Frank M. Andrews, Nicholas
Frank, Carla S. Sommardahl, Benjamin R. Buchanan, Sarah
B. Elliott, and Vern A. Allen
J Vet
Intern Med 2006;20:1202–1206
The study was performed to evaluate the efficacy of omeprazole
powder in sterile water, administered intravenously, on
gastric juice pH in adult horses with naturally occurring
gastric ulcers. Omeprazole (0.5 mg/kg, IV) was administered
once daily for 5 days to 6 adult horses with gastric ulcers.
Gastric juice was aspirated through the biopsy channel
of an endoscope and pH was measured before and 1 hour
after administration of omeprazole on day 1, and then
before and after administration of omeprazole on day 5.
Gastric ulcer scores were recorded on day 1 before administration
of omeprazole and on day 5, 23 hours after the 4th daily
dose. Gastric juice pH and ulcer scores were compared
between the times. When compared with the pre-injection
value (2.01 ± 0.42), mean ± SD gastric juice
pH was significantly higher when measured 1 hour after
administration of the initial dose (4.35 ± 2.31),
and before (5.27 ± 1.74) and 1 hour after (7.00
± 0.25) administration of omeprazole on day 5.
Nonglandular gastric ulcer number score significantly
decreased from a mean ± SD of 3.2 ± 0.80
to 2.0 ± 1.1, but nonglandular gastric ulcer severity
score remained the same. Few glandular ulcers were seen
in the study, and scores did not change. Because of its
potent and long duration of action on gastric juice pH,
this intravenous formulation of omeprazole may show promise
for treatment of equine gastric ulcer syndrome (EGUS)
in horses with dysphagia, gastric reflux, or other conditions
that restrict oral intake of omeprazole paste.a
Aspiration of gastric juice and measurement of pH can
be of use to determine whether the desired pH > 4.0
has been reached after omeprazole treatment.
Key words: Equine; Equine
Gastric Ulcer Syndrome; Gastroenterology; Stomach.
Introduction
Omeprazole is a substituted benzimidazole that decreases
gastric acid secretion and increases gastric juice pH by
blocking the H+, K+ ATPase (proton
pump) in the secretory membrane of the parietal cell.1
This drug is also classified as a proton-pump inhibitor.
Gastric juice pH (<4.0), long periods of no feed intake
and environmental stress are presumed causes of gastric
ulcers in man and horses.2–5 In vitro studies
in horses have revealed that nonglandular stomach mucosa
when exposed to HCl at pH < 4.0 have significantly
decreased tissue sodium transport and resistance, with histopathologic
evidence of cell swelling.3,4 Furthermore, healing
rates of esophageal, gastric, and duodenal ulcers in people
strongly correlate with control of gastric juice pH by proton-pump
inhibitors.6 Also, a similar correlation was
observed after 8 weeks of treatment with protonpump inhibitors
in human patients with erosive esophagitis (gastroesophageal
reflux disease [GERD]) and healing rates and duration of
intragastric pH > 4.0 (r = 0.87; P < .05).7
Because gastric ulcer disease in the squamous region of
horse stomach has been likened to GERD in people, and inhibition
of gastric acid secretion and maintenance of the gastric
juice pH above 4.0 is the mainstay of treatment for gastric
ulcer disease in humans and equine gastric ulcer syndrome
(EGUS).8–10
Omeprazole pastea increases gastric juice pH
and is effective in the treatment and prevention of EGUS,
but this formulation can only be administered PO.11,12
However, administration of oral medications in horses with
gastric reflux or dysphagia is contraindicated, so an intravenous
formulation of omeprazole would be helpful to increase gastric
juice pH in horses with these conditions.
The purpose of this study was to determine the effect
of intravenously administered omeprazoleb on
gastric juice pH and gastric ulcer score. Results of this
study will aid in the evaluation of this formulation for
treatment of EGUS in horses that cannot receive the oral
paste formulation, or that require aggressive treatment
to prevent gastric rupture secondary to severe gastric ulceration.
