Comparison of the effects of intracerebroventricular administration of glucagon-like peptides 1 and 2 on hypothalamic appetite regulating factors and sleep-like behavior in chicks.

Glucagon-like peptide (GLP)-1 and GLP-2, proglucagon-derived brain-gut peptides, function as anorexigenic neuropeptides in mammals. We previously showed that central administration of GLP-1 and GLP-2 potently suppressed food intake in chicks. GLP-1 and GLP-2 specifically activate their receptors GLP-1 receptor (GLP1R) and GLP-2 receptor (GLP2R), respectively in chickens. In adult chickens, GLP1R and GLP2R are expressed in different brain regions. These findings raise the hypothesis that both GLP-1 and GLP-2 function as anorexigenic peptides in the chicken brain but the mechanisms underlying the anorexigenic effects are different between them. In the present study, we compared several aspects of GLP-1 and GLP-2 in chicks. GLP1R mRNA levels in the brain stem and optic lobes were significantly higher than in other parts of the brain, whereas GLP2R mRNA was densely expressed in the telencephalon. Intracerebroventricular administration of either GLP-1 or GLP-2 significantly reduced the mRNA levels of corticotrophin releasing factor and AMP-kinase (AMPK) α1. The mRNA level of proopiomelanocortin was significantly increased, and those of AMPKα2 and GLP2R were significantly decreased by GLP-2, whereas the mRNA level of pyruvate dehydrogenase kinase 4 was significantly increased, and that of GLP1R was significantly decreased by GLP-1. Intracerebroventricular administration of either GLP-1 or GLP-2 induced sleep-like behavior in chicks. Our findings suggest that the anorexigenic peptides GLP-1 and GLP-2 induce similar behavioral changes in chicks, but the mechanism may differ between them.

Intracerebroventricular administration of chicken glucagon-like peptide-2 potently suppresses food intake in chicks.

Glucagon-related peptides, such as glucagon-like peptide (GLP)-1, GLP-2 and oxyntomodulin (OXM), are processed from an identical precursor proglucagon. In mammals, all of these peptides are suggested to be involved in the central regulation of food intake. We previously showed that intracerebroventricular administration of chicken OXM and GLP-1 significantly suppressed food intake in chicks. Here, we show that central administration of chicken GLP-2 potently suppresses food intake in chicks. Male 8-day-old chicks (Gallus gallus domesticus) were used in all experiments. Intracerebroventricular administration of chicken GLP-2 significantly suppressed food intake in chicks. Plasma glucose concentration was significantly decreased by chicken GLP-2, whereas plasma nonesterified fatty acid concentration was significantly increased. Intracerebroventricular administration of chicken GLP-2 did not affect plasma corticosterone concentration. In addition, the anorexigenic effect of GLP-2 was not reversed by the corticotropin-releasing factor (CRF) receptor antagonist α-helical CRF, suggesting that CRF is not a downstream mediator of the anorexigenic pathway of GLP-2 in chicks. Intracerebroventricular administration of an equimolar amount of GLP-1 and GLP-2, but not OXM, significantly suppressed food intake in both broiler and layer chicks. All our findings suggest that GLP-2 functions as a potent anorexigenic peptide in the brain, as well as GLP-1, in chicks.

Correlation analysis of hypothalamic mRNA levels of appetite regulatory neuropeptides and several metabolic parameters in 28-day-old layer chickens.

Various lines of evidence suggest that appetite-related neuropeptides in the hypothalamus are regulated by adiposity signals such as leptin and insulin in mammals. In the present study, we examined age-dependent changes in the weight of abdominal fat and hypothalamic mRNA levels of neuropeptide Y (NPY, an orexigenic neuropeptide) and proopiomelanocortin (POMC, a precursor of anorexigenic neuropeptides) in growing chickens at 7, 14, 21 and 28 days of age. Hypothalamic NPY mRNA levels were significantly (P < 0.05) decreased after 14 days of age, whereas hypothalamic POMC mRNA levels were significantly (P < 0.05) increased at 28 days of age. The percentage of abdominal fat was significantly increased after 14 days of age in chickens. We next examined the correlation of hypothalamic NPY and POMC mRNA levels and several parameters at 28 days of age. There were no significant correlations between hypothalamic mRNA levels of NPY or POMC and the percentage of abdominal fat. These findings suggest that the gene expressions of NPY and POMC do not depend on adiposity in chickens, at least in 28-day-old layer chickens.

