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Aliment Pharmacol Ther 2004; 19: 1105–1110.
Effect of splitting the dose of esomeprazole on gastric acidityand nocturnal acid breakthrough J . H A M M E R & B . S C H M I D TUniversita¨tsklinik fu¨r Innere Medizin IV, Abteilung fu¨r Gastroenterologie und Hepatologie, Vienna, Austria Results: Median gastric 24-h pH was higher during 2 · 20 mg esomeprazole on day 2 (P < 0.01), no Background: Twice-daily dosing is increasingly used to differences were detected on day 6. Night-time gastric improve gastric acid control, although not all proton- pump inhibitors are more effective when doses are split.
2 · 20 mg esomeprazole on all study days (P < 0.05).
Standard dose esomeprazole provides better gastric acid Nocturnal acid breakthrough was observed on all study control than other standard dose proton-pump inhibitors.
days in subjects receiving 1 · 40 mg, but in only 85% Aims: To compare the effect of standard dose esomep- (first night), 64% (second night), and 45% of subjects razole (1 · 40 mg) with 20 mg b.d. on gastric acidity.
(sixth night) with 2 · 20 mg (P < 0.05).
Methods: Thirteen healthy subjects participated in this Conclusion: Splitting the esomeprazole dose improves crossover study, receiving esomeprazole 2 · 20 mg and initial acid suppression, this effect starts at the first 1 · 40 mg for 7 days in random order with a washout night. Maximal benefit is achieved on day 2, while the period of at least 7 days. Gastric 24-h pH was measured effect on night-time acid control is detectable during the has improved remarkably over the last decades, there are still patients and conditions that do not respond The prevalence of abnormal oesophageal acid exposure adequately to currently available therapy regimens.5, 6 of the oesophagus increases across the spectrum of Healing of reflux oesophagitis and relief of symptoms is gastro-oesophageal reflux disease (GERD), as one pro- directly related to the percentage of time that the gastric gresses from non-erosive reflux disease through erosive pH is maintained above a pH of 4.0 over a 24 h oesophagitis to Barrett’s oesophagus.1 Therapy of acid- period.7–9 Several regimens have been used to improve related disorders of the oesophagus aims to reduce acid the degree of intragastric pH control, including pre- load of the oesophagus by suppressing gastric acid scription of an additional dose of histamine type 2 production.2 Earlier generations of proton-pump inhib- receptor antagonists or splitting the dose of the PPI.
itors (PPIs) in standard doses once daily have achieved The night-time interval may require special considera- 80–85% symptom relief and healing in GERD, while tion.10 During the night period, patients with GERD and newer agents achieve healing and symptom relief in also healthy subjects continue to secrete acid and even higher percentages, reaching up to 95%.3, 4 decrease the intragastric pH < 4 for at least 1 However, while therapy of gastric acid-related disorders continuous hour, even when taking PPI such asomeprazole or lansoprazole twice daily.11, 12 The literature on the effect of splitting the PPI dose on Correspondence to: Dr J. Hammer, Universita¨tsklinik fu¨r Innere Medizin IV, gastric acidity is divergent for the different PPIs. Gastric Wa¨hringer Gu¨rtel 18–20, 1090 Vienna, Austria.
E-mail: [email protected] acid control with omeprazole 40 mg once daily could be significantly improved when the dose was divided and taken before breakfast and dinner.11, 13 Lansoprazole,which has been proven to be similar effective as A dual electrode antimony pH catheter (diameter omeprazole when given once daily, has been less 2.1 mm), connected to a Flexilog 2000 ambulatory pH effective with split dosing when compared with omep- recorder (Oakfield Instrument, Ltd, Oxfordshire, England, razole twice daily. Finally, splitting the dose of pantop- Great Britain, UK), was used to continuously record pH razole did not have any benefit on gastric acidity over a values at 4-s intervals. The electrodes were calibrated prior to each recording as per the recommendations of the Recent studies have suggested that esomeprazole manufacturer in buffers of pH 1.1 and 7.0 at room tem- (ESO), the S-isomer of omeprazole, improves gastric perature. The electrodes were positioned 15 cm apart on acid control as well as healing of GERD compared with the tube. The tube was introduced into the subject’s other PPIs that are currently available on the mar- stomach via the intranasal route. The position of the ket.15–21 The pharmacological difference to the racemic electrodes were obtained by determining the pH-step mixture, omeprazole, is due to a decreased first-pass between the stomach and the oesophagus with the prox- elimination and decreased systemic clearance that imal electrode; thereafter, the tube was 5 cm withdrawn.
