A Randomized Phase III Clinical Trial of Plecanatide, a Uroguanylin Analog, in Patients With Chronic Idiopathic Constipation.

OBJECTIVES: This study assessed the efficacy and safety of plecanatide, a guanylate cyclase-C (GC-C) agonist and the first uroguanylin analog approved for the treatment of chronic idiopathic constipation (CIC). METHODS: This phase III, multicenter, double-blind, placebo-controlled study randomized 1,394 patients with CIC. Patients received either plecanatide (3 or 6 mg) or placebo, orally, once daily, for 12 weeks. The primary efficacy endpoint was the percentage of patients who were durable overall complete spontaneous bowel movement (CSBM) responders over the 12-week treatment period. Patients were instructed to record their daily bowel movements, stool consistency scores, and abdominal symptoms in an electronic diary. Treatment-emergent adverse events (AEs) were collected. RESULTS: Each dose of plecanatide resulted in a significantly greater percentage of durable overall CSBM responders (21.0%, 3 mg; 19.5%, 6 mg) as compared with placebo (10.2%; P<0.001 for both). Plecanatide (3 and 6 mg) also significantly increased mean weekly CSBM frequency from baseline (increase of 2.5 and 2.2/week, respectively) vs. placebo (1.2/week; P<0.001 for both) and mean weekly spontaneous bowel movement frequency (increase of 3.2 and 3.1/week, respectively) vs. placebo (1.3/week; P<0.001, for both) over the 12-week treatment period. Both plecanatide doses significantly improved all secondary and additional efficacy endpoints. The most common AE, diarrhea, occurred in 1.3% (placebo), 5.9% (3 mg) and 5.7% (6 mg) of patients. CONCLUSIONS: Plecanatide significantly improved constipation and its related symptoms with a low rate of adverse events. These results suggest that plecanatide will be a useful treatment option in the management of CIC. ClinicalTrials.gov: NCT01982240.

New pharmacological treatment options for irritable bowel syndrome with constipation.

INTRODUCTION: Constipation predominant irritable bowel syndrome (IBS-C) is a common disorder and accounts for a large number of ambulatory visits. Sensory abnormalities, that is, presence of abdominal pain and discomfort, distinguish IBS-C from chronic idiopathic constipation. AREA COVERED: This review focuses on the pharmacology, efficacy, safety, and future of prucalopride, YKP-10811, DSP-6952, dexloxiglumide, linaclotide, plecanatide, tenapanor, and elobixibat. EXPERT OPINION: It is now well established that treatment focusing only on bowel transit provides incomplete relief to patients with IBS-C. Improved understanding of pathophysiology of IBS-C has led to use of sensory end points like complete spontaneous bowel movements and the FDA combined end point (abdominal pain and complete spontaneous bowel movements) in clinical trials. A number of drugs are in development and provide hope for this challenging group of patients. However, because of recent failures secondary to ineffectiveness and/or adverse events, we cautiously await how clinical data play out in larger studies and in clinical practice.

Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: a randomized, placebo-controlled study.

BACKGROUND: The γ-aminobutyric acid type B-receptor agonist lesogaberan (AZD3355) has been developed for use in patients with gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy (partial responders). This study aimed to explore the dose-response effect of lesogaberan on reflux episodes in partial responders. METHODS: In this randomized, single-centre, double-blind, crossover, placebo-controlled study, partial responders taking optimised PPI therapy were given 30, 90, 120 and 240 mg doses of lesogaberan. Each dose was given twice (12 h apart) during a 24-h period, during which impedance-pH measurements were taken. RESULTS: Twenty-five patients were included in the efficacy analysis and 27 in the safety analysis. The effect of lesogaberan on the mean number of reflux episodes was dose-dependent, and all doses significantly reduced the mean number of reflux episodes relative to placebo. Lesogaberan also dose-dependently reduced the mean number of acid reflux episodes (except the 30 mg dose) and weakly acid reflux episodes (all doses) significantly, relative to placebo. Regardless of dose, lesogaberan had a similar effect on the percentage of time with esophageal pH < 4 [mean reduction: 68.5% (30 mg), 54.2% (90 mg), 65.9% (120 mg), 72.1% (240 mg); p < 0.05 except 90 mg dose]. No adverse events led to discontinuation and no serious adverse events occurred during active treatment. CONCLUSIONS: Lesogaberan inhibited reflux in a dose-dependent manner in partial responders taking optimised PPI therapy, and these effects were significant versus placebo. All lesogaberan doses were well tolerated and were not associated with clinically relevant adverse events. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01043185.