Intracerebroventricular administration of chicken oxyntomodulin suppresses food intake and increases plasma glucose and corticosterone concentrations in chicks.

Central administration of proglucagon-derived peptides, glucagon, glucagon-like peptide-1 (GLP-1), and oxyntomodulin (OXM), suppresses food intake in both mammals and birds. Recent findings suggest that GLP-1 receptor is involved in the anorexigenic action of OXM in both species. However, mammalian (bovine) OXM was used in chicken studies, even though the amino acid sequence and peptide length of chicken OXM differ from those of bovine OXM. In the present study, we examined the effect of chicken OXM on food intake and plasma components in chicks to investigate the mechanisms underlying the OXM effect. Male 8-day-old chicks (Gallus gallus domesticus) were used in all experiments. Intracerebroventricular administration of chicken OXM significantly suppressed food intake in chicks. Plasma concentrations of glucose and corticosterone were significantly increased by chicken OXM. These phenomena were also observed after bovine OXM injection in chicks. In contrast, central administration of chicken GLP-1 significantly decreased plasma glucose concentration and did not affect plasma corticosterone concentration. We previously showed that central administration of chicken glucagon significantly increased plasma concentrations of glucose and corticosterone in chicks. All our findings suggest that the mechanism underlying the anorexigenic action of OXM is similar to that of glucagon in chicks.

Intracerebroventricular administration of novel glucagon-like peptide suppresses food intake in chicks.

Glucagon-related peptides such as glucagon, glucagon-like peptide-1, and oxyntomodulin suppress food intake in mammals and birds. Recently, novel glucagon-like peptide (GCGL) was identified from chicken brain, and a comparatively high mRNA expression level of GCGL was detected in the hypothalamus. A number of studies suggest that the hypothalamus plays a critical role in the regulation of food intake in mammals and birds. In the present study, we investigated whether GCGL is involved in the central regulation of food intake in chicks. Male 8-day-old chicks (Gallus gallus) were used in all experiments. Intracerebroventricular administration of GCGL in chicks significantly suppressed food intake. Plasma glucose level was significantly decreased by GCGL, whereas plasma corticosterone level was not affected. Central administration of a corticotrophin-releasing factor (CRF) receptor antagonist, α-helical CRF, attenuated GCGL-suppressed food intake. It seems likely that CRF receptor is involved in the GCGL-induced anorexigenic pathway. All our findings suggest that GCGL functions as an anorexigenic peptide in the central nervous system of chicks.

Histology of symptomatic gastroesophageal reflux disease: is it predictive of response to proton pump inhibitors?

BACKGROUND AND AIM: To examine the differences in esophageal histopathology between non-erosive reflux disease (NERD) and reflux esophagitis (RE), and to investigate whether baseline esophageal histopathology can predict the therapeutic response to proton pump inhibitors (PPIs). METHOD: The subjects comprised 94 patients with NERD (n = 71) or mild RE (n = 23). Tissue was biopsied from 5 cm above the squamo-columnar junction (SCJ), and the degree or presence of nine histopathological markers was assessed. The patients were treated with rabeprazole (RPZ) 10 mg once daily for 4 weeks. If complete heartburn relief was not achieved, RPZ was increased to 10 mg twice daily for another 2 weeks, and then to 20 mg twice daily for another 2 weeks if heartburn remained. RESULTS: Features of esophageal histopathology 5 cm above the SCJ differed between NERD and RE patients. The esophageal histopathology in patients unresponsive to RPZ was characterized by Protein Gene Product (PGP) 9.5 negativity in those with NERD, and intraepithelial bleeding in those with RE. In addition, the combination of dilated intercellular spaces (DIS) (+)/PGP 9.5 (-) was indicative of strong resistance to PPI therapy in NERD patients. CONCLUSION: The therapeutic efficacy of PPI can be predicted from the features of biopsied esophageal tissue. Factors predictive of resistance to treatment with PPI are negativity for PGP 9.5 in NERD patients and intraepithelial bleeding in RE patients.

