Gastroesophageal reflux disease (GERD), a common disorder with troublesome symptoms caused by reflux of gastric contents into the esophagus, has adverse impact on quality of life. A variety of medications have been used in GERD treatment, and acid suppression therapy is the mainstay of treatment for GERD. Although proton pump inhibitor is the most potent acid suppressant and provides good efficacy in esophagitis healing and symptom relief, about one-third of patients with GERD still have persistent symptoms with poor response to standard dose PPI. Antacids, alginate, histamine type-2 receptor antagonists, and prokinetic agents are usually used as add-on therapy to PPI in clinical practice. Development of novel therapeutic agents has focused on the underlying mechanisms of GERD, such as transient lower esophageal sphincter relaxation, motility disorder, mucosal protection, and esophageal hypersensitivity. Newer formulations of PPI with faster and longer duration of action and potassium-competitive acid blocker, a newer acid suppressant, have also been investigated in clinical trials. In this review, we summarize the current and developing therapeutic agents for GERD treatment. 1. Introduction Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder in the general population, and its prevalence is increasing worldwide [1]. According to the Montreal definition, GERD is diagnosed when the reflux of stomach contents causes troublesome symptoms and/or complications [2], and it is the most common outpatient gastrointestinal disease diagnosed in USA [3]. Reflux from stomach causes symptoms like heartburn and regurgitation, which are the cardinal symptoms of GERD, and other symptoms, such as chest pain, asthma, hoarseness, and sleep disturbance, are also considered as atypical or extraesophageal symptoms of GERD [4]. Troublesome symptoms of GERD have adverse impact on health-related quality of life (HRQL) [5], and patients with more frequent or more severe symptoms have lower HRQL, work productivity, and sleep quality [5, 6]. Chronic reflux is also an important risk factor of esophageal adenocarcinoma [7]. There are many factors contributing to GERD, including transient lower esophageal sphincter relaxation (TLESR), reduced LES pressure, impaired esophageal mucosal defense, poor esophageal clearance, visceral hypersensitivity, hiatal hernia, and delayed gastric emptying, and TLESRs is the predominant mechanism of reflux formation [8]. Obesity is an independent risk factor for development of GERD and is also associated with its complications,
References
[1]
H. B. El-Serag, “Time trends of gastroesophageal reflux disease: a systematic review,” Clinical Gastroenterology and Hepatology, vol. 5, no. 1, pp. 17–26, 2007.
[2]
N. Vakil, S. V. Van Zanten, P. Kahrilas et al., “The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus,” American Journal of Gastroenterology, vol. 101, no. 8, pp. 1900–1943, 2006.
[3]
A. F. Peery, E. S. Dellon, J. Lund et al., “Burden of gastrointestinal disease in the United States: 2012 update,” Gastroenterology, vol. 143, no. 5, pp. 1179–1187.
[4]
I. M. Modlin and S. F. Moss, “Symptom evaluation in gastroesophageal reflux disease,” Journal of Clinical Gastroenterology, vol. 42, no. 5, pp. 558–563, 2008.
[5]
P. Wahlqvist, M. Karlsson, D. Johnson, J. Carlsson, S. C. Bolge, and M. A. Wallander, “Relationship between symptom load of gastro-oesophageal reflux disease and health-related quality of life, work productivity, resource utilization and concomitant diseases: survey of a US cohort,” Alimentary Pharmacology and Therapeutics, vol. 27, no. 10, pp. 960–970, 2008.
[6]
J. Tack, A. Becher, C. Mulligan, and D. A. Johnson, “Systematic review: the burden of disruptive gastro-oesophageal reflux disease on health-related quality of life,” Alimentary Pharmacology and Therapeutics, vol. 35, no. 11, pp. 1257–1266, 2012.
[7]
J. Lagergren, R. Bergstr？m, A. Lindgren, and O. Nyrén, “Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma,” New England Journal of Medicine, vol. 340, no. 11, pp. 825–831, 1999.
[8]
G. E. E. Boeckxstaens, “Review article: the pathophysiology of gastro-oesophageal reflux disease,” Alimentary Pharmacology and Therapeutics, vol. 26, no. 2, pp. 149–160, 2007.
[9]
H. B. El-Serag, D. Y. Graham, J. A. Satia, and L. Rabeneck, “Obesity is an independent risk factor for GERD symptoms and erosive esophagitis,” American Journal of Gastroenterology, vol. 100, no. 6, pp. 1243–1250, 2005.
[10]
A. M. Ryan, M. Duong, L. Healy et al., “Obesity, metabolic syndrome and esophageal adenocarcinoma: epidemiology, etiology and new targets,” Cancer Epidemiology, vol. 35, no. 4, pp. 309–319, 2011.
