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Introduction
Equine gastric ulcer syndrome (EGUS) is highly prevalent in all ages and affects horse performance and fitness (Andrews and Nadeau, 1999; Doucet et al., 2003). Large numbers of stabled horses undergo intense work routines, which can predispose to gastrointestinal problems such as gastric ulcers. EGUS is usually associated with changes in attitude, poor appetite, weight loss, decreased physical performance, diarrhea, abdominal discomfort or recurrent colic episodes (Murray et al., 1996; Birkmann et al., 2014), and is a common pathology in horses (Videla and Andrews, 2009). Anti-ulcer treatments generally consist in neutralizing stomach acidity using antacids or to reduce acid secretion with antisecretory drugs, aiming to provide a favorable environment for healing. Proton-pump inhibitors such as omeprazole are commonly used to suppress gastric acid secretion (Daurio et al., 1999; Ruiz JD et al., 2012). Histamine-2 (H2) antagonists such as ranitidine or cimetidine (Campbell-Thompson and Merritt, 1987) are also commonly used for this purpose. Ranitidine (6.6 mg/Kg, orally administered) tended to increase gastric fluid pH>6 for a longer time (166 +/- 106 mins) compared with famotidine (98 +/- 110 mins), and higher doses are necessary in horses than those recommended in humans (Murray and Grodinsky, 1992). Omeprazole blocks H+ secretion from parietal cell membranes by irreversibly joining the H+, K+ ATPase proton pump (Holt and Howden, 1991). Pharmaceutical preparations for oral administration of omeprazole range from tablets to enteric-coated granules developed to release the drug in the intestine, thus preventing it from being degraded by the acidic environment of the stomach (Daurio et al., 1999; Ruiz JD et al., 2012). Oral administration of 4 mg/Kg omeprazole once daily is highly effective for healing gastric ulcers in horses (Doucet et al., 2003; McClure et al., 2005; McKeever et al., 2006; Sykes et al., 2014). However, oral administration of medications in horses with gastrointestinal disorders such as gastric reflux or dysphagia is contraindicated, so intravenous (IV) administration of omeprazole is an alternative route to increase gastric pH (Rand et al., 2014). Andrews et al. (2006) administered 0.5 mg/Kg IV omeprazole once daily for five days to six adult horses, and observed that gastric pH increased from 2 to 4.35 one hour after administration on the first day of the treatment. They also reported a pH of 5.27 ± 1.74 before omeprazole was administered 23 hours after the 4th daily dose was given. However, pH was very different among horses and time, whereas only 3 out of 6 horses had gastric pH above 4.0 one hour after omeprazole administration on the first day of the treatment, and it was above 4.0 in 5 of the 6 animals on day five (Andrews et al., 2006).
The objective of this study was to determine the effect of a single IV dose of 1 or 2 mg/Kg omeprazole on gastric pH in Colombian Creole horses.
Material and methods
Ethical considerations
All experimental procedures were approved by the Institutional Committee for the Care and Use of Animals of CES University (Medellin, Colombia; Act No 3-2013).
Animals
Seven healthy Colombian Creole horses (four males and three females) averaging seven years of age (range 4-10 years) and weighing 292 ± 63 Kg were used in the study. The horses were part of a herd used for training practices with CES University veterinary students and were kept on grazing pastures. Animals underwent physical examination and were dewormed one month before the start of the study. Blood work parameters before the study (complete blood count, creatinine, blood urea nitrogen, and alkaline phosphatase) were within the normal range for horses. Food was withheld 12 h before administering the drug. The animals were fasted throughout the 24 h duration of the study and water was provided ad libitum at all times.
Treatments
Each horse received all three IV treatments (control, 1, and 2 mg/Kg omeprazole) with a 7-day interval between treatments.
Lyophilized omeprazole powder (Omezol lyo BEST, S. A. laboratories, Bogotá, Colombia) was diluted in 100 ml 0.9% NaCl and IV administered between 7:00 and 8:00 a.m on the day of the treatment using an 18-gauge x 1.5-inch needle.
Gastric juice samples for pH measurements were collected in glass bottles through a nasogastric tube and pH was measured immediately after collection using a portable pH-meter at time 0 (before injection) and at 1, 2, 3, 5, 7, 9, 11, and 24 hours postinjection. The pH-meter was calibrated using standard solutions (pH 4.0 and 7.0) before each collection time.
Statistic analysis
Data on gastric pH before injection and 1, 2, 3, 5, 7, 9, 11, and 24 hours post-injection were analyzed with STATGRAPHICS software (Statpoint Technologies, Inc. VA, USA). Results are presented as the mean ± SD, but plotted as mean ± standard error of the mean (SEM) for the ease of graphical illustration. Statistical differences between pH values were determined by analysis of variance (ANOVA) blocked by horse, with repeated measurements of pH. Significance was considered when p ≤ 0.05.
