B. W. Sykes

European College of Equine Internal Medicine consensus statement-Equine Gastric Ulcer Syndrome in adult horses

The term Equine Gastric Ulcer Syndrome (EGUS) was first used in 1999 to describe gastric ulceration in the horse. However, as discussed by Merritt, the terminology is commonly misused. The committee reinforces the importance of distinguishing between diseases of the squamous and glandular mucosa because, as discussed in this statement, important differences exist between the two. In human medicine, the term peptic ulcer disease (PUD) is used as an umbrella term to describe erosive and ulcerative diseases of the stomach and it is recognized that a large number of individual diseases are present under the term. Furthermore, while some different diseases might share similarities in pathophysiology and treatment regimens, it is recognized in human medicine that the direct extrapolation of either from one specific disease (such as NSAID-associated ulceration) to another (such as Helicobacter pylori associated ulceration) is inappropriate. The committee recognizes that the terminology for EGUS requires clarification and proposes that the nomenclature be: Equine Gastric Ulcer Syndrome (EGUS) as a general all encompassing term to describe erosive and ulcerative diseases of the stomach consistent with the use of the term PUD in man; Equine Squamous Gastric Disease (ESGD) and Equine Glandular Gastric Disease (EGGD) as terms that more specifically describe the affected region anatomically.Within ESGD, both primary and secondary disease is recognized. Primary ESGD, the more common of the 2 forms, occurs in animals with an otherwise normal gastrointestinal tract. In contrast, secondary ESGD occurs in animals with delayed gastric outflow secondary to an underlying abnormality such as pyloric stenosis. The pathophysiology of EGGD remains to be elucidated and as such further subclassification of lesion type is not possible at this time. Instead, the committee recommends the use of descriptive terminology with a clear distinction of the anatomical region affected (cardia, fundus, antrum, or pylorus as shown in Figure 2) and the gross appearance of the lesion. The committee emphasizes that the affected region of the stomach should be clearly identified when communicating research and clinical findings. A summary of the proposed terminology is depicted in Figure 1. Recommendation: Expansion of the existing EGUS terminology to specifically identify squamous and glandular disease as ESGD and EGGD, respectively, as shown in Figure 1.

A comparison of two doses of omeprazole in the treatment of equine gastric ulcer syndrome: A blinded, randomised, clinical trial

REASONS FOR PERFORMING THE STUDY Studies on omeprazole have reported that doses as low as 0.7 mg/kg bwt per os are potent suppressors of acid production. Yet, to date, no studies have compared treatment efficacy of different doses in clinical cases of equine gastric ulceration. Furthermore, no studies have been performed to compare the healing response of the squamous and glandular mucosa to acid suppression therapy. OBJECTIVES To compare: 1) the efficacy of 2 doses of omeprazole in the treatment of primary squamous and glandular gastric ulceration; and 2) the healing response of primary squamous and glandular gastric ulceration to acid suppression therapy. STUDY DESIGN A blinded, randomised, dose-response clinical trial. METHODS Twenty Thoroughbred racehorses with grade ≥2/4 glandular ulceration were identified on gastroscopy. Seventeen horses also had grade ≥2/4 squamous ulceration. Horses were randomly assigned to one of 2 groups. Horses received either 2.0 g (high dose: 4.0 mg/kg bwt) or 0.8 g (low dose: 1.6 mg/kg bwt) of oral omeprazole per os once daily. Gastroscopy was repeated at 28-35 days. RESULTS Time and dose significantly affected grades of squamous (P<0.0001, P = 0.02) and glandular (P = 0.006 and 0.005) ulceration. Data analysis did not support our hypothesis that the lower dose would have similar effects (i.e. be noninferior) to the higher dose when considering ulcer healing and ulcer improvement. Improvement was more likely with the high dose for the squamous (P = 0.05) but not glandular (P = 0.4) mucosa. The percentage of glandular ulcers that improved was less than squamous ulcers (P = 0.02). CONCLUSIONS The results suggest that a dose-response exists for the treatment of both squamous and glandular ulcers. Improvement of glandular ulcers was not as complete as observed with squamous ulcers and current equine gastric ulcer syndrome treatment recommendations may not be appropriate for glandular disease.

A comparison of three doses of omeprazole in the treatment of equine gastric ulcer syndrome: A blinded, randomised, dose–response clinical trial

