Comparison of gastric pH with omeprazole magnesium 20.6 mg (Prilosec OTC) o.m. famotidine 10 mg (Pepcid AC) b.d. and famotidine 20 mg b.d. over 14 days of treatment.

BACKGROUND: The onset of acid inhibition for proton pump inhibitors is slower than with H2RAs and generally considered to be at a steady-state after 5 days. Thus, little direct comparison data exists between H2RAs and proton pump inhibitors for gastric acid suppression on day 1 of therapy. Furthermore, the durability of their acid suppression has not been systematically compared. AIM: To compare the effects of 20.6 mg omeprazole magnesium o.m. (Ome-Mg 20), famotidine 10 mg b.d. (Fam 10) and famotidine 20 mg b.d. (Fam 20) on intragastric pH on day 1 and throughout 14 days of dosing. METHODS: The study was a randomized, double-blind, three-dosing regimens, three-period crossover. Healthy adults with frequent heartburn (> or =2 days/week) underwent 24-h gastric pH monitoring on days 0 (baseline), 1, 3, 7 and 14. RESULTS: Thirty-one subjects were included in the per-protocol analyses. On day 1, the mean percentage time pH > 4 (pH4%) was higher for Ome-Mg 20, 44.6%, than for Fam 10, 36.7% (P = 0.032), and not different from Fam 20, 46.9% (P = 0.541). The pH4% was higher for Ome-Mg 20 than either famotidine regimen on all subsequent monitoring days (P < 0.001). The 24-h area under the mean intragastric pH curve showed a similar pattern. Furthermore, after day 1, Ome-Mg 20 demonstrated an increasing and sustained effect in contrast to a decreasing effect for famotidine, consistent with H2RA tolerance. CONCLUSION: Gastric acid suppression on Ome-Mg 20 mg o.m. over 14 days was comparable with Fam 10 mg b.d. or Fam 20 mg b.d. on day 1, and superior thereafter.

Review article: physiologic and clinical effects of proton pump inhibitors on non-acidic and acidic gastro-oesophageal reflux.

The control of oesophageal acid exposure through gastric acid inhibition, as the basis for gastro-oesophageal reflux disease (GERD) treatment, arose from the apparent pH dependency of erosive oesophagitis and relationship to GERD symptoms. The current perception is that reflux disease is an entirely acid-mediated condition, and antisecretory therapies, particularly proton pump inhibitors, are the treatment of choice for patients with erosive and non-erosive reflux disease. A positive patient response to an empiric trial of proton pump inhibitor (PPI) therapy, or the 'PPI test', is commonly suggested as a method of GERD diagnosis. Recent studies have modified our understanding of the relationship between oesophageal acid exposure and GERD pathology, manifestations and symptoms. Whereas the use of PPIs to reduce oesophageal acid exposure in patients with erosions is associated with increased healing rates, non-erosive reflux disease patients are less likely to have an abnormal oesophageal pH profile. Patterns of oesophageal acid exposure, particularly nocturnal oesophageal acid exposure, have been linked to increased disease severity. Non-acidic reflux and the effect of PPIs on this parameter, including bile reflux and the toxicity of bile acids, may also be an important factor in GERD. This article explores some of these assumptions, practices and relationships, including: the association between oesophageal acid exposure and erosive and non-erosive gastro-oesophageal reflux disease; the effect of PPIs on oesophageal acid exposure in erosive oesophagitis patients; the influence of nocturnal acid secretion in GERD and the use of PPIs to control this parameter; the relevance of the PPI test for reflux disease diagnosis; and PPI influence on non-acidic reflux.

Effect of naproxen on gastric acid secretion and gastric pH.

BACKGROUND: The mechanisms for the non-steroidal anti-inflammatory drug-induced inflammation in the stomach are unclear. AIMS: To determine if naproxen (Naprosyn, Roche, Nutley, NJ, USA) alters basal acid output, pentagastrin-stimulated maximal acid output, or fasting gastrin. METHODS: Basal acid output and maximal acid output gastric aspirations were performed pre-naproxen and 7 days post-naproxen 500 mg b.d. in 24 healthy subjects. Volume, pH and acid mEq were determined. Fasting gastrin was obtained. Comparisons were made using paired t-tests (alpha = 0.05). RESULTS: Dosing with naproxen did not statistically decrease mean pH of the basal acid output gastric fluid (3.3 vs. 3.1; N.S.) or the pentagastrin-stimulated maximal acid output gastric fluid (2.7 vs. 2.6; N.S.). Basal acid output total volume was significantly decreased post-naproxen (84 vs. 61 mL/h; P = 0.01), with no change in maximal acid output total volume (196 vs. 188 mL/h; N.S.). Basal acid output mean gastric acidity was significantly increased post-naproxen (0.04 vs. 0.05 mEq/mL; P = 0.03), with no change in maximal acid output mean gastric acidity after naproxen (0.10 vs. 0.10; N.S.). Gastrin was not altered by dosing with naproxen. CONCLUSIONS: Naproxen does not influence total acid secreted but does decrease basal gastric fluid volume, thereby increasing basal gastric acid concentration. These observations define one mechanism by which non-steroidal anti-inflammatory drugs may induce gastric injury.

