The effects on intragastric acidity of per-gastrostomy administration of an alkaline suspension of omeprazole

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1 Aliment Pharmacol Ther 1999; 13: 1091±1095. The effects on intragastric acidity of per-gastrostomy administration of an alkaline suspension of omeprazole V. K. SHARMA, R. VASUDEVA & C. W. HOWDEN Division of Digestive Diseases and Nutrition, Department of Internal Medicine, University of South Carolina School of Medicine, Columbia, SC, USA Accepted for publication 5 April 1999 SUMMARY Background: It may be dif cult to administer proton pump inhibitors via gastrostomy. Previous studies have examined the effect of intact proton pump inhibitor granules in orange juice. This study examined the effect of an alkaline suspension of omeprazole (simpli ed omeprazole suspension (SOS)) on 24-h intragastric acidity. Methods: Six men with an established gastrostomy had a baseline 24-h intragastric ph study using methodology we have previously described. They then received 20 mg SOS o.d. for 7 days and had a repeat ph study at the end of this period. Four of the patients then received 20 mg SOS with 30 cc of liquid antacid (Mylanta, TM) per gastrostomy o.d. for a further 7 days and then underwent a third ph study. Results: SOS raised mean ph from 2.2 to 4.1. Intragastric ph was above 3, 4 and 5 for 35, 28 and 17% of the 24-h period at baseline, respectively; corresponding values after SOS were 63, 51 and 39%, respectively. Addition of liquid antacid to SOS did not further increase its ph-controlling effect. Conclusions: We found a statistically signi cant effect of o.d. SOS on intragastric ph when administered via gastrostomy. We found no additional bene t of administering SOS with liquid antacid. INTRODUCTION The proton pump inhibitor omeprazole is a noncompetitive inhibitor of gastric H +,K + -ATPase. 1 Like other proton pump inhibitors, omeprazole is a lipophilic weak base and is unstable in an acid environment. It is therefore usually administered as capsules of entericcoated, acid-resistant granules. The capsules release the drug in the neutral or alkaline environment of the duodenum. 1 The gelatin capsule prevents premature dissolution of the acid-resistant enteric coating by water or saliva that have a higher ph. Patients with a gastrostomy may need treatment for gastro-oesophageal re ux disease or peptic ulcer. Since Correspondence to: Dr Colin W. Howden, Division of Digestive Diseases, Rush-Presbyterian-St. Luke's Medical Center, 1725 West Harrison Street, Suite 206, Chicago, IL 60612, USA. such patients are typically unable to swallow intact capsules, they may be denied the bene ts of proton pump inhibitor treatment. We have previously shown that omeprazole and lansoprazole can be safely and effectively administered via a gastrostomy as intact, non-encapsulated granules in orange juice. 2, 3 However, there may still be perceived dif culties with administering granules through a gastrostomy or nasogastric tube of size smaller than 18 Fr because of concerns with tube blockage interfering adversely with drug delivery. We therefore studied the effect on intragastric acidity of a liquid formulation of omeprazole administered via gastrostomy. This has previously been termed `simpli ed omeprazole suspension' (SOS). 4±6 This formulation has been used in critically ill patients. 4, 6 However, this is the rst study to speci cally examine its pharmacodynamics in patients who were not critically ill. Ó 1999 Blackwell Science Ltd 1091

