Effects of intravenously administered esomeprazole sodium on gastric juice ph in adult female horses

E f f e c t s o f I n t r a v e n o u s l y A d m i n i s t e r e d E s o m e p r a z o l e S o d i u m o n G a s t r i c J u i c e p H i n A d u l t F e m a l e H o r s e s R. Videla, C.S. Sommardahl, S.B. Elliott, A. Vasili, and F.M. Andrews Background: Gastric ulcers are common in horses and treatment of horses that cannot be administered oral medication can Objectives: To evaluate the efficacy of esomeprazole sodium administered intravenously on gastric juice pH and gastric 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 andgastric 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 Æ 2.39 versus 6.43 Æ 1.18; P 5.002). Also, gastric juice pH was higher (P 5.001) 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.
Key words: Equine gastric ulcer syndrome; Gastric ulcers; Gastroenterology; Stomach.
Gastric ulcers, as part of the equine gastric ulcer syn- istration of oral medications in horses with gastric reflux drome (EGUS), commonly affect horses.1 The or dysphagia is contraindicated. Therefore, a formula- clinical signs associated with this syndrome are nonspe- tion for IV administration would be helpful to increase cific and include colic, poor hair coat, poor appetite, gastric juice pH and treat EGUS in horses with these decreased performance, diarrhea, weight loss, and de- pression.2,3 The prevalence of gastric ulcers approaches Esomeprazole, the S-enantiomer of omeprazole, pro- 100% in actively racing horses and 70.9% in pastured vides better gastric acid control and decreases inter- broodmares.4,5 Spontaneous healing does not typically individual variability in gastric juice pH, when compared occur in horses under training or exposed to other with omeprazole (mixture of S- and R-enantiomers) in peo- stressors. Current antiulcer pharmacological agents act ple with GERD.9-13 Its improved efficacy is likely because by suppressing hydrochloric acid secretion thereby increas- of esomeprazole's (S-enantiomer) lower first-pass hepatic ing gastric juice pH. This sets up a permissive environment metabolism, slower plasma clearance, and higher area un- for ulcer healing. Ulcers of the nonglandular stomach mu- der the curve (AUC) plasma concentration when compared cosa have been likened to gastroesophageal reflux disease with omeprazole.14 A higher plasma concentration results (GERD) in people, where the maintenance of the gastric in more drug available (dose-dependent effect) to enter and juice pH above 4.0 for 419 hours during the day and night inhibit parietal cell function and greater hydrochloric acid is necessary for healing.6,7 The proton pump inhibitor, om- suppression. Esomeprazole maintained intragastric pH 44 eprazole paste,a is the only pharmacologic agent approved when given PO, once daily, for 5 days in people; and also by the Federal Drug Administration (FDA) for treatment had a faster onset of action when compared with omepraz- ole and other racemic proton pump inhibitors.
in horses and foals 4 weeks and older.8 Unfortunately, In a recent study in horses, esomeprazole magnesium omeprazole paste can only be administered orally. Admin- (60 and 80 mg PO q24h) maintained gastric pH 4 5 up to6 hours after administration.15 However, administrationof oral medications is contraindicated in horses with From the Department of Large Animal Clinical Sciences, College gastric reflux or dysphagia, therefore, an IV formulation of Veterinary Medicine, University of Tennessee, Knoxville, TN (Vi- would be desirable in such conditions. A recent study, dela, Sommardahl, Elliott); Randlab Australia Pty Ltd, Australia (Vasili); and Equine Heath Studies Program, Department of Veter- increased gastric juice pH 1 hour after the 1st dose and inary Clinical Sciences, School of Veterinary Medicine, LouisianaState University, Baton Rouge, LA (Andrews).
23 hours after the 4th dose in horses.16 The purpose of Corresponding author: Dr Frank M. Andrews, Equine Health this study was to determine the effects of IV administered Studies Program, Department of Veterinary Clinical Sciences, School esomeprazole sodium on gastric juice pH and gastric of Veterinary Medicine, Louisiana State University, Baton Rouge, Submitted October 22, 2010; Revised January 17, 2011; Copyright r 2011 by the American College of Veterinary Internal Twelve healthy adult mixed-breed Quarter Horse mares (mean [range]: 12.5 years [7-18 years]) with mean bodyweight (ÆSD) of Esomeprazole for Treatment of Equine Gastric Ulcers 502 kg (Æ42 kg) were used in this study. Mares were not pregnant The clinician measuring the gastric juice pH was not masked to the and part of the University of Tennessee reproduction teaching herd.
