Research Article

Randomized controlled trial of effectiveness of lafutidine versus in uninvestigated dyspepsia

Somnath Maity, Supriyo Choudhury1, Avijit Hazra, Amal Kanti Das

ABSTRACT

Objectives: Lafutidine is a new H2-blocker in India claimed to be more potent and

effective than existing H2-blockers. Proton pump inhibitors (PPIs), by virtue of their

mechanism of action, have greater effi cacy than H2-blockers in suppression.

However, clinical trials comparing H2-blockers directly with PPIs are limited. We carried out a head-to-head comparison of the effectiveness of lafutidine versus the PPI pantoprazole in uninvestigated dyspepsia [CTRI/2013/12/004261]. Materials and Methods: A prospective, open label, randomized, controlled trial was conducted in a tertiary care hospital. Ambulatory adult patients with dyspepsia, not Departments of Pharmacology, Institute of Postgraduate Medical yet subjected to endoscopy, were recruited if they had at least moderately severe Education and Research, Kolkata, symptoms, defi ned as a score of ≥ 4 on a 7-point Global Overall Symptom (GOS) 1Pharmacology, College of Scale. Those with alarm features or signifi cant comorbidity were excluded. Subjects Medicine and Sagore Dutta received either once daily lafutidine 10 mg or pantoprazole 40 mg, orally, for 8 weeks. Hospital, Kolkata, West Bengal, Refl ux, dysmotility and pain scores were assessed by Modifi ed Frequency Scale for the India Symptoms of Gastroesophageal Refl ux Disease (mFSSGERD), and quality of life (QoL) by SF-8 scale. The latter had physical and mental components summarized by physical RReceived:eceived: 27-04-2014 component summary score (PCS) and a mental component summary score (MCS). RRevised:evised: 25-06-2014 Results: Of 122 patients enrolled, data of 57 on lafutidine and 60 on pantoprazole AAccepted:ccepted: 31-07-2014 were analyzed. At 4 weeks, proportion of subjects responding (GOS score ≤ 2) in the CCorrespondenceorrespondence to:to: two arms (lafutidine 45.61% vs. pantoprazole 48.33%, P = 0.854) or showing symptom Dr. Avijit Hazra, resolution (GOS score ≤ 1) (lafutidine 12.28% vs. pantoprazole 5.00%; P = 0.197) were E-mail: [email protected] comparable. Similarly at 8 weeks, both responder (lafutidine 52.63% vs. pantoprazole 56.67%; P = 0.712) and symptom resolution proportions (lafutidine 33.33% vs. pantoprazole 30%; P = 0.843) were comparable. Total score on mFSSGERD scale, as well as all its three component scores, and PCS and MCS scores on QoL SF-8 scale showed improvement but no statistically signifi cant difference between the two arms. Tolerability of both drugs was excellent. Conclusions: Lafutidine is well-tolerated and there is no clinically worthwhile difference between the two drugs in the empirical treatment of uninvestigated dyspepsia.

KKEYEY WWORDS:ORDS: Dyspepsia, lafutidine, pantoprazole, randomized controlled trial

Introduction represents a symptom cluster rather than a diagnosis. The first influential definition was the 1988 Working Party classification[1] Dyspepsia is a common problem. The term refers to symptoms arising from the upper gastrointestinal tract and that stated that dyspepsia includes any symptom referable to the upper gastrointestinal tract; symptoms need to be present for at AAccessccess thisthis articlearticle onlineonline least 4 weeks and include upper abdominal pain or discomfort, QQuickuick ResponseResponse Code:Code: heartburn, acid reflux, and . It subdivided WWebsite:ebsite: www.ijp-online.com dyspepsia patients, on the basis of symptom patterns, into DDOI:OI: 10.4103/0253-7613.140580 ‘ulcer-like’ (epigastric pain), ‘reflux-like’ (heartburn and acid regurgitation), ‘dysmotility-like’ (bloating and nausea) and ‘unclassifiable’ categories. In India, dyspepsia is more prevalent in metropolitan cities where it is reported by almost one-third of the population.[2] Uninvestigated dyspepsia

