Acid suppression plays an important role in the management

Transcription

1 J Vet Intern Med 2011;25:47 54 Efficacy of Oral Famotidine and 2 Omeprazole Formulations for the Control of Intragastric ph in Dogs K. Tolbert, S. Bissett, A. King, G. Davidson, M. Papich, E. Peters, and L. Degernes Background: Little is known about the efficacy of commonly used acid suppressants on intragastric ph in dogs. Objective: To compare the effect of oral famotidine, 2 formulations of omeprazole, and placebo on intragastric ph in dogs with a catheter-free, continuous ph monitoring system. Animals: Six healthy adult mixed-breed colony dogs. Methods: Utilizing a randomized, 4-way cross over, open-label study, dogs were administered famotidine PO ( mg/ kg q12h), omeprazole tablet ( mg/kg q24h), omeprazole reformulated paste (RP) (Gastrogard, mg/kg q24h), and placebo for 7 days followed by a 10-day washout period. Radiotelemetric ph capsules were placed with gastroscopy assistance to continuously record intragastric ph for 4 days (days 4 7 of dosing). The percentage of time that intragastric ph was 3 and 4 was compared among treatment groups using repeated measures of analysis of variance. Tukey s Studentized range test was used to determine which groups were different with a Results: Mean SD percent time intragastric ph was 3 and 4 was 22 8% and 14 6% for famotidine, 63 14% and 52 17% for omeprazole tablet, 54 17% and 44 18% for omeprazole RP, and 6 6% and 5 5% for placebo. Both omeprazole formulations significantly increased intragastric ph compared with famotidine and placebo, but omeprazole tablet and RP was not significantly different from each other. Conclusion: Oral omeprazole tablet and RP provide superior gastric acid suppression to famotidine, and should therefore be considered more effective for the treatment of acid related disorders in dogs. Key words: Acid disorders; Gastroenterology; Gastrointestinal. Acid suppression plays an important role in the management of gastric disease by preventing further injury from exposure to the acidic and proteolytic environment of the gastric lumen. 1,2 Omeprazole, a substituted benzimidazole proton pump inhibitor, is commonly used in both human and veterinary medicine. Early experimental work demonstrated omeprazole to be a potent acid suppressant in dogs, 3 but the optimal degree and duration of acid suppression for the treatment of canine acid-related disorders remain undefined. In people, optimal gastroduodenal ulcer healing and treatment of gastroesophageal reflux disease occur at an intragastric ph of 3 for approximately 75% of the day, and a ph of 4 for 67% of the day, respectively. 4 If these parameters are applied to dogs, commonly recommended oral doses of omeprazole ( mg/kg q24h) 5 are likely inadequate based on the authors clinical experience and results from a recent study. 6 In addition to concerns regarding the dose of omeprazole, only formulations approved for use in humans From the Department of Clinical Sciences (Tolbert, Bissett, King, Davidson, Degernes), and the Department of Molecular and Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC (Papich); and GlaxoSmithKline, Early Development Group, Biopharmaceutics Division, RTP, NC (Peters). This work was done at the College of Veterinary Medicine of North Carolina State University. This work was presented as an oral scientific abstract at the 2010 ACVIM Forum in Anaheim, California. Corresponding author: S. Bissett, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606; sally_bissett@ ncsu.edu. Submitted May 26, 2010; Revised August 20, 2010; Accepted October 18, Copyright r 2010 by the American College of Veterinary Internal Medicine /j x Abbreviations: RP reformulated paste and for use in horses are currently available for use in dogs. Use of the human formulations is not ideal, as the enteric coated tablets and microspheres should not be broken or crushed for dosing purposes, and the liquid is of low concentration and inappropriately flavored (pineapple). Although the omeprazole paste a for horses is of higher concentration and widely available, the oral bioavailability and efficacy of this formulation have not been evaluated in dogs. Previous investigations of intragastric ph in dogs have utilized invasive procedures to place ph catheters or measured intragastric ph indirectly. 6 8 Since 2002, new technology utilizing a catheterless, radiotelemetric ph monitoring device b became available. Minimal effects on gastric physiology are expected with this system, as continuous ph data are transmitted from ph capsules attached directly to the gastrointestinal mucosa. 9,10 Transmission of ph data from the capsule to an external radiofrequency receiver is guaranteed for up to 48 hours, but may last as long as 3 5 days. 9 Pharmaceutical researchers have administered Bravo ph capsules PO to dogs, but mucosal attachment for prolonged intragastric ph monitoring has not been reported. 11,12 The main purpose of this study was to compare the effect of placebo and higher than commonly used doses of oral famotidine and 2 formulations of omeprazole on canine intragastric ph. Additionally, we sought to evaluate the feasibility of the Bravo system as a means of monitoring continuous intragastric ph in dogs.

