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

Abbreviations EGGD equine glandular gastric disease EGUS equine gastric ulcer syndrome ESGD equine squamous gastric disease GERD gastroesophageal reflux disease PUD peptic ulcer disease Terminology The term Equine Gastric Ulcer Syndrome (EGUS) was first used in 1999 to describe gastric ulceration in the horse.1 However, as discussed by Merritt,2 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.3 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.3 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.4 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. Figure 1 A summary of the proposed terminology for describing erosive and ulcerative diseases of the horse's stomach. Figure 2 A postmortem specimen of the equine stomach depicting the anatomical regions of the stomach. Recommendation: Expansion of the existing EGUS terminology to specifically identify squamous and glandular disease as ESGD and EGGD, respectively, as shown in Figure  1. Prevalence The prevalence of gastric ulceration varies with breed, use, level of training, as well as between ESGD and EGGD. The highest prevalence of ESGD occurs in Thoroughbred racehorses with 37% of untrained horses affected, increasing to 80–100% within 2–3 months of race training.5, 6, 7 Standardbred racehorses have a similar overall ESGD prevalence of 44% that rises up to 87% in training,8, 9, 10 while 17–58% show/sport horses and 37–59% of pleasure horses are affected.11, 12, 13, 14, 15 Endurance horses have an ESGD prevalence of 48% during the out of competition period that rises to 66–93% during the competitive period, with lesions most prevalent in elite horses.16, 17 Horses that are rarely competed and predominantly used in their home environment have the lowest ESGD prevalence of 11%.18 The prevalence of EGGD is less well understood. Australian Thoroughbred racehorses have reported prevalences of between 47%6 and 65%.19 In endurance horses, the prevalence is 16% outside of the competition period and 27–33% while competing.16, 17 A retrospective study in the United Kingdom found EGGD in 54% of 191 leisure horses and in 64% of 493 sport horses.20 Comparably, 57% of horses used for a variety of purposes were reported to have EGGD in 2 separate studies.14, 21 The majority of EGGD lesions in all of the above studies were found within the pyloric antrum. Epidemiology A postmortem study of 3,715 horses over 72 years found significant associations between the presence of ulceration and breed (Thoroughbred and Standardbred breeds were more likely to have ulcers than cold‐blooded horses) and sex (a higher prevalence was reported in stallions than mares and geldings).22 In contrast, 2 large cross‐sectional studies of Thoroughbred racehorses documented no significant effect of age or sex on the likelihood of having ESGD.7, 23 Similarly, a large study in Standardbreds found no association between the presence of ESGD and age; however, there was an association between increasing age and worsening ulcer severity, the relative risk for which was greatest in geldings.8 In a retrospective study of 684 sport and leisure horses in the United Kingdom, no effect of age, sex or month of presentation was found on prevalence of ESGD or EGGD. However, a significant association was found between the Thoroughbred breed and the presence of ESGD in horses of any age.20 Together, these findings suggest that other factors such as intensity or duration of exercise outweigh any potential age or sex effect, but that a breed effect might be present with Thoroughbreds predisposed to ESGD. There are few large scale epidemiologic studies that investigated other risk factors for EGUS. Of those available, significant associations have been shown between ESGD and individual trainers, a metropolitan yard location (horses trained in urban areas were 3.9 × more likely to have gastric ulcers), a lack of direct contact with other horses, solid barriers instead of rails, and talk rather than music radio in the barn.23 Straw feeding and a lack of access to water in the paddock have been associated with an increased risk of EGUS in general.24 Further large scale work is required to better understand the epidemiologic factors which influence disease development, particularly EGGD which is largely unstudied at this point in time. Nutritional Risk Factors Pasture turnout is considered to reduce the risk of EGUS although evidence supporting this belief if cnflicting. Horses with access to some turnout were less likely to have ESGD, and this risk was even lower if they were turned out with other horses in one study of Thoroughbred racehorses in training.23 Conversely no effect of quality of pasture, or time at pasture (stabled, stable and pasture, pastured) was shown on ESGD prevalence in another study of Thoroughbred racehorses.25 In addition, there were no differences observed on intragastric pH in horses fed ad libitum grass hay and grain twice a day (1 kg/100 kg/d) when they were housed in a grass paddock, in a stall on their own or in a stall with an adjacent companion, suggesting that pasture turnout on its own might not affect