Clinical symptoms of FSSG in gastroesophageal reflux disease are critical for PPI treatment: Japanese multi-centers with 185 patients.

AIM: The main aim of this study was to determine whether questionnaire evaluations of clinical symptoms in gastroesophageal reflux disease were useful to assess proton pump inhibitor therapy. METHODS: A total of 185 Japanese patients (men, 88; women, 97; age: 55.7 ± 16.1 years) with gastroesophageal reflux disease were enrolled. The patients were divided based on the frequency scale for symptoms of gastroesophageal reflux disease: severe symptoms with scores ≥8 and mild symptoms with scores ≤7. Quality of life was evaluated with the Medical Outcomes Study 8-Item Short-Form Health Survey. All patients were treated with a proton pump inhibitor, rabeprazole (10 mg/day), for 8 weeks. RESULTS: Patients were classified into four groups: reflux esophagitis with severe symptoms (n = 92, 49.7%); reflux esophagitis with mild symptoms (n = 17, 9.2%); non-erosive reflux disease with severe symptoms (n = 66, 35.7%); and non-erosive reflux disease with mild symptoms (n = 10, 5.4%). The dysmotility score was high in non-erosive reflux disease with severe symptoms compared with reflux esophagitis with severe symptoms (9.1 ± 0.5 vs 6.8 ± 0.5, P < 0.05). The symptom score and quality of life in the severe symptoms groups for both reflux esophagitis and non-erosive reflux disease were significantly improved by rabeprazole treatment. Only the reflux score was improved by rabeprazole in the reflux esophagitis with mild symptoms group; no therapeutic effect was observed for the non-erosive reflux disease with mild symptoms group. CONCLUSIONS: Low scores on the frequency scale for the symptoms of gastroesophageal reflux disease indicate poor responsiveness to proton pump inhibitor treatment, and high scores indicate good responsiveness.

A study on the efficacy of rebamipide for patients with proton pump inhibitor-refractory non-erosive reflux disease.

BACKGROUND AND AIM: Reflux symptoms in patients with non-erosive reflux disease (NERD) cannot be easily controlled by treatment with proton pump inhibitors (PPI). The anti-inflammatory function of rebamipide may be effective for protecting the esophageal mucosa. This prospective randomized multicenter placebo-controlled study was performed to clarify the efficacy of rebamipide for NERD patients whose reflux symptoms were refractory to PPI treatment. METHODS: One hundred forty-nine patients were enrolled on the basis of a QUEST score of over 6 and absence of endoscopically proven esophageal mucosal breaks. All the patients were initially administered 15 mg of lansoprazole for 4 weeks, and the symptoms were then assessed using QUEST and GSRS. PPI-refractory patients were randomly assigned to administration of rebamipide or placebo t.i.d. for 4 weeks. RESULTS: Three of the 149 patients were lost to follow-up, and 60 among the remaining 146 patients were found to be PPI-refractory. Among these PPI-refractory patients, 31 were randomly assigned to a rebamipide group and 29 to a placebo group. At the end of drug administration, the QUEST and GSRS scores did not differ between the rebamipide and placebo groups, although a significantly higher proportion of patients in the rebamipide group showed amelioration of abdominal pain and diarrhea. CONCLUSION: Administration of rebamipide cannot effectively control reflux symptoms in NERD patients whose symptoms are refractory to PPI therapy.

Predicting the efficacy of proton pump inhibitors in patients with non-erosive reflux disease before therapy using dual-channel 24-h esophageal pH monitoring.

