlled safety study, 18 Thoroughbred horses (9 geldings and 9 females) ranging in age from 4 to 20 years received 20 mg/kg/day omeprazole (5x the recommended dose) or sham dosing for 91 days.⁶ In a second placebo-controlled tolerance study, six adult Thoroughbred horses (3 gelded males and 3 females) were treated with GASTROGARD at a dosage of 40 mg/kg/day (10x the recommended dose) or sham dosed for 3 weeks, then necropsied. In addition to twice-daily observations, physical examinations were conducted on days -1, 2, 9, and 21. In both studies, no treatment-related adverse effects on the animals' health were observed.⁶

A placebo-controlled study in foals evaluated the safety of GASTROGARD at doses of 4, 12, or 20 mg/kg (1x, 3x, or 5x the recommended dose) once daily for 13 weeks. Twenty-four Tennessee Walking Horse foals (12 female and 12 male) ranging in age from 66 to 110 days at study initiation were randomly assigned to treatment groups. Each foal was observed at least twice daily, and physical examinations were conducted at weeks 1, 2, 4, 8, and 13. Overall, GASTROGARD given orally to young horses at 1x, 3x, or 5x the recommended daily dose had no adverse effects on animal health.⁶

In a male reproductive safety study, 15 Thoroughbred and 5 Standardbred stallions between 3 and 12 years of age were randomly assigned to receive GASTROGARD at 12 mg/kg/day (3x the recommended dose) or sham dosing for 71 days. Semen quality, reproductive behavior, and genitalia were examined to assess breeding soundness. No treatment-related adverse effects on semen quality, testicular volume, or reproductive behavior were observed.⁶ A safety study in breeding mares has not been conducted.

In the clinical trials, GASTROGARD was used concomitantly with other therapies, which included anthelmintics, antibiotics, nonsteroidal and steroidal anti-inflammatory agents, diuretics, tranquilizers,and vaccines. No interactions were observed.

GASTROGARD Oral Paste for Equine Ulcers was highly effective at healing gastric ulcers in horses and preventing their recurrence. Efficacy was demonstrated in male and female adult horses and foals in a variety of clinical and field settings. GASTROGARD was well tolerated, and its high acceptance by horses resulted in negligible waste or underdosing. Only GASTROGARD offers these important and unique advantages to equine practitioners, trainers, and owners in the treatment of gastric ulcers:

• It is a highly effective inhibitor of acid secretion in horses, creating an intragastric environment in which ulcer healing can occur.
• It is proven to heal and improve ulcers and prevent their recurrence, even during training--not just alleviate their clinical signs.
• It is the only antiulcer medication for horses that elevates stomach pH throughout the 24 hours after dosing, allowing convenient once-daily dosing.
• It is the only antiulcerant that has been exhaustively investigated for efficacy and safety in equine use, and the only one approved by the U.S. Food and Drug Administration for this indication.
• The paste formulation of GASTROGARD has been developed specifically for ease of administration, efficacy, and acceptability in horses.

1. Murray MJ, Schusser GF, Pipers FS, Gross SJ. Factors associated with gastric lesions in Thoroughbred racehorses. Equine Vet J. 1996;28:368-374.
2. Murray MJ, Grodinsky C, Anderson CW, Radue PF, Schmidt GR. Gastric ulcers in horses: a comparison of endoscopic findings in horses with and without clinical signs. Equine Vet J. 1989;7(suppl):68-72.
3. Murray MJ. Overview of equine gastroduodenal ulceration, in Proceedings. AAEP 1997;43:382-387.
4. MacAllister CG, Andrews T, Deegan E, Ruoff W, Olovson S-G. A scoring system for gastric ulcers in the horse. Equine Vet J. 1997;29;430-433.
5. Murray MJ. Diagnosing and treating gastric ulcers in foals and horses. Veterinary Med. 1991 (Aug);820-827.
6. Freedom of Information (FOI) Summary for GASTROGARD Oral Paste for Horses.
7. Papich MG. Antiulcer therapy. Vet Clinics of North America. 1993;23:497-512.

Owner's Guide

Performance-Horse Owner's Guide to Equine Gastic Ulcers

• Studies show up to 93% of racehorses have ulcers
• Ulcers are not always easy to see
• There's too much at stake to lose to an ulcer
• GASTROGARD is the first and only FDA-approved equine medication proven to heal ulcers
• Ask your veterinarian if GASTROGARD is right for your horses

Recent scientific studies show that the problem of stomach ulcers is extremely common in performance horses. When a group of Thoroughbred horses in active race training were examined, 93% had ulcers. And ulcers were confirmed in 100% of horses that had raced. Event horses, hunters/jumpers, and other non-racing performance horses can also be at high risk. In fact, research has shown that almost 60% of these horses can have ulcers.²

While the majority of performance horses may be hampered by ulcers, a smaller number actually show symptoms. Often the symptoms do not occur, can be subtle, or not automatically associated with ulcers. This doesn't mean that horses without symptoms aren't affected.

If your horse has been off feed, has a poor coat, or has not been performing well, look for an ulcer.

Training a promising horse requires an enormous investment of time, money, and dedication. In fact, the average horse owner now spends up to $2,000 a month to keep and train a performance horse. With that kind of investment, you can't afford to risk your horses' health when you suspect an ulcer.

Today your veterinarian can prescribe a new ulcer treatment called GASTROGARD. GASTROGARD contains the same active ingredient found in the world's #1 human anti-ulcer medication.³ GASTROGARD was proven to heal or significantly improve 99% of horses with ulcers. GASTROGARD was also proven to keep ulcers from coming back with continued use at a lower dose.⁴ It comes in a convenient paste formulation that's given once a day. And unlike any other therapies, GASTROGARD is proven effective even while horses stay in training.⁴

If you suspect that your horses might be having ulcers, talk to your veterinarian about GASTROGARD. Because with all you have invested in your horses, losing to an ulcer is not an option.

1. Murray MJ, Schusser GF, Pipers FS, Gross SJ. Factors associated with gastric lesions in Thoroughbred racehorses. Equine Vet J. June 1996;28:368-374.
2. Murray MJ, Grodinsky C, Anderson CW, Radue PF, Schmidt GR. Gastric ulcers in horses with and without clinical signs. Equine Vet J. 1989;7 (suppl):68-72.
3. PRILOSEC represents 40% of AstraZeneca's 1998 Pro forma sales. The Pink Sheet. 1996;61 (8):16.
4. Freedom of Information (FOI) Summary for GASTROGARD Oral Paste for Horses

Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. GASTROGARD is indicated for the treatment and prevention of recurrence of gastric ulcers in horses and foals 4 weeks and older. In efficacy trials, no adverse reactions were observed. Safety in pregnant and lactating mares has not been determined.

DO NOT USE IN HORSES INTENDED FOR HUMAN CONSUMPTION.

KEEP THIS AND ALL DRUGS OUT OF REACH OF CHILDREN.