Effects of Intravenously Administered Esomeprazole Sodium on Gastric Juice pH in Adult Female Horses
Corresponding author: Dr Frank M. Andrews, Equine Health Studies Program, Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803; e-mail: firstname.lastname@example.org.
Background: Gastric ulcers are common in horses and treatment of horses that cannot be administered oral medication can be problematic.
Objectives: To evaluate the efficacy of esomeprazole sodium administered intravenously on gastric juice pH and gastric ulcer scores in horses.
Animals: Twelve adult female Quarter Horses.
Methods: Esomeprazole sodium (0.5 mg/kg IV) was administered once daily to 8 horses (treatment group) and saline (5 mL IV) was administered to 4 horses (control group) for 13 consecutive days. Gastroscopy was performed and gastric juice pH and gastric ulcer score were recorded before and 1 hour after the administration of esomeprazole sodium or saline on days 1 and 5, then on day 14, 23 hours after the 13th daily dose of esomeprazole sodium or saline.
Results: When compared with values before treatment, gastric juice pH was higher in esomeprazole sodium-treated horses after treatment (4.25 ± 2.39 versus 6.43 ± 1.18; P= .002). Also, gastric juice pH was higher (P= .001) in esomeprazole sodium-treated horses compared with saline-treated control horses on day 5 and on day 14 values. Gastric ulcers were seen in 5/12 (43%) horses in the study.
Conclusions and Clinical Importance: Esomeprazole sodium shows promise for treatment of gastric ulcers in horses with signs of dysphagia, gastric reflux, or other conditions that restrict oral intake of the current Federal Drug Administration-approved omeprazole paste.
Gastric ulcers, as part of the equine gastric ulcer syndrome (EGUS), commonly affect horses.1 The clinical signs associated with this syndrome are nonspecific and include colic, poor hair coat, poor appetite, decreased performance, diarrhea, weight loss, and depression.2,3 The prevalence of gastric ulcers approaches 100% in actively racing horses and 70.9% in pastured broodmares.4,5 Spontaneous healing does not typically occur in horses under training or exposed to other stressors. Current antiulcer pharmacological agents act by suppressing hydrochloric acid secretion thereby increasing gastric juice pH. This sets up a permissive environment for ulcer healing. Ulcers of the nonglandular stomach mucosa have been likened to gastroesophageal reflux disease (GERD) in people, where the maintenance of the gastric juice pH above 4.0 for >19 hours during the day and night is necessary for healing.6,7 The proton pump inhibitor, omeprazole paste,a is the only pharmacologic agent approved by the Federal Drug Administration (FDA) for treatment and prevention of recurrence of gastric ulcers in horses and foals 4 weeks and older.8 Unfortunately, omeprazole paste can only be administered orally. Administration of oral medications in horses with gastric reflux or dysphagia is contraindicated. Therefore, a formulation for IV administration would be helpful to increase gastric juice pH and treat EGUS in horses with these conditions.
Esomeprazole, the S-enantiomer of omeprazole, provides better gastric acid control and decreases interindividual variability in gastric juice pH, when compared with omeprazole (mixture of S- and R-enantiomers) in people with GERD.9–13 Its improved efficacy is likely because of esomeprazole's (S-enantiomer) lower first-pass hepatic metabolism, slower plasma clearance, and higher area under the curve (AUC) plasma concentration when compared with omeprazole.14 A higher plasma concentration results in more drug available (dose-dependent effect) to enter and inhibit parietal cell function and greater hydrochloric acid suppression. Esomeprazole maintained intragastric pH >4 when given PO, once daily, for 5 days in people; and also had a faster onset of action when compared with omeprazole and other racemic proton pump inhibitors.
In a recent study in horses, esomeprazole magnesium (60 and 80 mg PO q24h) maintained gastric pH > 5 up to 6 hours after administration.15 However, administration of oral medications is contraindicated in horses with gastric reflux or dysphagia, therefore, an IV formulation would be desirable in such conditions. A recent study, showed that omeprazole sodium (0.5 mg/kg IV) increased gastric juice pH 1 hour after the 1st dose and 23 hours after the 4th dose in horses.16 The purpose of this study was to determine the effects of IV administered esomeprazole sodium on gastric juice pH and gastric ulcer score in horses.