Influence of Demographic Factors on Clinical Outcomes in Adults With Chronic Idiopathic Constipation Treated With Plecanatide.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common condition that affects some patient groups more often. Demographic/clinical characteristics can differ in presentation and therapeutic response. The impact of these characteristics on plecanatide efficacy/safety was examined. METHODS: Data from 2 identically designed, randomized, phase 3 trials of adults with CIC receiving 3 mg of plecanatide, 6 mg of plecanatide, or placebo for 12 weeks were analyzed. Subgroups were baseline age, body mass index (BMI), race/ethnicity, and sex/gender. Endpoints included durable overall complete spontaneous bowel movement (CSBM) responder rate, weekly CSBMs and spontaneous bowel movements (SBMs), and adverse events. RESULTS: Overall (N = 2,639; 3 mg of plecanatide [n = 877]; 6 mg of plecanatide [n = 877]; and placebo [n = 885]), CSBM responder rates were significantly greater with 3 mg of plecanatide and 6 mg of plecanatide vs placebo in subgroups with those younger than 65 years ( P < 0.001), females ( P < 0.001), White individuals ( P < 0.001), and BMI <25 kg/m 2 ( P ≤ 0.004) and 25-30 kg/m 2 ( P < 0.001); as well, for 3 mg: 65 years or older ( P = 0.03), non-White individuals ( P < 0.001), and BMI ≥30 kg/m 2 ( P = 0.02). Improvement from baseline in weekly CSBM and SBM frequency occurred in all subgroups for both plecanatide doses vs placebo ( P ≤ 0.02) at week 12, except those aged 65 years or older for 6 mg of plecanatide. The most common adverse event was diarrhea (3 mg [4.9%]; 6 mg [5.4%]; and placebo [1.3%]). DISCUSSION: Pooled data from identically designed CIC trials strengthened the ability to identify meaningful subgroup comparisons regarding plecanatide efficacy and safety.

Long-term safety and effectiveness of lubiprostone, a chloride channel (ClC-2) activator, in patients with chronic idiopathic constipation.

BACKGROUND: Lubiprostone helps relieve constipation in short-term 4-week studies. There are limited data on long-term pharmacological treatment with lubiprostone for chronic idiopathic constipation. AIMS: To examine the long-term safety and effectiveness of lubiprostone in patients with chronic idiopathic constipation. METHODS: In this prospective, multicenter, open-labeled trial, 248 patients aged ≥18 years with chronic idiopathic constipation were directed to take lubiprostone 24 mcg BID as needed for 48 weeks. Patients were allowed to decrease the dose in response to the perceived severity of constipation and need for relief. Hematology and chemistry profiles and assessment of constipation symptoms and its severity were performed at all visits. Adverse events (AEs) were recorded. RESULTS: Of the 248 patients who entered the trial, 127 (51%) completed the trial. A dose reduction was observed in 17% of the patients, resulting in an average study medication exposure across the study of approximately 1.7 capsules (or approximately 40.8 mcg) per day. The most common treatment-related AEs were nausea (19.8%), diarrhea (9.7%), abdominal distension (6.9%), headache (6.9%), and abdominal pain (5.2%). No deaths were reported and of the 16 reported serious AEs, one was considered possibly treatment related. Average changes in serum electrolytes were not clinically relevant at any time point during the study. On average, lubiprostone significantly (p < 0.0001) reduced patient-reported constipation severity, abdominal bloating, and abdominal discomfort across 48 weeks when compared to baseline. CONCLUSIONS: During this 48-week open-label study, lubiprostone was well tolerated. Bowel symptoms consistently improved over 48 weeks in adult patients with chronic idiopathic constipation.

Plecanatide for the treatment of constipation-predominant irritable bowel syndrome.