[11]
K. E. L. McColl, A. Clarke, and J. Seenan, “Acid pocket, hiatus hernia and acid reflux,” Gut, vol. 59, no. 4, pp. 430–431, 2010.
[12]
G. E. Boeckxstaens, “Alterations confined to the gastro-oesophageal junction: the relationship between low LOSP, TLOSRs, hiatus hernia and acid pocket,” Best Practice and Research: Clinical Gastroenterology, vol. 24, no. 6, pp. 821–829, 2010.
[13]
Y. C. Chua and Q. Aziz, “Perception of gastro-oesophageal reflux,” Best Practice and Research: Clinical Gastroenterology, vol. 24, no. 6, pp. 883–891, 2010.
[14]
R. Carlsson, J. Dent, R. Watts et al., “Gastro-oesophageal reflux disease in primary care: an international study of different treatment strategies with omeprazole. International GORD Study Group,” European Journal of Gastroenterology and Hepatology, vol. 10, no. 2, pp. 119–124, 1998.
[15]
J. M. Inadomi, L. McIntyre, L. Bernard, and A. M. Fendrick, “Step-down from multiple- to single-dose proton pump inhibitors (PPIs): a prospective study of patients with heartburn or acid regurgitation completely relieved with PPIs,” American Journal of Gastroenterology, vol. 98, no. 9, pp. 1940–1944, 2003.
[16]
J. Behar, D. G. Sheahan, P. Biancani, H. M. Spiro, and E. H. Storer, “Medical and surgical management of reflux esophagitis. A 38 month report on a prospective clinical trial,” New England Journal of Medicine, vol. 293, no. 6, pp. 263–268, 1975.
[17]
K. G. Mandel, B. P. Daggy, D. A. Brodie, and H. I. Jacoby, “Review article: alginate-raft formulations in the treatment of heartburn and acid reflux,” Alimentary Pharmacology and Therapeutics, vol. 14, no. 6, pp. 669–690, 2000.
[18]
M. A. Kwiatek, S. Roman, A. Fareeduddin, J. E. Pandolfino, and P. J. Kahrilas, “An alginate-antacid formulation (Gaviscon Double Action Liquid) can eliminate or displace the postprandial 'acid pocket' in symptomatic GERD patients,” Alimentary Pharmacology and Therapeutics, vol. 34, no. 1, pp. 59–66, 2011.
[19]
P. W. Dettmar, J. Sykes, S. L. Little, and J. Bryan, “Rapid onset of effect of sodium alginate on gastro-oesophageal reflux compared with ranitidine and omeprazole, and relationship between symptoms and reflux episodes,” International Journal of Clinical Practice, vol. 60, no. 3, pp. 275–283, 2006.
[20]
I. R. Lai, M. S. Wu, and J. T. Lin, “Prospective, randomized, and active controlled study of the efficacy of alginic acid and antacid in the treatment of patients with endoscopy-negative reflux disease,” World Journal of Gastroenterology, vol. 12, no. 5, pp. 747–754, 2006.
[21]
P. Woodland, C. Lee, Y. Duraysami, R. Farre, P. Dettmar, and D. Sifrim, “Assessment and protection of esophageal mucosal integrity in patients with heartburn without esophagitis,” American Journal of Gastroenterology, vol. 108, no. 4, pp. 535–543, 2013.
[22]
V. Strugala, J. Avis, I. G. Jolliffe, L. M. Johnstone, and P. W. Dettmar, “The role of an alginate suspension on pepsin and bile acids—key aggressors in the gastric refluxate. Does this have implications for the treatment of gastro-oesophageal reflux disease?” Journal of Pharmacy and Pharmacology, vol. 61, no. 8, pp. 1021–1028, 2009.
[23]
D. Pouchain, M. A. Bigard, F. Liard, M. Childs, A. Decaudin, and D. McVey, “Gaviscon versus omeprazole in symptomatic treatment of moderate gastroesophageal reflux. A direct comparative randomised trial,” BMC Gastroenterology, vol. 12, article 18, 2012.
[24]
H. L. Smart and M. Atkinson, “Comparison of a dimethicone/antacid (Asilone gel) with an alginate/antacid (Gaviscon liquid) in the management of reflux oesophagitis,” Journal of the Royal Society of Medicine, vol. 83, no. 9, pp. 554–556, 1990.
[25]
N. Manabe, K. Haruma, M. Ito et al., “Efficacy of adding sodium alginate to omeprazole in patients with nonerosive reflux disease: a randomized clinical trial,” Diseases of the Esophagus, vol. 25, no. 5, pp. 373–380, 2012.
