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

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. bhavneesh@hotmail.com

Telephone: +1-718-2405000  Fax: +1-718-2406344

Received: 2007-01-17          Accepted: 2007-01-31

Abstract

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.

� 2007 The WJG Press. All rights reserved.

Key words: Asthma; reflux; Gastroesophageal reflux disease; antireflux therapy; prokinetic; omeprazole

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

http://www.wjgnet.com/1007-9327/13/1706.asp

INTRODUCTION

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^[1]. Various mechanisms contributing to GERD exacerbating asthma include a vagus-mediated reflex^[2], a local axonal reflex^[3], 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^[11].

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^[25] 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^[19]. 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

Patients

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 mg 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%^[26]. 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.

Study design

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^[30].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 mg 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.

Statistical analysis

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.

RESULTS

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).

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 mg and fluticasone propionate 250 mg 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.

DISCUSSION

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^[19] 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^[20] 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^[21] 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^[22] 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^[23] 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^[24] 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^[25]. 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^[31]. 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^[32]. 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^[33].

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^[34]. Cisapride (10 mg twice daily or 20 mg at bedtime) also prevents relapses in patients with mild esophagitis^[35]. Studies using metoclopramide also showed an improvement in reflux symptoms compared to placebo using metoclopramide 10 mg four times a d^[36]. 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^[37]. In a randomized, double-blind, controlled trial conducted in pediatric population, dom caused a significant reduction in vomiting compared to metoclopramide and placebo^[38]. 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)^[39]. However, Sekiguchi et al found that cisapride often actually exacerbated acid reflux in another study^[40]. 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.

REFERENCES

1      Richter JE. Gastroesophageal reflux disease and asthma: the two are directly related. Am J Med 2000; 108 Suppl 4a:
  153S-158S   PubMed

2      Wright RA, Miller SA, Corsello BF. Acid-induced esophagobronchial-cardiac reflexes in humans. Gastroenterology 1990;
  99: 71-73   PubMed

3      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   PubMed

4      Vincent D, Cohen-Jonathan AM, Leport J, Merrouche M, Geronimi A, Pradalier A, Soule JC. Gastro-oesophageal reflux
  prevalence and relationship with bronchial reactivity in asthma. Eur Respir J 1997; 10: 2255-2259   PubMed

5      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   PubMed

6      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   PubMed

7      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   PubMed

8      Harding SM. GERD, airway disease, and the mechanisms of interaction. In: Stein MR. Lung biology in health and
  disease, volume 129: gastroesophageal disease and airway disease. New York: Marcel Dekker, 1999: 139-178

9      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   PubMed

10    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   PubMed

11    Harding SM, Guzzo MR, Richter JE. 24-h esophageal pH testing in asthmatics: respiratory symptom correlation with
  esophageal acid events. Chest 1999; 115: 654-659   PubMed

12    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   PubMed

13    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
  PubMed

14    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   PubMed

15    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   PubMed

16    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   PubMed

17    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   PubMed

18    Harmanci E, Entok E, Metintas M, Vardareli E, Elbek O. Gastroesophageal reflux in the patients with asthma. Allergol
  Immunopathol (Madr) 2001; 29: 123-128   PubMed

19    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

        PubMed

20    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   PubMed

21    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   PubMed

22   Littner MR, Leung FW, Ballard ED 2nd, 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   PubMed

23    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   PubMed

24    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   PubMed

25    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   PubMed

26   Jamieson JR, Stein HJ, DeMeester TR, Bonavina L, Schwizer W, Hinder RA, Albertucci M. Ambulatory 24-h esophageal
 pH monitoring: normal values, optimal thresholds, specificity, sensitivity, and reproducibility. Am J Gastroenterol 1992;
 87: 1102-1111   PubMed

27    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   PubMed

28   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   PubMed

29    Pauwels RA, Lofdahl 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   PubMed

30    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   PubMed

31    Gibson PG, Henry RL, Coughlan JL. Gastro-oesophageal reflux treatment for asthma in adults and children. Cochrane
  Database Syst Rev 2000; : CD001496   PubMed

32    Harding SM. Gastroesophageal reflux: a potential asthma trigger. Immunol Allergy Clin North Am 2005; 25: 131-148

        PubMed

33    Mehta DI. Importance of non-acid reflux in asthma in children. Available
  from:http://clinicaltrials.gov/show/NCT00200980

34    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   PubMed

35    Blum AL, Adami B, Bouzo MH, Brandstatter G, Fumagalli I, Galmiche JP, Hebbeln H, Hentschel E, Huttemann W, SChutz
  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   PubMed

36    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   PubMed

37    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   PubMed

38    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   PubMed

39    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   PubMed

40    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

        PubMed

S- Editor  Wang J    L- Editor  Rampone B    E-Editor Chin GJ