Introduction: As an analogue of uroguanylin plecanatide binds to the Guanylate Cyclase-C receptor activating fluid and ion secretion in the small intestine with the same pH-dependent binding kinetics as the natural ligand. Plecanatide has been FDA approved as safe and effective for the indications of Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C).Areas covered: All clinical trial results supporting approval of plecanatide in IBS-C are reported, evaluated and interpreted in the context of the complex pathophysiology of functional diseases and the barriers that must be overcome for appropriate protocol design and conduct.Expert opinion: The Expert Opinion section discusses safety and efficacy of plecanatide for IBS-C. Broader consideration of some of the inherent challenges in understanding and treating functional gastrointestinal disorders includes: 1. the difficulty of understanding diseases with complex pathophysiology that clinically present with a few simple symptoms, 2. exploring the pathophysiology of functional diseases using pharmacophysiology, 3. value of 'Set Theory' in the evaluation of complex clinical data and 4. physiologic and pathophysiologic insight gained by evaluation 'physiologic redundancy' and 'conservation of function'.

Benefit-Risk Assessment of Plecanatide in the Treatment of Chronic Idiopathic Constipation.

Plecanatide, a uroguanylin analog, activates the guanylate cyclase C receptors in the epithelial lining of the gastrointestinal tract in a pH-dependent fashion initiating (1) the conversion of intracellular guanosine triphosphate to cyclic guanosine monophosphate, which increases the activity of the cystic fibrosis transmembrane conductance regulator to increase chloride and bicarbonate secretion into the intestinal lumen and (2) a decrease in activity of the sodium-hydrogen ion exchanger. The resulting ionic shifts cause an increase in lumenal fluid to facilitate digestion. Plecanatide has been approved by the FDA for use in chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation. This manuscript is a critical assessment of the therapeutic efficacy and potential risks associated with the use of plecanatide in CIC. The discussion of CIC as a clinical and investigative disorder focuses on the importance of this problem as well and the difficulties involved in clinical management and scholarly investigation of a symptom arising from multiple pathophysiologic mechanisms. Clinical data from studies of recently approved drugs for CIC are utilized to construct a platform for thoughtful understanding of CIC and of how changes in investigation guidelines influence the interpretation of study data and guide symptom management. Plecanatide is a safe and effective medication for the management of adults with CIC.

New developments in gastroesophageal reflux disease diagnosis and therapy.

PURPOSE OF REVIEW: Gastroesophageal reflux disease is a highly prevalent chronic condition in Western populations. It has a profound effect on our society in terms of economic cost and quality of life. There have been major advances in understanding of disease pathogenesis over the last few years which are summarized in this article. RECENT FINDINGS: With improved understanding of gastroesophageal reflux disease, newer developments in diagnostic techniques have evolved. The proton pump inhibitor test has been formally described as one of the initial diagnostic tests. Other new tests include multiple channel impedance monitoring, bilirubin reflux monitoring, Barostat measurements and intraluminal ultrasounds which, along with other newer technologies, are described in this review. SUMMARY: The mechanisms involved in the pathogenesis of gastroesophageal reflux disease are complex and multifactorial. The lower esophageal sphincter pressure, the motility of the esophageal body and the stomach, the composition of the reflux material and the sensitivity or resistance of the esophageal mucosa to the reflux material are important factors involved in the pathogenesis of disease-related symptoms and lesions. Based on our improving understanding, novel diagnostic tools are available to improve investigation of the disease.

Time esophageal pH < 4 overestimates the prevalence of pathologic esophageal reflux in subjects with gastroesophageal reflux disease treated with proton pump inhibitors.

BACKGROUND: A Stanford University study reported that in asymptomatic GERD patients who were being treated with a proton pump inhibitor (PPI), 50% had pathologic esophageal acid exposure. AIM: We considered the possibility that the high prevalence of pathologic esophageal reflux might simply have resulted from calculating acidity as time pH < 4. METHODS: We calculated integrated acidity and time pH < 4 from the 49 recordings of 24-hour gastric and esophageal pH from the Stanford study as well as from another study of 57 GERD subjects, 26 of whom were treated for 8 days with 20 mg omeprazole or 20 mg rabeprazole in a 2-way crossover fashion. RESULTS: The prevalence of pathologic 24-hour esophageal reflux in both studies was significantly higher when measured as time pH < 4 than when measured as integrated acidity. This difference was entirely attributable to a difference between the two measures during the nocturnal period. Nocturnal gastric acid breakthrough was not a useful predictor of pathologic nocturnal esophageal reflux. CONCLUSION: In GERD subjects treated with a PPI, measuring time esophageal pH < 4 will significantly overestimate the prevalence of pathologic esophageal acid exposure over 24 hours and during the nocturnal period.