[26]
D. M. McCarthy, “Drug therapy: sucralfate,” New England Journal of Medicine, vol. 325, no. 14, pp. 1017–1025, 1991.
[27]
B. Simon and P. Mueller, “Comparison of the effect of sucralfate and ranitidine in reflux esophagitis,” American Journal of Medicine, vol. 83, no. 3, pp. 43–47, 1987.
[28]
B. Simon, G. P. Ravelli, and H. Goffin, “Sucralfate gel versus placebo in patients with non-erosive gastro-oesophageal reflux disease,” Alimentary Pharmacology and Therapeutics, vol. 10, no. 3, pp. 441–446, 1996.
[29]
R. A. R. Ali and L. J. Egan, “Gastroesophageal reflux disease in pregnancy,” Best Practice and Research: Clinical Gastroenterology, vol. 21, no. 5, pp. 793–806, 2007.
[30]
D. G. Colin-Jones, “The role and limitations of H2-receptor antagonists in the treatment of gastro-oesophageal reflux disease,” Alimentary Pharmacology and Therapeutics, vol. 9, supplement 1, pp. 9–14, 1995.
[31]
M. Khan, J. Santana, C. Donnellan, C. Preston, and P. Moayyedi, “Medical treatments in the short term management of reflux oesophagitis,” Cochrane Database of Systematic Reviews, no. 2, Article ID CD003244, 2007.
[32]
B. van Pinxteren, K. E. Sigterman, P. Bonis, J. Lau, and M. E. Numans, “Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease,” Cochrane Database of Systematic Reviews, no. 11, Article ID CD002095, 2010.
[33]
R. Tutuian, P. O. Katz, and D. O. Castell, “Nocturnal acid breakthrough: pH, drugs and bugs,” European Journal of Gastroenterology and Hepatology, vol. 16, no. 5, pp. 441–443, 2004.
[34]
I. Mainie, R. Tutuian, and D. O. Castell, “Addition of a H2 receptor antagonist to PPI improves acid control and decreases nocturnal acid breakthrough,” Journal of Clinical Gastroenterology, vol. 42, no. 6, pp. 676–679, 2008.
[35]
A. Rackoff, A. Agrawal, A. Hila, I. Mainie, R. Tutuian, and D. O. Castell, “Histamine-2 receptor antagonists at night improve gastroesophageal reflux disease symptoms for patients on proton pump inhibitor therapy,” Diseases of the Esophagus, vol. 18, no. 6, pp. 370–373, 2005.
[36]
T. Tran, A. M. Lowry, and H. B. El-Serag, “Meta-analysis: the efficacy of over-the-counter gastro-oesophageal reflux disease therapies,” Alimentary Pharmacology and Therapeutics, vol. 25, no. 2, pp. 143–153, 2007.
[37]
N. Chiba, C. J. De Gara, J. M. Wilkinson, and R. H. Hunt, “Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis,” Gastroenterology, vol. 112, no. 6, pp. 1798–1810, 1997.
[38]
Y. Habu, K. Maeda, T. Kusuda et al., ““Proton-pump inhibitor-first” strategy versus “step-up” strategy for the acute treatment of reflux esophagitis: a cost-effectiveness analysis in Japan,” Journal of Gastroenterology, vol. 40, no. 11, pp. 1029–1035, 2005.
[39]
W. H. Wang, J. Q. Huang, G. F. Zheng et al., “Head-to-head comparison of H2-receptor antagonists and proton pump inhibitors in the treatment of erosive esophagitis: a meta-analysis,” World Journal of Gastroenterology, vol. 11, no. 26, pp. 4067–4077, 2005.
[40]
K. R. DeVault and D. O. Castell, “Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease,” American Journal of Gastroenterology, vol. 100, no. 1, pp. 190–200, 2005.
[41]
S. Ip, M. Chung, D. Moorthy et al., “Comparative effectiveness of management strategies for gastroesophageal reflux disease: update [internet],” 2011, http://www.ncbi.nlm.nih.gov/pubmed/22091471.
[42]
“Gastroesophageal reflux disease: drug therapy,” Revista da Associacao Medica Brasileira, vol. 57, no. 6, pp. 617–628, 2011.
[43]
A. S. Raghunath, A. P. S. Hungin, J. Mason, and W. Jackson, “Symptoms in patients on long-term proton pump inhibitors: prevalence and predictors,” Alimentary Pharmacology and Therapeutics, vol. 29, no. 4, pp. 431–439, 2009.