Safety and efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left-sided ulcerative colitis: a randomized, double-blind, active-controlled trial.

BACKGROUND: Alicaforsen is an antisense oligonucleotide inhibitor of intercellular adhesion molecule 1 protein expression with activity in subjects with ulcerative colitis and pouchitis. AIM: To compare the effects of alicaforsen enema to standard of care mesalazine (mesalamine) enema in subjects with mild to moderate active left-sided ulcerative colitis. METHOD: A randomized, double-blind, active-controlled multicentre clinical trial. Subjects received a nightly enema of 120 mg alicaforsen (n=55), 240 mg alicaforsen (n=50), or 4 g mesalazine (n=54) for 6 weeks, followed by a 24-week monitoring period. The primary end point was Disease Activity Index at week 6. Clinical improvement, remission and relapse were secondary end points. RESULTS: No significant difference was observed between treatment arms in the primary end point. However, the median duration of response to alicaforsen enema treatment was two- to threefold longer (128 and 146 days) in comparison with mesalazine (54 days). Complete mucosal healing occurred in 24% of the 240 mg alicaforsen group, when compared with 17% in the mesalazine. CONCLUSIONS: Alicaforsen enema demonstrated an acute response and safety profile similar to mesalazine enema, but was differentiated by a more durable response. The extended length of remission suggests that alicaforsen enema treatment may have a disease modifying effect.

The effects of changing temperature correction factors on measures of acidity calculated from gastric and oesophageal pH recordings.

BACKGROUND: Recently, Medtronic notified customers that new correction factors should be used for their Slimline and Zinetics24 single-use, internal-standard pH catheters. AIM AND METHODS: We selected 24-h recordings of oesophageal and gastric pH with the Zinetics24 from our archives for five healthy subjects and for five gastro-oesophageal reflux disease subjects who were studied at baseline and again after 8 days of treatment with a proton-pump inhibitor. All pH values obtained with the old correction factors were rescaled using the new correction factors. Values for median pH, integrated acidity and time pH < or = 4 were then calculated from pH values with old and new correction factors. RESULTS: The new correction factors changed values for median pH, integrated acidity and time pH < or = 4. Values for median pH and integrated acidity changed in a predictable, proportionate way, whereas values for time pH < or = 4 did not. CONCLUSIONS: The new correction factors will not change the interpretation of previously published results with median pH or integrated acidity. In contrast, values for time < or =4 cannot be converted in an obvious way with the new correction factors. Instead, the raw pH data will need to be rescaled and values for time pH < or = 4 recalculated using the rescaled pH data.

Intragastric acid control in non-steroidal anti-inflammatory drug users: comparison of esomeprazole, lansoprazole and pantoprazole.

BACKGROUND: Studies to date have not directly compared the pharmacodynamic efficacies of different proton pump inhibitors in controlling intragastric acidity in patients treated with non-steroidal anti-inflammatory drugs. AIM: To compare acid suppression with once-daily esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg in patients receiving non-selective or cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drug therapy. METHODS: In this multicentre, open-label, comparative, three-way crossover study, adult patients (n = 90) receiving non-steroidal anti-inflammatory drugs were randomized to one of six treatment sequences. At the study site, patients were administered esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg for 5 days each, with a washout period of > or =10 days between each treatment. Twenty-four-hour pH testing was performed on day 5 of each dosing period. RESULTS: The mean percentage of time during the 24-h pH monitoring period that gastric pH was >4.0 was significantly greater with esomeprazole (74.2%) compared with lansoprazole (66.5%; P < 0.001) and pantoprazole (60.8%; P < 0.001), and significantly greater with esomeprazole (P < 0.05) than with the comparators regardless of whether using non-selective vs. cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drugs. CONCLUSIONS: At the doses studied, esomeprazole treatment provides significantly greater gastric acid suppression than lansoprazole or pantoprazole in patients receiving non-selective or cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drugs.

A phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis.

BACKGROUND: Alicaforsen is an antisense oligonucleotide designed to inhibit expression of human intercellular adhesion molecule 1. Previous clinical studies have demonstrated activity of alicaforsen enema in ulcerative colitis and pouchitis. AIM: To determine the minimally effective dosing regimen of alicaforsen enema in subjects with mild to moderate left-sided ulcerative colitis. METHODS: Randomized, placebo-controlled, double-blind, two-dose ranging multicentre study. One hundred and twelve subjects were equally randomized to receive one of four alicaforsen enema regimens or placebo daily for 6 weeks. Primary end point was Disease Activity Index at week 6. Secondary end points included evaluation of clinical improvement, relapse rates and durability of response. Analysis of data were performed on the intent-to-treat population. RESULTS: No significant difference was observed between treatment arms and placebo in the primary end point. A prolonged reduction in mean% Disease Activity Index relative to baseline was observed in the daily 240 mg alicaforsen enema treatment arm in comparison with placebo from week 18 (51% vs. 18%, P=0.04) to week 30 (50% vs. 11%, P=0.03). CONCLUSIONS: Alicaforsen enema was safe and well tolerated at all doses studied. The durability of the response to alicaforsen enema treatment may suggests a disease-modifying effect.

Bioavailability and therapeutic activity of alicaforsen (ISIS 2302) administered as a rectal retention enema to subjects with active ulcerative colitis.

BACKGROUND: Alicaforsen is a phosphorothioate-modified antisense oligodeoxynucleotide designed to sequence-specifically reduce intercellular adhesion molecule 1 messenger RNA levels. AIMS: To determine the systemic and local bioavailability of alicaforsen, and its activity when administered as a once daily enema in subjects with active ulcerative colitis. METHODS An open-label study was conducted to assess the relative absorption (local and systemic pharmacokinetics) and pharmacologic activity of alicaforsen enema in subjects with active ulcerative colitis. Fifteen subjects received nightly enemas of alicaforsen (240 mg) for a treatment period of 6 weeks. Alicaforsen concentrations in plasma and colonic tissue biopsies were determined. Disease activity index and multiple measurements including endoscopy were used to assess alicaforsen activity in these subjects. RESULTS: Plasma concentrations of parent alicaforsen represented < 0.6% mean bioavailability when compared with historical intravenous area under the plasma concentration-time curves. Concentrations of the intact oligonucleotide in mucosal colonic tissue biopsies were orders of magnitude higher than those observed in plasma. A 46% reduction in mean Disease Activity Index and 33% rate of remission as defined by complete mucosal healing were observed at the end of treatment. Conclusion These data confirm that alicaforsen enema provides local treatment for a local disease with little meaningful systemic exposure.

Prucalopride induces high-amplitude propagating contractions in the colon of patients with chronic constipation: a randomized study.

BACKGROUND: This study compared prucalopride, a selective, prokinetic, 5-HT4 receptor agonist, with polyethylene glycol 3350 + electrolytes (PEG3350), an osmotic laxative, on colonic motility parameters, primarily high-amplitude propagating contractions (HAPCs) in patients with chronic constipation. METHODS: This randomized, cross-over, reader-blinded study was conducted at a single site in the USA. The study was open to men and women aged 18-75 years who met study inclusion criteria. Colonic manometry catheters were inserted the day before investigation. On the investigation days, patients received oral 2 mg prucalopride or 2 × 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [HAPC1 ]) in the 12 h after treatment administration. Analyses were also conducted at two co-primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm (HAPC2 ); and mean amplitude ≥75 mmHg, propagation ≥10 cm (HAPC3 ). Secondary endpoints included HAPC area under the curve (AUC), contraction force, amplitude, duration, and propagation velocity. KEY RESULTS: Thirteen women were enrolled, with 12 completing the study. Significantly more HAPC1 (8.7 ± 2.06 vs 2.9 ± 2.06; p = 0.012) and HAPC2 (9.0 ± 2.11 vs 3.3 ± 2.11; p = 0.017) were observed in the 12-h periods with prucalopride than with PEG3350. Prucalopride significantly increased mean propagation distance and velocity (HAPC2 ) and mean AUC, force, and amplitude (HAPC3 ) compared with PEG3350. Adverse events were mild or moderate. CONCLUSIONS & INFERENCES: Prucalopride was superior to PEG3350 in inducing HAPCs in patients with chronic constipation. ClinicalTrials.gov number NCT01707667.