Materials and Methods
Animals and Study Design
Six healthy adult mixed-breed Quarter Horse mares (mean:
8.2 years of age; range 4–12 years of age) with a
mean weight ± SD of 432 ± 29 kg were used
in the study. The mares were part of the University of Tennessee
reproduction teaching herd housed at the university farm
in a pasture environment. Before entering the study, the
horses had normal physical examinations and were dewormed
1 month before starting the study. The horses were vaccinated,
as part of a regular scheduled maintenance program, 6 months
before starting the study. Two weeks before the beginning
of the study, the horses were transported to the veterinary
teaching hospital, where they were housed individually in
stalls measuring 3.7 x 3.7 m, and horses were fed brome
grass hay ad libitum and grainc (1 kg, twice
daily). The mares were chosen because of temperament and
handling to facilitate passing of the endoscope and were
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
#1402).
Each horse served as its own control. Omeprazole (0.5 mg/kg),
sterile powderb reconstituted with sterile water,
was administered intravenously between 8 AM and 10 AM each
morning for 5 consecutive days, via 18-gauge, 1.5-inch needle.
Table 1: Click image to see full size
Endoscopic Examination and Gastric
Ulcer Scoring
Horses were evaluated on days 1 and 5 of the study after
feed and water were removed for 12 and 4 hours, respectively.
Horses were restrained in stocks and sedated with detomidined
(5 mg, IV), 15 minutes before each endoscopic procedure.
A 3-m gastroscopee was then introduced into the
fundic portion of the stomach, and gastric juice was aspirated
through the biopsy channel under suction. The horses underwent
endoscopy, and gastric juice was collected before and 1
hour after omeprazole administration on days 1 and 5, so
that each horse underwent endoscopy twice, 1 hour apart,
on these 2 days. The horses were muzzled and not allowed
access to feed or water during the period between endoscopic
procedures.
During each endoscopic procedure, gastric juice was collected
and the stomach insufflated using an air compressor attached
to the biopsy canal. The stomach was given a gastric ulcer
score on days 1 and 5, only during the first endoscopic
procedure, using a previously published gastric ulcer scoring
system.13
Measurement of Gastric Juice
pH
Gastric juice was collected in a covered glass bottle from
the endoscope biopsy channel. The pH was measured immediately
after collection using a portable pH meterf with
attached probe. The pH meter was calibrated using standard
pH 4.0 and 7.0 solutions before the beginning of each collection
period.
Statistical Analysis
Values for gastric juice pH and gastric ulcer score before
and after treatment on days 1 and 5 were compared statistically
using a statistical analysis program.g Results
are presented as mean ± SD values. Statistical difference
for gastric juice pH values and gastric ulcer scores was
determined using a mixed analysis of variance (ANOVA) blocked
on horse (with repeated measures for pH) and statistical
significance was considered when P < .05.
Results
Horses were clinically normal during the study period.
No adverse responses to omeprazole, the gastroscopic procedure,
or aspiration of the gastric juice were detected. Mean body
weight did not change significantly during the study period
(bwt).
Gastric juice pH was low in all horses before omeprazole
administration and varied from 1.54 to 2.65. On day 1, mean
± SD gastric juice pH significantly increased from
2.01 ± 0.42 before omeprazole administration to 4.35
± 2.31, 1 hour after omeprazole administration (Table
1). However, only 3 of 6 horses had gastric juice pH values
of >4.0. On day 5, gastric juice pH was 5.27 ±
1.74 before omeprazole was administered (23 hours after
the 4th daily dose was given) and only 5 of 6 horses had
a gastric juice pH of >4.0 (Table 1). One hour after
the 5th daily omeprazole dose, mean gastric juice pH significantly
increased to 7.00 ± 0.25 and all horses had gastric
juice pH of >4.0.