[44]
R. Fass, “Proton-pump inhibitor therapy in patients with gastro-oesophageal reflux disease: putative mechanisms of failure,” Drugs, vol. 67, no. 11, pp. 1521–1530, 2007.
[45]
D. Sifrim and F. Zerbib, “Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors,” Gut, vol. 61, no. 9, pp. 1340–1354, 2012.
[46]
J. P. Galmiche, S. Bruley Des Varannes, P. Ducrotté et al., “Tenatoprazole, a novel proton pump inhibitor with a prolonged plasma half-life: effects on intragastric pH and comparison with esomeprazole in healthy volunteers,” Alimentary Pharmacology and Therapeutics, vol. 19, no. 6, pp. 655–662, 2004.
[47]
R. H. Hunt, D. Armstrong, C. James et al., “Effect on intragastric pH of a PPI with a prolonged plasma half-life: comparison between tenatoprazole and esomeprazole on the duration of acid suppression in healthy male volunteers,” American Journal of Gastroenterology, vol. 100, no. 9, pp. 1949–1956, 2005.
[48]
R. H. Hunt, D. Armstrong, M. Yaghoobi, and C. James, “The pharmacodynamics and pharmacokinetics of S-tenatoprazole-Na 30 mg, 60 mg and 90 mg versus esomeprazole 40 mg in healthy male subjects,” Alimentary Pharmacology and Therapeutics, vol. 31, no. 6, pp. 648–657, 2010.
[49]
D. C. Metz, M. Vakily, T. Dixit, and D. Mulford, “Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy,” Alimentary Pharmacology and Therapeutics, vol. 29, no. 9, pp. 928–937, 2009.
[50]
C. R. Emerson and N. Marzella, “Dexlansoprazole: a proton pump inhibitor with a dual delayed-release system,” Clinical Therapeutics, vol. 32, no. 9, pp. 1578–1596, 2010.
[51]
T. Hershcovici, L. K. Jha, and R. Fass, “Dexlansoprazole MR—a review,” Annals of Medicine, vol. 43, no. 5, pp. 366–374, 2011.
[52]
R. D. Lee, M. Vakily, D. Mulford, J. Wu, and S. N. Atkinson, “Clinical trial: the effect and timing of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR, a novel Dual Delayed Release formulation of a proton pump inhibitor—evidence for dosing flexibility,” Alimentary Pharmacology and Therapeutics, vol. 29, no. 8, pp. 824–833, 2009.
[53]
R. Fass, D. A. Johnson, W. C. Orr et al., “The effect of dexlansoprazole MR on nocturnal heartburn and GERD-related sleep disturbances in patients with symptomatic GERD,” American Journal of Gastroenterology, vol. 106, no. 3, pp. 421–431, 2011.
[54]
A. L. Frelinger, R. D. Lee, D. J. Mulford et al., “A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers,” Journal of the American College of Cardiology, vol. 59, no. 14, pp. 1304–1311, 2012.
[55]
R. Fass, J. Inadomi, C. Han, R. Mody, J. O'Neil, and M. C. Perez, “Maintenance of heartburn relief after step-down from twice-daily proton pump inhibitor to once-daily dexlansoprazole modified release,” Clinical Gastroenterology and Hepatology, vol. 10, no. 3, pp. 247–253, 2012.
[56]
C. W. Howden, “Review article: immediate-release proton-pump inhibitor therapy—potential advantages,” Alimentary Pharmacology and Therapeutics, vol. 22, no. 3, pp. 25–30, 2005.
[57]
P. O. Katz, F. K. Koch, E. D. Ballard et al., “Comparison of the effects of immediate-release omeprazole oral suspension, delayed-release lansoprazole capsules and delayed-release esomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients with night-time GERD symptoms,” Alimentary Pharmacology and Therapeutics, vol. 25, no. 2, pp. 197–205, 2007.
[58]
C. W. Howden, E. D. Ballard, F. K. Koch, T. C. Gautille, and R. G. Bagin, “Control of 24-hour intragastric acidity with morning dosing of immediate-release and delayed-release proton pump inhibitors in patients with GERD,” Journal of Clinical Gastroenterology, vol. 43, no. 4, pp. 323–326, 2009.
[59]
R. Banerjee, D. N. Reddy, N. M. Guda et al., “Oral buffered esomeprazole is superior to i.v. pantoprazole for rapid rise of intragastric pH: a wireless pH metry analysis,” Journal of Gastroenterology and Hepatology, vol. 25, no. 1, pp. 43–47, 2010.