Materials and Methods
Twelve healthy adult mixed-breed Quarter Horse mares (mean [range]: 12.5 years [7–18 years]) with mean bodyweight (±SD) of 502 kg (±42 kg) were used in this study. Mares were not pregnant and part of the University of Tennessee reproduction teaching herd. Before entering the study, horses were healthy as indicated by physical examination and vaccinated and dewormed as part of a regular scheduled maintenance program. Mares were chosen because of temperament and handling to facilitate passing of the endoscope and not prescreened based on ulcer score. All procedures performed in this study were approved by the Institutional Animal Care and Use Committee at the University of Tennessee (IACUC # 1727).
Mares were randomly assigned to treatment (n = 8) and control (n = 4) groups stratified by ulcer score. Esomeprazole sodiumb (0.5 mg/kg IV) sterile powder was reconstituted with sterile water and administered between 8:00 am and 10:00 am once daily for 13 consecutive days to the treatment group. The control group received saline (5 mL IV) for the same period. Mares were housed at the university farm in a pasture environment, except on day 1, horses were transported to the Veterinary Teaching Hospital (VTH) and housed in individual stalls (3.7 m × 3.7 m) until day 5. An IV catheter was placed in either jugular vein of each mare the evening before gastroscopy and treatment (day 1). The IV catheter was used for administration of sedative agents before endoscopic examinations and for administration of esomeprazole sodium or saline during the first 5 days of the study. On day 5, the IV catheter was removed and mares were returned to the pasture at the research farm. From day 6 to 13, esomeprazole sodium was administered daily via 20 G 1.5 in. needle. The mares were fed grass hay ad libitum when stalled and supplemented with the same type of grass hay (round bale) when they were in the pasture. Horses were not fed concentrates during the study period. Horses were divided into 3 groups of 4 mares each for ease of scoping and management. Each group consisted of at least 1 saline-treated control. The different groups were overlapped, which allowed the study to be completed in 21 days. Part of the study was conducted at the VTH to make use of the facilities and personnel. However, the mares were taken back to the university pasture between endoscopies to avoid overcrowding at the VTH.
Endoscopic Examination and Gastric Ulcer Scoring
All horses were endoscopically examined on days 1, 5, and 14, but gastric ulcers scores were only recorded on days 1 and 14. Before the gastroscopy procedure feed and water were withheld for 12 and 4 hours, respectively. Horses were restrained in stocks and sedated with xylazinec (220 mg IV) 10 minutes before each endoscopic procedure. A 3 m gastroscoped was introduced into the dependent glandular region of the stomach, and at least 60 mL of gastric juice was aspirated through the biopsy channel with the suction device attached to the endoscope system. Gastric juice was collected before and 1 hour after esomeprazole sodium or saline administration on days 1 and 5, so that each horse underwent endoscopy twice, 1 hour apart, on these 2 days. Gastric juice was also collected with the endoscope on day 14, 23 hours after the 13th daily dose of esomeprazole sodium or saline. Mares were muzzled and not allowed access to feed or water between the hourly endoscopic procedures.
After gastric juice was collected the stomach was insufflated with an air compressor attached to the biopsy channel. The stomach of each horse was given a gastric ulcer score (range 0–4 for number of ulcers; range 0–5 for lesion severity) on day 1, during the 1st endoscopic procedure, and again on day 14 based on a previously published scoring system for horses.17
Measurement of Gastric Juice pH
Gastric juice pH was collected from the biopsy channel, before insufflation of the stomach, directly into a closed glass jar and measured immediately with a portable pH metere with attached electrode. The pH meter was calibrated with standard pH (4.0, 7.0, and 10.0) solutions before the beginning of each collection period. The clinician measuring the gastric juice pH was not masked to the treatment groups; however, the aspirate was taken from the first observed gastric juice fluid.
Mean gastric juice pH values before and after treatments on days 1, 5, and 14 from horses were compared by Statistical Analysis System.f A mixed model procedure was used for analysis of variance. A complete randomized design was run with split plot treatment arrangement. Gastric juice pH values were expressed as mean ± standard error of the mean. Although the horses were processed in groups of 3, no period effect was seen, so data collected on the horses was grouped together and analyzed. The level of statistical significance was set at P < .05.