2 48 Tolbert et al Materials and Methods Dogs Six healthy adult Beagle and mixed breed hound dogs (2 neutered females, 4 neutered males), aged 4 7 years (median 4.5 years) and weighing kg (median 18.7 kg), were the subjects of this study. All dogs lacked clinical signs of gastrointestinal disease and were deemed healthy based on normal physical examination, CBC, and serum biochemistry profile performed within 6 months of study entry, and a normal PCV, total protein, blood urea nitrogen, blood glucose, and urinalysis performed at study entry. Starting 3 weeks before the study, dogs were acclimatized to wearing vests. Dogs were fed a commercial dog food, c water was provided ad libitum, and the dogs were housed in AALAC-accredited facilities at North Carolina State University. The Institutional Animal Care and Use Committee approved the protocol for this study. Study Design In a randomized, open-label, crossover design, dogs were administered placebo PO (250 mg lactose d q12h), famotidine e,f ( mg/kg q12h), omeprazole tablets g ( mg/kg q24h), or omeprazole reformulated paste (RP) a ( mg/kg q24h) for 7 consecutive days followed by a 10-day washout period. The aim was to dose the omeprazole at 2 mg/kg/d; however, the enteric coated omeprazole tablets could not be split for optimal titration and therefore a dosing range that closely approximated 2 mg/kg/d was used and kept consistent between the omeprazole tablet and RP. Since the dose of omeprazole chosen was approximately 2-fold the commonly used dose, the dose of famotidine used was also increased 2-fold to make comparison of these drugs fair. Dogs were randomized to a treatment schedule via a random number generator. Omeprazole RP was formulated the day before each treatment period to a concentration of 40 mg/ml by suspending an approved equine oral paste formulation (Gastrogard) in sesame oil h at a ratio of 1 : 9 and stored at controlled cold temperature (71C) and protected from light. Dogs were medicated (7:00 AM, 6:00 PM), fed (7:30 AM, 5:00 PM), and exercised (8:00 AM, 5:30 PM) twice daily during treatment periods. Omeprazole was administered in the morning with placebo in the evening, so that all dogs received treatments twice daily. Clinical signs, including change in attitude, appetite, vomiting, number of defecations, and fecal consistency, were recorded at least twice daily. Feces were graded from 1 to 7 by a standardized fecal scoring system. i Placement of Intragastric ph Monitor On day 4 of each treatment period, the morning meal was withheld and dogs were anesthetized for gastroscopy-assisted placement of a Bravo ph capsule. Dogs were anesthetized in an order determined by a random number generator. Dogs were premedicated with butorphanol j (0.1 mg/kg IV), an IV catheter was placed, and general anesthesia was induced with thiopental k (6 10 mg/kg IV to effect) and maintained with isoflurane l after placement of an endotracheal tube. Gastroscopy was performed with dogs in left lateral recumbency to aid positioning and attachment of the ph capsule to the fundic mucosa, 8 14 cm distal to the lower esophageal sphincter depending on size of the dog. This location was kept consistent between treatment arms. Immediately before placement, the capsule and receiver were calibrated with commercial buffer solutions (ph 1.07 and 7.01) according to manufacturer s instructions. The capsule, preassembled with a catheter delivery system, was introduced into the stomach transorally. Once positioning of the capsule was verified, mucosal attachment of the ph capsule was achieved according to manufacturer s instructions by the use of suction and a lock and pin mechanism. The delivery system was withdrawn and mucosal attachment of the capsule confirmed by direct endoscopic view as the stomach was inflated and deflated with air. ph Recordings Intragastric ph recordings were obtained telemetrically at 6 second sampling intervals for 96 hours (days 4 7 of treatment) after capsule placement. Data receivers were kept in close proximity to the dogs via vests or by attaching the receiver to the dog s cage. After 48 hours of ph data acquisition (the maximal amount of data held by the receiver), ph data were uploaded from receiver to computer by manufacturer software. m The percent time that intragastric ph was 3 and 4 was calculated by the computer software. Immediately following data upload, the receiver was reset and placed back on the dog to obtain a 2nd 48 hours of data. A left lateral abdominal radiograph was obtained to verify capsule location if the intragastric ph remained 43 at the time of data upload. Two additional capsules were tested in vitro for ph drift, defined as a change in the capsule s ph recording of a ph reference solution over time, for a 96-hour period (4 days). This was achieved by submersing the capsules