[60]
G. Morelli, H. Chen, G. Rossiter, B. Rege, and Y. Lu, “An open-label, parallel, multiple-dose study comparing the pharmacokinetics and gastric acid suppression of rabeprazole extended-release with esomeprazole 40 mg and rabeprazole delayed-release 20 mg in healthy volunteers,” Alimentary Pharmacology and Therapeutics, vol. 33, no. 7, pp. 845–854, 2011.
[61]
L. Laine, P. O. Katz, D. A. Johnson et al., “Randomised clinical trial: a novel rabeprazole extended release 50 mg formulation versus esomeprazole 40 mg in healing of moderate-to-severe erosive oesophagitis—the results of two double-blind studies,” Alimentary Pharmacology and Therapeutics, vol. 33, no. 2, pp. 203–212, 2011.
[62]
Y. Chowers, T. Atarot, V. S. Pratha, and R. Fass, “The effect of once daily omeprazole and succinic acid (VECAM) vs once daily omeprazole on 24-h intragastric pH,” Neurogastroenterology and Motility, vol. 24, no. 5, pp. 426–431, 2012.
[63]
J. J. Heidelbaugh, D. C. Metz, and Y. X. Yang, “Proton pump inhibitors: are they overutilised in clinical practice and do they pose significant risk?” International Journal of Clinical Practice, vol. 66, no. 6, pp. 582–591, 2012.
[64]
N. Vakil, “Prescribing proton pump inhibitors: is it time to pause and rethink?” Drugs, vol. 72, no. 4, pp. 437–445, 2012.
[65]
K. S. Yu, K. S. Bae, J. H. Shon et al., “Pharmacokinetic and pharmacodynamic evaluation of a novel proton pump inhibitor, YH1885, in healthy volunteers,” Journal of Clinical Pharmacology, vol. 44, no. 1, pp. 73–82, 2004.
[66]
W. A. Simon, M. Herrmann, T. Klein et al., “Soraprazan: setting new standards in inhibition of gastric acid secretion,” Journal of Pharmacology and Experimental Therapeutics, vol. 321, no. 3, pp. 866–874, 2007.
[67]
K. Gedda, C. Briving, K. Svensson, I. Maxvall, and K. Andersson, “Mechanism of action of AZD0865, a K+-competitive inhibitor of gastric H+,K+-ATPase,” Biochemical Pharmacology, vol. 73, no. 2, pp. 198–205, 2007.
[68]
P. J. Kahrilas, J. Dent, K. Lauritsen et al., “A Randomized, comparative study of three doses of AZD0865 and esomeprazole for healing of reflux esophagitis,” Clinical Gastroenterology and Hepatology, vol. 5, no. 12, pp. 1385–1391, 2007.
[69]
J. Dent, P. J. Kahrilas, J. Hatlebakk et al., “A randomized, comparative trial of a potassium-competitive acid blocker (AZD0865) and esomeprazole for the treatment of patients with nonerosive reflux disease,” American Journal of Gastroenterology, vol. 103, no. 1, pp. 20–26, 2008.
[70]
J. Matsukawa, Y. Hori, H. Nishida, M. Kajino, and N. Inatomi, “A comparative study on the modes of action of TAK-438, a novel potassium-competitive acid blocker, and lansoprazole in primary cultured rabbit gastric glands,” Biochemical Pharmacology, vol. 81, no. 9, pp. 1145–1151, 2011.
[71]
Y. Hori, J. Matsukawa, T. Takeuchi, H. Nishida, M. Kajino, and N. Inatomi, “A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animals,” Journal of Pharmacology and Experimental Therapeutics, vol. 337, no. 3, pp. 797–804, 2011.
[72]
Y. Arikawa, H. Nishida, O. Kurasawa et al., “Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin e fumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB),” Journal of Medicinal Chemistry, vol. 55, no. 9, pp. 4446–4456, 2012.
[73]
D. Sifrim, R. Holloway, J. Silny, J. Tack, A. Lerut, and J. Janssens, “Composition of the postprandial refluxate in patients with gastroesophageal reflux disease,” American Journal of Gastroenterology, vol. 96, no. 3, pp. 647–655, 2001.
[74]
T. Hershcovici, H. Mashimo, and R. Fass, “The lower esophageal sphincter,” Neurogastroenterology and Motility, vol. 23, no. 9, pp. 819–830, 2011.
[75]
F. Zerbib, “Medical treatment of GORD. Emerging therapeutic targets and concepts,” Best Practice and Research: Clinical Gastroenterology, vol. 24, no. 6, pp. 937–946, 2010.
[76]
C. M. McDermott, T. P. Abrahams, E. Partosoedarso et al., “Site of action of GABAB receptor for vagal motor control of the lower esophageal sphincter in ferrets and rats,” Gastroenterology, vol. 120, no. 7, pp. 1749–1762, 2001.