2 1092 V. K. SHARMA et al. PATIENTS AND METHODS This was an open-label study with each patient serving as his own control. All patients with a gastrostomy who were resident in the WJB Dorn Veterans' Affairs Medical Center (Columbia, SC) or its af liated nursing home were considered eligible for the study. We excluded patients with a history of upper gastrointestinal tract surgery, acute illness or known sensitivity to omeprazole. Informed consent was obtained from each patient or his legal representative before enrolment in the study. Patients did not receive any other acid-suppressing medicines, anticholinergics, or prokinetic agents for 1 week before starting, and during, the study. Other prescribed medicines that were considered necessary for patient care were continued during the study. We have previously described the procedure for measurement of intragastric ph via the gastrostomy. 2, 3 Brie y, baseline 24-h intragastric ph data were obtained using a Zinetics 24 single sensor internal reference monocrystalline antimony ph probe (Zinectics Medical Inc., Salt Lake City, UT) and Digitrapper Mark III (Synectic Medical Inc., Irving, TX). The probe was passed through the gastrostomy tube (Flexi o Magna- Port TM, Ross Laboratories, Columbus, OH) to a predetermined length of 42 cm. It was secured to the external end of the gastrostomy tube with adhesive tape so that the electrode was 2±3 cm from the internal bumper of the gastrostomy tube within the gastric lumen. As in previous studies, 2, 3 we did not con rm the electrode position radiologically. However, we consistently obtained good ph recordings. Following the baseline 24-h intragastric ph study, six patients were given 7 days of o.d. dosing with SOS 20 mg. To prepare the SOS, a 20-mg capsule of omeprazole was opened and its contents poured into a standard 15 cc syringe. Following that, 10 cc of 8.4% sodium bicarbonate solution was drawn into the syringe. The syringe was gently shaken for 10± 15 min until a white suspension of omeprazole had been obtained. This freshly prepared suspension was administered through the gastrostomy tube and ushed into the gastric lumen using an additional 10±15 cc of tap water. A 24-h intragastric ph study, identical to the baseline study, was repeated after 7 days of o.d. dosing with SOS. Following the second intragastric ph study, four of the patients received an additional 7 days of o.d. dosing with SOS 20 mg given with 30 cc of a liquid antacid (Mylanta TM), via the gastrostomy. This was performed to see if the addition of a liquid antacid would have any additional ph-raising effect over SOS alone. A third 24- h intragastric ph study, identical to the rst two, was performed at the end of this 7-day dosing period. During the study, patients received continuous feeding via their gastrostomy on the days when intragastric ph was not measured. However, feedings were brie y discontinued for 2 h before and for 1 h after administration of SOS. On the days of the intragastric ph studies, patients received bolus rather than continuous feeding via their gastrostomy (Osmalite-HN, 2 cans t.d.s.). If required, the probe was brie y removed for tube feedings or for the administration of any prescribed non-study medications. The probe was then re-positioned at the 42 cm mark. The times of removal of the probe, and the duration of the probe being outside the stomach were similar during each 24-h ph study. Other prescribed medicines were given at the same time as the feedings to minimize the time that the probe was outside the stomach. Intragastric ph data are summarized as mean standard deviation. Results at baseline were compared to those on SOS alone and to those on SOS and liquid antacid using paired Student's t-tests (two-tailed). P- values of 0.05 or less were regarded as statistically signi cant. SPSS 7.1 for Windows (SPSS Inc., Chicago, IL) was used for data analysis. This study was approved by the WJB Dorn Veterans Affairs Medical Center/University of South Carolina School of Medicine Human Studies Subcommittee. RESULTS Six men (mean age 69.2; s.d. 9.8) met the enrolment criteria and were included in the study. Each successfully completed 7 days of o.d. dosing with SOS. Two patients who completed this rst part of the study were discharged before they could complete the second phase of the study, which consisted of SOS and liquid antacid. SOS was well tolerated whether given with or without the liquid antacid; no adverse events were observed during the study. Mean ( s.d.) 24-h intragastric ph was at baseline. This rose to after 7 days of dosing with SOS 20 mg (P < 0.01). The effect of SOS was highly consistent with an appreciable rise in mean intragastric ph seen in all patients. These data are depicted in Figure 1.