Elobixibat, the first-in-class Ileal Bile Acid Transporter inhibitor, for the treatment of Chronic Idiopathic Constipation.

INTRODUCTION: Elobixibat is the first in class ileal bile acid transporter (IBAT) inhibitor. IBAT inhibitors block ileal absorption of bile acids by: (1) interrupting the enterohepatic circulation of bile resulting in a fall in serum cholesterol and (2) increasing the delivery of bile acids into the colon. Increasing colonic bile acids causes mucosal fluid secretion and enhances colonic motor activity. Changes in colonic physiology may be useful in treating constipation. Areas covered: In this review, the author reviews the prevalence and medical cost of Chronic Idiopathic Constipation (CIC) and the heterogeneity of the CIC patient population as a complicating factor in drug development and clinical care. He also reviews the history of Bile Acid cathartics and the complex pharmacophysiology of bile therapy with fluid and electrolyte shifts, colonic motor function changes and mucosal immunologic activation. Finally, the author reviews elobixabat development and the clinical trials that demonstrate improvement in constipation. Expert opinion: The early phases of elobixibat development provide confirmation of high IBAT binding affinity which translates into the expected inhibition of enterohepatic bile acid circulation and enhanced delivery of ileal bile acids to the colon associated with expected physiological changes. Elobixibat as a treatment of CIC appears promising.

Efficacy and safety of plecanatide in treating constipation predominant irritable bowel syndrome.

INTRODUCTION: Uroguanylin interacting with intestinal Guanylate Cyclase C (GC-C) receptors plays an important role in gastrointestinal fluid and electrolyte homeostasis. Plecanatide is the first uroguanylin analog that stimulates GC-C receptors on gastrointestinal mucosa with pH-sensitive receptor binding. Binding to the GC-C receptor activates intracellular conversion of GTP to cGMP resulting in the stimulation of intestinal fluid secretion. Areas covered: Herein, all published research regarding the development of and clinical experience with plecanatide is reviewed. Clinical study results in patients with Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C) are also reviewed. Success in the treatment of CIC and IBS-C is supported by beneficial effects on stool viscosity, Complete Spontaneous Bowel Movements and visceral sensation. Finally, the discussion within focuses on the importance of plecanatide in understanding the physiology of uroguanylin, the pathophysiology of IBS-C and the potential for development of uroguanylin and guanylin analogs. Expert opinion: Given this broad spectrum of potential activity for GC-C agonists, it would not be surprising to see that the use of agents such as plecanatide in new areas grow to a level even greater than the use for the present CIC and IBS-C indications.

Pilot, Randomized, Blinded, Placebo-Controlled Trial Investigating the Correlation Between Acid Control and Heartburn Relief with 14 Days of Esomeprazole Treatment.

INTRODUCTION: Reflux symptoms are frequently associated with esophageal acid exposure. However, other potential causes unrelated to acid secretion are possible, and the relationship between acid control and symptomatic improvement remains unclear. This study investigated the correlation between individual intragastric pH control and heartburn relief among subjects with frequent heartburn who are likely to self-treat with over-the-counter (OTC) medications. We hypothesized that improved acid control would provide greater symptomatic improvement among individuals representative of an OTC population. METHODS: This phase 4, single-center, randomized, double-blind, placebo-controlled study was conducted in subjects without diagnosed gastroesophageal reflux disease or other gastrointestinal conditions who were experiencing frequent heartburn (≥ 3 episodes/week; ≥ 2 nighttime episodes/week over past 30 days) that was responsive to treatment. Subjects entered a 7-day run-in phase, received placebo BID (before breakfast and dinner), and completed symptom diaries. During the treatment phase, subjects received esomeprazole 20 mg BID, esomeprazole 20 mg then placebo, or placebo BID. Subjects underwent 24-h intragastric pH monitoring at baseline and day 14 and completed daily symptom diaries. RESULTS: In the per-protocol population (n = 39), mean (SD) change from baseline in percentage of time with intragastric pH > 4 was 58.7% (± 26.4%) versus 41.0% (± 30.4%) for those who did and did not achieve 24-h heartburn relief. Significant correlations were observed between change in percentage of time with intragastric pH > 4 and 24-h heartburn relief (OR 1.028; 95% CI 1.001, 1.055; P = 0.0442) and complete resolution (OR 1.034; 95% CI 1.003, 1.065; P = 0.0301). CONCLUSIONS: Individuals with greater improvements in duration of intragastric acid suppression had an increased likelihood of achieving heartburn relief and resolution. These results indicate that individuals not adequately controlling their intragastric pH may require an escalation in dose of their acid-suppressive therapy, assessment with 24-h pH monitoring, or a change in treatment regimen to address non-reflux-related etiologies of their heartburn. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02708355. FUNDING: Pfizer Consumer Healthcare, Madison, NJ, USA. Plain language summary available for this article.

Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies.

BACKGROUND: A gluten-free diet is the only means to manage coeliac disease, a permanent immune intolerance to gluten. We developed a therapeutic vaccine, Nexvax2, designed to treat coeliac disease. Nexvax2 is an adjuvant-free mix of three peptides that include immunodominant epitopes for gluten-specific CD4-positive T cells. The vaccine is intended to engage and render gluten-specific CD4-positive T cells unresponsive to further antigenic stimulation. We assessed the safety and pharmacodynamics of the vaccine in patients with coeliac disease on a gluten-free diet. METHODS: We did two randomised, double-blind, placebo-controlled, phase 1 studies at 12 community sites in Australia, New Zealand, and the USA, in HLA-DQ2·5-positive patients aged 18-70 years who had coeliac disease and were on a gluten-free diet. In the screening period for ascending dose cohorts, participants were randomly assigned (1:1) by central randomisation with a simple block method to a double-blind crossover, placebo-controlled oral gluten challenge. Participants with a negative interferon γ release assay to Nexvax2 peptides after the screening oral gluten challenge were discontinued before dosing. For the biopsy cohorts, the screening period included an endoscopy, and participants with duodenal histology who had a Marsh score of greater than 1 were discontinued before dosing. Participants were subsequently randomly assigned to either Nexvax2 or placebo in ascending dose cohorts (2:1) and in biopsy cohorts (1:1) by central randomisation with a simple block method. In the three-dose study, participants received either Nexvax2 60 µg, 90 µg, or 150 µg weekly, or placebo over 15 days; in a fourth biopsy cohort, patients received either Nexvax2 at the maximum tolerated dose (MTD) or placebo. In the 16-dose study, participants received Nexvax2 150 µg or 300 µg or placebo twice weekly over 53 days; in a third biopsy cohort, patients also received either Nexvax2 at the MTD or placebo. In the 4-week post-treatment period, ascending dose cohorts underwent a further double-blind crossover, placebo-controlled oral gluten challenge, which had a fixed sequence, and biopsy cohorts had a gastroscopy with duodenal biopsies and quantitative histology within 2 weeks without oral gluten challenge. Participants, investigators, and study staff were masked to the treatment assignment, except for the study pharmacist. The primary endpoint was the number and percentage of adverse events in the treatment period in an intention-to-treat analysis. Both trials were completed and closed before data analysis. Trials were registered with the Australian New Zealand Clinical Trials Registry, numbers ACTRN12612000355875 and ACTRN12613001331729. FINDINGS: Participants were enrolled from Nov 28, 2012, to Aug 14, 2014, in the three-dose study, and from Aug 3, 2012, to Sept 10, 2013, in the 16-dose study. Overall, 62 (57%) of 108 participants were randomly assigned after oral gluten challenge and 20 (71%) of 28 participants were randomly assigned after endoscopy. In the three-dose study, nine participants were randomly allocated to Nexvax2 60 µg and three to placebo (first cohort), nine were allocated to Nexvax2 90 µg and four to placebo (second cohort), eight were allocated to Nexvax2 150 µg and four to placebo (third cohort), and three were allocated to Nexvax2 150 µg and three to placebo (biopsy cohort). In the 16-dose study, eight participants were randomly allocated to Nexvax2 150 µg and four to placebo (first cohort), ten were allocated to Nexvax2 300 µg and three to placebo (second cohort), and seven were allocated to Nexvax2 150 µg and seven to placebo (biopsy cohort). The MTD for Nexvax2 was 150 µg because of transient, acute gastrointestinal adverse events with onset 2-5 h after initial doses of the vaccine, similar to those caused by gluten ingestion. In the ascending dose cohorts in the three-dose study, six (55%) of 11 placebo recipients, five (56%) of nine who received Nexvax2 60 µg, seven (78%) of nine who received Nexvax2 90 µg, and five (63%) of eight who received Nexvax2 150 µg had at least one treatment-emergent adverse event, as did all three (100%) placebo recipients and one (33%) of three Nexvax2 150 µg recipients in the biopsy cohort. In the ascending dose cohorts of the 16-dose study, five (71%) of seven placebo-treated participants, six (75%) of eight who received Nexvax2 150 µg, and all ten (100%) who received Nexvax2 300 µg had at least one treatment-emergent adverse event, as did six (86%) of seven placebo recipients and five (71%) of seven Nexvax2 150 µg recipients in the biopsy cohort. Vomiting, nausea, and headache were the only treatment-emergent adverse events that occurred in at least 5% of participants in either study. Among participants given the MTD, eight gastrointestinal treatment-emergent adverse events occurred in four (50%) of eight participants in the third cohort and none (0%) of three participants in the biopsy cohort in the three-dose study, and five events occurred in five (63%) of eight participants in the first cohort and three events in two (29%) of seven participants in the biopsy cohort of the 16-dose study. Median villous height to crypt depth ratio in distal duodenal biopsies was not significantly different between those who received the vaccine at the MTD on either schedule and those who received placebo. Of the participants who completed the post-treatment oral gluten challenge per protocol, interferon γ release assay to Nexvax2 peptides was negative (responders to treatment) in two (22%) of nine placebo-treated participants in the three-dose study versus two (33%) of six who received Nexvax2 60 µg, five (63%) of eight who received Nexvax2 90 µg, and six (100%) of six who received Nexvax2 150 µg (p=0·007); in the 16-dose study, none (0%) of five placebo-treated participants had a negative assay versus six (75%) of eight who received Nexvax2 150 µg (p=0·021). INTERPRETATION: The MTD of Nexvax2 was 150 µg for twice weekly intradermal administration over 8 weeks, which modified immune responsiveness to Nexvax2 peptides without deterioration in duodenal histology. The gastrointestinal symptoms that followed the first intradermal administration of the vaccine resembled those associated with oral gluten challenge. These findings support continued clinical development of this potential therapeutic vaccine for coeliac disease. FUNDING: ImmusanT.