[77]
A. Lehmann, M. Antonsson, M. Bremner-Danielsen, M. Flardh, L. Hansson-Branden, and L. Karrberg, “Activation of the GABA(B) receptor inhibits transient lower esophageal sphincter relaxations in dogs,” Gastroenterology, vol. 117, no. 5, pp. 1147–1154, 1999.
[78]
I. Lidums, A. Lehmann, H. Checklin, J. Dent, and R. H. Holloway, “Control of transient lower esophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in normal subjects,” Gastroenterology, vol. 118, no. 1, pp. 7–13, 2000.
[79]
L. Cange, E. Johnsson, H. Rydholm et al., “Baclofen-mediated gastro-oesophageal acid reflux control in patients with established reflux disease,” Alimentary Pharmacology and Therapeutics, vol. 16, no. 5, pp. 869–873, 2002.
[80]
Q. Zhang, A. Lehmann, R. Rigda, J. Dent, and R. H. Holloway, “Control of transient lower oesophageal sphincter relaxations and reflux by the GABAB agonist baclofen in patients with gastro-oesophageal reflux disease,” Gut, vol. 50, no. 1, pp. 19–24, 2002.
[81]
M. A. Van Herwaarden, M. Samsom, H. Rydholm, and A. J. P. M. Smout, “The effect of baclofen on gastro-oesophageal reflux, lower oesophageal sphincter function and reflux symptoms in patients with reflux disease,” Alimentary Pharmacology and Therapeutics, vol. 16, no. 9, pp. 1655–1662, 2002.
[82]
M. F. Vela, R. Tutuian, P. O. Katz, and D. O. Castell, “Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH,” Alimentary Pharmacology and Therapeutics, vol. 17, no. 2, pp. 243–251, 2003.
[83]
G. H. Koek, D. Sifrim, T. Lerut, J. Janssens, and J. Tack, “Effect of the GABAB agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors,” Gut, vol. 52, no. 10, pp. 1397–1402, 2003.
[84]
W. C. Orr, S. Goodrich, S. Wright, K. Shepherd, and M. Mellow, “The effect of baclofen on nocturnal gastroesophageal reflux and measures of sleep quality: a randomized, cross-over trial,” Neurogastroenterology and Motility, vol. 24, no. 6, pp. 553–559, 2012.
[85]
X. Xu, Q. Chen, S. Liang, H. Lu, and Z. Qiu, “Successful resolution of refractory chronic cough induced by gastroesophageal reflux with treatment of baclofen,” Cough, vol. 8, no. 1, article 8, 2012.
[86]
R. Lal, J. Sukbuntherng, E. H. L. Tai et al., “Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen,” Journal of Pharmacology and Experimental Therapeutics, vol. 330, no. 3, pp. 911–921, 2009.
[87]
L. B. Gerson, F. J. Huff, A. Hila et al., “Arbaclofen placarbil decreases postprandial reflux in patients with gastroesophageal reflux disease,” American Journal of Gastroenterology, vol. 105, no. 6, pp. 1266–1275, 2010.
[88]
N. B. Vakil, F. J. Huff, A. Bian, D. S. Jones, and D. Stamler, “Arbaclofen placarbil in GERD: a randomized, double-blind, placebo-controlled study,” American Journal of Gastroenterology, vol. 106, no. 8, pp. 1427–1438, 2011.
[89]
G. E. Boeckxstaens, H. Rydholm, A. Lei, J. Adler, and M. Ruth, “Effect of lesogaberan, a novel GABAB-receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects,” Alimentary Pharmacology and Therapeutics, vol. 31, no. 11, pp. 1208–1217, 2010.
[90]
G. E. Boeckxstaens, H. Beaumont, V. Mertens et al., “Effects of lesogaberan on reflux and lower esophageal sphincter function in patients with gastroesophageal reflux disease,” Gastroenterology, vol. 139, no. 2, pp. 409–417, 2010.
[91]
G. E. Boeckxstaens, H. Beaumont, J. G. Hatlebakk et al., “A novel reflux inhibitor lesogaberan (AZD3355) as add-on treatment in patients with GORD with persistent reflux symptoms despite proton pump inhibitor therapy: a randomised placebo-controlled trial,” Gut, vol. 60, no. 9, pp. 1182–1188, 2011.
[92]
N. J. Shaheen, H. Denison, K. Bjorck, M. Karlsson, and D. G. Silberg, “Efficacy and safety of lesogaberan in gastro-oesophageal reflux disease: a randomised controlled trial,” Gut, 2012.