3 SIMPLIFIED OMEPRAZOLE SUSPENSION VIA GASTROSTOMY 1093 Figure 1. Mean 24-h intragastric ph at baseline, following 7 days of o.d. dosing with SOS 20 mg (n ˆ 6), and following 7 days of o.d. dosing with SOS 20 mg and Mylanta TM 30 cc (n ˆ 4). In the four individuals who went on to receive 7 days of dosing with SOS 20 mg and liquid antacid, mean ( s.d.) 24-h intragastric ph was at baseline. This rose to after SOS alone, and was after SOS and liquid antacid (P < 0.01 vs. baseline; P > 0.05 vs. SOS alone). During the baseline study, intragastric ph was held above 3, 4 and 5 for 35%, 28% and 17%, respectively, of the recording period. Following 7 days of o.d. dosing with SOS 20 mg, the corresponding gures were 63%, 51% and 39% (P < 0.05 for each comparison with baseline). After 7 days of o.d. dosing with SOS 20 mg and liquid antacid, the corresponding gures were 64%, 56% and 42% (P < 0.05 for each comparison with baseline; P > 0.05 for each comparison with SOS 20 mg alone). These data are depicted in Figure 2. DISCUSSION Omeprazole is a lipophilic weak base that is acid-labile. It is usually administered by mouth as enteric-coated granules contained in a gelatin capsule. The acidresistant enteric coating of the granules is activated at a ph of 6.0 or above. The gelatin capsule prevents the enteric-coated granules from coming into contact with water or saliva that might activate the coating prematurely. Gastric acid dissolves the gelatin capsule releasing omeprazole granules into the gastric lumen. The Figure 2. Proportion (%) of 24-h recording period during which the intragastric ph was maintained above 3,4 and 5 at baseline, following 7 days of o.d. dosing with SOS 20 mg (n ˆ 6), and following 7 days of o.d. dosing with SOS 20 mg and Mylanta TM 30 cc (n ˆ 4). acidic ph in the stomach prevents dissolution of the enteric coating. The more alkaline environment of the small intestine dissolves the coating to release the drug for absorption. 1 Acid could protonate the drug within the gastric lumen and thereby reduce its absorption. Disruption of the enteric coating of the granules, for example, by crushing them, might render the medication ineffective by exposing it to gastric acid. We have previously shown that both omeprazole and lansoprazole can be safely and effectively administered via gastrostomy when given as intact granules in orange juice. 2, 3 After 7 days of o.d. dosing, omeprazole 20 mg as intact granules suspended in orange juice raised mean intragastric ph from 1.8 to 4.9 (P < ) in 14 gastrostomy patients. 2 Presumably, the orange juice maintained a suf ciently acidic milieu around the granules until they reached the duodenum where the enteric coating dissolved and the drugs were absorbed as usual. This method of administration prevented any premature activation of the enteric coating and any inactivation of either drug by gastric acid. Administering the granules in orange juice also prevented clumping in the gastrostomy tube and avoided possible blockage. SOS 20 mg actually produced a quantitatively smaller effect on intragastric ph than the same dose of non-encapsulated intact omeprazole granules in a similar patient population. 2 SOS is a relatively novel formulation obtained by suspending omeprazole granules in 8.4% sodium bicar-

4 1094 V. K. SHARMA et al. bonate solution. 4±6 However, there is no agreed standard method for preparing SOS. Given the lack of published data concerning the stability of this formulation, we prepared SOS freshly for each patient and each administration. This alkaline suspension neutralizes gastric acid with which omeprazole might come into contact. It maintains a neutral milieu around the omeprazole and so prevents its intraluminal protonation. Omeprazole can then be absorbed from the small intestine and transported to the parietal cells where it irreversibly binds and inactivates canalicular H +,K + - ATPase. Phillips et al. 4 and Lasky et al. 6 studied SOS in critically ill patients in an attempt to limit bleeding from stressrelated gastric mucosal disease. SOS was given via nasogastric tube as two doses of 40 mg, 8 h apart, followed by 20 mg each morning for the duration of the study; ph data were obtained by nasogastric aspiration. The mean baseline values for intragastric ph in these studies were 3.5 and 3.3, respectively; with SOS these increased to 7.1 and 6.7 (P < 0.005). The higher baseline ph seen in these critically ill patients compared to our patients probably resulted in less intragastric degradation and greater bioavailability of the rst dose of omeprazole. Furthermore, the use of a larger loading dose of omeprazole may have contributed to their results, showing an apparently greater antisecretory effect of SOS than we found. No patients in these uncontrolled studies developed evidence of clinically signi cant upper gastrointestinal bleeding. Mohiuddin and colleagues studied the effects of 7 days of oral administration of omeprazole in sodium bicarbonate (two Alka Seltzer Gold TM tablets dissolved in 240 cc of water). 