treatment groups; however, the aspirate was taken from the first Before entering the study, horses were healthy as indicated by phys- ical examination and vaccinated and dewormed as part of a regularscheduled maintenance program. Mares were chosen because of temperament and handling to facilitate passing of the endoscopeand not prescreened based on ulcer score. All procedures performed Mean gastric juice pH values before and after treatments on days in this study were approved by the Institutional Animal Care and 1, 5, and 14 from horses were compared by Statistical Analysis Use Committee at the University of Tennessee (IACUC # 1727).
System.f A mixed model procedure was used for analysis of variance. A Mares were randomly assigned to treatment (n 5 8) and control complete randomized design was run with split plot treatment arrange- (n 5 4) groups stratified by ulcer score. Esomeprazole sodiumb ment. Gastric juice pH values were expressed as mean Æ standard error (0.5 mg/kg IV) sterile powder was reconstituted with sterile water of the mean. Although the horses were processed in groups of 3, no and administered between 8:00 AM and 10:00 AM once daily for 13 period effect was seen, so data collected on the horses was grouped consecutive days to the treatment group. The control group received together and analyzed. The level of statistical significance was set at saline (5 mL IV) for the same period. Mares were housed at the university farm in a pasture environment, except on day 1, horses A statistical analysis was not performed on gastric ulcer scores were transported to the Veterinary Teaching Hospital (VTH) and (number and severity) because of the low number of mares affected.
housed in individual stalls (3.7 m  3.7 m) until day 5. An IV cath-eter was placed in either jugular vein of each mare the evening before gastroscopy and treatment (day 1). The IV catheter was usedfor administration of sedative agents before endoscopic examina- tions and for administration of esomeprazole sodium or saline ijk ¼ m þ Ti þ H  ðTÞij þ Sk þ Sk  Tij þ S  H  ðTÞijk during the first 5 days of the study. On day 5, the IV catheter was where Yijk represent the dependent variable (pH) for the ith treatment removed and mares were returned to the pasture at the research (T) on the whole plot treatment for the jth plot replicate (horse) (H) farm. From day 6 to 13, esomeprazole sodium was administered and kth subplot (time) (S); m, represents the overall mean.
daily via 20 G 1.5 in. needle. The mares were fed grass hay ad libitumwhen stalled and supplemented with the same type of grass hay(round bale) when they were in the pasture. Horses were not fed con- centrates during the study period. Horses were divided into 3 groups Horses were clinically normal during the study period.
of 4 mares each for ease of scoping and management. Each groupconsisted of at least 1 saline-treated control. The different groups were No adverse responses to esomeprazole administration, overlapped, which allowed the study to be completed in 21 days. Part the gastroscopy procedure, or aspiration of gastric of the study was conducted at the VTH to make use of the facilities juice were observed. On day 1, gastric ulcers were found and personnel. However, the mares were taken back to the university in 5/12 horses (42%) in this study. Two horses had gastric pasture between endoscopies to avoid overcrowding at the VTH.
ulcers in the nonglandular mucosa, 2 horses hadgastric ulcers in the glandular mucosa, and 1 horse had Endoscopic Examination and Gastric Ulcer Scoring gastric ulcers in both nonglandular and glandular mucosa.
Gastric juice pH values from all the horses were in- All horses were endoscopically examined on days 1, 5, and 14, but cluded in the statistical analysis. Gastric juice pH varied gastric ulcers scores were only recorded on days 1 and 14. Before the from 1.7 to 7.9 before esomeprazole or saline adminis- gastroscopy procedure feed and water were withheld for 12 and 4hours, respectively. Horses were restrained in stocks and sedated with tration. Although gastric juice pH was variable between xylazinec (220 mg IV) 10 minutes before each endoscopic procedure. A horses, mean values were not statistically different 3 m gastroscoped was introduced into the dependent glandular region (P 5.250) between treated (4.25 Æ 2.39) and control of the stomach, and at least 60 mL of gastric juice was aspirated (5.47 Æ 1.03) horses on day 1 before treatment.
through the biopsy channel with the suction device attached to the On day 1, mean gastric juice pH significantly increased endoscope system. Gastric juice was collected before and 1 hour after from 4.25 Æ 2.39 to 6.43 Æ 1.18, 1 hour after esomepraz- esomeprazole sodium or saline administration on days 1 and 5, so that ole administration when compared with values before each horse underwent endoscopy twice, 1 hour apart, on these 2 days.