[93]
C. L. Frisby, J. P. Mattsson, J. M. Jensen, A. Lehmann, J. Dent, and L. A. Blackshaw, “Inhibition of transient lower esophageal sphincter relaxation and gastroesophageal reflux by metabotropic glutamate receptor ligands,” Gastroenterology, vol. 129, no. 3, pp. 995–1004, 2005.
[94]
C. Keywood, M. Wakefield, and J. Tack, “A proof-of-concept study evaluating the effect of ADX10059, a metabotropic glutamate receptor-5 negative allosteric modulator, on acid exposure and symptoms in gastro-oesophageal reflux disease,” Gut, vol. 58, no. 9, pp. 1192–1199, 2009.
[95]
F. Zerbib, C. Keywood, and G. Strabach, “Efficacy, tolerability and pharmacokinetics of a modified release formulation of ADX10059, a negative allosteric modulator of metabotropic glutamate receptor 5: an esophageal pH-impedance study in healthy subjects,” Neurogastroenterology and Motility, vol. 22, no. 8, pp. 859–865, 2010.
[96]
F. Zerbib, S. Bruley Des Varannes, S. Roman et al., “Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease,” Alimentary Pharmacology and Therapeutics, vol. 33, no. 8, pp. 911–921, 2011.
[97]
W. O. Rohof, A. Lei, D. P. Hirsch et al., “The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers,” Alimentary Pharmacology and Therapeutics, vol. 35, no. 10, pp. 1231–1242, 2012.
[98]
D. Ang, K. Blondeau, D. Sifrim, and J. Tack, “The spectrum of motor function abnormalities in gastroesophageal reflux disease and barrett's esophagus,” Digestion, vol. 79, no. 3, pp. 158–168, 2009.
[99]
D. Armstrong and D. Sifrim, “New pharmacologic approaches in gastroesophageal reflux disease,” Gastroenterology Clinics of North America, vol. 39, no. 3, pp. 393–418, 2010.
[100]
M. P. Curran and D. M. Robinson, “Mosapride: in gastrointestinal disorders,” Drugs, vol. 68, no. 7, pp. 981–991, 2008.
[101]
K. Arai, Y. Takeuchi, H. Watanabe, A. Tsukurimichi, N. Uchida, and M. Imawari, “Prokinetics influence the pharmacokinetics of rabeprazole,” Digestion, vol. 78, no. 2-3, pp. 67–71, 2008.
[102]
H. Iida, M. Inamori, T. Fujii et al., “Early effect of oral administration of omeprazole with mosapride as compared with those of omeprazole alone on the intragastric pH,” BMC Gastroenterology, vol. 12, article 25, 2012.
[103]
Y. C. Hsu, T. H. Yang, W. L. Hsu et al., “Mosapride as an adjunct to lansoprazole for symptom relief of reflux oesophagitis,” British Journal of Clinical Pharmacology, vol. 70, no. 2, pp. 171–179, 2010.
[104]
H. Miwa, K. Inoue, K. Ashida et al., “Randomised clinical trial: efficacy of the addition of a prokinetic, mosapride citrate, to omeprazole in the treatment of patients with non-erosive reflux disease—a double-blind, placebo-controlled study,” Alimentary Pharmacology and Therapeutics, vol. 33, no. 3, pp. 323–332, 2011.
[105]
S. Futagami, K. Iwakiri, T. Shindo et al., “The prokinetic effect of mosapride citrate combined with omeprazole therapy improves clinical symptoms and gastric emptying in PPI-resistant NERD patients with delayed gastric emptying,” Journal of Gastroenterology, vol. 45, no. 4, pp. 413–421, 2010.
[106]
Y. K. Cho, M. G. Choi, E. Y. Park et al., “Effect of mosapride combined with esomeprazole improves esophageal peristaltic function in patients with gastroesophageal reflux disease: a study using high resolution manometry,” Digestive Diseases and Sciences, vol. 58, no. 4, pp. 1035–1041, 2013.
[107]
Y. S. Kim, T. H. Kim, C. S. Choi et al., “Effect of itopride, a new prokinetic, in patients with mild GERD: a pilot study,” World Journal of Gastroenterology, vol. 11, no. 27, pp. 4210–4214, 2005.
[108]
T. Nonaka, T. Kessoku, Y. Ogawa et al., “Does postprandial itopride intake affect the rate of gastric emptying?: a crossover study using the continuous real time13C breath test (BreathID system),” Hepato-Gastroenterology, vol. 58, no. 105, pp. 224–228, 2011.