Comparison of the effects of intravenously and orally administered esomeprazole on acid output in patients with symptoms of gastro-oesophageal reflux disease.

BACKGROUND: Intravenous esomeprazole may be beneficial for patients who cannot take oral medications. AIM: To compare intravenous esomeprazole with oral esomeprazole for effects on maximal acid output during pentagastrin stimulation in patients with gastro-oesophageal reflux disease symptoms. METHODS: In four separate open-label, randomized, two-way crossover studies, adult patients were administered esomeprazole 20 or 40 mg once daily either orally or intravenously (by 15-min infusion or 3-min injection) for 10 days and switched to the other formulation with no washout period. Basal acid output and maximal acid output were measured on days 11, 13 and 21. RESULTS: In the four studies (total of 183 patients), least-squares mean maximal acid output ranged from 3.0 to 4.1 mmol/h after intravenous esomeprazole 40 or 20 mg and from 2.2 to 3.3 mmol/h after oral esomeprazole 20 or 40 mg. Differences between formulations were small and not statistically significant but did not meet the prospectively defined criterion for non-inferiority of the intravenous formulation. Median basal acid output values ranged from 0.04 to 0.27 mmol/h after intravenous administration and from 0.05 to 0.25 mmol/h after oral esomeprazole. CONCLUSIONS: Intravenous esomeprazole is an acceptable alternative to the oral formulation for treatment of up to 10 days of duration.

The fractal nature of human gastro-oesophageal reflux.

BACKGROUND: We are unaware of the analyses of time series data resulting from 24 h recordings of human gastric or oesophageal pH. As a result, we have no understanding of the quantitative changes in gastric or oesophageal acidity over time, the patterns that might characterize these changes, or the physiological significance of gastro-oesophageal reflux. AIM: To examine the time series for gastric and oesophageal pH. METHODS: Detrended fluctuation analysis and lag analysis were used to analyse data from 24 h recordings of oesophageal and gastric pH in five normal subjects and five subjects with gastro-oesophageal reflux disease. RESULTS: Analyses of the patterns of gastric and oesophageal pH over time in normal subjects and subjects with gastro-oesophageal reflux disease indicate that the fluctuations in pH are self-similar across different time scales and are consistent with an underlying fractal process. Furthermore, there is a significant statistical association between sequential pH values separated by as much as 2.2 h. CONCLUSIONS: We hypothesize that the self-similar, fractal pattern encodes information about gastric acidity and that the oesophagus decodes this information and, when appropriate, may signal the stomach to reduce gastric acidity. Subjects with gastro-oesophageal reflux disease might have an impaired oesophageal-gastric feedback mechanism that results in increased gastric acid, which reflux from the stomach into the oesophagus.

The role of the mast cell in clinical gastrointestinal disease with special reference to systemic mastocytosis.

The gastrointestinal tract is a rich source of mast cells with an enormous surface area that permits a high degree of interaction between the mast cell and intestinal luminal contents. The active metabolic products of the mast cell influence gastrointestinal secretion, absorption, and motility through paracrine effects of local mast cell degranulation and also cause systemic effects through the release of cellular products into the blood stream. Systemic mastocytosis influences physiologic function through the systemic effects of mast cell products released from focal (e.g., bone marrow) or wide spread increases in mast cell number. Local gastrointestinal proliferation of mast cells in response to recognized (e.g., gluten in celiac sprue) or obscure stimuli can alter gastrointestinal function and induce systemic symptoms. Celiac sprue, inflammatory bowel disease, and non-ulcer dyspepsia are three examples of gastrointestinal diseases in which mast cells can be implicated in the pathophysiology of the symptoms.

New therapeutic agents in the treatment of inflammatory bowel disease.

Despite intense investigation, the etiology of inflammatory bowel disease (IBD) remains unknown. Recent studies with new therapeutic agents provide insight into the pathogenesis of IBD through analysis of the clinical response to pharmacologic agents whose mechanism of action is understood. Until new agents are established, IBD will be treated with conventional drugs directed toward modifying the inflammatory responses responsible for gastrointestinal mucosal damage. Sulfasalazine, mesalamine (5-aminosalicylic acid), and corticosteroids will continue to be the mainstay of therapy for the foreseeable future. Antibiotics such as metronidazole and immunosuppressants such as 6-mercaptopurine and methotrexate are useful in Crohn's disease and ulcerative colitis in selected cases. Many new exciting agents are being investigated and show encouraging results in the treatment of IBD. This article reviews the agents used in IBD with an emphasis on new therapeutic agents.