treatment, but this was not significantly different than Gastric juice was also collected with the endoscope on day 14, 23 control values (6.19 Æ 1.29, P 5.567) at the same time hours after the 13th daily dose of esomeprazole sodium or saline.
point. Four of eight (50%) horses had pH 4 4.0 before Mares were muzzled and not allowed access to feed or water betweenthe hourly endoscopic procedures.
esomeprazole treatment. This increased to 7/8 horses After gastric juice was collected the stomach was insufflated with (88%), 1 hour after the 1st dose of esomeprazole.
an air compressor attached to the biopsy channel. The stomach of On day 5, 23 hours after the 4th daily dose of each horse was given a gastric ulcer score (range 0-4 for number esomeprazole, gastric juice pH was higher than control of ulcers; range 0-5 for lesion severity) on day 1, during the 1st horses (4.35 Æ 2.10 versus 2.08 Æ 0.33, P 5.002), but not endoscopic procedure, and again on day 14 based on a previously significantly different from pretreatment values (4.35 Æ 2.10 versus 4.25 Æ 2.39, P 5.870). Also, in this group 5/8(63%) of horses had gastric juice pH 4 4.0, whereas none of the control horses had gastric juice pH 4 4 at this sametime point. However, 1 hour after the 5th daily dose of Gastric juice pH was collected from the biopsy channel, before insufflation of the stomach, directly into a closed glass jar and mea- esomeprazole, gastric juice pH significantly (P 5.002) sured immediately with a portable pH metere with attached increased from 4.35 Æ 2.10 to 6.70 Æ 0.70 and was electrode. The pH meter was calibrated with standard pH (4.0, 7.0, higher than both values before treatment and control and 10.0) solutions before the beginning of each collection period.
values. Furthermore, all of the esomeprazole-treated horses (8/8; 100%) had a gastric juice pH 4 4.0, 1 hour The high gastric juice pH in some horses could have after treatment, whereas none of the control horses had been caused by the length of feed withdrawal. Although gastric juice pH 4 4.0 after saline treatment.
feed was withheld from the horses in this study for 12 On day 14, 23 hours after the 13th daily dose, gastric hours, a longer period (19-24 hours) could be required to juice pH was significantly (P 5.002) higher in the achieve a low and less variable gastric juice pH in all esomeprazole-treated horses compared with values horses.24,25 Furthermore, although horses were muzzled before treatment on day 1 and control values at the same during the feed withholding period, some of the horses time point (5.46 Æ 1.34 versus 4.25 Æ 2.39 and 2.79 Æ could have been able to eat manure or bedding through 0.94). Six of 8 (75%) had gastric juice pH 4 4.0 at this the muzzle or some horse could have taken their muzzles off while in the stall. This could have led to the observed Five of 12 (43%) horses in this study had gastric ulcers.
higher gastric juice pH seen in some of the horses.
Nonglandular gastric ulcers were seen in 3 horses and Esomeprazole given IV (0.5 mg/kg bwt) resulted in a varied in number score from 1 to 3 and severity score significant increase in gastric juice pH in horses in this from 1 to 2. Glandular ulcers were seen in 3 horses and study. One hour after the 1st dose, gastric juice pH in- varied in number score from 1 to 2 and varied in severity creased significantly and pH was 44 in 7 of 8 (88%) horses, compared with 4 of 8 (50%) horses before treat-ment. Sustained gastric juice pH 4 4.0 is considered important in healing of esophageal and gastric erosionsand ulcers in people with GERD.6,26 Because nonglan- Gastric juice pH was variable and high in the horses dular gastric ulcer disease is similar to GERD in people, (mean 4.66 Æ 2.12; range 1.99-7.90) before esomeprazole a sustained pH 4 4 maybe needed to facilitate ulcer or saline treatment. Considerable interhorse variation healing. Based on results reported here, esomeprazole is in gastric juice pH has been reported before and after potent at increasing gastric juice pH. This is consistent treatment with omeprazole.16,18,19 However, although with reports in people, when compared with omepraz- variability in gastric juice pH values exist between horses, ole.9 The proposed mechanism for improved efficacy is there appears to be good intraindividual reproducibility that esomeprazole has a lower first-pass hepatic metabo- for recordings repeated in the same horse. Also, repeated lism, which results in slower plasma clearance and higher sampling of gastric juice leads to altered gastric juice pH AUC plasma concentration when compared