A statistical analysis was not performed on gastric ulcer scores (number and severity) because of the low number of mares affected.
Mathematical Statistical Model
where Yijk represent the dependent variable (pH) for the ith treatment (T) on the whole plot treatment for the jth plot replicate (horse) (H) and kth subplot (time) (S); μ, represents the overall mean.
Horses were clinically normal during the study period. No adverse responses to esomeprazole administration, the gastroscopy procedure, or aspiration of gastric juice were observed. On day 1, gastric ulcers were found in 5/12 horses (42%) in this study. Two horses had gastric ulcers in the nonglandular mucosa, 2 horses had gastric ulcers in the glandular mucosa, and 1 horse had gastric ulcers in both nonglandular and glandular mucosa.
Gastric juice pH values from all the horses were included in the statistical analysis. Gastric juice pH varied from 1.7 to 7.9 before esomeprazole or saline administration. Although gastric juice pH was variable between horses, mean values were not statistically different (P= .250) between treated (4.25 ± 2.39) and control (5.47 ± 1.03) horses on day 1 before treatment.
On day 1, mean gastric juice pH significantly increased from 4.25 ± 2.39 to 6.43 ± 1.18, 1 hour after esomeprazole administration when compared with values before treatment, but this was not significantly different than control values (6.19 ± 1.29, P= .567) at the same time point. Four of eight (50%) horses had pH > 4.0 before esomeprazole treatment. This increased to 7/8 horses (88%), 1 hour after the 1st dose of esomeprazole.
On day 5, 23 hours after the 4th daily dose of esomeprazole, gastric juice pH was higher than control horses (4.35 ± 2.10 versus 2.08 ± 0.33, P= .002), but not significantly different from pretreatment values (4.35 ± 2.10 versus 4.25 ± 2.39, P= .870). Also, in this group 5/8 (63%) of horses had gastric juice pH > 4.0, whereas none of the control horses had gastric juice pH > 4 at this same time point. However, 1 hour after the 5th daily dose of esomeprazole, gastric juice pH significantly (P= .002) increased from 4.35 ± 2.10 to 6.70 ± 0.70 and was higher than both values before treatment and control values. Furthermore, all of the esomeprazole-treated horses (8/8; 100%) had a gastric juice pH > 4.0, 1 hour after treatment, whereas none of the control horses had gastric juice pH > 4.0 after saline treatment.
On day 14, 23 hours after the 13th daily dose, gastric juice pH was significantly (P= .002) higher in the esomeprazole-treated horses compared with values before treatment on day 1 and control values at the same time point (5.46 ± 1.34 versus 4.25 ± 2.39 and 2.79 ± 0.94). Six of 8 (75%) had gastric juice pH > 4.0 at this time point.
Five of 12 (43%) horses in this study had gastric ulcers. Nonglandular gastric ulcers were seen in 3 horses and varied in number score from 1 to 3 and severity score from 1 to 2. Glandular ulcers were seen in 3 horses and varied in number score from 1 to 2 and varied in severity score from 1 to 2.
Gastric juice pH was variable and high in the horses (mean 4.66 ± 2.12; range 1.99–7.90) before esomeprazole or saline treatment. Considerable interhorse variation in gastric juice pH has been reported before and after treatment with omeprazole.16,18,19 However, although variability in gastric juice pH values exist between horses, there appears to be good intraindividual reproducibility for recordings repeated in the same horse. Also, repeated sampling of gastric juice leads to altered gastric juice pH values. However, a previous report in horses where gastric juice samples were taken from horses at 0.5, 2, 4, 8, 18, 24, 36, 42, 48, 60, and 72 hours showed minimal variability in gastric juice pH values within the same horse over multiple sampling periods and these data are similar to data reported on horses in this study.20 Esomeprazole treatment resulted in a significant increase in gastric juiced pH 1 hour after administration and gastric juice pH (6.43 ± 1.18; range 3.54–7.51) had a narrow range, compared with values before treatment (4.25 ± 2.39; range 1.72–7.90). Esomeprazole treatment decreases interindividual variability in gastric juice pH in people and in horses when administered orally.9,11,15
Gastric juice pH on day 1, before esomeprazole or saline treatment, was higher than a previous report, when gastric juice was aspirated from the stomach in standing horses sedated with detomidine.16 The reason for the higher gastric juice pH measured in this study is unknown, but xylazine administration could have played a role. Xylazine, an α-2 agonist, delays gastric emptying in horses, but to a lesser extent than detomidine.21,22 The delay in gastric emptying could have allowed bicarbonate-rich bile to reflux into the stomach from the duodenum, which could have increased gastric juice pH in these horses.23 However, mean gastric juice pH was low in some of the horses on day 1 and the control horses after sedation on day 5, so xylazine administration did not likely cause of the increased gastric juice pH in these horses. Variation in gastric juice pH measurements could have been produced by the fact that the gastric juice pH was measured a single time at each sampling time. It is possible that by a continuous pH measurement technique could have decreased this type of error.
