Sharma B, Sharma M, Daga MK, Sachdev GK, Bondi E. Effect of omeprazole and domperidone on adult asthmatics with gastroesophageal reflux. World J Gastroenterol 2007; 13(11): 1706-1710
Corresponding Author of This Article
Bhavneesh Sharma, MD, Department of Internal Medicine, Brookdale University Hospital and Medical Center, State University of New York, Brooklyn, New York 11212, United States. firstname.lastname@example.org
Article-Type of This Article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Bhavneesh Sharma, Manisha Sharma, Elliott Bondi, Brookdale University Hospital and Medical Center, Division of Pulmonary and Critical Care Medicine, State University of New York, Brooklyn, New York 11212, United States
Mradul Kumar Daga, Gopal Krishan Sachdev, University of Delhi, Maulana Azad Medical College, Divisions of Pulmonary Medicine and Gastroenterology, New Delhi 110002, India
ORCID number: $[AuthorORCIDs]
Author contributions: All authors contributed equally to the work.
Supported by a research grant from the University of Delhi, No. 52301/01 and Glaxo Smithkline Pharmaceuticals Limited and Dr. Reddy’s Laboratories Ltd, No. 9834512
Correspondence to: Bhavneesh Sharma, MD, Department of Internal Medicine, Brookdale University Hospital and Medical Center, State University of New York, Brooklyn, New York 11212, United States. email@example.com
Telephone: +1-718-2405000 Fax: +1-718-2406344
Received: January 17, 2007 Revised: January 25, 2006 Accepted: January 31, 2007 Published online: March 21, 2007
AIM: To study the effect of combined omeprazole (Ome) and domperidone (Dom) therapy on asthma symptoms and pulmonary function in asthmatics with gastroesophageal reflux.
METHODS: We selected 198 asthmatics with gastroesophageal reflux diagnosed by 24-h esophageal pH monitoring to receive Ome 20 mg twice daily and Dom 10 mg three times daily or placebo for 16 wk (1:1 double-blind randomization). Spirometry was done at baseline and after 16 wk of treatment. The primary outcome measures were: mean daily daytime and nighttime asthma symptom scores. Mean daily reflux symptom scores, albuterol use as rescue medication (number of puffs), daytime and nighttime peak expiratory flow rate (PEFR), postbronchodilator forced expiratory volume in 1 second (FEV1) and postbronchodilator forced vital capacity (FVC) were secondary outcome measures.
RESULTS: Comparison of mean change from baseline between antireflux therapy and placebo groups revealed significant reduction in daytime asthma symptom score (17.4% vs 8.9%), nighttime asthma symptom score (19.6% vs 5.4%), reflux symptom score (8.7% vs 1.6%) and rescue medication use (23.2% vs 3.1%) after antireflux therapy compared to mean change in placebo group (P < 0.001). There was significant improvement in morning PEFR (7.9% vs 0.2%), evening PEFR (9.8% vs 0.5%), FEV1 (11.1% vs 3.78%) and FVC (9.3% vs 1.52%) in the antireflux therapy group compared to placebo on comparing the mean change from baseline after 16 wk (P < 0.01).
CONCLUSION: Combined therapy with Ome and Dom in adult asthmatics with gastroesophageal reflux may be beneficial by reducing asthma symptoms, rescuing medication use, and improving pulmonary function.
Citation: Sharma B, Sharma M, Daga MK, Sachdev GK, Bondi E. Effect of omeprazole and domperidone on adult asthmatics with gastroesophageal reflux. World J Gastroenterol 2007; 13(11): 1706-1710
Gastroesophageal reflux disease (GERD) and asthma are two common diseases that afflict millions of people all over the world. The exact relationship between GERD and asthma has been a source of constant debate. GERD is reportedly the most common trigger in difficult-to-control asthma. Various mechanisms contributing to GERD exacerbating asthma include a vagus-mediated reflex, a local axonal reflex, heightened bronchial reactivity[4,5], and microaspiration[6,7]. GERD is more prevalent in asthmatics compared with control populations and asthmatics frequently associate GERD symptoms with their asthma symptoms. Previous studies have estimated the prevalence of GERD in adult asthmatics at between 34% and 80%[8-10]. Asthma symptoms also correlated with esophageal pH events on 24-h esophageal pH monitoring.