498 Indian Journal of Pharmacology | October 2014 | Vol 46 | Issue 5 Maity, et al.: Lafutidine versus pantoprazole in uninvestigated dyspepsia describes patients matching the 1988 Working Party definition , or other ulcer healing agents within of dyspepsia who have not yet undergone endoscopic 15 days prior to enrollment (but not antacids), concomitant investigation.[3] Empirical therapy with antacids, antisecretory use of psychotropic drugs and history of alcohol or substance and prokinetic agents has long been the approach for most abuse were other exclusion criteria. primary care physicians in the initial management of patients Subjects were randomized (simple balanced randomization with uninvestigated dyspepsia.[4,5] by computer generated list) to two groups of 61 subjects

Lafutidine is the newest H2 receptor antagonist to each. One group received tablet lafutidine 10 mg (brand used be introduced in India. It suppresses both daytime and LAFAXID-10, marketed by M/s Zuventus Pharmaceuticals, nighttime acid secretion through reversible H2 receptor Mumbai) while the other received tablet pantoprazole antagonism and can provide effective symptom relief in 40 mg (brand used PAN-40, marketed by M/s Alkem gastroesophageal reflux disease at single daily doses.[6] It has Laboratories, Mumbai). Both drugs were administered as a additional mucoprotective effect that is independent of its acid single daily morning dose before breakfast for 8 weeks. Each antisecretory activity. A recent study has reported that improved subject underwent one follow-up study visit at 4 weeks following mucosal host-defense via capsaicin-sensitive afferent nerves commencement of trial medication and the treatment concluded may contribute to the therapeutic action of lafutidine.[7] The at 8 weeks. protective effects may be the result of activation of capsaicin The primary efficacy variable was GOS Scale score which sensitive calcitonin gene related peptide (CGRP)[8,9] which is obtained by a validated 7-point Likert scale.[11] Subjects produces nitric oxide (NO) in endothelial cells. NO participates were asked to rate the overall severity of their dyspepsia in the regulation of gastric mucosal blood flow through symptoms during the previous one month on following 7 vasodilatation in the gastric microvasculature.[10] CGRP released points: (1) no problem, (2) minimal problem (can be easily from afferent neurons in the gastric mucosa stimulates D cells ignored without effort), (3) mild problem (can be ignored in the antral and fundic glands and increases with effort), (4) moderate problem (cannot be ignored but secretion from D cells. Somatostatin inhibits gastric acid does not influence daily activities), (5) moderately severe secretion, acting directly on somatostatin receptors on parietal problem (cannot be ignored and occasionally limits daily cells and indirectly by decreasing gastrin from antral G cells. activities), (6) severe problem (cannot be ignored and often Pantoprazole is a proton pump inhibitor (PPI) widely used limits concentration on daily activities) and (7) very severe in India. There are few published reports on head-to-head problem (cannot be ignored, markedly limits daily activities comparison between pantoprazole and H2-receptor blockers and often requires rest). Subjects achieving overall severity in general and pantoprazole and lafutidine in particular. We score ≤ 2 in this scale were considered as responders and therefore sought to compare the effectiveness of lafutidine those achieving score of ≤ 1 were considered as having versus pantoprazole in uninvestigated dyspepsia. attained symptom resolution. Secondary efficacy measures used were the Modified Materials and Methods Frequency Scale for the Symptoms of Gastroesophageal The study was designed as a single center, prospective, Reflux Disease (mFSSGERD)[12] and Quality of Life (QOL) as parallel group, open label, randomized controlled trial. measured by short form-8 (SF-8) questionnaire scores.[13] The It has been registered with Clinical Trials Registry mFSSGERD scale provided total score (Q-T), reflux score (Q-R), India [CTRI/2013/12/004261]. dyspepsia score (Q-D) and pain score (Q-P). The SF-8 was After obtaining institutional ethics committee approval, divisible into a physical component summary score (PCS) patients of either sex, aged between 18–55 years, attending and a mental component summary score (MCS). Variation the outpatient clinic in General Medicine in a teaching Hospital between pre- and post-treatment scores were compared in in Kolkata with a complaint of dyspepsia were screened both the groups. between June 2011–May 2012. Patients symptomatic for at Safety was evaluated at each visit by thorough history least 1 month with moderate-to-severe symptoms (score ≥ 4 and clinical examination. Complaints of the patient as well on the 7-point Global Overall Symptoms [GOS] scale) were as adverse events noted by the investigators were recorded included after obtaining written informed consent. Pregnant or as treatment emergent adverse events. In addition, routine lactating women, patients with alarm features (unintentional blood counts and tests of hepatorenal function were done at weight loss, recurrent vomiting, dysphagia, hemetemesis, baseline and at study end. Compliance with study medication melena, fever, jaundice, or anemia), history of any serious was assessed by the traditional pill count method. (including peptic ulcers, malignancy, The sample size was calculated to detect a difference of esophageal dysmotility, a previous endoscopic diagnosis 25% in the responder rate (assuming the rate to be 50% in the of erosive gastroesophagitis or Barrett’s esophagus), control arm and 75% in the test drug arm) with 80% power gastrointestinal surgery within 30 days, or history of angina and 5% probability of type 1 error. This returned a requirement pectoris, were excluded. Patients who showed laboratory of 58 subjects per arm. Keeping a margin of 5% for dropouts, test abnormalities [hemoglobin < 9.5 g/dL, total leukocyte the recruitment target was set at 61 subjects per arm. The count < 3000/μL, platelet count < 75000/μL, aspartate modified intention to treat approach was used during analysis; aminotransferase (AST) or alanine aminotransferase (ALT) >120 IU/L, data of all patients presenting for at least one post-baseline creatinine > 1.5 mg/dL] were also excluded. Treatment visit were included. Numerical variables were compared with non-steroidal anti-inflammatory drugs (NSAIDs), between groups by Student’s unpaired t-test, if normally