gastric pH per se.26 Similarly, free access to fibrous feed or frequent forage feeding is widely considered to reduce the risk of gastric ulceration although strong evidence supporting this belief if also lacking. Feeding alfalfa hay and grain results in higher gastric pH and less peptic injury to the gastric squamous mucosa than feeding brome grass hay or coastal Bermuda hay with no grain.27, 28 Furthermore, in a study evaluating the influence of a high fiber diet versus an iso‐energetic low fiber diet both the number and severity of ESGD lesions was greater in the high fiber diet group.29 Together, these findings suggest that that the impact of forage feeding in the absence of other risk factor reduction might not be as great as previously believed. There is an increased likelihood of ESGD (severity score ≥2/5) when straw is the only forage provided24 suggesting that forage type might also be important. An increased time between forage meals (>6 hours between meals), compared with more frequent forage feeding ( 80% are consistently observed with 7–14 days of triple treatment, including antimicrobials.3 Extrapolating from this; antimicrobials are anecdotally popular for the treatment of EGGD in the horse. However, antimicrobials do not improve healing of non H. pylori‐associated ulceration in humans.3 Furthermore, no evidence exists to support their use in the horse with a single, clinical trial documenting no benefit of the addition of trimethoprim–sulphadimidine over omeprazole monotherapy.89 Recommendation: In line with the profession's obligations for responsible stewardship of antimicrobials, and given A) the failure of bacterial agents to be definitely established as a contributory factor to EGGD and B) the absence of clinical trials supporting their use, it is the committee's opinion that the routine use of antimicrobials in the treatment of EGGD is not justified until their efficacy is appropriately documented. Alternatively, given the proposed role of failed mucosal defenses in the pathogenesis of EGGD, the use of mucosal protectants as a component of treatment is logical. Furthermore, their use is not complicated by ethical considerations as antimicrobials are. Sucralfate is the best studied. Its mechanism of action is likely a combination of adherence to ulcerated mucosa, stimulation of mucous secretion, prostaglandin E synthesis and enhanced blood flow all of which are likely to be beneficial in EGGD.90 Supporting its use, a recent study reported a 67.5% healing rate for EGGD of the pyloric antrum using omeprazole (GastroGard1) at 4 mg/kg PO once daily and sucralfate at 12 mg/kg PO twice daily.91 Further studies investigating the role of sucralfate and the potential for interactions between it and omeprazole, as reported in human medicine, are required. Considering the above factors the authors’ recommendation for the treatment of EGGD include the use of omeprazole as outlined for ESGD plus the addition of sucralfate at 12 mg/kg PO twice daily as summarized in Table 3. Given the positive response recently reported to this combination91 control examination at 4 weeks appears logical. It is the committee's opinion that a minimum of 8 weeks of combination therapy should be completed before additional therapies are considered. Further it is recommended that in such cases, further investigation into the underlying cause of disease, such a mucosal biopsy, appears justified before empirical treatment is continued. Table 3 Treatment recommendations for Equine Glandular Gastric Disease (EGGD) John Wiley & Sons, Ltd Pharmaceutical Prevention The pharmacological approach to prevention of ESGD is similar to treatment. Prevention should be approached on a case by case basis, wherein the greater the ability to impact on risk factors (as discussed below), the lower the need for additional treatment. Omeprazole in the form of buffered and enteric coated formulations is typically used at 1.0 mg/kg PO once daily for prevention.92, 93 To date, specific guidelines for the prevention of EGGD have not been developed although the efficacy of omeprazole as a prophylactic for EGGD is unclear with 23% of horses experiencing worsening of their EGGD grade in a series of recent studies, despite omeprazole treatment at doses ranging from 1–4 mg/kg PO once daily.19, 82, 87 Interestingly, in humans, the efficacy of long‐term acid suppression treatment in the prevention of non H. pylori, non‐NSAID associated ulceration has also been questioned.94 At the time of writing, the exact role of omeprazole for the prevention of EGGD is unclear; however, its use as per the recommendations for ESGD is logical until further defined. Nutraceuticals Nutraceuticals are appealing because of their ease of use and availability. Pectin‐lecithin complexes have been studied experimentally and increase the total mucus concentration in gastric juice.95 Two studies failed to demonstrate a protective effect in fed/fasting models of ESGD, despite initially promising results from a small case series.96 More recently, the combination of an antacid (magnesium hydroxide), a pectin‐lecithin complex and Saccharomyces cerevisiae has