Previous studies on the effect of antireflux therapy on asthma have shown inconsistent results[12-24]. Most of these studies have been done in small groups of patients with different proton-pump inhibitors and were done for short durations of anti-reflux therapy. There is limited data on the use of prokinetic agents in asthmatics with GERD and so far, only one study has explored the effect of a combination of a proton pump inhibitor and a prokinetic agent in asthmatics with GERD. The present study was done to study the effect of combined therapy with omeprazole, a proton-pump inhibitor and domperidone, a prokinetic agent on asthma symptoms and pulmonary function in asthmatics with GERD.
MATERIALS AND METHODS
A total of 410 adult asthma patients attending the outpatient medicine and pulmonary clinics of Lok Nayak Hospital, a tertiary teaching hospital affiliated with Maulana Azad Medical College, University of Delhi, India, were screened after obtaining informed consent. The study was approved by the Institutional Review Board of the hospital. All patients underwent 24-h esophageal pH monitoring to detect GERD. The inclusion criteria of the study at screening included the following: (1) > 18 years of age; (2) > 12% improvement in FEV1 (in litres) after inhalation of 180 μg of albuterol; (3) mild-to-moderate persistent asthma; (4) no exacerbations or significant change in asthma medications during past weeks of screening; and (5) GERD as diagnosed by 24-hour esophageal pH monitoring. GERD was defined as positive if the total time for which pH was < 4 was > 4.5%. Exclusion criteria included the following: (1) any unstable chronic medical condition; (2) history of smoking in past or present; (3) history of any other lung disease except asthma; and (4) use of antireflux medications including antacids, histamine-2-receptor antagonists, proton pump inhibitors or prokinetic agents. GERD was diagnosed in 247 asthmatics after 24-h esophageal pH monitoring. Of 247 patients with GERD, 18 patients had history of smoking, 10 patients had history of recent asthma exacerbation, 8 patients were receiving omeprazole therapy, 5 patients were receiving antacids and 2 patients withdrew the consent. After screening, remaining 204 patients for selected for randomization, of which 198 patients completed the study.
At initial screening (Figure 1), a detailed medical history, physical examination and laboratory tests were done from July 4, 2001 to August 18, 2003 in all asthmatics with GERD who met the inclusion and exclusion criteria. After screening, each patient was given albuterol metered-dose inhaler (Ventolin; Glaxo Smithkline Pharmaceuticals Limited, Mumbai, India) for use as rescue medication, a peak flow meter and a diary. Patients were instructed to record daily daytime and nighttime asthma symptoms, reflux symptoms, morning and evening peak expiratory flow rates more than 3 h after albuterol use and albuterol use as rescue medication. Asthma symptoms included wheezing, chest tightness, dysnea and cough and were graded on a scale of 0-4 (1-none, 2-mild, 3-moderate, 4-severe). Reflux symptoms included heartburn, regurgitation, dysphagia, belching and hoarseness and were graded similarly. This asthma symptom scale has been used in previous studies[27-29]. Randomization was done after initial screening and all patients received white capsules containing omeprazole 20 mg (Ome; Dr. Reddy’s Laboratories; Hyderabad, India) to be taken orally 1 h before breakfast and 1 h before the evening meal and domperidone (Dom; Dr. Reddy’s Laboratories, Hyderabad, India) 10 mg orally 3 times daily (1 h before breakfast, lunch and evening meal) or identical placebo capsules (1:1 double-blind randomization). We used Ome 20 mg twice daily as this dose has been shown to cause adequate acid suppression in a previous study.All patients underwent flow-volume spirometry at baseline using standard reference values. Inhaled beta-2 agonists were held for at least 8 h, and oral beta-2 agonists and inhaled anticholinergics were held for at least 12 h before pulmonary function tests. Spirometry was done before and 30 min after inhalation of 180 μg of inhaled albuterol and was repeated after antireflux therapy for 16 wk. The primary outcome measures were: mean daily daytime and nighttime asthma symptom scores. Mean daily reflux symptom scores, albuterol use (number of puffs), daytime and nighttime peak expiratory flow rate (PEFR), postbronchodilator forced expiratory volume in 1 s (FEV1) and postbronchodilator forced vital capacity (FVC) were secondary outcome measures.