with om- values. However, a previous report in horses where gas- eprazole.14 Higher AUC results in more esomeprazole tric juice samples were taken from horses at 0.5, 2, 4, 8, available to enter the parietal cell and inhibit gastric acid 18, 24, 36, 42, 48, 60, and 72 hours showed minimal vari- secretion. Horses in the study presented here had higher ability in gastric juice pH values within the same horse pretreatment mean gastric juice pH (4.25 Æ 2.39) than over multiple sampling periods and these data are similar horses in the previous omeprazole trial (2.01 Æ 0.42). If to data reported on horses in this study.20 Esomeprazole horses in this study would have had a lower mean gastric treatment resulted in a significant increase in gastric juice pH, a higher dose of esomeprazole could have been juiced pH 1 hour after administration and gastric juice required to increase gastric juice pH 4 4. However, pH (6.43 Æ 1.18; range 3.54-7.51) had a narrow range, mean gastric juice pH increased from a mean of 2.03- compared with values before treatment (4.25 Æ 2.39; 6.64 in the 4 horses with low gastric juice pH, 1 hour after range 1.72-7.90). Esomeprazole treatment decreases esomeprazole treatment. Thus, esomeprazole appears to interindividual variability in gastric juice pH in people have a potent effect on gastric juice pH, as these 4 horses and in horses when administered orally.9,11,15 experienced at least a 4 pH unit increase in gastric juice Gastric juice pH on day 1, before esomeprazole or saline treatment, was higher than a previous report, when Collection of gastric juice before esomeprazole admin- gastric juice was aspirated from the stomach in standing istration on day 5 and day 14 provided an opportunity to horses sedated with detomidine.16 The reason for the assess its effects 23 hours after administration of the 4th higher gastric juice pH measured in this study is and 13th daily dose, respectively. Twenty-three hours unknown, but xylazine administration could have played after esomeprazole treatment, gastric juice pH was a role. Xylazine, an a-2 agonist, delays gastric emptying significantly higher than values measured in control in horses, but to a lesser extent than detomidine.21,22 horses. Also, 5 of 8 horses had gastric juice pH 4 4.0, The delay in gastric emptying could have allowed 23 hours after the 4th daily dose and 6 of 8 horses had bicarbonate-rich bile to reflux into the stomach from the gastric juice pH 4 4, 23 hours after the 13th daily dose.
duodenum, which could have increased gastric juice pH These data suggest that esomeprazole sodium adminis- in these horses.23 However, mean gastric juice pH was tered IV has a long duration of effect. This is in contrast low in some of the horses on day 1 and the control horses to a previous report that showed esomeprazole magne- after sedation on day 5, so xylazine administration did sium (40 and 80 mg PO) did not result in a sustained not likely cause of the increased gastric juice pH in these increase in gastric juice pH, 24 hours after the 4th daily horses. Variation in gastric juice pH measurements could dose.15 It should be mentioned that the dose of have been produced by the fact that the gastric juice pH esomeprazole magnesium used in that previous study was measured a single time at each sampling time. It is was 4-8 times lower than the esomeprazole sodium used possible that by a continuous pH measurement technique in the study reported here. Therefore, because of the could have decreased this type of error.
lower dose and oral administration, it is likely the AUC Esomeprazole for Treatment of Equine Gastric Ulcers plasma concentrations were much lower in that pre- current data on the efficacy of esomeprazole in healing vious study compared with the study presented here.
gastric ulcer in horses. However, a previous study Esomeprazole is dose dependent so IV administration showed that omeprazole sodium (0.5 mg/kg IV once would likely produce higher AUC plasma concentrations daily) significantly decreased the number of gastric ulcers leading to a more potent effect on gastric juice pH than in horses after 5 days of treatment.16 Also, a higher AUC the PO-administered esomeprazole magnesium.27 Also, plasma concentration translates into better healing rates it could be that the increase in pH was missed because of for esophageal and gastric ulcers in people.14,26 However, the timing of sampling in horses in this study. A previous esomeprazole sodium AUC plasma concentration was study showed that panoprazole administered to neonatal not measured in horses in this study.
