The Impact of Two Recommended Withholding Periods for Omeprazole and the Use of a Nutraceutical Supplement on Recurrence of Equine Gastric Ulcer Syndrome in Thoroughbred Racehorses.

The impact of recommended withholding periods (RWPs) for omeprazole on the recurrence of Equine Gastric Ulcer Syndrome (EGUS) is unknown. The study was designed to compare the effect of two RWPs on EGUS recurrence post-omeprazole treatment and to determine if a nutraceutical supplement would reduce EGUS recurrence when administrated during an RWP. The study was a blinded, randomized clinical trial. Part 1: Horses were allocated to an RWP0 or RWP2 and crossed over after 4-weeks. Horses received oral omeprazole once daily, except during the RWPs at the end of the treatment periods. Part 2: Horses received omeprazole for 21 days prior to an RWP2 during which they received a nutraceutical supplement. Gastroscopy was performed on Day 0 and pre- and post- RWP. Part 1: More horses were affected by Equine Squamous Gastric Disease (ESGD) after the '2-clear-days' RWP than the 'not on race-day' RWP (p = 0.012). The prevalence of ESGD post-RWP for '2-clear-days' did not differ from day 0 (p = 0.478). Part 2: The prevalence of ESGD post-RWP was lower than on Day 0 (p = 0.046). A difference in recurrence of ESGD was present between the two common RWPs. The implications of this on the welfare of Thoroughbred racehorses warrant further discussion.

Identification and kinetics of microsomal and recombinant equine liver cytochrome P450 enzymes responsible for in vitro metabolism of omeprazole.

In humans, omeprazole is metabolised by cytochrome P450 (CYP450) CYP2C19 and CYP3A4 with differences in CYP2C19 genotypes leading to variable response to therapy. Despite a wide use of omeprazole in horses with evidence of variable therapeutic efficiency, information regarding enzymatic metabolism is not currently available. This study aims to describe the in vitro kinetics of omeprazole metabolism and determine which enzyme(s) are responsible for omeprazole metabolism in horses. Omeprazole (0-800 uM) was incubated with liver microsomes and a panel of equine recombinant CYP450s (eq-rCYP). Metabolite concentrations were quantified by LC-MS and the kinetics of metabolites' formation were calculated by non-linear regression analysis. The in vitro liver microsomes formed three metabolites (5-hydroxy-omeprazole, 5-O-desmethyl-omeprazole and omeprazole-sulfone). The 5-O-desmesthyl-omeprazole formation was best fitted to a two enzyme Michaelis-Menten (MM) model with the high affinity site Clint double that of the low affinity site. For 5-hydroxy-omeprazole the best fit was to a 1 enzyme MM model with a Clint higher than for 5-O-desmesthyl-omeprazole (0.12 vs 0.09 pmol/min/pmol P450). The formation of omeprazole-sulfone was negligible. Recombinant CYP3A89 and CYP3A97 produced substantial amounts of 5-hydroxy-omeprazole (1551.72 ng/mL and 1665.33 ng/mL, respectively), while 5-O-desmethyl-omeprazole and omeprazole-sulfone were formed to a much lesser extent by multiple eq-rCYP from the CYP2C and CYP3A family. In vitro metabolism of omeprazole in horses is different to that in humans, with major metabolites produced by the CYP3A family. The current study provides the basis for further investigations of CYP450 single nucleotide polymorphisms that could affect omeprazole metabolism and therapeutic efficacy.

Diagnostic accuracy of blood sucrose as a screening test for equine gastric ulcer syndrome (EGUS) in weanling foals.

BACKGROUND: Equine gastric ulcer syndrome is an important cause of morbidity in weanling foals. Many foals are asymptomatic, and the development of an inexpensive screening test to ensure an early diagnosis is desirable. The objective of this study was to determine the diagnostic accuracy of blood sucrose for diagnosis of EGUS in weanling foals. RESULTS: 45 foals were studied 7 days before and 14 days after weaning. The diagnostic accuracy of blood sucrose for diagnosis of gastric lesions (GL); glandular lesions (GDL); squamous lesions (SQL) and clinically significant gastric lesions (CSL) at 45 and 90 min after administration of 1 g/kg of sucrose via nasogastric intubation was assessed using ROC curves and calculating the AUC. For each lesion type, sucrose concentration in blood was compared to gastroscopy; and sensitivities (Se) and specificities (Sp) were calculated across a range of sucrose concentrations. Cut-off values were selected manually to optimize Se. Because of concerns over the validity of the gold standard, additional Se, Sp, and lesion prevalence data were subsequently estimated and compared using Bayesian latent class analysis. Using the frequentist approach, the prevalence of GL; GDL; SQL and CSL before weaning was 21; 9; 7 and 8% respectively; and increased to 98; 59; 97 and 82% respectively after weaning. At the selected cut-off, Se ranged from 84 to 95% and Sp ranged from 47 to 71%, depending upon the lesion type and time of sampling. In comparison, estimates of Se and Sp were consistently higher when using a Bayesian approach, with Se ranging from 81 to 97%; and Sp ranging from 77 to 97%, depending upon the lesion type and time of sampling. CONCLUSIONS: Blood sucrose is a sensitive test for detecting EGUS in weanling foals. Due to its poor specificity, it is not expected that the sucrose blood test will replace gastroscopy, however it may represent a clinically useful screening test to identify foals that may benefit from gastroscopy. Bayesian latent class analysis represents an alternative method to evaluate the diagnostic accuracy of the blood sucrose test in an attempt to avoid bias associated with the assumption that gastroscopy is a perfect test.