The high gastric juice pH in some horses could have been caused by the length of feed withdrawal. Although feed was withheld from the horses in this study for 12 hours, a longer period (19–24 hours) could be required to achieve a low and less variable gastric juice pH in all horses.24,25 Furthermore, although horses were muzzled during the feed withholding period, some of the horses could have been able to eat manure or bedding through the muzzle or some horse could have taken their muzzles off while in the stall. This could have led to the observed higher gastric juice pH seen in some of the horses.
Esomeprazole given IV (0.5 mg/kg bwt) resulted in a significant increase in gastric juice pH in horses in this study. One hour after the 1st dose, gastric juice pH increased significantly and pH was >4 in 7 of 8 (88%) horses, compared with 4 of 8 (50%) horses before treatment. Sustained gastric juice pH > 4.0 is considered important in healing of esophageal and gastric erosions and ulcers in people with GERD.6,26 Because nonglandular gastric ulcer disease is similar to GERD in people, a sustained pH > 4 maybe needed to facilitate ulcer healing. Based on results reported here, esomeprazole is potent at increasing gastric juice pH. This is consistent with reports in people, when compared with omeprazole.9 The proposed mechanism for improved efficacy is that esomeprazole has a lower first-pass hepatic metabolism, which results in slower plasma clearance and higher AUC plasma concentration when compared with omeprazole.14 Higher AUC results in more esomeprazole available to enter the parietal cell and inhibit gastric acid secretion. Horses in the study presented here had higher pretreatment mean gastric juice pH (4.25 ± 2.39) than horses in the previous omeprazole trial (2.01 ± 0.42). If horses in this study would have had a lower mean gastric juice pH, a higher dose of esomeprazole could have been required to increase gastric juice pH > 4. However, mean gastric juice pH increased from a mean of 2.03–6.64 in the 4 horses with low gastric juice pH, 1 hour after esomeprazole treatment. Thus, esomeprazole appears to have a potent effect on gastric juice pH, as these 4 horses experienced at least a 4 pH unit increase in gastric juice pH after treatment.
Collection of gastric juice before esomeprazole administration on day 5 and day 14 provided an opportunity to assess its effects 23 hours after administration of the 4th and 13th daily dose, respectively. Twenty-three hours after esomeprazole treatment, gastric juice pH was significantly higher than values measured in control horses. Also, 5 of 8 horses had gastric juice pH > 4.0, 23 hours after the 4th daily dose and 6 of 8 horses had gastric juice pH > 4, 23 hours after the 13th daily dose. These data suggest that esomeprazole sodium administered IV has a long duration of effect. This is in contrast to a previous report that showed esomeprazole magnesium (40 and 80 mg PO) did not result in a sustained increase in gastric juice pH, 24 hours after the 4th daily dose.15 It should be mentioned that the dose of esomeprazole magnesium used in that previous study was 4–8 times lower than the esomeprazole sodium used in the study reported here. Therefore, because of the lower dose and oral administration, it is likely the AUC plasma concentrations were much lower in that previous study compared with the study presented here. Esomeprazole is dose dependent so IV administration would likely produce higher AUC plasma concentrations leading to a more potent effect on gastric juice pH than the PO-administered esomeprazole magnesium.27 Also, it could be that the increase in pH was missed because of the timing of sampling in horses in this study. A previous study showed that panoprazole administered to neonatal foals resulted in peak pH values 2–3 hours after administration.28 Peak gastric juice pH could have been missed because samples were taken 1 hour after administration of esomeprazole.