Figure 1 Study design for GERD therapy.
Statistical analysis was done using SPSS 12.0 (SPSS Inc, Chicago, Illinois, United States) statistical software. Comparison between baseline and post-treatment parameters within treatment groups was done using paired t test. Comparison of mean percentage change from baseline after 16 wk of therapy between two treatment groups was done using Fisher’s exact test. P values were two-sided and were considered significant at < 0.05.
At baseline (Table 1), the antireflux therapy and placebo groups were matched with no significant difference between various parameters like age, sex, body mass index, asthma symptoms, reflux symptoms, rescue medication use, FEV1 and FVC. There was no significant difference in medication compliance between antireflux therapy and placebo groups based on pill counts (95.2% ± 7.4% vs 96.7% ±6.3%, P = 0.87).
Table 1 16-wk primary and secondary outcome measures of antireflux therapy (mean ± SD).
bP < 0.01 vs Baseline, BMI: Body mass index; PEFR: Peak expiratory flow rate; FEV1: Forced vital capacity in 1 s; FVC: Forced vital capacity.
There was 17.4% reduction in the daytime asthma symptom score (P = 0.0002), 19.6% reduction in nighttime asthma symptom score (P = 0.0007) and 8.7% reduction in reflux symptom score after antireflux therapy compared to baseline (P = 0.0001). Antireflux therapy resulted in 23.2% reduction in rescue medication use (P = 0.0001), 7.9% improvement in morning PEFR (P = 0.005), 9.8% improvement in evening PEFR (P = 0.003), 11.1% improvement in FEV1 (L) (P = 0.001) and 9.3% improvement in FVC (L) compared to baseline (P = 0.002).
Comparison of mean change from baseline between antireflux therapy and placebo groups revealed significant reduction in daytime asthma symptom score (17.4% vs 8.94%, P = 0.0001), nighttime asthma symptom score (19.6% vs 5.4%, P = 0.0001), reflux symptom score (8.7% vs 1.6%, P = 0.0003) and rescue medication use (23.2% vs 3.08%, P = 0.0001) after antireflux therapy compared to mean change in placebo group. There was significant improvement in morning PEFR (7.9% vs 0.2%, P = 0.004), evening PEFR (9.8% vs 0.5%, P = 0.002), FEV1 in L (11.1% vs 3.78%, P = 0.0013) and FVC in L (9.3% vs 1.52%, P = 0.0023) in the antireflux therapy group compared to placebo on comparing the mean change from baseline after 16 wk. These results are demonstrated in Table 1. Improvement in primary and secondary outcome measures was seen in all 99 patients treated with antireflux therapy.
Maintenance medication and adverse events
All patients were treated with one inhalation of salmetrol 50 μg and fluticasone propionate 250 μg taken two times everyday at 8:00 and 20:00 (Seretide; Glaxo Smithkline Pharmaceuticals Limited, Mumbai, India). There was no significant difference in the maintenance mediation dose between two treatment groups at baseline. There was no change in the maintenance medication during the treatment period in two treatment groups.
There was no significant difference in treatment-emergent adverse events between antireflux therapy and placebo groups over 16 wk of treatment (64% vs 60%, P = 0.7). The percentages of severe adverse events were similar in the two treatment groups (10% vs 8%, P = 0.4). The severe adverse events included myalgia (4%), aggression (3%), thrombocytopenia (1%), urticaria (1%) and Steven-Johnson syndrome (1%) in the antireflux therapy group.
This study shows a significant improvement in daytime and nocturnal asthma symptoms, reflux symptoms, daytime and nighttime PEFR, FEV1 and FVC after omeprazole and domperidone therapy for 16 wk compared to placebo. This is the second study in medical literature investigating the effect of combined therapy with a proton-pump inhibitor and prokinetic agent in asthmatics. In an earlier study, Jiang et al used Ome 20 mg once daily and Dom 10 mg thrice daily for 6 wk in 30 asthmatics. They found significant improvement in VC, VC%, FVC, FVC%, FEV1, FEV1%, PEF, PEF% and bronchial hyper-responsiveness as measured by histamine bronchoprovocation test.
