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.

Heartburn requiring frequent antacid use may indicate significant illness.

BACKGROUND: Many otherwise healthy individuals with episodic heartburn self-medicate with over-the-counter antacids. We evaluated clinical characteristics of subjects who had never been medically diagnosed as having any upper gastrointestinal tract disorder and who used antacids for symptomatic relief of heartburn. SUBJECTS AND METHODS: Subjects with at least 3 months of frequent heartburn relieved by antacids, and with heartburn on at least 4 of 7 days during the week prior to study entry, had their medical history and gastrointestinal pathological characteristics recorded. Tests included esophagogastroduodenoscopy, esophageal motility and sensitivity studies, and 24-hour pH monitoring. RESULTS: Of 178 subjects screened, 13 were excluded on the basis of other gastrointestinal diseases at baseline, including diffuse esophageal spasm, peptic ulcer disease, dysplastic columnar metaplasia of the esophagus (Barrett's esophagus), and adenocarcinoma. Ten subjects were ineligible because of insufficient baseline heartburn. The remaining 155 eligible subjects had heartburn for an average of 11 years. Forty-seven percent had daily symptoms and 70% described heartburn severity as moderate, even though on endoscopy most (53%) had normal-appearing esophageal mucosa (grade 0 or 1). Esophageal acid sensitivity was present in 86% of subjects. Mean lower esophageal sphincter pressures and esophageal contractile amplitudes were at the lower limits of normal and total esophageal acid contact time was slightly increased. CONCLUSIONS: Chronic heartburn can reflect a wide range of diagnostic findings, including important underlying pathological features, and may warrant a full medical examination to detect such abnormal conditions and to permit selection of appropriate therapy.

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.

A single dose of ranitidine 150 mg modulates oesophageal acid sensitivity in patients with functional heartburn.

BACKGROUND: The rapid onset and symptomatic response to histamine-2 receptor antagonists prior to the pharmacological effect on acid secretion suggests a different mechanism of action. AIM: To determine if ranitidine decreases oesophageal sensitivity to chemical and mechanical stimulation, potentially via oesophageal histamine receptors. METHODS: A total of 18 patients with functional heartburn received oral ranitidine 150 mg b.d. or placebo for 7 consecutive days in a double-blind randomized crossover design and underwent Barostat balloon distention and Bernstein acid infusion on study day 1 (90 min postdose) and study day 7. First sensation and pain were recorded and pain severity was rated on a 5-point Likert scale and a 100 mm visual analogue scale. Least square mean values were generated and one-tailed t-tests were performed. RESULTS: After a single dose of ranitidine 150 mg, time to pain with oesophageal acid infusion was increased by 29% (P < 0.05) and visual analogue scale and Likert scores were decreased by 20% (P < 0.06) and 23% (P < 0.02), respectively compared with placebo. After 1 week of ranitidine, positive alterations in sensory parameters persisted. Balloon distention sensory parameters were not altered by ranitidine. CONCLUSIONS: Ranitidine significantly decreased oesophageal sensitivity to acid. Failure of ranitidine to improve balloon sensory parameters supports existence of multiple sensory pathways in the oesophagus.

Effects of antacid formulation on postprandial oesophageal acidity in patients with a history of episodic heartburn.

BACKGROUND: Heartburn self-treatment with antacids is extremely common. If the oesophagus is the primary site of antacid action, chewable antacids might raise the oesophageal pH more effectively than swallowable tablets. AIM: To establish a model to assess postprandial acid reflux and to compare the onset and duration of action on oesophageal pH of different antacid formulations. METHODS: Twenty subjects with a history of episodic heartburn underwent eight pH monitoring sessions each for 5.5 h postprandially. One hour after consuming a meal consisting of chili, cheese, raw onions and cola, subjects received 750 mg, 1500 mg and 3000 mg of either chewable or swallowable CaCO3 tablets, an effervescent bicarbonate solution or placebo. Oesophageal and gastric pH data were collected. RESULTS: Mean intra-oesophageal pH remained lower than baseline for more than 1 h (pH range 5-5.5) postprandially, indicating reflux of somewhat acidic intragastric contents into the oesophagus. The onset of action on oesophageal pH was similar for all antacids (30-35 min). The duration of action on pH varied: chewable tablets and effervescent bicarbonate had relatively long durations of action (oesophagus, 40-45 min; stomach, 100-180 min); swallowable tablets had little effect. CONCLUSIONS: The meal model used in this study dependably produced acidic gastro-oesophageal reflux. Antacids increased oesophageal pH independent of gastric pH, demonstrating that chewing antacids controls oesophageal acidity more effectively than swallowing antacid tablets.

The effects of capsaicin on reflux, gastric emptying and dyspepsia.