Results
Gastric juice pH was low in all horses before omeprazole administration, ranging from 1.6 to 3.2. One hour after injecting 1 mg/Kg omeprazole, gastric pH increased significantly (p ≤ 0.05) from 2.4 ± 0.4 to 6.5 ± 1 (range 4.6 to 7.5). Similarly, horses injected with 2 mg/Kg omeprazole had a significant increase in gastric pH from 2.2 ± 0.5 before injection to 6.9 ± 0.3 (range 6.3 to 7.1) one hour after the injection (p ≤ 0.05). Figure 1 shows that no significant difference was observed between both omeprazole doses (p>0.05). The control group showed no statistical difference at any time after the injection compared with time 0 (pre-treatment values; p>0.05).
As shown in Figure 1, both 1 and 2 mg/Kg omeprazole induced significant increase in gastric pH (pH>4.6 in all horses) from 1 to 11 hours after the injection, compared with the control group and pre-treatment values (p ≤ 0.05). Gastric pH between horses treated with 1 and 2 mg/Kg omeprazole did not differ significantly from 1 to 11 hours postadministration (p>0.05).
Figure 1 Mean ± standard error of the mean (SEM) of gastric pH in adult horses after IV omeprazole dosages of 1 or 2 mg/Kg body weight (BW) and control. Values with different letters indicate significant differences (p ≤ 0.05). Omeprazole was administered immediately after the first collection of gastric juice at 0 h.
Whereas gastric pH of horses injected with 1 mg/Kg omeprazole decreased to 2.8 ± 0.3 at 24 h post-injection, it remained elevated at 5.7 ± 0.87 for the group treated with 2 mg/Kg. At 24 hours post-administration, a significant difference was found between both omeprazole groups (p ≤ 0.05, Figure 1).
No adverse reactions related to omeprazole administration or the nasogastric intubation procedures were observed throughout the study.
Discussion
No significant differences were observed in gastric pH baseline (pH fluctuated from 1.6 to 3.2) at time 0 prior to omeprazole administration. This is consistent with some reports of minimal inter-individual variability in baseline gastric pH (Tellez et al., 2005; Andrews et al., 2006). Nevertheless, other studies have reported significant inter-horse variations (Daurio et al., 1999; JD Ruiz et al., 2012).
Both omeprazole injections (1 and 2 mg/Kg) increased gastric pH after one hour of injection, with values above 4 for all horses (range 4.6 to 7.5). Other researchers found gastric pH increased above 4 during the first hour only in three out of six horses treated with 0.5 mg/Kg IV omeprazole (Andrews et al., 2006). In the present study, pH remained above 4 for up to 11 hours after injection of either 1 or 2 mg/Kg omeprazole; which is the minimum pH that should be maintained for as long as possible in order to improve the healing rate of gastric lesions (Armstrong, 2004). However, only the highest omeprazole dose in our study (2 mg/Kg) was able to maintain the pH above 4 for 24 h after injection in every horse treated; which is similar to results reported by other researchers using 4 mg/Kg orally (Daurio et al., 1999). Our results clearly indicate that a single dosage of 2 mg/ Kg IV omeprazole inhibits gastric acid secretion for 24 hours. After absorption, omeprazole is transferred from the plasma to the acid secretory canaliculi of parietal cells (Holt and Howden, 1991) and covalently binds to H+, K+ ATPase (Bays and Finch, 1990), so the anti-secretory effect of omeprazole on parietal cells persist long after plasma concentrations have decreased (Holt and Howden, 1991).
Previous reports have shown that sedating agents can modify the solid and liquid phase of gastric emptying in horses, with possible effects on gastric pH (Doherty et al., 1999; Sutton et al., 2002). In the present study, the effect on gastric pH could only be attributed to omeprazole, since alpha-2 agonist tranquilizers -commonly administered for horse manipulation- were not used.
This study demonstrates that administering a single dosage of 1 mg/Kg IV omeprazole is not enough to increase gastric pH above 4 for 24 hours. However, a dose of 2 mg/Kg IV omeprazole produced a sustained increase of gastric pH above 4 during 24 hours, which is considered essential for gastric ulcer healing. Since the effect of omeprazole on gastric pH is not only dose but also time dependent, a limitation of this study was whether repeated daily administration of 1 mg/Kg IV, or even lower doses, could achieve and maintain steady states of gastric juice pH above 4 during few days after starting the therapy.
In summary, a dose-time-response relationship exists between omeprazole and gastric pH in horses, confirming that treatment with 1 or 2 mg/Kg IV omeprazole is effective to increase gastric pH.