shown promise as a prophylactic agent for both ESGD and EGGD.97 Similarly, a feed supplement consisting of salts of organic acids in combination with B‐vitamins might be beneficial in the management of ESGD98 and a preparation containing sea buckthorn berries appeared to have protective effects against the development of EGGD in a fasting model of disease.99 Antacids appear to give some symptomatic relieve, however, their effect is short‐lived (≤2 hours)85, 100 and their use as a sole therapeutic agent is not justified. Nutritional Management In providing the following recommendations it is recognized that, as discussed above, strong evidence supporting some nutritional recommendations is lacking. Considering this, the following recommendations are based on the committee's interpretation of the available literature and their collective opinion as to what represents the current best practice. Furthermore, to date little evidence exists for the role of diet in EGGD and as such the following recommendations are based primarily on risk factors identified for ESGD. Although the evidence supporting such a recommendation is conflicting; continuous access to good quality grass pasture is considered ideal. Free choice, or at least frequent feedings (4–6 meals/day), of hay might be a suitable replacement. Horses fed hay should receive a minimum of 1.5 kg (DM)/100 kg bodyweight per day.39 Overweight horses and ponies at risk of EGUS should receive a minimum amount of high quality forage (1.5 kg (DM)/100 kg bodyweight per day) that is mature and has low energy content. If low energy forage is not available then a mixture of high quality forage and straw divided into a minimum of 4 feedings might be a suitable alternative. Straw should not be the only forage provided but can be safely included in the ration at <0.25 kg (DM)/100 kg BW. Horses should be fed grain and concentrates as sparingly as possible. Feeding of sweet feed should be avoided as a large quantity of VFAs could be produced if greater than 1 to 2 kg of sweet feed is fed per meal. Grains like barley and oats can be substituted to decrease fermentation to VFAs. The diet should not exceed 2 g/kg bodyweight of starch intake per day or more than 1 g/kg bodyweight of starch per meal.24 Concentrate meals should not be fed less than 6 hours apart.39 Vegetable oils such as corn oil might help reduce the risk of EGGD. Ponies with gastric cannulas fed 45 mL corn oil PO once daily by dose syringe had significantly lower gastric acid output and increased prostaglandin concentration in their gastric juice compared to the non oil dosed animals.101 Studies evaluating the use of oil in the management of naturally occurring EGGD are needed to document if these effects are clinically relevant. Water should be provided continuously. An increased risk of ESGD has been shown with electrolyte pastes or hypertonic solutions given PO,102 but not when electrolytes were mixed in feed or given in lower doses in water. As such the committee considers the use of electrolytes with feed to be safe.

The nadir esophageal pH of reflux observed during pH monitoring in the postprandial period is often more acidic than the concomitant intragastric pH. This paradox prompted the discovery of the "acid pocket", an area of unbuffered gastric acid that accumulates in the proximal stomach after meals and serves as the reservoir for acid reflux in healthy individuals and gastroesophageal reflux disease (GERD) patients. However, there are differentiating features between these populations in the size and position of the acid pocket, with GERD patients predisposed to upward migration of the proximal margin onto the esophageal mucosa, particularly when supine. This upward migration of acid, sometimes referred to as an "acid film", likely contributes to mucosal pathology in the region of the squamocolumnar junction. Furthermore, movement of the acid pocket itself to a supradiaphragmatic location with hiatus hernia increases the propensity for acid reflux by all conventional mechanisms. Consequently, the acid pocket is an attractive target for GERD therapy. It may be targeted in a global way with proton pump inhibitors that attenuate acid pocket development, or with alginate/antacid combinations that colocalize with the acid pocket and displace it distally, thereby demonstrating the potential for selective targeting of the acid pocket in GERD.

The effect of oral omeprazole on pentagastrin stimulated gastric acid secretion was studied in 11 healthy subjects. Doses of 20-80 mg produced dose dependent inhibition of acid secretion, with total suppression at the highest dose. Omeprazole was absorbed and eliminated from plasma rapidly and the inhibitory effect was related to the area under the plasma concentration time curve. The duration of action was long and single doses of 20 and 40 mg reduced acid secretion significantly for one and three days, respectively. Omeprazole in a dose of 15 mg given once daily for five days, suppressed acid secretion continuously, the inhibitory effect stabilising after three days at a predose inhibition of about 30% and a postdose inhibition of about 80%.