AIMS: To evaluate capsaicin's effects on heartburn, dyspepsia, gastric acidity and emptying, and gastro-oesophageal reflux, and to test the hypothesis that capsaicin induces heartburn and exacerbates symptoms by sensitizing the oesophagus. METHODS: Eleven heartburn sufferers underwent two separate pH monitoring sessions and assessments of gastric emptying (13C-octanoic acid breath test), heartburn and dyspepsia (100 mm VAS) after a non-irritant meal. The meal consisted of a sausage biscuit with egg, cheese and 30 g raw onion, 8 oz chocolate milk and a peppermint patty. Thirty minutes prior to meal consumption, subjects were administered a placebo capsule. On visit 1, subjects consumed the meal containing 100 microl 13C-octanoic acid cooked in the egg, over 15 min. On visit 2, subjects consumed the meal plus 5 mg capsaicin in gelatin capsules. RESULTS: Oesophageal and gastric pH profiles and gastric emptying were not different between meals. Capsaicin did not alter mean heartburn and dyspepsia scores (P > 0.05), but significantly decreased time to peak heartburn (120 min vs. 247 min; P < 0.003). Time to peak dyspepsia was not altered by capsaicin (P > 0.05). CONCLUSION: Capsaicin enhances noxious postprandial heartburn, presumably by direct effects on sensory neurons.

Clinical effectiveness of a new antacid chewing gum on heartburn and oesophageal pH control.

BACKGROUND: Oesophageal acid neutralization with antacids depends on the duration of oesophageal antacid exposure and acid neutralizing capacity. A gum that releases antacid as it is chewed could take advantage of both mechanisms to enhance heartburn relief. METHODS: Twenty-four subjects were crossed over to four regimens: placebo, chewable antacid tablets (1000 mg CaCO3), lower dose gum (600 mg CaCO3) and higher dose gum (900 mg CaCO3). A dual pH probe was placed, subjects ate a standardized provocative meal and self-dosed once as needed. Symptoms were recorded every 15 min using visual analogue and Likert scales. SYMPTOMS: Both gums decreased heartburn compared to placebo for 120 min. Higher dose gum decreased heartburn more than chewable antacids up to 120 min post-dose. pH: Active chewable antacid and gums immediately increased oesophageal pH, with significant improvement 15-30 min post-dose. SUMMARY: (i) both gums promptly decreased heartburn and elevated oesophageal pH; (ii) both gums provided sustained relief for 120 min; (iii) antacid gums provided faster and more prolonged symptom relief and pH control than chewable antacids. CONCLUSIONS: Calcium carbonate gum effectively neutralizes oesophageal acidity and relieves symptoms following a meal, and is superior to chewable antacids in terms of the duration of heartburn relief.

Integrated acidity and rabeprazole pharmacology.

BACKGROUND: Integrated gastric and oesophageal acidity can be calculated from measurements of gastric and oesophageal pH and used to quantify gastric and oesophageal acidity over time. Rabeprazole is a new proton pump inhibitor that is effective in treating gastro-oesophageal reflux disease (GERD). AIM: To use measurement of integrated gastric and oesophageal acidity to determine the onset, duration and overall effect of rabeprazole in subjects with GERD. METHODS: Subjects with GERD were required to have oesophageal pH less-than-or-equal 4 for at least 10% of a 24-h recording. Effects of 20 mg rabeprazole on 24-h gastric and oesophageal pH were measured on days 1 and 7 of dosing. Integrated gastric and oesophageal acidity were calculated from time-weighted average hydrogen ion concentrations at each second of the 24-h record. RESULTS: At steady-state, 20 mg rabeprazole inhibited gastric acidity by 89% and oesophageal acidity by 95%. The first dose of rabeprazole inhibited gastric and oesophageal acidity by at least 70% of the steady-state effect. Oesophageal acidity could be divided into monophasic and biphasic patterns, and rabeprazole had different effects on oesophageal and gastric acidity in these two GERD subpopulations. The onset of action of the first dose of rabeprazole on gastric acidity was 4 h and on oesophageal acidity was 4 h in monophasic subjects and 7 h in biphasic subjects. Integrated acidity was more sensitive than time pH less-than-or-equal 4 in measuring the inhibitory actions of rabeprazole. CONCLUSIONS: Integrated gastric and oesophageal acidity are quantitative measurements that provide useful and novel information regarding the pathophysiology of GERD as well as the impact of antisecretory agents such as rabeprazole.

Managing heartburn at the 'base' of the GERD 'iceberg': effervescent ranitidine 150 mg b.d. provides faster and better heartburn relief than antacids.