REASONS FOR PERFORMING THE STUDY A previous study demonstrated that a dose effect between 1.6 and 4.0 mg/kg bwt of omeprazole per os s.i.d. is present in the treatment of equine gastric ulceration. In the same study, healing of glandular ulceration appeared inferior to healing of squamous ulceration. However, several limitations were recognised in that study and further investigation is warranted. OBJECTIVES To further investigate the presence of a dose relationship in the treatment of gastric ulceration under conditions that may favour omeprazole efficacy such as administration prior to exercise and after a brief fast, and potential differences between the response of squamous and glandular ulceration to omeprazole therapy. STUDY DESIGN A blinded, randomised, dose-response clinical trial. METHODS Sixty Thoroughbred racehorses with grade ≥2/4 squamous and/or glandular ulceration were identified by gastroscopy. Horses were randomly assigned to receive either 1.0, 2.0 or 4.0 mg/kg bwt of enteric coated omeprazole per os s.i.d. 1-4 h prior to exercise. Gastroscopy was repeated at approximately 28 days. RESULTS The lower doses studied (1.0 and 2.0 mg/kg bwt) were noninferior to the reference dose (4.0 mg/kg bwt) in the treatment of squamous ulceration. Healing was greater in squamous ulceration than glandular ulceration (86% vs. 14%; P<0.0001). Improvement in ulcer grade was more likely in squamous lesions than glandular lesions (96% vs. 34%; P<0.0001). Worsening of the glandular ulcer grade was observed in 36% of horses. CONCLUSIONS The results of this study suggest that, under the conditions studied, where omeprazole is administered before exercise and following a brief fast, doses of omeprazole as low as 1 mg/kg bwt per os s.i.d. may be as effective as higher doses. The proportion of glandular ulceration that heals with 28 days of omeprazole therapy is less than that of squamous ulceration.

Administration of trimethoprim-sulphadimidine does not improve healing of glandular gastric ulceration in horses receiving omeprazole: a randomised, blinded, clinical study

BackgroundInterest in Equine Gastric Ulcer Syndrome (EGUS) has recently increased in part due to a growing awareness of the differences between squamous and glandular disease. The pathophysiology and epidemiology of squamous and glandular disease are different and recently it has been shown that the response of glandular gastric ulceration to monotherapy with omeprazole is poor. Given these differences it has been recommended that specific treatment guidelines be formulated for equine glandular disease and that adjunctive therapies be investigated. Along these lines it has been suggested that the addition of antimicrobials may enhance healing. The objective of this study was to investigate whether the addition of trimethoprim-sulphadimidine to omeprazole therapy would result in superior healing of naturally occurring equine glandular ulceration compared with omeprazole monotherapy.ResultsCombination therapy of omeprazole plus trimethoprim-sulphadimidine could not be demonstrated to be superior to omeprazole monotherapy. Healing of the glandular mucosa was observed in 7/15 (47%; 95% CI 24 to 71%) and 3/13 (23%; 95% CI 7% to 50%) of horses in the TMPS and OMEP groups, respectively (OR = 1.8; 95% CI 0.32 to 10.0; p = 0.67). Improvement of the glandular mucosa was observed in 12/15 (80%; 95% CI 56 to 94%) and 9/13 (69%; 95% CI 42 to 89%) of horses in the TMPS and OMEP groups, respectively (OR = 2.9; 95% CI 0.6 to 15.0; p = 0.25).ConclusionsThe results of the present study do not support the addition of trimethoprim-sulphadimidine to therapeutic protocols for equine glandular ulceration. Several limitations were present in the study and the use of antimicrobials as an adjunctive treatment warrants further investigation. However, given the potential deleterious consequences associated with the indiscriminate use of antimicrobials, the inclusion of antimicrobials in treatment regimes for EGUS is not justified until their efficacy is further validated.

The effect of feeding on the pharmacokinetic variables of two commercially available formulations of omeprazole.

The objectives of this study were to investigate the impact of formulation (enteric coated and buffered) and feeding on pharmacokinetic variables associated with the oral administration of omeprazole in the horse. Six thoroughbred racehorses were studied in a crossover design. Each received 2 g of an enteric coated or buffered formulation in both the fed and fasted state. Plasma omeprazole concentrations were determined by UHPLC-MS. The effects of feeding or formulation on AUC0-inf_obs, half-life, Tmax or Cmax were not statistically significant. However, a wider-than-expected degree of variation was present and examination of the raw data suggests that an effect of feeding, wherein the bioavailability of omeprazole may be reduced in the fed animal, may be present. Further investigation in a larger population of animals to assess the factors that contribute to the wide degree of absorption observed is warranted.

Pharmacokinetics and bioequivalence testing of five commercial formulations of omeprazole in the horse.

Omeprazole is widely used in the treatment of equine gastric ulcer syndrome. To date, little is known about the relative pharmacokinetics of the different formulations making comparisons between products difficult. The objectives of the study were to investigate the relative pharmacokinetics of five commercially available formulations of omeprazole in the horse and to test for bioequivalence of four of the formulations using one of the formulations as a reference standard. Twelve mature Thoroughbred horses were fasted for 16 h then administered 2 g of each formulation in a cross-over design. Serial blood samples were collected and plasma omeprazole concentration was determined by ultra high-performance liquid chromatography-mass spectrometry (UHPLC-MS). No significant differences were present between three of the formulations and the reference formulation, while the fourth formulation had a lower Cmax and longer Tmax than the reference formulation. Bioequivalence against the reference formulation could not be demonstrated for any of the formulations tested. The findings of the study suggested that the method of protection utilised by different formulations of omeprazole (enteric-coated granules vs. buffering) does not significantly alter the pharmacokinetics of the drug. Further work to establish bioequivalence is needed before direct comparisons can be drawn between different formulations.