in 50 ml of buffer solution (ph 7.01) that was refreshed daily, in addition to rinsing the capsules with normal saline and submersing in buffer solutions of ph 4.00 and 1.07 for 15 minutes each day. The ph of the dogs drinking water was also tested at this time. To evaluate the effect of capsule location on intragastric ph, 1 dog on placebo had a ph capsule placed in the antrum (approximately 5 cm cranial to the pylorus) in addition to a ph capsule located in the gastric fundus as described above. Plasma Omeprazole Concentrations On days 1 and 7 of each treatment period, 3 4 ml of blood was obtained via jugular venipuncture and collected in heparinized tubes 1 and 2 hours postmedication. The tubes were immediately centrifuged at 250g for 10 minutes and the plasma separated and stored at 801C. Four months later, plasma collected during placebo and omeprazole treatment arms was thawed and analyzed with high performance liquid chromatography with ultraviolet detection. Because the assay was previously developed in our laboratory for another species, 13 a partial validation was performed to ensure that it was accurate and reliable for measuring omeprazole in canine plasma. The limit of quantification was 0.01 mcg/ml. A null value was assigned to all measurements determined to be below the limit of quantification. Statistical Analysis Repeated measures analysis of variance (by Proc GLM n ) was used to compare (1) the percent time intragastric ph was 3 or4 between groups (placebo control and 3 treatments) during the 96- hour period after ph capsule placement (days 4 7 of treatment); (2) the percent time intragastric ph was in 1 of 8 ph categories (0 1, 1 2, 2 3, 3 4, 4 5, 6 7, 7 8) for days 4 7 of treatment between groups; and (3) the adverse effects of treatments by comparing (a) the 7-day mean fecal scores; (b) the 7-day mean number of defecations where fecal score was 4; and (c) the mean number of days where fecal score was 4 between treatment groups. When a significant treatment effect was observed, Tukey s Studentized range test was used to determine which of the 4 groups were significantly different from each other. Paired t-tests were used (1) to determine if there was a day of treatment effect (days 4 versus 6) on percent time intragastric ph was 3or4 within each group; (2) to compare percent time intragastric ph was 3or4 for the 1st and 2nd 12 hours postdosing on days 5 6 of treatment; (3) to determine if there was a food buffering effect in the placebo control group, based upon percent time intra-

3 Acid Suppression in Dogs 49 gastric ph was 2, or 3, or 4 during the 2-hour postprandial period after meals on days 5 6 of treatment, compared with the next 10 hours (2 dogs were excluded from this analysis because of inconsistencies in eating promptly when fed); and (4) to compare plasma omeprazole concentrations for dogs receiving omeprazole tablets and omeprazole RP. Ideally day 7 (rather than day 6) would have been compared with day 4 in evaluating for a day of treatment effect, but was not used because of missing data from early ph capsule loss. Data from days 4 and 7 were excluded from the above analyses looking at time periods related to medication and feeding as (1) dogs were fasted and ph recordings did not begin immediately postmedication on day 4 (the day of ph capsule placement), and (2) there was substantial missing data on day 7 from early ph capsule loss. In addition, a lower ph cutoff of 2 was included in the analysis to evaluate for a food buffering effect as intragastric ph was much lower for dogs given placebo. Lastly, analysis of variance was used to determine if the randomized order of treatment had an effect on percent time intragastric ph was 3or4 within each group during days 4 7 of treatment. Data analysis was performed by commercially available software, m and statistical significance was determined at P.05. Results In Vitro ph Evaluations There was no observable ph drift for the 2 ph capsules tested in vitro over 96 hours for any of the ph buffer solutions tested (1.07, 4.00, and 7.01). The ph readings adjusted rapidly to daily changes of buffer solution, and all ph values remained within 0.53 U of the buffer solutions and in the same range as those obtained on the 1st day of capsule testing ( for ph solution 1.07; for ph solution 4.00; for ph solution 7.01). The ph of fresh tap water samples ranged from 8.2 to 8.7. Experience with the Bravo System Throughout the course of the study, 25 Bravo capsules were successfully attached to the gastric mucosa (24 fundic, 1 antral) without complications or adverse effects. Total procedure times for gastroscopy-assisted capsule placement ranged from 5 to 25 minutes, with most procedures taking o15 minutes. Technically the procedure was simple, although manipulation of the capsule delivery device so