Diagnostic accuracy of blood sucrose as a screening test for equine gastric ulcer syndrome (EGUS) in adult horses.

BACKGROUND: Equine gastric ulcer syndrome (EGUS) is common in adult horses, particularly those involved in performance disciplines. Currently, detection of EGUS by gastroscopy is the only reliable ante mortem method for definitive diagnosis; however it is unsuitable as a screening test because it is expensive, time consuming, and is not readily available to most veterinarians. Sucrose permeability testing represents a simple, economical alternative to gastroscopy for screening purposes, and the feasibility of this approach in the horse has been previously reported. The aim of this study was to determine the diagnostic accuracy of blood sucrose as a screening test for EGUS in a large group of adult horses with and without naturally occurring gastric disease. RESULTS: One hundred and one adult horses with or without naturally occurring gastric ulceration were studied. The diagnostic accuracy of blood sucrose for diagnosis of gastric lesions (GL), glandular lesions (GDL), squamous lesions (SQL), and clinically significant lesions (CSL) at 45 and 90 min after administration of 1 g/kg of sucrose via nasogastric intubation was assessed using receiver operator characteristics (ROC) curves and calculating the area under the curve (AUC). For each lesion type, sucrose concentration in blood was compared to gastroscopy, as the gold standard, and sensitivities (Se) and specificities (Sp) were calculated across a range of sucrose concentrations. Ulcer grading was performed blindly by one observer; and the results were validated by comparing them with that of two other observers, and calculating the level of agreement. Cut-off values were selected manually to optimize Se. The prevalence of GL, GDL, SQL, and CSL was 83, 70, 53 and 58% respectively. At the selected cut-offs, Se ranged from 51 to 79% and Sp ranged from 43 to 72%, depending upon the lesion type and time of sampling. CONCLUSIONS: Blood sucrose is neither a sensitive or specific test for detecting EGUS in this population of adult horses with naturally occurring gastric ulceration. Further studies aimed at evaluating the performance characteristics of the test in different study populations are warranted. Given the limitations of endoscopy, due consideration should also be given to alternative methods for comparison of blood sucrose with a gold standard.

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.

Comparison of the effects of enteral psyllium, magnesium sulphate and their combination for removal of sand from the large colon of horses.

Prospective studies documenting the efficacy and side effects of medical treatment for colonic sand accumulation in horses are limited. The purpose of the study was to compare the effect of enteral administration of magnesium sulphate (MgSO4), psyllium mucilloid (psyllium), and a combination of MgSO4 and psyllium on the evacuation of large accumulations of sand in the large colon of adult horses. Thirty-four horses with naturally acquired, large sand accumulations (>5 cm × 15 cm) identified on abdominal radiography were randomly allocated to one of three treatment groups: (1) 1 g/kg psyllium (n = 12); (2) 1 g/kg MgSO4 (n = 10), or (3) their combination (n = 12). Treatments were administered once a day via nasogastric intubation and continued for a total of 4 days. Lateral radiographs of the ventral abdomen were repeated on day 4 of treatment. If the area of sand in the radiographic image was <25 cm(2) on day 4, the sand accumulation was considered resolved. Of 12 horses treated with a combination of psyllium and MgSO4, nine evacuated the sand from the ventral colon within 4 days. In comparison, only 3/12 horses treated with psyllium and 2/10 horses treated with MgSO4 resolved (both significantly different from the combination; P <0.05). Large accumulations of sand in the large colon of horses can be treated medically. Administering a combination of psyllium and MgSO4 via nasogastric intubation once daily for a total of 4 days was a more effective treatment than either constituent alone.

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

BACKGROUND: Interest 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. RESULTS: Combination 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). CONCLUSIONS: The 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.