[109]
P. Joshi, S. Bhoir, A. M. Bhagwat, K. Vishwanath, and R. K. Jadhav, “Identification of forced degradation products of itopride by LC-PDA and LC-MS,” Indian Journal of Pharmaceutical Sciences, vol. 73, no. 3, pp. 287–291, 2011.
[110]
W. F. Ezzat, S. A. Fawaz, H. Fathey, and A. El Demerdash, “Virtue of adding prokinetics to proton pump inhibitors in the treatment of laryngopharyngeal reflux disease: prospective study,” Journal of Otolaryngology, vol. 40, no. 4, pp. 350–356, 2011.
[111]
B. J. Chun and D. S. Lee, “The effect of itopride combined with lansoprazole in patients with laryngopharyngeal reflux disease,” European Archives of Oto-Rhino-Laryngology, vol. 270, no. 4, pp. 1385–1390, 2013.
[112]
H. Suzuki, J. M. Inadomi, and T. Hibi, “Japanese herbal medicine in functional gastrointestinal disorders,” Neurogastroenterology and Motility, vol. 21, no. 7, pp. 688–696, 2009.
[113]
H. Kawahara, A. Kubota, T. Hasegawa et al., “Effects of rikkunshito on the clinical symptoms and esophageal acid exposure in children with symptomatic gastroesophageal reflux,” Pediatric Surgery International, vol. 23, no. 10, pp. 1001–1005, 2007.
[114]
T. Morita, K. Furuta, K. Adachi et al., “Effects of rikkunshito (TJ-43) on esophageal motor function and gastroesophageal reflux,” Journal of Neurogastroenterology Motility, vol. 18, no. 2, pp. 181–186, 2012.
[115]
K. Tominaga, R. Iwakiri, K. Fujimoto et al., “Rikkunshito improves symptoms in PPI-refractory GERD patients: a prospective, randomized, multicenter trial in Japan,” Journal of Gastroenterology, vol. 47, no. 3, pp. 284–292, 2012.
[116]
Y. Araki, K. I. Mukaisho, Y. Fujiyama, T. Hattori, and H. Sugihara, “The herbal medicine rikkunshito exhibits strong and differential adsorption properties for bile salts,” Experimental and Therapeutic Medicine, vol. 3, no. 4, pp. 645–649, 2012.
[117]
R. Fass, M. Shapiro, R. Dekel, and J. Sewell, “Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease—where next?” Alimentary Pharmacology and Therapeutics, vol. 22, no. 2, pp. 79–94, 2005.
[118]
C. H. Knowles and Q. Aziz, “Visceral hypersensitivity in nonerosive reflux disease,” Gut, vol. 57, no. 5, pp. 674–683, 2008.
[119]
B. Nojkov, J. H. Rubenstein, S. A. Adlis et al., “The influence of co-morbid IBS and psychological distress on outcomes and quality of life following PPI therapy in patients with gastro-oesophageal reflux disease,” Alimentary Pharmacology and Therapeutics, vol. 27, no. 6, pp. 473–482, 2008.
[120]
R. Fass and D. Sifrim, “Management of heartburn not responding to proton pump inhibitors,” Gut, vol. 58, no. 2, pp. 295–309, 2009.
[121]
H. Lee, J. H. Kim, B. H. Min et al., “Efficacy of venlafaxine for symptomatic relief in young adult patients with functional chest pain: a randomized, double-blind, placebo-controlled, crossover trial,” American Journal of Gastroenterology, vol. 105, no. 7, pp. 1504–1512, 2010.
[122]
S. S. C. Rao, R. S. Mudipalli, J. M. Remes-Troche, C. L. Utech, and B. Zimmerman, “Theophylline improves esophageal chest pain—a randomized, placebo-controlled study,” American Journal of Gastroenterology, vol. 102, no. 5, pp. 930–938, 2007.
[123]
J. D. Brederson, P. R. Kym, and A. Szallasi, “Targeting TRP channels for pain relief,” European Journal of Pharmacology, 2013.
[124]
A. L. Krarup, L. Ny, M. ？strand et al., “Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain,” Alimentary Pharmacology and Therapeutics, vol. 33, no. 10, pp. 1113–1122, 2011.
[125]
A. L. Krarup, L. Ny, J. Gunnarsson et al., “Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive gastroesophageal reflux disease and a partial response to PPI treatment is not associated with analgesia to esophageal experimental pain,” Scandinavian Journal of Gastroenterology, vol. 48, no. 3, pp. 274–284, 2013.
[126]
R. Fass, “Therapeutic options for refractory gastroesophageal reflux disease,” Journal of Gastroenterology and Hepatology, vol. 27, supplement 3, pp. 3–7, 2012.