BACKGROUND AND AIM: We aimed to determine whether reflux- and symptom-related parameters can predict the efficacy of proton pump inhibitors (PPI) in non-erosive reflux disease (NERD). METHODS: Twenty-seven NERD patients who had experienced heartburn more than once a week within the previous month were enrolled. Intraesophageal pH before therapy was measured simultaneously at 5 and 15 cm above the esophagogastric junction (EGJ) for 24 h. The PPI rabeprazole was administered at a dose of 10 mg once daily for 4 weeks. In the event that heartburn was not relieved, the dose was increased to 10 mg twice daily for an additional 2 weeks, and again to 20 mg twice daily for another 2 weeks. RESULTS: Univariate analysis demonstrated no significant associations between any reflux- or symptom-related parameters at either site and complete heartburn relief after 4 weeks, or cumulative complete heartburn relief after 8 weeks. However, post-hoc analysis demonstrated more satisfactory heartburn relief after 4 weeks in patients with a high symptom index compared with those with a low symptom index, at 5 cm above the EGJ (P = 0.009). Cumulative satisfactory heartburn relief after 8 weeks was also greater in patients with a high total number of acid reflux episodes compared with those with a low total number of episodes, at 15 cm above the EGJ (P = 0.037). CONCLUSIONS: Pre-therapeutic pH monitoring in the lower and mid-esophagus is useful for predicting the efficacy of PPI in NERD patients.

Investigation of pretreatment prediction of proton pump inhibitor (PPI)-resistant patients with gastroesophageal reflux disease and the dose escalation challenge of PPIs-TORNADO study: a multicenter prospective study by the Acid-Related Symptom Research Group in Japan.

BACKGROUNDS: Some non-erosive reflux disease (NERD) and reflux esophagitis (RE) patients are unresponsive to a proton pump inhibitor (PPI) at standard dose. We investigated the predictive marker of the efficacy of PPI for GERD patients including NERD and RE treated with standard and increased doses of a PPI. METHODS: Patients with symptomatic gastroesophageal reflux disease (GERD) (NERD and RE) were treated with rabeprazole (RPZ) 10 mg once daily for 4 weeks. The RPZ dosage was increased to 10 mg twice daily for an additional 2 weeks and again to 20 mg twice daily for another 2 weeks if heartburn was not relieved. Baseline characteristics and efficacy of RPZ were assessed on the basis of a heartburn diary and frequency scale for symptoms of GERD (FSSG). RESULTS: Complete heartburn relief rates after 4 weeks were 42.5% (31/73) and 67.9% (19/28) in NERD and RE groups, respectively, which rose to 68.9 and 91.7% after dose escalation. Multivariate analysis revealed that parameters associated with resistance to RPZ 10 mg once daily were female, non-smoking, frequent heartburn, low score for question 4 (Q4) of the FSSG (subconsciously rubbing the chest), and high scores for Q3 (heavy stomach after meal) and Q7 (unusual sensation in the throat). Frequent heartburn and a high score for Q7 were associated with resistance to RPZ 20 mg twice daily. FSSG scores of patients resistant to RPZ were significantly higher in comparison with responders before and during treatment. CONCLUSIONS: FSSG could predict response to a PPI for symptomatic GERD. Increase of RPZ dose is useful for treatment of GERD refractory to the standard dose of RPZ.

Comparison of endoscopic findings with symptom assessment systems (FSSG and QUEST) for gastroesophageal reflux disease in Japanese centres.