that the well of the capsule was oriented toward the mucosa was occasionally challenging. Of 25 capsules attached to the gastric mucosa, 21 (84%) remained in the stomach for the 96-hour recording period, while 4 (16%) capsules detached and exited the stomach early. Inspection of the ph data combined with abdominal radiographs or examination of the dogs stool (for ph signal) was used to confirm early capsule loss. For capsules that exited the stomach early, the time of gastric emptying was readily determined from the ph data because of a rapid and sustainable rise of ph above 4 (Fig 1). This occurred in 2 dogs receiving omeprazole tablets at 68 and 70 hours after placement (dogs 1 and 3), and in 2 dogs receiving omeprazole RP at 46 and 68 hours after placement (dogs 3 and 5). For these capsules, ph data were excluded from analysis once ph readings were sustained above 4. Fig 1. Forty-eight hours ph recording of 2 dogs given omeprazole tablet (days 6 7 of treatment). (A) Dog with early ph capsule loss from the stomach (arrow). ph signal is lost (gray shaded area) when the capsule is passed in the feces. (B) Dog with capsule in stomach exhibiting wide ph fluctuations. Signal interference of the radiotelemetric system is observed (gray line).

4 50 Tolbert et al Approximately 2,090 hours of intragastric ph recordings (representing 1,254,000 ph readings) were obtained during the study. Since 2,304 hours (96 hours per dog for each treatment) was the maximum possible data acquisition, the overall missing data rate was 9.3%. Most of the missing data (73%) occurred in the 2nd 48-hour recording period because of early capsule loss. The remaining missing data (2.5% of all possible data) were due to signal interference of the radiotelemetric system. This occurred intermittently in all treatment groups, but was most pronounced when the receivers were not located directly on the dog. Intragastric ph Recordings For the percent time intragastric ph was 3 and 4, both omeprazole formulations raised the dogs intragagstric ph to a much greater degree than famotidine and placebo (Fig 2). However, the percent time intragastric ph was 3 and 4 did not differ significantly for dogs given omeprazole tablet compared with omeprazole RP. In addition, the percent time intragastric ph was 3 and 4 did not differ significantly for dogs given famotidine compared with placebo. For all dogs, intragastric ph fluctuated widely (o1 8) in each treatment group, except for 1 placebo control dog where the ph remained below 4 for the entire recording period. Large ph fluctuations were mostly because of rapid rises of ph above 4 (ph peaks) that lasted 10 minutes to 5 hours, and occurred 2 8 times per dog over the 96-hour recording period. Approximately 50% of the ph peaks correlated to fasting periods that began 10 or more hours after feeding. Despite these peaks, the mean (SD) percent time intragastric ph was 3 and 4 was only % and % for the placebo control group. Although wide ph fluctuations occurred in all treatment groups, there were marked differences in the overall distribution of intragastric ph between groups (Fig 3). Fig 2. Comparison of drug effect on intragastric ph. Circles represent the mean (SD) percent time that intragastric ph was 3 (black circles) and 4 (open circles) for 6 dogs given placebo, famotidine, omeprazole tablet (OT), and omeprazole reformulated paste (ORP) on days 4 7 of treatment. Values were significantly increased compared with famotidine and placebo. The percent time that intragastric ph was 3 and 4 was also used to determine if there was an effect of order of treatment, day of treatment, and time of day (with regards to drug administration and feeding) on intragastric ph between or within certain groups. For all groups of dogs, the order of treatment did not significantly affect the percent time intragastric ph was 3 and 4 over the 96-hour recording period (all P values 4.05). Likewise, no significant differences were identified for the percent time intragastric ph was 3 and 4 comparing days 4 and 6 of treatment within each group (all P values.19). For both omeprazole groups, the percent time intragastric ph was 3 and 4 on days 5 6 of treatment was higher for the 1st 12-hour postdosing compared with the rest of the day, but these only differed significantly for omeprazole RP (Table 1). There were no significant differences between the 1st and 2nd 12-hour periods after dosing within the placebo control and famotidine groups (all P values 4.18). Additionally, no food buffering effect on intragastric ph was identified for the placebo control group (Table 1). Lastly, the intragastric ph of the antrum as measured in 1 dog given placebo, was very similar to the ph measured by the capsule in the fundus except that rises in intragastric ph were generally higher and lasted longer. This