Mean ± SD nonglandular gastric ulcer number score
significantly decreased from 3.2 ± 0.8 on day 1 to
2.0 ± 1.1 on day 5 (Table 1). The nonglandular gastric
ulcer severity score did not change between day 1 (1.5 ±
0.5) and day 5 (1.8 ± 1.0). Two horses in this study
had glandular ulcers and both healed during the study period,
but there was no significant difference in glandular ulcer
scores during the study period.
Discussion
Gastric juice pH was variable but low (mean 2.01 ±
0.42; range 1.54–2.64) in all of the horses before
omeprazole administration. After omeprazole administration,
there was considerable variation in pH (range, 1.65–6.77)
between horses. Considerable interhorse variation has been
reported in basal and posttreatment gastric juice pH measurements
in horses. 11,14 However, although variability
in gastric juice pH measurements exists among horses, there
appears to be good intra-individual reproducibility for
recordings repeated in the same horse.11,14 Also,
repeated sampling of gastric juice may lead to altered gastric
juice pH results. However, a previous report in horses where
gastric juice samples were take from horses at 0.5, 2, 4,
8, 18, 24, 36, 42, 48, 60, and 72 hours revealed minimal
variability in gastric juice pH measurements within the
same horse over these multiple sampling periods, and these
data are similar to data reported on horses in this study.15
Omeprazole given intravenously (0.5 mg/kg bwt) resulted
in a significant increase in gastric juice pH in horses
in this study. One hour after the first dose, mean gastric
juice pH increased to greater than 4.0 in 3 of 6 horses.
Gastric juice pH values obtained before and after a single
intravenous dose of omeprazole in horses in this study were
similar to previous reports in the literature in horses
with gastric cannulae.14,16 In those studies,
gastric juice pH values increased from a mean of 2.6 to
a mean of 5.7, 30 minutes after the first omeprazole dose
(0.5 mg/kg, IV), and only 4 of 7 horses had a gastric juice
pH > 4.0. The onset of action of this intravenous formulation
of omeprazole was rapid and potent. Omeprazole has a potent
inhibitory effect on gastric acid secretion that results
from strong binding of the inhibitory molecule of omeprazole
to the H+, K+ ATPase enzyme (proton
pump) in the gastric parietal cell.17–19
Omeprazole accumulates in the acidic secretory canaliculi
of the gastric parietal cell because of its weak base properties
(pKa = 4.0). Once inside the canaliculi, the omeprazole
molecule is rapidly transformed into its active form and
binds to the H+, K+ ATPase enzyme,
which is in close proximity.
However, another explanation for the increase in gastric
juice pH in these horses after omeprazole administration
could have been related to the effect of the sedative agent,
detomidine, on gastric emptying. Alpha-2 agonists, detomidine
(0.01 mg/kg, IV) and to a lesser extent xylazine (0.5 and
1.0 mg/kg, IV), have been shown to delay solid and liquid
phase gastric emptying in horses,20,21 which
could have raised gastric juice pH by increasing the amount
of bicarbonate-rich duodenal reflux present in the stomach
during the second endoscopic examination. Furthermore, other
alpha-2 agonists clonidine, guafacine, and B-HT 920 have
been shown to decrease gastric secretion in rats.22
However, the effect of sedation on gastric juice pH seems
less likely because results in the horses studied here were
similar to those reported in nonsedated and sedated horses
administered omeprazole intravenously,14 subcutaneously,15
and intramuscularly.23 Also, during the second
endoscopic procedure, the volume of gastric juice in the
stomach by visual examination did not appear to be increased
compared with the first endoscopic procedure. However, the
volume was only estimated by visual examination and no quantitative
measurements were done. Small changes in gastric fluid may
not have contributed to the increase in gastric juice pH
seen in the stomach of these horses, but the amount of duodenal
reflux did not contribute to a noticeable increase in gastric
juice pH, because gastric juice pH data were similar to
previous studies. Therefore, from these results, we concluded
that sedation with detomidine may have altered gastric juice
volume but had little effect on gastric juice pH in the
horses in this study. However, including a parallel control
group or another measurement of gastric juice pH 1 hour
after sedation, before treatment, may have been helpful
to confirm the effects of sedation on gastric juice pH,
but neither was included in this study.