The effects of dose and diet on the pharmacodynamics of omeprazole in the horse

BACKGROUND Conflicting data are presented in the current literature regarding the efficacy of omeprazole for suppressing gastric acidity in the horse. OBJECTIVES The objective of this study was to investigate the duration of intraday acid suppression achieved with two doses of omeprazole under two different dietary conditions. STUDY DESIGN A four-way crossover design. METHODS Six adult Thoroughbred horses instrumented with percutaneous gastrotomy tubes were used. Intragastric pH was measured for continuous 23 h periods (08.00-07.00 h) for six consecutive days (Days 0-5). Baseline data was recorded on Day 0 and omeprazole administered on Days 1-5. Two doses (1 mg/kg and 4 mg/kg bwt per os once a day) and two diets (a high grain/low fibre [HG/LF] and ad libitum hay [HAY)] diet) were studied. Data for the percent (%) time pH was above 4 (%tpH>4) and median intraday pH was reported for two measurement locations and analysed using generalised estimating equations. RESULTS An effect of both diet and dose was evident with mean %tpH>4 and the mean of the median intraday pHs typically higher at the higher (4 mg/kg bwt) dose and in HG/LF diet. The overall efficacy of omeprazole in raising intragastric pH was good under the HG/LF conditions but relatively poor in the HAY diet. A cumulative effect of dosing, not previously reported in the horse, was observed. CONCLUSIONS The overall efficacy of omeprazole in raising ventral gastric pH was less than previously reported. Both dose and diet may play a role in the efficacy of omeprazole in the horse. Therefore, the use of singular dosing recommendations that encompass all horse types and management conditions may not be appropriate and dosing recommendations that take into account the diet of the horse may be advantageous.

Preliminary investigations into a novel, long-acting, injectable, intramuscular formulation of omeprazole in the horse

BACKGROUND Pilot investigations have suggested that a novel, long-acting, injectable i.m. formulation of omeprazole (LA-OMEP) can induce acid suppression for up to 7 days following a single injection. OBJECTIVES To investigate the pharmacodynamics and assess the clinical efficacy of the LA-OMEP formulation. STUDY DESIGN Part A comprised a pharmacodynamic study. Part B consisted of a pilot clinical trial. METHODS Part A enrolled six adult Thoroughbred horses with percutaneous gastrotomy tubes. Intragastric pH was measured for continuous 23-h periods (08.00-07.00 h) for eight consecutive days (days 0-7). A single 2.0-g dose of a 100 mg/mL LA-OMEP formulation was administered at 08.00 h on day 1. In Part B, 26 horses with squamous or glandular gastric disease were enrolled based on routine gastroscopic evaluation. Once enrolled, horses received 2.0 g of the 100 mg/mL LA-OMEP formulation by i.m. injection on days 0 and 7. Repeat gastroscopy was performed on days 14 (23 horses) or 16 (one horse). RESULTS In Part A, the percentage of time during which pH was above 4 exceeded 66% for days 1-4 in all horses and days 1-7 in four of the six horses studied. In Part B, healing was observed in all 22 (100%, 95% confidence interval [CI] 89-100%) horses with squamous disease and in nine of 12 (75%, 95% CI 47-92%) horses with glandular disease. Improvement, by at least one grade, was observed in all 22 (100%, 95% CI 89-100%) horses with squamous disease and in all 12 (100%, 95% CI 81-100%) horses with glandular disease. No worsening of lesions was observed. Lesion grade decreased over time in both the squamous (P<0.0001) and glandular (P = 0.0024) mucosa. MAIN LIMITATIONS Small sample sizes. CONCLUSIONS The results of the present study compare favourably with previous reports on the pharmacodynamics of omeprazole and the clinical outcomes of trials reporting response to oral omeprazole therapy.

Pharmacokinetics of esomeprazole following intravenous and oral administration in healthy dogs

Investigation into the pharmacokinetic profile of esomeprazole was conducted using eight healthy dogs after intravenous (IV) and oral (po) administration in a two-part randomized crossover study. The dogs were fasted for a minimum of 12 hours and then received esomeprazole either intravenously (dose range 0.93–1.48 mg/kg) or orally using an enteric-coated formulation (dose range 0.95–1.50 mg/kg). After a 1-week washout period, the dogs received an alternative treatment. Serial blood samples were collected at predetermined time points, and plasma esomeprazole concentrations were determined by using ultra-high-performance liquid chromatography–mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Then, the area under the plasma concentration/time curve (AUC) and maximal plasma concentration (Cmax) values were normalized to a 1.0 mg/kg dose of esomeprazole, that is, AUC/dose. Median (range) dose-normalized peak plasma concentration (Cmax) values for the IV and po formulations were 4.06 µg/mL (2.47–4.57 µg/mL) and 1.04 µg/mL (0.31–1.91 µg/mL), respectively. The median (range) time-to-peak concentration (Tmax) for the po formulation was 105 minutes (45–360 minutes). Median (range) plasma terminal half-life (t½) was 45.56 minutes (39.43–64.20 minutes) for the IV formulation and 63.97 minutes (44.02–109.94 minutes) for the enteric-coated po formulation. The median (range) po bioavailability was 63.33% (32.26%–79.77%). Clinically, both po and IV formulations were well tolerated with minimal side effects observed.