Results of past studies investigating the effect of proton-pump inhibitor therapy on asthma outcome have shown variable results. Some recent studies using different proton pump inhibitors in asthmatics include those by Calabrese et al using pantoprozole 80 mg daily in 34 asthmatics for 6 mo (25 patients had a complete recovery of esophagitis and reflux symptoms and 27 patients had normalization of FEV1), Kiljander et al using esomeprazole 40 mg twice daily for 16 wk in 350 asthmatics with GERD and nocturnal respiratory symptoms (significant improvement in morning and evening PEFR), Littner et al using lansoprozole 30 mg twice daily for 24 wk in 207 asthmatics with acid reflux symptoms (reduction in asthma exacerbations and improved asthma quality of life, but no improvement in asthma symptoms or pulmonary function), Gopal et al using Ome 20 mg daily for 4 wk in 70 asthmatics with significant reflux (significant improvement in asthma symptom scores and pulmonary function), and Eryuksel et al using pantoprozale 40 mg daily for 3 mo in 28 asthmatics with laryngopharyngeal reflux as shown by indirect videolaryngoscopy (significant reduction in asthma and laryngopharyngeal sreflux symptoms). On reviewing the combined results of 12 studies examining medical therapy in 326 treated asthmatics with GERD in a meta-analysis, asthma symptoms improved in 69%, medication use was reduced in 62%, and evening PEFR rates improved in 26% of patients; however, pulmonary function did not improve. A recent Cochrane Database review examined 12 randomized controlled trials studying antireflux therapy in asthmatics and noted no overall improvement in asthma after GERD therapy. However, they concluded that subgroups of patients may benefit and pointed out the importance of examining predictors of asthma response.
The role of non-acid reflux in asthmatics who do not respond to proto-pump inhibitor therapy has been described. We speculate that a sub-group of asthmatics may have increased bronchial responsiveness on exposure to non-acid reflux including bile acids, bile salts and pancreatic enzymes. Combined therapy with a proton pump inhibitor and prokinetic agent may help asthmatics with gastroesophageal reflux by reducing acid as well as non-acid reflux. A new technique, esophageal impedance monitoring makes it possible to detect non-acid reflux and may provide future directions to exploring the relationship between non-acid reflux and asthma. A large on-going trial is exploring the prevalence of acid and non-acid GERD in moderate to severe asthma children aged 1-18 years referred for gastrointestinal evaluation.
We used Dom, a prokinetic agent in addition to omeprazole to treat GERD in our study. Prokinetics have been shown to have a definite role in the treatment of gastroesophageal reflux disease. In short term treatment of gastro-esophageal reflux disease, cisapride (10 mg four times a day or 20 mg twice daily) has proved more effective than placebo and nearly as effective as H2 blockers in relieving symptoms and healing esophagitis. Cisapride (10 mg twice daily or 20 mg at bedtime) also prevents relapses in patients with mild esophagitis. Studies using metoclopramide also showed an improvement in reflux symptoms compared to placebo using metoclopramide 10 mg four times a d. Domperidone, the prokinetic agent used in our study, is a dopamine antagonist,which does not cross the blood–brain barrier and thus has a better safety profile, with no significant CNS side effects and only a minor incidence of gynecomastia and galactorrhea. Domperidone acts by increasing lower esophageal sphincter tone and by enhancing upper gastrointestinal separately, acting on one of the pathophysiological mechanisms of GERD. It antagonizes the inhibitory effect of dopamine, resulting in stimulation of gastric muscle contraction. This provides a mechanism for the gastrokinetic effect of domperidone. In a randomized, double-blind, controlled trial conducted in pediatric population, Dom caused a significant reduction in vomiting compared to metoclopramide and placebo. A study comparing different maintenance therapies for reflux esophagitis has concluded that addition of prokinetic with antisecretory agent decreases relapse (relapse rate 20% with Ome and only 11% with combination of Ome and cisapride). However, Sekiguchi et al found that cisapride often actually exacerbated acid reflux in another study. The use of combination therapy with omeprazole and domperidone should be monitored closely in asthmatics.