Although there was a significant increase in mean gastric
juice pH > 4.0 after a single intravenous dose in the
study reported here, 3 of 6 horses had gastric juice pH
of > 4.0, which is considered important in ulcer healing.8,9,24
Omeprazole’s ability to inhibit gastric acid secretion
and increase gastric juice pH is dose and time dependent
and varies among horses. The 3 horses that had lower gastric
juice pH values after administration of omeprazole in this
study also had the lowest gastric pH before treatment. Thus,
horses with lower initial gastric juice pH may require a
higher dose of omeprazole to acutely decrease gastric secretion
and increase gastric juice pH above 4.0. Aspiration of gastric
juice in horses 1 hour after administration of omeprazole
(0.5 mg/kg, IV) is potentially a useful tool to identify
horses that require a higher dose of omeprazole. If it is
determined that the initial dosage is too low for an individual
horse, then additional omeprazole could be administered
to increase gastric juice pH above 4.0 in that horse. Alternatively,
all horses could be given a 1.0 mg/kg loading dose of omeprazole
with the aim of raising gastric juice pH values above 4.0
in all horses; however, this was not measured in the study
presented here but is a reasonable expectation because a
previous report revealed that intravenous administration
of omeprazole at 0.25, 0.5, and 1.0 mg/kg, IV doses resulted
in a dosedependent inhibition of gastric acid secretion
and increase in gastric juice pH.h In the same
study, a dose of omeprazole (1.0 mg/kg, IV) resulted in
all horses having a gastric juice pH of >4.0, with the
mean pH being 7.5.
Collection of gastric juice before omeprazole was administered
on day 5 also provided an opportunity to assess the effects
of this drug 23 hours after administration (on day 4). When
measured at this time point, gastric juice pH values were
significantly higher than day 1 pre-administration values
(mean pH of 5.4). This long duration of action is similar
to previous reports in the literature in which pH increased
to 5.5 and 5.7 in horses 22 hours after the 4th oral (4.0
mg/kg) or intravenous (0.5 mg/kg) omeprazole dose was administered,
respectively.11,14 Omeprazole has a cumulative
inhibitory effect on gastric acid secretion in horses during
the first days of repeated daily administration.14 According
to previous reports, the steady state of this inhibitory
effect is reached after 5 daily doses in horses. In the
study reported here, there was a marked inhibitory effect
on gastric acid secretion after the 5th daily dose compared
with 1 hour after the first dose. The long duration of effect
suggests that this intravenous formulation of omeprazole
is effective in increasing gastric juice pH above 4.0 when
administered once daily. Results also indicate that the
dosage of 0.5 mg/kg, IV, given once daily may be sufficient
to induce steady-state gastric acid inhibition by the 5th
day in horses. Use of a higher dose or more frequent administration
of omeprazole may shorten the time required for steadystate
gastric acid inhibition to be achieved. In humans, steady
state can be reached in only 3 days if a 0.5 mg/kg, IV,
once daily dosage is administered.19
Mean nonglandular gastric ulcer number score significantly
decreased from 3.2 to 2.0, during the 5- day study period.
These results are not surprising because intravenous administration
of omeprazole results in a rapid increase in gastric juice
pH, which sets up a permissive environment to allow ulcers
to begin to heal. However, although the gastric ulcer number
score was decreased in these horses, continued treatment
is necessary to achieve gastric ulcer healing. It has been
shown that 14 to 28 days of omeprazole administration, PO,
is required to achieve significant gastric ulcer healing
in horses.11,12 It has also been demonstrated
in another study that gastric ulcer healing is dose dependent
in horses; a significant decrease in nonglandular ulcer
scores was detected when a higher dosage of omeprazole (1.0
mg/kg, PO, once daily) was administered for 14 days instead
of a placebo.i Gastric ulcer healing did not
differ significantly between horses that received omeprazole
or placebo after 14 days, but these groups differed significantly
after 28 days of treatment. Unfortunately, there is no current
data on the effects of intravenously administered omeprazole
on gastric ulcer healing in horses, and extrapolation from
oral data may not be appropriate; however, human data suggest
that the greater area under the plasma concentration curve
(AUC) translates into better healing rates in GERD and gastric
ulcers.24 However, AUC was not measured in the
horses in this study.