foals resulted in peak pH values 2-3 hours after admin- IV administration of esomeprazole sodium can be use- istration.28 Peak gastric juice pH could have been missed ful in the treatment and prevention of gastric ulcers in because samples were taken 1 hour after administration horses with restricted oral intake because of gastric reflux, such as duodenitis-proximal jejunitis (DPJ) and Esomeprazole-treated horses in the study presented postoperative ileus or in horses with dysphagia or facial here had a higher gastric juice pH 23 hours after treat- bone fractures. Horses with DPJ have a higher preva- ment on days 4 and 13, when compared with control lence of gastric ulceration (68%) compared with horses. The pH data reported in the horses in this horses with large colon impactions (32%) or large study are similar to gastric juice pH in horses 23 hours colon volvulus (14%).31 Parenteral administration of after administration of omeprazole IV.16 Therefore, esomeprazole could be indicated in some horses with di- esomeprazole sodium appears to produce a long dura- agnosed DPJ or other conditions that have a high tion of acid suppression. Similar to omeprazole, esomeprazole accumulates in the acidic secretory canal- In conclusion, IV administration of esomeprazole iculi of the gastric parietal cell because of its low pKa sodium (0.5 mg/kg) caused a rapid and sustained increase (4.0).13 Once inside the canaliculi, it is rapidly protonated in gastric juice pH in horses after the 1st and 5th daily to its active cyclic sulphenamide form and binds cova- doses. Esomeprazole sodium appears to have a more lently and irreversibly to the H1, K1, ATPase enzyme.9 pronounced acid suppressive effect. This IV formulation The long duration of effect suggests that this formulation of esomeprazole sodium should only be used in horses of esomeprazole is effective in increasing gastric juice with restricted oral intake that cannot consume the pH 4 4.0 when administered once daily.
current FDA-approved oral omeprazole paste or in The prevalence (43%) of gastric ulcers in the nonpreg- horses with severe gastric ulceration that are at risk of nant pastured mares in the study reported here was lower than previous reports in nonpregnant broodmares(70.9%).5 The difference in gastric ulcer prevalence couldbe because of differences in breed, environmental condi-tions, diet and level of stress.8 Horses in the study presented here were Quarter Horse and Quarter Horsemixed breed horses, whereas previous studies have a GastroGard, Merial Limited, Duluth, GAb focused on Thoroughbred mares. The prevalence of Randlab Australia Pty Ltd, Peakhurst, NSW, Australia gastric ulcers in Quarter Horses is 40%.29,30 Tempera- Rompun, Bayer Animal Health, Shawnee Mission, KS ment was cited has a possible reason for the lower e Acumet AP61 Portable pH meter, Fischer Scientific, Pittsburgh, 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 gastriculcer 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 The authors acknowledge Dr Nicola's Villarino for the horses developed new nonglandular ulcers during the statistical analysis and Dr Karen Kalck for technical as- study period. Glandular gastric ulcer scores were low and scores improved in the esomeprazole-treated horses,whereas scores increased slightly in untreated controlhorses. These findings suggest that nonglandular gastric ulcers undergo spontaneous healing in some horseshoused in a pasture environment. An alternative expla- 1. Anon. Recommendations for the diagnosis and treatment of equine gastric ulcer syndrome (EGUS). Equine Vet Educ 1999;1: nation is that esomeprazole treatment could have had an effect on healing and preventing new gastric ulcers from 2. Vatistas NJ, Snyder JR, Carlson G, et al. Cross-sectional occurring. This explanation seems plausible, but in lieu study of gastric ulcers of the squamous mucosa in Thoroughbred of the small number of horses with ulcers in the study racehorses. Equine Vet J 1999;29(Suppl):34-39.
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Pharmacol Ther 2004;20(Suppl 6):30-37.
20. Tellez E, Ocampo L, Bernad M, et al. Pharmacodynamic 7. Murray MJ, Eichorn ES, Jeffrey SC. Histological character- study of a long-acting parenteral formulation of omeprazole in istics of induced acute peptic injury in equine gastric squamous horses. J Vet Pharmacol Therap 2005;28:587-589.
epithelium. Equine Vet J 2001;33:554-560.
21. Sutton DGM, Preston T, Christley RM, et al. The effects of 8. Buchanan BR, Andrews FM. Treatment and prevention of xylazine, detomidine, acepromazine and butorphanol on equine equine gastric ulcer syndrome. Vet Clin North Am Equine Pract solid phase gastric emptying rate. Equine Vet J 2002;34:486-492.
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