H2-receptor blockers, proton pump inhibitors, prokinetic agents, distributed, and by Mann-Whitney U-test, if otherwise.

Indian Journal of Pharmacology | October 2014 | Vol 46 | Issue 5 499 Maity, et al.: Lafutidine versus pantoprazole in uninvestigated dyspepsia

Categorical variables, such as the proportion of responders Only few adverse events were encountered during the and proportion attaining symptom resolution, were compared study. Two patients in lafutidine arm complained of transient between groups by Fisher’s exact test. Median mFSSGERD and one in the pantoprazole arm complained of and QoL scores over time were assessed for statistically headache. All recorded adverse events were mild and settled significant change by Friedman’s analysis of variance (ANOVA) spontaneously. Laboratory parameters (data not shown) did with Dunn’s multiple comparison test as post hoc test. All not show any statistically significant changes in either group. analyses were two-tailed and P < 0.05 was considered Hospitalizations or other serious adverse events were not statistically significant. Statistica version 6 [Tulsa, Oklahoma: encountered during the study. Adherence was excellent for StatSoft Inc., 2001] and GraphPad Prism version 4 [San Diego, over 90% subjects in both study arms, as assessed at the California: GraphPad Software Inc., 2005] software were used final visit. for analysis. Discussion Results The pathophysiology of uninvestigated dyspepsia is Of the 61 patients randomized to each of the two groups, complex and diverse group of diseases present with upper 57 on lafutidine and 60 on pantoprazole were considered gastrointestinal complaints. The impact on QoL varies with analyzable. Figure 1 shows the flow of patients during the study. a proportion of subjects showing marked deterioration. As seen from Table 1, demography and baseline characteristics In this study we evaluated the overall dyspepsia problem were comparable in the two groups. over 8 weeks (by GOS scale) as well as different groups of At the end of both week 4 and week 8 after commencement symptoms (by mFSSGERD). The GOS scale is a validated of treatment [Figure 2], there was no statistically significant outcome measure and has been used successfully in the difference in the proportion of responders between the two Canadian Adult Dyspepsia Empiric Treatment (CADET ) Clinical treatment groups (week 4: lafutidine 45.61% vs. pantoprazole Trials Program. In the validation of the GOS study, it has 48.33%, P = 0.854; week 8: lafutidine 52.63% vs. pantoprazole been shown that a change in GOS from ≥ 4–≤2 is rated as 56.67%; P = 0.712). The proportion of subjects showing clinically important by patients.[11] The mFSSGERD scale used symptom resolution [Figure 3] were also comparable at in this study is also a validated scale and has been employed both week 4 (lafutidine 12.28% vs. pantoprazole 5.00%; successfully to assess different symptom groups in earlier P = 0.197) and week 8 (lafutidine 33.33% vs. pantoprazole studies.[12] Further, both physical and mental dimensions of 30%; P = 0.843). QoL were measured and compared between the groups using Patients in both the treatment groups showed significant a standardized instrument.[13] reduction in symptom scores over 4 and 8 weeks in mFSSGERD A meta-analysis evaluating the efficacy of H2-receptor scale (reflux symptoms, dysmotility symptoms and pain symptoms) antagonist in non-ulcer functional dyspepsia has shown [14] and improvement in both physical and mental component that H2-blockers are superior to placebo. PPIs are subscores on the QoL SF-8 scale [Table 2 and Figure 4]. In both the more potent inhibitors of gastric acid secretion than arms, symptom relief on all components of the mFSSGERD scale the H2-receptor antagonists and give better results in were noted at 4 weeks. There was further reduction at 8 weeks, acid-peptic disorders, including better patient satisfaction.[15,16] although the changes from fourth to eight week were mostly not Most clinicians acknowledge the advantage of PPIs over significant statistically. Significant QoL improvement was also seen H2-receptor antagonists, because the former exert stronger at 4 weeks and this was sustained at 8 weeks. and longer acid suppression than the latter.[17] Clinical trials comparing a PPI (e.g. , ) with a