results in an increase of the area under the plasma Twenty-four hour ambulatory intragastric and distal concentration–time curve; this in turn is related to a oesophageal pH recording was performed after an prolonged availableness at the proton pump.22, 23 ESO overnight fast on days 1, 2 and 6 during both study is readily absorbed, the highest plasma concentration is series. Subjects were allowed to follow their daily being reached after approximately 1.5 h. Up to an routine. They were instructed to take the meals always ingested amount of 40 mg, plasma concentrations at the same time during the study period with a similar increase proportional to the ingested dose. Like all other composition and calorie content according to their PPIs, the antisecretory effect lasts longer than the individual preferences. The compositions of the meals plasma half-life. All PPI, including ESO, increase their were chosen individually by the study subjects.
inhibitory effect on the proton pump within the firsttreatment days until the effect reaches a plateau after The effect of drugs on gastric acidity can be quantified Subjects were asked to participate in two series, receiving by 24-h pH monitoring. In the present study, we 1 · 40 mg or 2 · 20 mg ESO, respectively, over a 7-day hypothesized that the effect of once daily ESO on gastric period with a washout phase between study series of at acidity can be further improved by splitting the dose.
least 7 days and up to 3 weeks. The order of the two series We expected that especially night-time acid secretion was determined at random. Subjects were instructed to would be affected by a twice daily regimen.
ingest the drugs with a small amount of water approxi-mately 15–30 min before breakfast (1 · 40 mg and firstdose of 20 mg b.d.) and dinner (second dose of 20 mg b.d.). The first dose was given in the study centre afterpositioning of the pH-tube and was dissolved in 125 mL of water. As soon as the tube was in position, the Thirteen healthy volunteers (seven female, six male; pH-recording was started. The tube was left in position for mean age 30.6 years, range: 20–52 years) were recrui- 48 h (days 1 and 2). At the end of day 2, the tube was ted by public advertisement. None had a history of gently removed. Subjects returned to the study centre on gastrointestinal complaints and abdominal surgery day 6, when the pH tube was repositioned for another (except appendectomy and cholecystectomy) and none used medication on a regular basis. Subjects were notallowed to use any medication during the study period.
All subjects tested negative for Helicobacter pylori withthe [13C] urea breath test. Subjects signed an informed Data collected from the Flexilog 2000 were downloaded consent for the protocol that was approved by the Ethics onto an IBM-compatible computer that utilized Flexilog Committee of the University Hospital of Vienna, Austria.
software (Oakfield Instrument, Ltd) to analyse the data.
Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 1105–1110 E S O M E P R AZ O L E D O S E S P L I T T I N G From the oesophageal and gastric recordings, the in acid suppression were detected on day 6 (P > 0.05).
median pH and the percentage of time with a pH above Gastric acid suppression with 2 · 20 mg ESO treatment 4 were calculated for three time periods: the daytime was comparable on days 2 and 6 (P > 0.05).
interval (08:00–20:00 hours), the night-time interval(22:00–07:00 hours) and the full 24 h. Nocturnal acid breakthrough was defined as a trop in gastric pH under4 that lasted longer than 1 h.
During daytime hours, 2 · 20 mg ESO increased the Gastric pH values were also converted to acid concen- median gastric pH (P < 0.05) and percentage time with trations and these concentrations were then plotted for gastric pH > 4 (P < 0.01) and decreased gastric AUC of the total 24 h period as well as for the day- and night- acidity on day 2 (P < 0.05), but not on day 1 and day 6 time intervals for each of the doses and study days.
Integration of the area under the resulting curves (AUC) During night-time, gastric acid suppression was signi- was performed using the trapezoid rule and provided an ficantly improved by 2 · 20 mg ESO compared with estimate of the 24-h intragastric acidity.