Esomeprazole-treated horses in the study presented here had a higher gastric juice pH 23 hours after treatment on days 4 and 13, when compared with control horses. The pH data reported in the horses in this study are similar to gastric juice pH in horses 23 hours after administration of omeprazole IV.16 Therefore, esomeprazole sodium appears to produce a long duration of acid suppression. Similar to omeprazole, esomeprazole accumulates in the acidic secretory canaliculi of the gastric parietal cell because of its low pKa (4.0).13 Once inside the canaliculi, it is rapidly protonated to its active cyclic sulphenamide form and binds covalently and irreversibly to the H+, K+, ATPase enzyme.9 The long duration of effect suggests that this formulation of esomeprazole is effective in increasing gastric juice pH > 4.0 when administered once daily.
The prevalence (43%) of gastric ulcers in the nonpregnant pastured mares in the study reported here was lower than previous reports in nonpregnant broodmares (70.9%).5 The difference in gastric ulcer prevalence could be because of differences in breed, environmental conditions, diet and level of stress.8 Horses in the study presented here were Quarter Horse and Quarter Horse mixed breed horses, whereas previous studies have focused on Thoroughbred mares. The prevalence of gastric ulcers in Quarter Horses is 40%.29,30 Temperament was cited has a possible reason for the lower prevalence of gastric ulcers in the Quarter Horse breed. Horses in the study presented here were chosen for their good temperament and ease of handling for endoscopy, which could have influenced the low observed gastric ulcer prevalence.
Gastric ulcers in horses in the study reported here were generally mild before treatment. Nonglandular gastric ulcers were zero in all horses on day 14 and none of the horses developed new nonglandular ulcers during the study period. Glandular gastric ulcer scores were low and scores improved in the esomeprazole-treated horses, whereas scores increased slightly in untreated control horses. These findings suggest that nonglandular gastric ulcers undergo spontaneous healing in some horses housed in a pasture environment. An alternative explanation is that esomeprazole treatment could have had an effect on healing and preventing new gastric ulcers from occurring. This explanation seems plausible, but in lieu of the small number of horses with ulcers in the study conclusions must be formulated with caution, as statistically analysis was not done. Unfortunately, there is no current data on the efficacy of esomeprazole in healing gastric ulcer in horses. However, a previous study showed that omeprazole sodium (0.5 mg/kg IV once daily) significantly decreased the number of gastric ulcers in horses after 5 days of treatment.16 Also, a higher AUC plasma concentration translates into better healing rates for esophageal and gastric ulcers in people.14,26 However, esomeprazole sodium AUC plasma concentration was not measured in horses in this study.
IV administration of esomeprazole sodium can be useful in the treatment and prevention of gastric ulcers in horses with restricted oral intake because of gastric reflux, such as duodenitis-proximal jejunitis (DPJ) and postoperative ileus or in horses with dysphagia or facial bone fractures. Horses with DPJ have a higher prevalence of gastric ulceration (68%) compared with horses with large colon impactions (32%) or large colon volvulus (14%).31 Parenteral administration of esomeprazole could be indicated in some horses with diagnosed DPJ or other conditions that have a high prevalence of gastric ulcers.
In conclusion, IV administration of esomeprazole sodium (0.5 mg/kg) caused a rapid and sustained increase in gastric juice pH in horses after the 1st and 5th daily doses. Esomeprazole sodium appears to have a more pronounced acid suppressive effect. This IV formulation of esomeprazole sodium should only be used in horses with restricted oral intake that cannot consume the current FDA-approved oral omeprazole paste or in horses with severe gastric ulceration that are at risk of gastric perforation.
aGastroGard, Merial Limited, Duluth, GA
bRandlab Australia Pty Ltd, Peakhurst, NSW, Australia
cRompun, Bayer Animal Health, Shawnee Mission, KS
dKarl Storz G34-300, Goleta Heights, CA
eAcumet AP61 Portable pH meter, Fischer Scientific, Pittsburgh, PA
fSAS, version 9.2, 2008, Cary, NC
The authors acknowledge Dr Nicolás Villarino for the statistical analysis and Dr Karen Kalck for technical assistance.