Figure 1: Flow of patients in the two study arms H2-receptor antagonist (e.g. , ) demonstrate

Assessed for eligibility 156 Excluded: 34 Figure 2: Responder rate at 4 weeks and 8 weeks after starting (Not meeting eligibility treatment (White bar = Lafutidine, Grey bar = Pantoprazole) criteria: 30 Unwilling to attend as per 60 56.67% Randomized 122 schedule: 4) 52.63% 48.33% 45.61%

BASELINE BASELINE Received Lafutidine: 61 Received Pantoprazole: 61 40

WEEK 4 WEEK 4 Came for follow-up visit: 57 Came for follow-up visit: 60 Lost to follow-up: 4 Lost to follow-up: 1 20

WEEK 8 WEEK 8 Responder rate (%) Completed the study: 56 Completed the study: 59 Further lost to follow-up: 1 Further lost to follow-up: 1

Analyzed: 57 Analyzed: 60 0 Completed the study: 56 Completed the study: 59 4 weeks 8 weeks Satisfied modified ITT criteria: 1 Satisfied modified ITT criteria: 1 (p = 0.854) (p = 0.712)

500 Indian Journal of Pharmacology | October 2014 | Vol 46 | Issue 5 Maity, et al.: Lafutidine versus pantoprazole in uninvestigated dyspepsia superiority of PPI over the latter in dyspepsia. However, in the capsaicin-sensitive afferent neurons and stimulates the release current study, the results suggest that lafutidine is as effective of CGRP which, in turn, inhibits acid secretion and stimulates as pantoprazole in uninvestigated dyspepsia. Both appeared mucosal blood flow.[9,10] In addition to gastroesophageal to alleviate all three groups of dyspeptic symptoms (viz. reflux reflux disease, clinical trials have reported lafutidine to be symptoms, pain and dysmotility symptoms) over the 8 weeks effective in eradication[19] and prevention treatment period and both drugs had excellent tolerance. of non-steroidal anti-inflammatory drug (NSAID) induced Although pantoprazole inhibits the final common pathway of ulceration.[20] Our experience is in conformity with an earlier acid secretion, lafutidine, the new H2 receptor antagonist was study which suggests that both lafutidine and comparable in effectiveness. This can possibly be explained by provide symptom relief and are adequate empiric therapy in the potent and long-lasting action of lafutidine on the human patients with heartburn-dominant uninvestigated dyspepsia.[21] H receptor and potential additional mechanisms of 2 In our case, the study cohort included patients with heartburn [8,18] action of lafutidine. Gastroprotective effect of Lafutidine as well as other kinds of dyspeptic symptoms. We did not is independent of its acid antisecretory activity. It activates encounter any published reports of head-to-head comparison of lafutidine and pantoprazole. Table 1: This study had its share of limitations. Blinding could Baseline demographic and clinical summary of the study not be achieved as we depended on commercially available subjects products and failed to find brands with tablets closely