In conclusion, our data suggests that combined therapy with Ome and Dom for 16 wk in asthmatics with GERD may be beneficial by reducing asthma symptoms and rescue medication use, and improving pulmonary function.
S- Editor Wang J L- Editor Rampone B E-Editor Chin GJ
Richter JE. Gastroesophageal reflux disease and asthma: the two are directly related.Am J Med. 2000;108 Suppl 4a:153S-158S.
Wright RA, Miller SA, Corsello BF. Acid-induced esophagobronchial-cardiac reflexes in humans.Gastroenterology. 1990;99:71-73.
Fischer A, McGregor GP, Saria A, Philippin B, Kummer W. Induction of tachykinin gene and peptide expression in guinea pig nodose primary afferent neurons by allergic airway inflammation.J Clin Invest. 1996;98:2284-2291.
Vincent D, Cohen-Jonathan AM, Leport J, Merrouche M, Geronimi A, Pradalier A, Soulé JC. Gastro-oesophageal reflux prevalence and relationship with bronchial reactivity in asthma.Eur Respir J. 1997;10:2255-2259.
Cuttitta G, Cibella F, Visconti A, Scichilone N, Bellia V, Bonsignore G. Spontaneous gastroesophageal reflux and airway patency during the night in adult asthmatics.Am J Respir Crit Care Med. 2000;161:177-181.
Tuchman DN, Boyle JT, Pack AI, Scwartz J, Kokonos M, Spitzer AR, Cohen S. Comparison of airway responses following tracheal or esophageal acidification in the cat.Gastroenterology. 1984;87:872-881.
Jack CI, Calverley PM, Donnelly RJ, Tran J, Russell G, Hind CR, Evans CC. Simultaneous tracheal and oesophageal pH measurements in asthmatic patients with gastro-oesophageal reflux.Thorax. 1995;50:201-204.
Harding SM. GERD, airway disease, and the mechanisms of interaction.Lung biology in health and disease, volume 129: gastroesophageal disease and airway disease. New York: Marcel Dekker; 1999;139-178.
Nagel RA, Brown P, Perks WH, Wilson RS, Kerr GD. Ambulatory pH monitoring of gastro-oesophageal reflux in "morning dipper" asthmatics.BMJ. 1988;297:1371-1373.
Sontag SJ, O'Connell S, Khandelwal S, Miller T, Nemchausky B, Schnell TG, Serlovsky R. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy.Gastroenterology. 1990;99:613-620.
Kiljander TO, Salomaa ER, Hietanen EK, Terho EO. Gastroesophageal reflux in asthmatics: A double-blind, placebo-controlled crossover study with omeprazole.Chest. 1999;116:1257-1264.
Ford GA, Oliver PS, Prior JS, Butland RJ, Wilkinson SP. Omeprazole in the treatment of asthmatics with nocturnal symptoms and gastro-oesophageal reflux: a placebo-controlled cross-over study.Postgrad Med J. 1994;70:350-354.
Meier JH, McNally PR, Punja M, Freeman SR, Sudduth RH, Stocker N, Perry M, Spaulding HS. Does omeprazole (Prilosec) improve respiratory function in asthmatics with gastroesophageal reflux? A double-blind, placebo-controlled crossover study.Dig Dis Sci. 1994;39:2127-2133.
Teichtahl H, Kronborg IJ, Yeomans ND, Robinson P. Adult asthma and gastro-oesophageal reflux: the effects of omeprazole therapy on asthma.Aust N Z J Med. 1996;26:671-676.
Levin TR, Sperling RM, McQuaid KR. Omeprazole improves peak expiratory flow rate and quality of life in asthmatics with gastroesophageal reflux.Am J Gastroenterol. 1998;93:1060-1063.
Boeree MJ, Peters FT, Postma DS, Kleibeuker JH. No effects of high-dose omeprazole in patients with severe airway hyperresponsiveness and (a)symptomatic gastro-oesophageal reflux.Eur Respir J. 1998;11:1070-1074.
Harmanci E, Entok E, Metintas M, Vardareli E, Elbek O. Gastroesophageal reflux in the patients with asthma.Allergol Immunopathol (Madr). 2001;29:123-128.