Intragastric acidity after switching from 5-day treatment with intravenous pantoprazole 40 mg/d to 5-day treatment with oral esomeprazole 40 mg/d or pantoprazole 40 mg/d: an open-label crossover study in healthy adult volunteers.

BACKGROUND: After a course of IV proton pump inhibitor therapy, patients might require continued oral antisecretory therapy. A direct comparison of therapeutic alternatives could assist physicians in decisions regarding optimal acid-suppressive therapy. Oral esomeprazole might control intragastric acidity more effectively compared with other acid-suppressive agents after IV therapy. OBJECTIVE: The aim of this study was to compare intragastric acid control on day 5 of administration of esomeprazole magnesium versus pantoprazole 40 mg PO QD after switching from 5 days of treatment with pantoprazole 40 mg IV in healthy volunteers. METHODS: This randomized, open-label, comparative, 2-way crossover study was conducted at the Oklahoma Foundation for Digestive Research, Oklahoma City, Oklahoma, between October and December 2004. Healthy, Helicobacter pylori-negative adults were randomly assigned to 1 of 2 dosing sequences: pantoprazole IV followed by esomeprazole PO or pantoprazole IV followed by pantoprazole PO. All study medications were administered for 5 days at a dose of 40 mg QD. IV pantoprazole was administered over 2 minutes; all medications were administered 30 minutes before breakfast. There was a 10- to 21-day washout period between each 10-day dosing period. All doses were administered at the study site. Before oral study drug administration on days 1 and 5, 24-hour pH monitoring was performed using a pH catheter positioned 10 cm distal to the lower esophageal sphincter in the stomach. The primary end point was percentage of time with pH >4 (%t pH >4) during the 24-hour pH-monitoring period. Tolerability was assessed using spontaneous reporting, laboratory analysis, and vital-sign measurement. RESULTS: Of 42 subjects randomized to treatment sequences, 4 were withdrawn during the study because of invalid pH data; 38 subjects (24 men, 14 women; mean [SD] age, 25.2 [8.1] years) had assessable data. Day-5 %t pH >4 was 68.5% with esomeprazole and 53.3% with pantoprazole (P < 0.001). Day-1 %t pH >4 was 62.5% with esomeprazole and 51.0% with pantoprazole (P < 0.001). The most common adverse events were rhinitis (2 subjects each with pantoprazole IV and PO; 1 subject with esomeprazole) and headache (2 subjects with esomeprazole; 1 subject with pantoprazole IV). CONCLUSIONS: The results of this study in healthy adult volunteers suggest that switching from pantoprazole 40 mg IV to esomeprazole 40 mg PO QD more effectively suppresses intragastric acid compared with switching from pantoprazole 40 mg IV to pantoprazole 40 mg PO QD. All 3 treatments were well tolerated.