BACKGROUND AND AIM: We compared endoscopic findings of the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG), a written questionnaire developed in Japan, to that for the questionnaire for the diagnosis of reflux esophagitis (QUEST) for the diagnosis of reflux esophagitis. METHODS: We registered 475 patients with untreated symptoms of upper abdominal pain (male/female: 252/223, average age 52.4 +/- 17.8 years). Subjects were assessed first with the FSSG and QUEST questionnaires, then by endoscopy, before allocation to a gastric ulcer (GU), duodenal ulcer (DU), gastroesophageal reflux disease (GERD) or functional dyspepsia (FD) group. RESULTS: On the basis of the endoscopic findings the diagnoses for the 475 subjects were as follows: FD 52.2%, DU 7.6%, GU 7.8%, and GERD 32.4% (Grade M 10.1%, Grade A + B 20.2%, Grade C + D 2.3%). There was no difference between the FSSG and QUEST in sensitivity, specificity or accuracy for any condition. The FSSG score rose with increasing endoscopic severity of GERD, but there was no correlation between the QUEST score and endoscopic severity. The FSSG total score was inferior to QUEST in terms of distinguishing GERD from other conditions, but when only the questions relating to reflux symptoms were used, the FSSG was able to distinguish GERD from other conditions as well as QUEST. CONCLUSIONS: The FSSG score reflects the severity of the endoscopic findings of GERD.

Comparing the acid-suppressive effects of three brands of generic lansoprazole with the original: pharmacokinetic bioequivalence tests do not necessarily guarantee pharmacodynamic equivalence.

Generic drugs contain the same active ingredient as an original drug and have their bioequivalence proved by pharmacokinetic tests. However, few studies have been reported on whether these bioequivalence studies infer pharmacodynamic equivalence. In this study, in eight healthy Helicobacter pylori-negative CYP2C19 extensive metabolizers, we compared the acid-suppressive effects of repeated administration of 15 mg of three brands of generic lansoprazole, Taiproton, Tapizol, and Lansoral, with those of the original lansoprazole, Takepron. Median intragastric pH value for 24-h and % pH > 4 for daytime (08:00-20:00 h) and night-time were significantly higher with any lansoprazole formulation, compared with the control (P < 0.05, Wilcoxon signed-rank test). However, during the daytime, % pH > 4 with Tapizol was significantly lower than the original (P < 0.05). Compared with the original, no significantly larger, but no small range of inter-subject variations were observed in these two parameters for each of the three brands of generic lansoprazole (Bartlett test). Pharmacokinetic bioequivalence tests do not necessarily guarantee pharmacodynamic equivalence.

Validity of endoscopic classification of nonerosive reflux disease.

BACKGROUND: Minimal changes, such as erythema without sharp demarcation or whitish turbidity of the lower esophageal mucosa, have recently been used for endoscopic classification of nonerosive reflux disease (NERD) in Japan. This study examined the usefulness of such changes in characterizing the pathophysiology of NERD. METHODS: Physicians specializing in esophageal endoscopy performed endoscopy on 115 patients with NERD. Based on the presence or absence of minimal changes, patients were categorized as displaying NERD with minimal changes (grade M, n = 49) or with no minimal changes or mucosal breaks (grade N, n = 66). Clinical features, quality of life (QOL) scores, and ambulatory 24-h esophageal pH values were compared between groups. Ambulatory 24-h esophageal pH values were monitored in 31 patients (14 grade M and 17 grade N patients) who gave consent out of 115 patients. RESULTS: In ambulatory 24-h esophageal pH monitoring, 57.1% (8/14) of grade M patients had pH < 4 more than 4% of the time (abnormal acid reflux) compared with 11.8% (2/17) in the grade N group, a significant difference (P = 0.018). QOL scores did not differ significantly between grades and were significantly lower in both groups compared with the general Japanese population. No significant differences were observed in patient background between the grade M and grade N groups. CONCLUSIONS: Frequency of abnormal acid reflux with NERD is higher in patients with minimal changes than in patients without such changes. Minimal changes are most likely attributable to gastric acid reflux.

Pharmacokinetic and pharmacodynamic properties of lafutidine after postprandial oral administration in healthy subjects: comparison with famotidine.