was reflected in the percent time intragastric ph was 3, which was 12.3% for the antrum compared with 4.7% for the fundus over the 96-hour recording period. Adverse Effects of Treatment All dogs remained interactive and energetic throughout the study. Four dogs had an excellent appetite for the study duration, while 2 dogs ate inconsistently within each treatment group. Vomiting was documented in all dogs and groups, with a total number of vomiting episodes of 13 (2 placebo, 5 famotidine, 2 omeprazole tablet, 4 omeprazole RP). For all dogs and groups, the majority of defecations per day and fecal scores varied from 1 to 3, respectively. Fecal scores as high as 6 7 were recorded within each group during the treatment periods. The mean (SD) fecal scores for the 7-day treatment periods were for placebo, for famotidine, for omeprazole tablet, and for omeprazole RP. These were significantly higher for omeprazole tablet compared with placebo, but did not differ significantly between the other groups. In addition, there were no significant differences in the mean number of defecations or the average number of days with a fecal score 4 for the 7-day treatment period among the different groups (P 5.14 and.35, respectively). Plasma Omeprazole Concentrations Plasma concentrations of omeprazole were detected in all samples except for 1: a 1-hour postdosing sample obtained on day 7 of treatment from a dog given omeprazole tablet. The mean (SD) plasma omeprazole concentrations at 1- and 2-hour postadministration on day 1 of treatment were and mcg/ ml for omeprazole tablet and and 0.65

5 Acid Suppression in Dogs 51 Fig 3. Intragastric ph distribution for 6 dogs receiving placebo (A), famotidine (B), omeprazole tablet (C), and omeprazole RP (D). Circles represent the mean (SD) percent time in a specific ph for days 4 7 of treatment. Significantly different from placebo; # significantly different from placebo and famotidine mcg/ml for omeprazole RP. The mean (SD) plasma omeprazole concentrations at 1- and 2-hour postadministration on day 7 of treatment were and mcg/ml for omeprazole tablet and and mcg/ml for omeprazole RP. There were no statistically significant differences between omeprazole plasma concentrations (tablet versus RP) for any of the time points measured (all P values 4.40).

6 52 Tolbert et al Table 1. Effect of time of day on intragastric ph with regards to omeprazole administration and feeding Hours Postdosing Rest of Day P Value OT (n 5 6) MPT ph MPT ph ORP (n 5 6) MPT ph MPT ph Placebo (n 5 4) 2 Hours Postfeeding Rest of Day P Value MPT ph MPT ph MPT ph OT, omeprazole tablet; ORP, omeprazole reformulated paste; MPT, mean percent time. Values represent the mean (SD) percent time that intragastric ph was 3 and 4 on days 5 6 of treatment. P values represent within group comparisons. Discussion The main aim of the present study was to examine the efficacy of oral famotidine and omeprazole, 2 acid suppressants commonly used in dogs for the treatment of acid related disorders. To do this, we chose to analyze the percent time intragastric ph was 3 and 4 for comparisons, as mean or median ph values do not accurately represent intragastric ph because of the wide ph fluctuations that occur. 12,14 Additionally, the percent time intragastric ph is sustained above 3 and 4 has been shown to be 1 of 3 key parameters in the treatment of acid related disorders in people. 4 Our results clearly demonstrated that both omeprazole tablet and RP were significantly better at raising intragastric ph than famotidine when evaluated by percent time intragastric ph was 3 and 4. This difference is most likely a result of their differing mechanisms of action regarding acid secretion. Although this finding was expected for omeprazole tablets based on prior studies in humans and dogs, 15,16 we were also able to demonstrate that the omeprazole paste approved for use in horses (administered as a RP) is efficacious in dogs. Although this study does not meet the criteria necessary to determine true bioequivalence between formulations, we were unable to detect a significant difference between the plasma concentrations produced from each formulation. Several reports have suggested the basal (fasting) gastric ph of dogs is higher or more variable than the basal gastric ph of people. 12,17 19 For this reason, much of the literature available on the effect of acid suppressants in dogs was derived from dogs administered pentagastrin, or other acid stimulatory pharmaceutical agents, in order to mimic human gastric ph. 3,8,12 The gastric ph of dogs has also been shown to fluctuate widely throughout the day, demonstrating the need for continuous ph monitors in studying the effect of acid suppressants. 