1 · 40 mg on all study days (Table 1). Nocturnal acid Comparisons between study days were performed using breakthrough was observed in all subjects receiving Student’s t-test for paired observations. The proportion 1 · 40 mg on all study days. Each individual subject of subjects with nocturnal acid breakthrough was had between 1 and 3 episodes of nocturnal acid compared using McNemar’s test for paired proportions.
A P-value of <0.05 was considered significant.
During 2 · 20 mg ESO, nocturnal acid breakthrough was observed in only 85% (first night), 64% (secondnight), and 45% of subjects (sixth night) (P < 0.05 vs.
1 · 40 mg ESO) (Table 1) During the sixth night, foursubjects still had 1 episode of nocturnal acid break- through and two had 2 episodes (Figure 2b).
increased the median gastric 24 h pH (P < 0.01) and percentage time with gastric pH > 4 (P < 0.05) on day 2and decreased gastric AUC of acidity on day 1 (P < 0.01) On all study days no differences in oesophageal acid and day 2 (P < 0.01) (Table 1, Figure 1). No differences parameters were found with the two different regimens Table 1. Parameters of gastric acidity in subjects treated with 1 · 40 and 2 · 20 mg esomeprazole on day 1, day 2 and day 6. Data aregiven as mean ± s.d.
P-value 1 · 40 mg 2 · 20 mg P-value 1 · 40 mg 2 · 20 mg Percentage time pH > 4.0 36.0 (20.3) 44.4 (20.6) N.S.
Percentage time pH > 4.0 50.1 (25.3) 36.9 (15.9) N.S.
Percentage time pH > 4.0 29.7 (15.7) 46.3 (22.4) 0.05 Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 1105–1110 acid breakthrough is present in a high proportion ofhealthy subjects at baseline and that a once daily dose ofESO could not eliminate this phenomenon. Splitting the dose had a significant effect on nocturnal acid control, and this effect increased from day 1 to day 6, the end of Acid-induced injury of the oesophagus depends on the pH of the refluxate and the healing rate of erosive oesophagitis by acid inhibitors is directly related to theduration of suppression of gastric acid secretion Figure 1. Time (h) per 24-h period with a pH above 4. Dataare given as mean ± S.E.M., shaded area ¼ 1 · 40 mg achieved over a 24-h period.7, 9 Several recent studies esomeprazole, white area ¼ 2 · 20 mg esomeprazole. *P < 0.05 have demonstrated that ESO suppresses gastric acidity more potently than other PPIs.15, 16 Our data demon-strated that by splitting the daily dose, gastric acid control can further be improved. The maximal 24 h gastric acidity that has been achieved on day 6 during once daily dosing, has already been achieved on the Splitting the dose of omeprazole has also been shown to provide superior intragastric pH control whencompared with a double dose given once daily, whereas such a benefit has not been documented for other PPIs.11, 13, 14 The differences in PPI effect might be due to a variable reversibility of binding to the proton pump among the PPIs.24, 25 Proton-pump inhibition was generally thought to be irreversible, but this has recently been challenged. Binding of omeprazole for instance, seems to be reversed in vivo, while binding of pantoprazole to the proton pump seems to be truly irreversible, suggesting a longer duration of acid Figure 2. Number of nocturnal acid breakthrough episodes suppression with pantoprazole treatment; thus, the rate during the 3 study days; (a) during 1 · 40 mg esomeprazole, of recovery of the proton pump might be higher with omeprazole, leaving more proton pumps susceptible foranother application 12 h after the morning dose. Thus, of ESO. Median 24-h pH in the oesophagus remained at the reversibility of binding of omeprazole and ESO might a level above 6.5 during all three measurement days be of some clinical benefit by allowing the option to split and remained above 6.3 during the night-time periods, the dose whereby the effect on gastric acid suppression Oesophageal acid exposure was not significantly different among the two ESO regimens in our study.