Jiang SP, Liang RY, Zeng ZY, Liu QL, Liang YK, Li JG. Effects of antireflux treatment on bronchial hyper-responsiveness and lung function in asthmatic patients with gastroesophageal reflux disease.World J Gastroenterol. 2003;9:1123-1125.
Calabrese C, Fabbri A, Areni A, Scialpi C, Zahlane D, Di Febo G. Asthma and gastroesophageal reflux disease: effect of long-term pantoprazole therapy.World J Gastroenterol. 2005;11:7657-7660.
Kiljander TO, Harding SM, Field SK, Stein MR, Nelson HS, Ekelund J, Illueca M, Beckman O, Sostek MB. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial.Am J Respir Crit Care Med. 2006;173:1091-1097.
Littner MR, Leung FW, Ballard ED, Huang B, Samra NK. Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms.Chest. 2005;128:1128-1135.
Gopal B, Singhal P, Gaur SN. Gastroesophageal reflux disease in bronchial asthma and the response to omeprazole.Asian Pac J Allergy Immunol. 2005;23:29-34.
Eryuksel E, Dogan M, Golabi P, Sehitoglu MA, Celikel T. Treatment of laryngopharyngeal reflux improves asthma symptoms in asthmatics.J Asthma. 2006;43:539-542.
Field SK, Sutherland LR. Does medical antireflux therapy improve asthma in asthmatics with gastroesophageal reflux?: a critical review of the literature.Chest. 1998;114:275-283.
Ayres JG, Campbell LM. A controlled assessment of an asthma self-management plan involving a budesonide dose regimen. OPTIONS Research Group.Eur Respir J. 1996;9:886-892.
Robinson DS, Campbell D, Barnes PJ. Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial.Lancet. 2001;357:2007-2011.
Pauwels RA, Löfdahl CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, Ullman A. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group.N Engl J Med. 1997;337:1405-1411.
Harding SM, Richter JE, Guzzo MR, Schan CA, Alexander RW, Bradley LA. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome.Am J Med. 1996;100:395-405.
Gibson PG, Henry RL, Coughlan JL. Gastro-oesophageal reflux treatment for asthma in adults and children.Cochrane Database Syst Rev. 2000;CD001496.
Harding SM. Gastroesophageal reflux: a potential asthma trigger.Immunol Allergy Clin North Am. 2005;25:131-148.
Tytgat GN, Janssens J, Reynolds JC, Wienbeck M. Update on the pathophysiology and management of gastro-oesophageal reflux disease: the role of prokinetic therapy.Eur J Gastroenterol Hepatol. 1996;8:603-611.
Blum AL, Adami B, Bouzo MH, Brandstätter G, Fumagalli I, Galmiche JP, Hebbeln H, Hentschel E, Hüttemann W, SChütz E. Effect of cisapride on relapse of esophagitis. A multinational, placebo-controlled trial in patients healed with an antisecretory drug. The Italian Eurocis Trialists.Dig Dis Sci. 1993;38:551-560.
McCallum RW, Fink SM, Winnan GR, Avella J, Callachan C. Metoclopramide in gastroesophageal reflux disease: rationale for its use and results of a double-blind trial.Am J Gastroenterol. 1984;79:165-172.
Takahashi T, Kurosawa S, Wiley JW, Owyang C. Mechanism for the gastrokinetic action of domperidone. In vitro studies in guinea pigs.Gastroenterology. 1991;101:703-710.
De Loore I, Van Ravensteyn H, Ameryckx L. Domperidone drops in the symptomatic treatment of chronic paediatric vomiting and regurgitation. A comparison with metoclopramide.Postgrad Med J. 1979;55 Suppl 1:40-42.
Vigneri S, Termini R, Leandro G, Badalamenti S, Pantalena M, Savarino V, Di Mario F, Battaglia G, Mela GS, Pilotto A. A comparison of five maintenance therapies for reflux esophagitis.N Engl J Med. 1995;333:1106-1110.
Sekiguchi T, Nishioka T, Matsuzaki T, Sugiyama M, Kusano M, Horikoshi T, Toki M, Ohwada T, Kobayashi S. Comparative efficacy of acid reflux inhibition by drug therapy in reflux esophagitis.Gastroenterol Jpn. 1991;26:137-144.