matching. Dyspepsia of different symptom groups (that is predominant Lafutidine Pantoprazole P value (n=57) (n=60) ‘ulcer-like’, ‘reflux-like’ and ‘dysmotility-like’) have not been Gender (Male: 33 (57.9%): 36 (60.0%): 0.852 compared in the this study. The observation period was limited Female) 24 (42.1%) 24 (40.0%) to 8 weeks. Further, rebound dyspepsia after withdrawal of Age (year) 36.5±11.23 35.6±10.18 0.617 study drug was not assessed. Weight (kg) 61.4±9.75 59.8±10.52 0.396 Notwithstanding these limitations, we can conclude that GOS score 4 (4-5) 4 (4-5) 0.550 there is no clinically worthwhile difference between the two mFSSGERD Q-T 16 (15-18) 17 (15-19) 0.426 drugs in the empirical treatment of uninvestigated dyspepsia, at mFSSGERD Q-R 8 (7-9) 8 (7.5-9.5) 0.920 least in the relatively short term. Further studies are needed to mFSSGERD Q-D 6 (5-8) 6 (6-8) 0.462 assess comparative effectiveness in other kinds of acid-peptic mFSSGERD Q-P 1 (1-2) 1 (1-3) 0.785 disorders, such as and NSAID gastropathy, SF-8 PCS score 40 (39-44) 40 (38-42) 0.305 as well as effects upon long-term treatment. SF-8 MCS score 42 (40-44) 42 (38-44) 0.558 Abbreviations: GOS=Global overall symptoms Scale; Q-T=mFSSGERD Acknowledgements (Modifi ed Frequency Scale for the Symptoms of Gastroesophageal Refl ux Disease) total score; Q-R=mFSSGERD Refl ux Score; Q-D=mFSSGERD The authors are grateful to Prof. Tapas Das, Former Head, Dept. Dyspepsia Score; Q-P=mFSSGERD Pain Score; SF-8 PCS=Quality of life of General Medicine, IPGME&R, Kolkata, for his encouragement and SF-8 Physical component summary; SF-8 MCS=Quality of life SF-8 Mental Component Summary permission to access patients in his department. We are also thank Prof. Values are stated as mean±standard deviation or median (Interquartile range). Pradip Kumar Mitra, Director, IPGME&R, for enabling the necessary Counts are provided for gender distribution. logistical support for the study. P values in the last column are from intergroup comparison by Fisher’s exact test (for gender), Student’s independent samples t test (for age and weight) or Mann-Whitney U test (for other variables) Figure 4: Changes in Quality of Life Short Form 8 (SF-8) scores in the study groups (PCS = physical component summary; MCS = mental component summary).*** indicates P< 0.001 in comparison Figure 3: Proportion showing symptom resolution at 4 weeks and 8 to corresponding pre-treatment score. (White box = Lafutidine, Grey weeks (White bar = Lafutidine, Grey bar = Pantoprazole) box = Pantoprazole)

50 65 *** 60 *** 40 *** 55 33.33% *** 30.00% 50 30 45 SCORE 20 40 12.28% 35 10 Resolution of symptoms of Resolution (%) 5.00% 30

0 25 4 weeks 8 weeks pre post pre post (p = 0.197) (p = 0.843) PCS MCS

Indian Journal of Pharmacology | October 2014 | Vol 46 | Issue 5 501 Maity, et al.: Lafutidine versus pantoprazole in uninvestigated dyspepsia

Table 2:

Response to treatment in the study groups over time

Scores Lafutidine (n=57) Pantoprazole (n=60) Baseline 4 weeks 8 weeks P value Baseline 4 weeks 8 weeks P value (post-hoc) (post-hoc) GOS score 4 (4-5) 3 (2-3) 2 (1-3) <0.001 vs. BL 4 (4-5) 3 (2-4) 2 (1-3) <0.001 vs. BL NS 4 w vs. 8 w <0.05 4 w vs 8 w mFSSGERD Q-T 16 (15-18) 8 (5-12) 6 (0-10) <0.001 vs. BL 16 (15-19) 8 (5-12) 6 (0-10) <0.001 vs. BL NS 4 w vs. 8 w <0.001 4 w vs 8 w mFSSGERD Q-R 8 (7-9) 4 (2-6) 3 (0-5) <0.001 vs. BL 8 (6.5-9.5) 4 (2.5-5.5) 3 (0-5) <0.001 vs. BL NS 4 w vs. 8 w NS 4 w vs 8 w mFSSGERD Q-D 6 (5-8) 4 (2-5) 3 (0-5) <0.001 vs. BL 6 (6-8) 4 (3-5) 3 (0-5) <0.001 vs. BL NS 4 w vs. 8 w NS 4 w vs 8 w mFSSGERD Q-P 1 (1-2) 1 (0-1) 0 (0-1) <0.001 vs. BL 1 (1-3) 0 (0-1) 0 (0-0) <0.001 vs. BL NS 4 w vs. 8 w NS 4 w vs 8 w SF-8 PCS score 42 (40-44) 46 (44-48) 46 (45-50) <0.001 vs. BL 42 (38-44) 45 (44-47) 47 (44-50) <0.001 vs. BL NS 4 w vs. 8 w NS 4 w vs 8 w SF-8 MCS score 40 (39-44) 46 (44-49) 47 (45-51) <0.001 vs. BL 40 (38-42) 45.5 (43.5-48) 48 (45-51) <0.001 vs. BL NS 4 w vs. 8 w <0.01 4 w vs. 8 w Abbreviations: GOS=Global overall symptoms scale; Q-T=mFSSGERD (Modifi ed Frequency Scale for the Symptoms of Gastroesophageal Refl ux Disease) Total Score; Q-R=mFSSGERD Refl ux Score; Q-D=mFSSGERD Dyspepsia Score; Q-P=mFSSGERD Pain Score; SF-8 PCS=Quality of Life SF-8 Physical Component Summary; SF-8 MCS=Quality of Life SF-8 Mental Component Summary; BL=baseline; NS=Not signifi cant; vs.=Versus; w=Week Values are stated as Median (Interquartile range). P values in the table have been obtained from Friedman’s analysis of variance and Dunn’s Multiple Comparison test as post hoc test