Review article: refractory distal colitis -- explanations and options.

Distal colitis refractory to standard therapy is a complex and challenging problem. Physiological differences between the right and left colon may be exploited for maximum therapeutic benefit. Over-reliance on oral therapy should be seen as one of the reasons for treatment failure and delivery systems should target therapy to the distribution of the disease in doses proven to be therapeutically beneficial. The clinician should also be cognizant of potential adverse effects of standard therapies, particularly colitis due to mesalazine, which may mimic worsening disease. Numerous endogenous and exogenous factors that may exacerbate the underlying inflammatory bowel disease are discussed. This review explores the potential mechanisms why distal colitis may be refractory to therapy and addresses newer therapies that, while still in the investigatory stages, offer hope for a widening armamentarium of therapeutic modalities.

Oesophageal pH has a power-law distribution in control and gastro-oesophageal reflux disease subjects.

BACKGROUND: We are unaware of any solid theoretical or pathophysiological basis for selecting pH 4 or any other pH value to assess oesophageal acid exposure or to define oesophageal reflux episodes. AIM: To examine the frequency of different oesophageal pH values in control and GERD subjects. METHODS: Oesophageal pH was measured for 24 h in 57 gastro-oesophageal reflux disease subjects and 26 control subjects. Histograms were constructed using the 21,600 values from each recording and bins of 0.25 pH units. RESULTS: Compared with controls, gastro-oesophageal reflux disease subjects had significantly more low pH values and significantly fewer high pH values. In both gastro-oesophageal reflux disease and control subjects, the frequency of oesophageal pH values was characterized by a power-law distribution indicating that the same relationship that describes low pH values also describes high pH values, as well as all values in between. CONCLUSIONS: The distribution of oesophageal pH values indicates that a variety of different pH values can be used to assess oesophageal acid exposure, but raises important questions regarding how oesophageal reflux episodes are defined.

Frequency analyses of gastric pH in control and gastro-oesophageal reflux disease subjects treated with a proton-pump inhibitor.

BACKGROUND: We are unaware of any solid theoretical or pathophysiological basis for selecting pH 4 or any other pH value to assess gastric acidity. AIM: To examine the frequency of different gastric pH values in control and GERD subjects. METHODS: Gastric pH was measured for 24 h in 26 control subjects, 26 gastro-oesophageal reflux disease subjects at baseline and the same 26 gastro-oesophageal reflux disease subjects during treatment with a proton-pump inhibitor. Histograms were constructed using the 21 600 values generated from each recording and bins of 0.25 pH units. RESULTS: The distribution of gastric pH values in gastro-oesophageal reflux disease subjects was significantly different from that in controls and in some instances the distributions detected significant differences that were not detected by integrated acidity. Proton-pump inhibitor treatment significantly altered the distribution of gastric pH values and the nature of this alteration during the postprandial period was different from that during the nocturnal period. Using time pH< or =4 can significantly underestimate the magnitude of inhibition of gastric acidity caused by a proton-pump inhibitor. CONCLUSIONS: The distribution of gastric pH values provides a rationale for selecting a particular pH value to assess gastric acidity. In some instances, the distribution of gastric pH values detects significant differences between gastro-oesophageal reflux disease and normal subjects that are not detected by integrated acidity.

Meal-stimulated gastric acid secretion and integrated gastric acidity in gastro-oesophageal reflux disease.

BACKGROUND: No current methods exist to determine meal-stimulated gastric acid secretion in humans under conditions that approximate those of daily living with the ingestion of breakfast, lunch and dinner. METHODS: Gastric and oesophageal pH were measured in 26 healthy subjects and in 59 subjects with gastro-oesophageal reflux disease. Meal-stimulated gastric acid secretion was calculated from the buffer capacity of the meals determined in vitro and from the time required for the gastric pH to decrease to pH 2 in vivo following ingestion of the meal. RESULTS: There was a significant correlation between gastric secretion with each meal and the corresponding post-prandial integrated gastric acidity. There was also a significant correlation between meal-stimulated gastric secretion and integrated gastric acidity from 09.00 to 22.00 h in both subjects with gastro-oesophageal reflux disease and controls. In subjects with gastro-oesophageal reflux disease, gastric secretion and integrated gastric acidity from 09.00 to 22.00 h were significantly higher than those in controls. There was a significant correlation between oesophageal acidity and integrated gastric acidity from 09.00 to 22.00 h in subjects with gastro-oesophageal reflux disease. CONCLUSIONS: As post-prandial gastric acidity is increased in subjects with gastro-oesophageal reflux disease, it seems likely that increased gastric acidity is an important aetiological factor in this disease.