Only 2 horses had observed ulcers in the glandular mucosa
on day 1 before omeprazole treatment. The glandular gastric
ulcers were not present on the 5th day of the study. Ulcers
in the glandular mucosa have been shown to heal more rapidly
after omeprazole treatment at low doses (0.25 mg/kg, IV)
when compared with placebo.i However, because
of the small number of glandular ulcers seen in this study,
conclusions regarding healing of these ulcers should be
interpreted with caution.
Intravenous administration of omeprazole may be useful
for the treatment of EGUS in horses with restricted oral
intake because of gastric reflux, such as duodenitis-proximal
jejunitis (DPJ), postoperative ileus, dysphagia, or facial
bone fractures. Recently, Dukti et al,j showed that horses
with DPJ had a higher prevalence of gastric ulceration (68%)
compared with horses with large colon impactions (32%) or
large colon volvulus (14%). Thus, parenteral administration
of omeprazole may be indicated in some horses with diagnosed
DPJ.
In conclusion, intravenous administration of omeprazole
(0.5 mg/kg), after reconstitution of powdered drug with
sterile water, causes a rapid increase in gastric juice
pH that is maintained for 23 hours, after the 4th daily
dose. However, interhorse variation in gastric juice pH
after omeprazole (0.05 mg/kg, IV) administration was detected
in this study, which suggests that an intravenous loading
dose (1.0 mg/kg) should be considered to rapidly increase
gastric juice pH above 4.0 in treated horses. A maintenance
intravenous dose of omeprazole (0.5 mg/kg) may be sufficient
to keep gastric juice pH above 4.0 for 24 hours, and this
sustained increase in gastric pH may be necessary to facilitate
nonglandular gastric ulcer healing. However, this compounded
intravenous formulation of omeprazole should only be used
in horses with restricted oral intake that cannot receive
the current Food and Drug Administration (FDA)-approved
omeprazole paste,a or in horses with severe gastric
ulceration that are at risk of gastric perforation.
Footnotes
a Omeprazole paste, GastroGard, Merial Limited,
Duluth, GA
b Omeprazole for IV administration, Omeprazole
Sterile Powder, Premier Pharmacy Labs Inc, Weeki Wachee,
FL
c Grain, Co-op Supreme, Knoxville Co-op Inc,
Knoxville, TN
d Dormosedan (detomidine), Pfizer Animal Health
Inc, Exton, PA
e Gastroscope, ETM-Endotech, Mu¨nchen, Germany
f AP62, Accumet AP61 portable pH meter, Fischer
Scientific, Pittsburgh, PA
g Statistical analysis program, SAS 9.1 for
Windows, Cary, NC
h Blackford JT, Jenkins CC, Andrews FM, et al.
The dose effect of intravenous omeprazole on inhibiting
gastric acid secretion in horses. Proc Am Coll Vet Int Med
13th Annual Forum 1995, San Diego, CA (abstract)
i MacAllister CG, Andrews FM, Hardin L, et al.
The effects of PO administered omeprazole on healing of
flunixin-induced gastric ulcers in young horses. Proc Am
Coll Vet Int Med 14th Annual Forum 1996, San Antonio, TX
(abstract)
j Dukti SA, Perkins S, Murphy J, et al. Prevalence
of gastric ulceration in 100 horses presenting to a referral
hospital for abdominal pain. Proc International Colic Res
Symp 8th Symp 2005, Quebec City, Canada (abstract)
Acknowledgments
The authors wish to thank Dr Arnold Saxton for statistical
analysis and Charla Clevenger and Jacob Mason for technical
assistance. The study was supported by Premier Pharmacy
Labs Inc.
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