BACKGROUND: Many individuals with heartburn self-medicate with antacids for relief of their symptoms. AIM: To compare efficacy of effervescent ranitidine to as-needed calcium carbonate antacids in subjects who self-treat heartburn. METHODS: A total of 155 subjects with frequent antacid-responsive heartburn were randomized to receive effervescent ranitidine 150 mg tablets b.d., or as-needed calcium carbonate 750 mg for 12 weeks. Endoscopic oesophagitis severity and mucosal histology were assessed at baseline, and at weeks 6 and 12. Heartburn frequency, severity, and antacid consumption were recorded daily, and quality of life was assessed at baseline, and at weeks 6 and 12. RESULTS: Heartburn frequency and severity were significantly decreased after 1 day of ranitidine (P < 0.02). By week 6, ranitidine had significantly decreased rescue antacid consumption (7.3 tablets, P < 0.001) vs. antacids (14.1 tablets). Endoscopic oesophagitis healing (

Synergy between low-dose ranitidine and antacid in decreasing gastric and oesophageal acidity and relieving meal-induced heartburn.

BACKGROUND: The pathophysiology of recurrent postprandial heartburn and the basis for the effectiveness of antacids or low doses of histamine H2-receptor antagonists have not been well studied. METHODS: The selected subjects (n=26) had heartburn more than four times a week for at least 2 months, which was responsive to antacids. Gastric pH and oesophageal pH were measured for 1 h before, during, and 4.5 h after ingestion of a meal over 0.5 h. Heartburn severity was assessed at 15-min intervals beginning at the end of the meal. Each subject randomly received placebo, 75 mg ranitidine, 420 mg calcium carbonate, and ranitidine plus calcium carbonate. Values for pH were converted to acid concentration (mM) and integrated acidity was calculated from the cumulative, time-weighted means of the acid concentrations for every second of the postprandial recording period. RESULTS: There was a close temporal relationship between heartburn and oesophageal acidity. Most oesophageal acid exposure occurred over a 90-min period that began approximately 45 min after the end of the meal. During this period the gastric acid concentration was less than 5% of maximal. Ranitidine significantly decreased gastric but not oesophageal acidity, whilst antacid significantly decreased oesophageal but not gastric acidity. Ranitidine plus antacid significantly decreased both gastric and oesophageal acidity. Antacid alone and ranitidine plus antacid significantly decreased heartburn severity. CONCLUSIONS: Determining integrated gastric and oesophageal acidity provides novel information regarding the pathophysiology of meal-induced heartburn as well as the actions of low-dose ranitidine and antacid. For subjects with meal-induced heartburn, treatment with low-dose ranitidine plus antacid is particularly effective in decreasing gastric and oesophageal acidity as well as heartburn severity.

Integrated acidity and the pathophysiology of gastroesophageal reflux disease.

OBJECTIVES: The aim of this study was to demonstrate that integrated esophageal and gastric acidity values, calculated from 24-h pH recordings, can provide more precise quantitative temporal data than the conventional pH parameters historically associated with gastroesophageal reflux disease (GERD) investigations. METHODS: Esophagogastroduodenoscopy results and pH tracings from 20 GERD subjects with > or =10% esophageal acid contact time were studied. Integrated gastric and esophageal acidity were calculated from time-weighted average hydrogen ion concentrations at each second of the 24-h recording period. RESULTS: Integrated esophageal acidity correlated with grade of esophagitis. Two quite distinct GERD subtypes were identified, with either a monophasic or biphasic pattern of integrated esophageal acidity. "Biphasic" subjects differed from "monophasic" subjects in terms of magnitude and pattern of integrated esophageal acidity. Although both groups had significant integrated nocturnal gastric acidity, only the biphasic GERD subjects had concomitant increases in nocturnal integrated esophageal acidity. Esophagitis grade was correlated with magnitude rather than pattern of integrated esophageal acidity, and it was possible to calculate a reflux coefficient that seems to provide an estimate of the quantitative motor disturbance present in GERD. CONCLUSIONS: Integrated esophageal and gastric acidity provide quantitative measures of GERD pathophysiology and, compared to conventional pH parameters, should enhance evaluation of therapeutic interventions.

Esophageal hypersensitivity may be a major cause of heartburn.

OBJECTIVE: Little is known about esophageal nociceptive thresholds in chronic heartburn sufferers with normal clinical findings. The aim of this study was to evaluate and to characterize the pathogenesis of heartburn in subjects who chronically use antacids and had not sought medical attention. METHODS: Subjects (N = 152) with chronic heartburn of > or = 3 months duration underwent endoscopic grading of the esophagus, esophageal manometry, Bernstein testing, intraesophageal balloon distention (IEBD), and 24-h esophageal pH monitoring. RESULTS: Normal acid contact time (ACT < or = 6%) was observed in 43% of these subjects with recurrent heartburn. Of subjects with normal ACT, 64% had normal LES pressure (> or = 10 mm Hg), 79% had normal esophageal endoscopy, 89% developed heartburn during Bernstein acid infusion, and 52% perceived IEBD as painful. CONCLUSIONS: Approximately 30% of individuals chronically using antacids for heartburn had esophageal sensitivity to mechanical or chemical stimuli despite negative endoscopy and pH monitoring. Our findings suggest that a significant subset of typical heartburn sufferers have a lower threshold for esophageal sensation and pain, which may influence options for pharmacological intervention in such subjects.