It should be noted that subjects in this study did not The results of the present study demonstrate that gastric have gastro-oesophageal reflux, thus intra-oesophageal acid suppression with ESO, the most potent PPI pH measurement were not expected to be abnormal and currently on the market, can further be improved in in fact, there was very little nocturnal reflux in our the initial period of the treatment when the daily dose is study group. Future clinical studies have to demonstrate divided into a morning and an evening dose. The whether also oesophageal acid exposure in patients with beneficial effect was more pronounced during the night gastro-oesophageal reflux disease can be reduced signi- period and was detectable already in the first night of ficantly by splitting the ESO dose. In the present study, treatment. Our study has also confirmed that nocturnal we have evaluated the effect of splitting the ESO dose on Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 1105–1110 E S O M E P R AZ O L E D O S E S P L I T T I N G gastric acid suppression during the initial week of treatment. It cannot be inferred from our data whether 1 Van Herawaarden MA, Samsom M, Smout AJPM. Excess the effect of splitting the dose persists longer than the gastrooesophageal reflux in patients with hiatus hernia is caused by mechanisms other than transient LES relaxations.
A series of observations have demonstrated that an Gastroenterology 2000; 119: 1439–46.
increase in nocturnal acid production occurs in 2 Tutuian R, Castell DO. Management of gastroesophageal reflux disease. Am J Med Sci 2003; 326: 309–18.
subjects with GERD as well as in healthy subjects.10 3 Kahrilas PJ, Falk GW, Johnson DA, et al. Esomeprazole This also occurs in the presence of PPI therapy and it improves healing and symptom resolution as compared with has been suggested that this so called nocturnal acid omeprazole in reflux oesophagitis patients: a randomized breakthrough might be responsible for nocturnal controlled trial. Aliment Pharmacol Ther 2000; 14: 1249–58.
oesophageal acid exposure and persisting symptoms 4 Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole of GERD, although this concept has been questioned (40 mg) compared with lansoprazole (30 mg) in the treat-ment of erosive esophagitis. Am J Gastroenterol 2002; 97: recently.26 Studies have suggested that addition of H2 receptor antagonists at bedtime to an existing b.d. PPI 5 Hatlebakk JG, Katz PO, Castell DO. Medical therapy. Man- regimen is more effective than PPI therapy alone in agement of the refractory patient. Gastroenterol Clin North reducing nocturnal acid breakthrough.27 However, the effect of H2 receptor antagonists on nocturnal 6 Katz PO. Lessons learned from intragastric pH monitoring.
J Clin Gastroenterol 2001; 33: 107–13.
acid is only temporary and is not detectable after 7 Pursnani KG, Mohiuddin MA, Geisinger KR, Weinbaum G, 1 week of treatment.26, 28 In contrast, our findings Katzka DA, Castell DO. Experimental study of acid burden suggest that splitting the ESO dose improves gastric and acute oesophagitis. Br J Surg 1998; 85: 677–80.
night-time acid control and this effect increases 8 Smith JL, Opekun AR, Larkai E, Graham DY. Sensitivity of the during the first week. After 1 week of treatment, less esophageal mucosa to pH in gastroesophageal reflux disease.
than half of the subjects remained to have nocturnal 9 Bell NJ, Burget D, Howden CW, Wilkinson J, Hunt RH. Appro- acid breakthrough. The present study does not allow priate acid suppression for the management of gastrooesopha- to conclude whether the proportion of subjects with geal reflux disease. Digestion 1992; 51 (Suppl. 1): 59–67.
nocturnal acid breakthrough would further decrease 10 Peghini PL, Katz PO, Bracy N, Castell DO. Nocturnal recovery during longer ESO application with a split dose of gastric acid secretion with twice daily dosing of proton pump inhibitors. Am J Gastroenterol 1998; 93: 763–7.
11 Hatlebakk JG, Katz PO, Kuo B, Castell DO. Nocturnal gastric It has to be pointed out that our study was conducted acidity and acid breakthrough on different regimens of in healthy subjects, thus should be extrapolated with omeprazole 40 mg daily. Aliment Pharmacol Ther 1998; 12: caution to patients with acid-related disorders. Our subjects were all tested H. pylori-negative. It has been 12 Katz PO, Hatlebakk JG, Castell DO. Gastric acidity and acid shown that PPI therapy in H. pylori-negative healthy breakthrough with twice-daily omeprazole or lansoprazole.
subjects is associated with a higher rate of nocturnal Alimen Pharmacol Ther 2000; 14: 709–14.