Effect of esophageal acid and prophylactic rabeprazole on performance in runners.

INTRODUCTION: Acid reflux occurs during exercise. The effects of esophageal acid and prophylactic antisecretory treatment on exercise performance are unknown. AIMS: To determine 1) the effect of esophageal acid perfusion during exercise on pulmonary function and exercise performance, and 2) whether acid suppression with rabeprazole (RAB) 20 mg x d(-1) increases exercise performance during esophageal acid infusion. METHODS: This was a two-phase study. Twenty-four conditioned runners (11 with heartburn, 13 without) completed phase 1. Sixteen runners with heartburn completed phase 2 (RAB). For phase 1, esophageal evaluation, baseline maximum exertion test, and a standard Bruce protocol maximal stress test were performed. Runners were randomized to sham esophageal infusion (NG tube placed in the distal esophagus, no fluid) or esophageal acid perfusion (0.1 N HCl perfused) during exercise. Subjects were crossed over to the alternate perfusion. For phase 2, runners underwent three sessions with both acid and sham perfusion during running; the sessions were randomly conducted on different days at baseline and 8 and 12 wk of RAB 20 mg. RESULTS: For phase 1, esophageal function and sensitivity were normal. There was no difference in airway resistance or work capacity between groups. The acid-perfusion group significantly decreased time to exhaustion in the no-heartburn group (23.13 to 20.66 min) with a decrease in energy expenditure. For phase 2, time to exhaustion was significantly decreased with acid perfusion at all time points (P < 0.05). Total energy expenditure during exercise was less in each acid-perfusion test. No difference in pulmonary function was present at week 12 versus baseline. CONCLUSIONS: Esophageal acid perfusion decreased performance. In runners with heartburn, suppression of endogenous acid secretion did not improve exercise performance. Changes in cardiopulmonary function do not explain the decreased exercise performance during acid perfusion.

Esophageal reflux in conditioned runners, cyclists, and weightlifters.

INTRODUCTION: Gastroesophageal reflux disease is a disorder in which gastric contents move from stomach to esophagus. Exercise is a recognized contributing factor to reflux in healthy volunteers and is reported to be proportional to exercise intensity and the type of exercise. Our aim was to explore changes in physiology occurring in conditioned runners, cyclists, and weightlifters. METHODS: Ten subjects from each sport with >3-month history of exercise-induced heartburn were enrolled. Subjects underwent evaluation of fasting and fed esophageal pH, heart rate, GI symptom, and perceived exertion during standardized exercise routines at 65% (60 min) and 85% (20 min) of their maximal capabilities. RESULTS: Weightlifters experienced the most heartburn and reflux: 18.51 +/- 17.34% time esophageal pH

Evaluation of esophageal sensation.

Dramatic progress has been made over the past decade in the sophistication and availability of equipment to test esophageal motility and sensation. High-resolution esophageal manometry and impedance have moved from the research clinic into clinical practice. Some of the testing is costly and time consuming, and requires extensive experience to perform the testing and properly interpret the results. These sensory studies are valuable in the interpretation of clinical problems, and provide important research information. Clinicians should evaluate the research studies to advance their understanding of the pathophysiology of the esophagus.