Determination of the reduction in gastric acidity necessary to prevent pathological oesophageal reflux in patients with gastro-oesophageal reflux disease treated with a proton pump inhibitor.

BACKGROUND: In subjects with gastro-oesophageal reflux disease treated with a gastric antisecretory agent, the extent to which gastric acidity needs to be reduced to prevent pathological oesophageal acid exposure is not known. METHODS: Gastric and oesophageal pH were measured in 26 healthy subjects and in 59 subjects with gastro-oesophageal reflux disease. In 27 of the subjects with gastro-oesophageal reflux disease, pH was also recorded on days 1, 2 and 8 of treatment with 20 mg omeprazole and 20 mg rabeprazole in a randomized, two-way, cross-over fashion. RESULTS: Receiver operating characteristic analysis was used to determine values for the integrated oesophageal acidity and time oesophageal pH

Heartburn severity can predict pathologic oesophageal reflux in gastro-oesophageal reflux disease patients treated with a proton-pump inhibitor.

BACKGROUND: In gastro-oesophageal reflux disease (GERD) subjects treated with a gastric anti-secretory agent, it is not known whether there is a relationship between heartburn severity and oesophageal acid exposure. METHODS: Oesophageal pH and heartburn severity were determined in 27 GERD subjects at baseline and on days 1, 2 and 8 of treatment with 20 mg omeprazole or 20 mg rabeprazole in a randomized, two-way crossover fashion. RESULTS: Receiver operating characteristic (ROC) analysis was used to determine values for heartburn severity that gave optimal cut-off points for distinguishing between normal and pathologic oesophageal reflux. Using these cut-off points, we found that the probability of no pathologic oesophageal reflux (Y) could be best fitted by an exponential equation: Y = a(e-bX) + c, where a, b and c are constants and X is the value of heartburn severity. There was close agreement between predicted and observed percentages of subjects with pathologic oesophageal reflux during different days of treatment. CONCLUSIONS: In GERD subjects treated with a proton-pump inhibitor, the value of heartburn severity following a single standard meal can predict the likelihood of pathologic oesophageal reflux over the entire 24-h period.

Cisapride inhibits meal-stimulated gastric acid secretion and post-prandial gastric acidity in subjects with gastro-oesophageal reflux disease.

BACKGROUND AND AIMS: KCNQ1 potassium channels in human gastric parietal cells are thought to be involved in gastric acid secretion. As cisapride can inhibit similar channels in other tissues and is an effective treatment for nocturnal heartburn, we examined the effects of cisapride on gastric and oesophageal acidity, gastric emptying and heartburn severity in subjects with gastro-oesophageal reflux disease. METHODS: Subjects (n = 11) had suffered from heartburn four times or more per week for at least 6 months. Gastric pH and oesophageal pH were measured before, during and after a standard meal ingested over 15 min. Each subject received placebo or 10 mg cisapride orally, 30 min before the beginning of the meal. Meal-stimulated gastric acid secretion was calculated from the amount of HCl required to titrate the homogenized standard meal to pH 2 in vitro and the time required for the pH of the ingested meal to decrease to pH 2 in vivo. Heartburn severity was assessed at 15-min intervals beginning at the end of the meal. Gastric emptying of solids was measured using a [(13)C]-octanoic acid breath test. RESULTS: Cisapride significantly decreased meal-stimulated gastric acid secretion by 20%, decreased integrated gastric and oesophageal acidity by 50-60% and transiently increased the expiration of (13)CO(2). Cisapride did not significantly alter heartburn severity. CONCLUSIONS: The cisapride-induced decreases in meal-stimulated gastric acid secretion, gastric acidity and oesophageal acidity in subjects with gastro-oesophageal reflux disease can account for its beneficial clinical effects. These results also raise the possibility that gastric KCNQ1 potassium channels are important in meal-stimulated gastric acid secretion and possibly in the pathophysiology of gastro-oesophageal reflux disease.