11,19 To date, nasally passed ph catheters, and gastric fistulation with aspiration of gastric contents, have been the main techniques employed for continuous measurement of intragastric ph in dogs. 3,6 Nasogastric ph catheters are uncomfortable, often require a restraint device, and may migrate from their original position leading to inaccurate ph monitoring, which can affect reproducibility of the study. 20,21 Gastric fistulation causes general discomfort to the animal and requires frequent aspiration of gastric contents, which may disrupt gastrointestinal homeostasis and thus affect the reliability of ph measurements. 9,21 A specific aim of this study was to evaluate the use of the Bravo system for prolonged intragastric ph monitoring in dogs. This system is a noninvasive, catheter-free, radiotelemetric device marketed for the diagnosis of gastroesophageal reflux disease in people, which utilizes ph capsules attached directly to the gastrointestinal mucosa. In the present study, ph capsules were attached to the canine gastric mucosa with endoscopic assistance and were well tolerated, easy to place, and provided a minimum of 46 hours of continuous ph data. Although the Bravo system is intended for hours of data acquisition per capsule, 9 we were able to demonstrate that 96 hours of ph data could be obtained without any evidence of ph drift. The main problem encountered with this system in dogs was early capsule detachment. Despite this, only 4 of 25 capsules (16%) were lost from the stomach within 96 hours of placement, and the time of gastric emptying was easily ascertained from the ph data caused by a rapid and persistent rise of ph above 4 as described previously. 11,12 The intragastric ph recordings of dogs in this study displayed wide fluctuations and lacked an obvious food buffering effect, which supports previous work. 11,12,19 Wide ph fluctuations in placebo control dogs of the present study were mostly because of intermittent (0 2 daily) rapid rises of ph above 4 that presumably occurred because of duodenogastric reflux 22 or the intake of chlorinated tap water. Interestingly, half of the ph peaks in our study occurred 10 or more hours postprandially, which helps to explain the high or variable basal gastric ph reported for dogs. 6,11,12 Overall, however, the intragastric ph of our placebo control dogs was very low: it remained below 2 for more than 85% of the time, with a mean percent time intragastric ph 4 of only 4.7%. This is very similar to the mean percent time intragastric ph 4 of 4.4% reported for healthy

7 Acid Suppression in Dogs 53 people, 23 but considerably lower than the continuous gastric ph data previously reported for dogs. 6 The mean percent time intragastric ph was 4 previously reported for nonfasted, nonmedicated dogs was 12.8%, and ranged from 17.2 to 22.6% for nonfasted dogs given placebo (depending on the day of testing). 6 The reason for this difference of intragastric ph between studies is unclear, but could be explained by the shorter washout period and drug carryover effect described in the earlier study, 6 large interdog variation of intragastric ph between dog colonies, altered gastric physiology associated with the presence of a gastric feeding tube, or differences in the diets, stress levels, and methods of ph measurement between studies. The use of ph catheters might have contributed to the higher intragastric ph, as catheters have a tendency to migrate and could have moved into the gastric antrum where the intragastric ph is likely to be higher. 21,23,24 In the present study, results from the placement of a ph capsule in both the gastric antrum and fundus of 1 dog support that gastric antral ph is also likely to be higher in dogs. The ability of both omeprazole tablet and RP to substantially raise intragastric ph in dogs as shown in this study has important clinical implications. The omeprazole product formulated for horses is approved for veterinary use, widely available, inexpensive, and can be easily reformulated to a suitable concentration for use in dogs. In addition, the paste form and lack of enteric coating lend this product to dosing that can be titrated and administrated via gastric feeding tube if necessary. Further work to evaluate the stability of the omeprazole RP is indicated and currently in progress so that the compounded formulation meets the standards established by the United States Pharmacopeia General Chapter h795i. 25 Despite the use of higher than commonly recommended doses of omeprazole in the present study, both formulations produced intragastric ph values that were lower than the criteria described for the optimal treatment of acid-related disorders in people. This suggests that either our dosage of omeprazole for dogs is inadequate or the criteria established for people are not appropriate for use in dogs and warrants further study. The mean percent time intragastric ph of 3 and 4 reported here