References participating in the Central Louisiana Medication Access Program (CMAP). Qual Life Res 2005;14:665-73. 1. Colin-Jones DG, Bloom B, Boderner G. Management of dyspepsia: Report of a 14. Redstone HA, Barrowman N, Veldhuyzen Van Zanten SJ. H2-receptor antagonists working party. Lancet 1988;331:576-9. in the treatment of functional (nonulcer) dyspepsia: A meta-analysis of randomized 2. Shah SS, Bhatia SJ, Mistry FP. Epidemiology of dyspepsia in the general controlled clinical trials. Aliment Pharmacol Ther 2001;15:1291-9. population in Mumbai. Indian J Gastroenterol 2001;20:103-6. 15. Hansen AN, Bergheim R, Fagertun H, Lund H, Wiklund I, Moum B. Long-term 3. Mahadeva S, Goh KL. Epidemiology of functional dyspepsia: A global perspective. management of patients with symptoms of gastro-oesophageal refl ux disease – a World J Gastroenterol 2006;12:2661-6. Norwegian randomised prospective study comparing the effects of 4. Jones MP. Evaluation and treatment of dyspepsia. Postgrad Med J 2003;79:25-9. and ranitidine treatment strategies on health-related quality of life in a general 5. Talley NJ. Dyspepsia: Management guidelines for the millennium. Gut practitioners setting. Int J Clin Pract 2006;60:15-22. 2002;50:72-8. 16. Jeong HY, Lee BS, Sung JK, Lee TY, Yoon SJ, Kim SJ, et al. A randomized, 6. Nakano M, Ajioka H, Abe M, Kiniwa M. Possible involvement of host defense prospective, comparative, multicenter study of rabeprazole and ranitidine in the mechanism in the suppression of rat acute refl ux esophagitis by the particular treatment of refl ux esophagitis. Korean J Gastroenterol 2006;47:15-21. histamine H receptor antagonist lafutidine. Pharmacology 2012;90:205-11. 2 17. Prichard PJ, Yeomans ND, Mihaly GW, Jones DB, Smallwood RA, Louis WJ. 7. Inamori M, Iida H, Hosono K, Endo H, Sakamoto Y, Takahashi H, et al. The Effect of daily oral omeprazole on 24 hour intragastric acidity. J Br Med (Clin Res histamine H receptor antagonist lafutidine in Japanese patients with non-erosive 2 Ed) 1983;287:1378-9. refl ux disease. Hepatogastroenterology 2010;57:1430-4. 18. Nakano M, Kitano S, Nanri M, Kiniwa M. Lafutidine, a unique histamine 8. Fukushima Y, Otsuka H, Ishikawa M, Asano T, Anai M, Katsube T, et al. Potent H2-receptor antagonist, inhibits distention-induced gastric acid secretion through and long-lasting action of lafutidine on the human histamine H receptor. Digestion 2 an H2 receptor-independent mechanism. Eur J Pharmacol 2011;658:236-41. 2001;64:155-60. 19. Kudo T, Fujinami H, Ando T, Nishikawa J, Ogawa K, Hosokawa A, et al. 9. Shimatani T, Inoue M, Kuroiwa T, Xu J, Nakamura M, Tazuma S, et al. Comparison of lafutidine and rabeprazole in 7-day second-line amoxicillin- and Lafutidine, a newly developed antiulcer drug, elevates postprandial intragastric metronidazole-containing triple therapy for Helicobacter pylori: A pilot study. pH and increases plasma calcitonin gene-related peptide and somatostatin Helicobacter 2012;17:277-81. concentrations in humans: Comparisons with . Dig Dis Sci 20. Kato M, Kamada G, Yamamoto K, Nishida U, Imai A, Yoshida T, et al. 2006;51:114-20. Lafutidine prevents low-dose aspirin and loxoprofen induced gastric injury: 10. Itoh H, Naito T, Takeyama M. Lafutidine changes levels of somatostatin, A randomized, double-blinded, placebo controlled study. J Gastroenterol Hepatol calcitonin gene-related peptide, and secretin in human plasma. Biol Pharm Bull 2010;25:1631-5. 2002;25:379-82. 21. Dewan B, Philipose N. Lafutidine 10 mg versus rabeprazole 20 mg in the 11. Veldhuyzen van Zanten SJ, Chiba N, Armstrong D, Barkuns AN, Thomson AB, treatment of patients with heartburn-dominant uninvestigated dyspepsia: Mann V, et al. Validation of a 7-point global overall symptom scale to measure A randomized, multicentric trial. Gastroenterol Res Pract 2011;Epub 2011 May 5; the severity of dyspepsia symptoms in clinical trials. Aliment Pharmacol Ther doi: 10.1155/2011/640685. 2006;23:521-9. 12. Nagahara A, Asaoka D, Hojo M, Oguro M, Shimada Y, Ishikawa D, et al. Observational comparative trial of the effi cacy of proton pump inhibitors versus Cite this article as: Maity S, Choudhury S, Hazra A, Das AK. Randomized histamine-2 receptor antagonists for uninvestigated dyspepsia. J Gastroenterol controlled trial of effectiveness of lafutidine versus pantoprazole in Hepatol 2010;25 Suppl 1:S122-8. uninvestigated dyspepsia. Indian J Pharmacol 2014;46:498-502. 13. Lefante JJ Jr, Harmon GN, Ashby KM, Barnard D, Webber LS. Use of the SF-8 to assess health-related quality of life for a chronically ill, low-income population Source of Support: Nil. Confl ict of Interest: None.

502 Indian Journal of Pharmacology | October 2014 | Vol 46 | Issue 5 Copyright of Indian Journal of Pharmacology is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.