13 Kuo B, Castell DO. Optimal dosing of omeprazole 40 mg daily: acid breakthrough compared with H. pylori-positive effects on gastric and esophageal pH and serum gastrin in subjects,29 possibly because the presence of H. pylori healthy controls. Am J Gastroenterol 1996; 91: 1532–8.
infection leads to a more profound suppression of acid 14 Moennikes H, Weber S, Tebbe J, et al. Comparison of pan- toprazole 20 mg twice daily with 40 mg once daily on In conclusion, splitting the dose of ESO improves acid intragastric pH in healthy volunteers. Gastroenterology1998; 114: A232.
suppression in the first week of treatment. By twice daily 15 Miner P Jr, Katz PO, Chen Y, Sostek M. Gastric acid control dosing, maximal 24-h acid suppression is already with esomeprazole, lansoprazole, omeprazole, pantoprazole, achieved on the second day of treatment, while night- and rabeprazole: a five-way crossover study. Am J Gast- time acid control as well as acid breakthrough improved continuously within the first week of treatment by 16 Hatlebakk JG. Review article: gastric acidity – comparison of esomeprazole with other proton pump inhibitors. AlimentPharmacol Ther 2003; 17 (Suppl. 1): 10–5.
17 Ro¨hss K, Wilder-Smith CH, Claar-Nilsson, Lundin C, Hassel- gren G. Esomeprazole 40 mg provides more effective acidcontrol than standard doses of all other proton pump inhib- There was no financial support required for this study.
itors. Gastroenterology 2001; 120: A419.
Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 1105–1110 18 Castell DO, Kahrilas PF, Richter JE, et al. Esomeprazole 24 Shin JM, Sachs G. Biochemical reversal of proton pump (40 mg) compared with lansoprazole (30 mg) in the treat- inhibition in vivo. Gastroenterology 2003; 124: A444.
ment of erosive esophagitis. Am J Gastroenterol 2002; 97: 25 Shin JM, Sachs G. Restoration of acid secretion following treatment with proton pump inhibitors. Gastroenterology 19 Richter JE, Kahrilas PJ, Johanson J, et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients 26 Ours TM, Fackler WK, Richter JE, Vaezi MF. Nocturnal acid with erosive esophagitis: a randomized controlled trial. Am J breakthrough: clinical significance and correlation with esophageal acid exposure. Am J Gastroenterol 2003; 98: 20 Scholten T, Gatz G, Hole U. Once-daily pantoprazole 40 mg and esomeprazole 40 mg have equivalent overall efficacy in 27 Peghini PL, Katz PO, Castell DO. Ranitidine controls noc- relieving GERD-related symptoms. Aliment Pharmacol Ther turnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998; 115: 21 Armstrong D, Bair D, James C, Tanser L, Escobedo S, Nevin K.
Oral esomeprazole vs. intravenous pantoprazole: a compar- 28 Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect ison of the effect on intragastric pH in healthy subjects.
of H2RA therapy on nocturnal gastric acid breakthrough.
Aliment Pharmacol Ther 2003; 18: 705–11.
Gastroenterology 2002; 122: 625–32.
22 Andersson T, Hassan-Alin M, Hasselgren G, Ro¨hss K, Weidolf L.
29 Katsube T, Adachi K, Kawamura A, et al. Helicobacter pylori Pharmacokinetic studies with esomeprazole, the (S)-isomer of infection influences nocturnal gastric acid breakthrough.
omeprazole. Clin Pharmacokinet 2001; 40: 411–26.
Aliment Pharmacol Ther 2000; 14: 1049–56.
23 Dent J. Review article: pharmacology of esomeprazole and 30 Gillen D, Wirz AA, Neithercut WD, Ardill JE, McColl KE.
comparisons with omeprazole. Aliment Pharmacol Ther Helicobacter pylori infection potentiates the inhibition of gas- tric acid secretion by omeprazole. Gut 1999; 44: 468–75.
Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 1105–1110

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