was similar to that previously reported where the dose used was considerably less. 6 However, it is difficult to make meaningful comparisons of the omeprazole data between our studies, given that the ph of the placebo control dogs was so different (as discussed previously). In addition, the use of an omeprazole suspension 6 resulted in superior acid suppression compared with tablets, but it was unclear whether the key determinant of this effect was because of the different formulation, higher total daily dose, or increased frequency of administration. Importantly, both studies were careful to administer omeprazole within an hour before feeding to maximize omeprazole s efficacy. Further analysis of our ph data demonstrated that omeprazole s effect on acid secretion substantially waned during the hour period postadministration; however, this effect was only significant for omeprazole RP. This may be caused by more rapid absorption, faster elimination, and less acid suppression for the hour period postadministration for omeprazole RP compared with omeprazole tablet. Our evidence supports a regimen of twice daily dosing rather than once-daily dosing for the use of omeprazole RP in dogs, although further work is still needed to define the most appropriate dose. An unexpected result of the present study was the poor performance of oral famotidine, especially since it was administered at a relatively high dose ( mg/kg q12h). Although differences were observed for intragastric ph of dogs given famotidine versus placebo, none of the results were significantly different. This was unexpected given that oral famotidine has been shown to be efficacious for reducing the severity of gastric lesions in racing sled dogs when used as a preventative, and that intravenous famotidine is known to significantly raise intragastric ph. 6,16,26 The small number of dogs in the present study, combined with high variability of intragastric ph among dogs, likely resulted in our inability to detect a significant difference between the famotidine and placebo control groups. Despite this, our results suggest that oral famotidine s ability to substantially raise intragastric ph in dogs is limited at the dose reported here, and is likely to be even less effective at the commonly used dose of 0.5 mg/kg q12h. Adverse gastrointestinal events have previously been described for dogs receiving oral omeprazole. 6,27 For this reason, we documented and compared the number of adverse events that occurred in the dogs of the present study. Reduced fecal quality was the most common adverse event identified, and dogs given omeprazole tablet had significantly higher (more liquid) mean fecal score compared with placebo. However, a difference in mean fecal score was not identified for dogs receiving omeprazole RP, and a similar mean number of defecations and days with a fecal score 4 was found for all groups. At least 1 vomiting episode was documented in all dogs and groups at some point throughout the study period, but there did not appear to be any association with treatment group or drug dosing. In conclusion, the results of the present study indicate that oral omeprazole was superior to famotidine for the suppression of gastric acid secretion in dogs. Additionally, omeprazole RP appears to be efficacious in dogs and can be considered as an alternative to the use of other omeprazole formulations, although twice daily dosing is advised due to a reduced duration of effect. Finally, the Bravo system was found to be a practical and useful tool for prolonged continuous measurement of canine intragastric ph. Footnotes a Reformulated paste was diluted to 40 mg/ml in sesame oil; Gastrogard, Merial, Atlanta, GA b Bravo ph monitoring system, Given Imaging, Yoqneam, Israel c Iams ProActive Health Minichunks, P & G Pet Care, Cincinnati, OH

8 54 Tolbert et al d Lactose 250 mg encapsulated in size # 3 gelatin capsule, Spectrum Chemical Mfg Corp, Gardena, CA e Ivax Pharmaceuticals (10 mg tablets), Miami, FL f Teva Pharmaceuticals (20 mg tablets), Tikva, Israel g Omeprazole Delayed Release Tablets 20 mg, Dexcel Ltd, Hadera, Israel h Sesame Oil N.F., Spectrum Chemical Mfg Corp i Faecal Scoring System, Nestlé Purina PetCare Company, St Louis, MO j Torbugesic 10 mg/ml injection, Fort Dodge Animal Health, Fort Dodge, IA k Pentothal 500 mg Kit, Abbott Laboratories, North Chicago, IL l Isoflo, Abbott Laboratories m Polygram Net Software, Given Imaging, Yoqneam, Israel n SAS 9.1.3, SAS Institute Inc, Cary, NC Acknowledgments The authors thank Maria Stone and Tonya Harris for technical support, and the Comparative Gastroenterology Society, Waltham, Merck-Merial Veterinary Scholars Program, and GlaxoSmithKline for their financial support. References 1. Wallmark B, Larsson H, Humble L. 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