7 This formulation of omeprazole raised intragastric ph above 4 for 65.1% of an 8-h recording period. This was not signi cantly different from the effect of 7 days of dosing with omeprazole 20 mg o.d. as intact capsules, which kept the ph above 4 for 68.7% of the recording period. In a comparative study with lansoprazole, Tolman and colleagues administered omeprazole 20 mg o.d. as intact capsules to 17 healthy adult men. After 5 days of o.d. dosing, intragastric ph was maintained above 3, 4 and 5 for 61%, 50% and 40% of the day, respectively. 8 This corresponds very closely to our results for SOS alone; intragastric ph was above 3, 4 and 5 for 63%, 51% and 39%, respectively, in our study. Furthermore, our results are consistent with those of Chiverton et al. 9 who administered omeprazole 20 mg as intact capsules o.d. in the morning for 7 days to six patients with healed duodenal ulcer. Baseline intragastric ph was 1.7 in that study and rose to 3.9 with omeprazole. We have not compared the pharmacodynamic response of SOS and intact omeprazole capsules in the same patients. However, the results from these previous studies suggest that the antisecretory effects of these two formulations are at least comparable. Our study has shown that SOS 20 mg per day suppresses intragastric acidity when given via a gastrostomy. In a previous study, we obtained a quantitatively greater effect on intragastric ph with intact omeprazole granules in orange juice. 2 However, we have not directly compared these two formulations in the same patients. The effect of SOS 20 mg that we obtained is similar to that previously reported with intact omeprazole capsules. 8, 9 While our results appear to be at variance to those of Phillips et al. 4 and Lasky et al., 6 this can probably be explained by differences in patient characteristics, dosing schedules and the methods used for intragastric ph measurement. Preliminary, uncontrolled studies of SOS suggest that it may be more effective than an intravenous H2-receptor antagonist for the treatment and prophylaxis of stress-related gastric mucosal disease. 4, 6 However, data on its effectiveness in other conditions are currently lacking. ACKNOWLEDGEMENTS Astra Merck (Wayne, PA) supported this study. REFERENCES 1 Howden CW. Clinical pharmacology of omeprazole. Clin Pharmacokinet 1991; 20: 38±49. 2 Sharma VK, Heinzelmann EJ, Steinberg EN, Vasudeva R, Howden CW. Nonencapsulated, intact omeprazole granules effectively suppress intragastric acidity when administered via a gastrostomy. Am J Gastroenterol 1997; 92: 848±51. 3 Sharma VK, Ugheoke EA, Vasudeva R, Howden CW. The pharmacodynamics of lansoprazole administered via gastrostomy as intact, non-encapsulated granules. Aliment Pharmacol Ther 1998; 12: 1171±4. 4 Phillips JO, Metzler MH, Palmieri TL, Huckfeldt RE, Dahl NG. A prospective study of simpli ed omeprazole suspension for the prophylaxis of stress-related mucosal damage. Crit Care Med 1996; 24: 1793± Zimmermann A, Walters JK, Katona B, Souney P. Alternative methods of proton pump inhibitor administration. Consultant Pharmacist 1997; 12: 990±8. 6 Lasky MR, Metzler MH, Phillips JO. A prospective study of omeprazole suspension to prevent clinically signi cant gastro-

5 SIMPLIFIED OMEPRAZOLE SUSPENSION VIA GASTROSTOMY 1095 intestinal bleeding from stress ulcers in mechanically ventilated trauma patients. J Trauma 1998; 44: 527±33. 7 Mohiuddin MA, Pursnani KG, Katzka DA, Gideon RM, Castell JA, Castell DO. Effective gastric acid suppression after oral administration of enteric-coated omeprazole granules. Dig Dis Sci 1997; 42: 715±9. 8 Tolman KG, Sanders SW, Buchi KN, Karol MD, Jennings DE, Ringham GL. The effects of oral doses of lansoprazole and omeprazole on gastric ph. J Clin Gastroenterol 1997; 24: 65±70. 9 Chiverton SG, Howden CW, Burget DW, Hunt RH. Omeprazole (20 mg) daily given in the morning or evening: a comparison of effects on gastric acidity, and plasma gastrin and omeprazole concentration. Aliment Pharmacol Ther 1992; 6: 103±11.