Lafutidine, a histamine H(2)-receptor antagonist, inhibits gastric acid secretion during the daytime, however, the relationship between the plasma concentration and the drug response remains unclear. The aim of this study was to compare the pharmacokinetic and pharmacodynamic properties of lafutidine and famotidine following postprandial oral administration. After a lafutidine tablet (10 mg), famotidine tablet (20 mg), or water only (control) was administered, blood samples were taken and intragastric pH was measured. The plasma concentrations of lafutidine and famotidine were determined by HPLC, and the median intragastric pH values per 30 min were used as the degrees of gastric acid suppression. Data were analyzed based on a one-compartment pharmacokinetic model and a sigmoid E(max) pharmacodynamic model. Lafutidine plasma concentrations rapidly increased after administration; famotidine required some time to increase the plasma concentrations, requiring an absorption lag time in the pharmacokinetic model. Between the plasma concentration and DeltapH (the difference in intragastric pH by the drug vs. control), lafutidine showed an anticlockwise hysteresis loop which indicated equilibration delay between the plasma concentration and effect site, requiring an effect site compartment in the pharmacodynamic model; famotidine showed more parallel relationship. These results indicated that the pharmacokinetic and pharmacodynamic properties of lafutidine after postprandial oral administration were different from those of famotidine at least 4.5 h after dosing.

Acid-suppressive effects of various regimens of omeprazole in Helicobacter pylori-negative CYP2C19 homozygous extensive metabolizers: which regimen has the strongest effect?

To achieve more potent and long-lasting acid suppression, omeprazole was administered for 7 days in 5 regimens: 10, 20, and 40 mg once daily (od), and 10 and 20 mg twice daily (bid), in 7 healthy Helicobacter pylori-negative CYP2C19 homozygous extensive metabolizers, and intragastric pH was continuously measured. The median intragastric pH and percent time pH > 4.0 for 24 hours increased dose dependently with 10, 20, and 40 mg od. Ten and 20 mg bid wre comparable to 20 and 40 mg od, respectively. Concerning percent time pH > 4.0 in the nighttime (20:00-8:00 hours), 20 mg bid was significantly superior to 40 mg od (P < .05). In 4 of the 5 regimens, all 7 subjects had nocturnal acid breakthrough, whereas with 20 mg bid it occurred in only 3. We concluded that, considering nighttime acid suppression, omeprazole 20 mg bid had the strongest effect.

Which has superior acid-suppressive effect, 10 mg omeprazole once daily or 20 mg famotidine twice daily? Effects of single or repeated administration in Japanese Helicobacter pylori-negative CYP2C19 extensive metabolizers.

Low-dose omeprazole is superior to full-dose famotidine in maintenance therapy for gastroesophageal reflux disease, whereas "on-demand" famotidine is more effective for relief of episodes of heartburn. To explain this apparent discrepancy, intragastric pH was measured for 24-hr seven times in eight Japanese Helicobacter pylori-negative cytochrome P450 2C19 extensive metabolizers; on Days 1, 8, and 15 of repeated administration of 10 mg of omeprazole once daily and of 20 mg of famotidine twice daily and before medication. During repeated administration of omeprazole, mean intragastric pH and % time that intragastric pH > 4.0 were significantly higher and became greater. With famotidine, although these parameters were significantly higher, the degrees became smaller. Consequently, acid-suppressive effect was in the order; omeprazole < famotidine on Day 1, omeprazole approximately famotidine on Day 8, and omeprazole >famotidine on Day 15. This discrepancy possibly results from the "potentiation" of acid-suppressive effect of omeprazole and the "tolerance" phenomenon in respect to famotidine.

The pharmacodynamic effect of omeprazole 10 mg and 20 mg once daily in patients with nonerosive reflux disease in Japan.

BACKGROUND: To evaluate the pharmacodynamic effect, efficacy, and safety of omeprazole 10 mg and 20 mg once daily in patients with nonerosive reflux disease (NERD) in Japan. METHODS: A total of 37 patients were randomized to omeprazole 10 mg or omeprazole 20 mg once daily for 4 weeks. Eligible patients had a history of moderate-to-severe heartburn for 2 days or more per week during the last 1 month or longer prior to the study screening, grade M or grade N on Hoshihara's modification of the Los Angeles classification (i.e., no sign of mucosal break on esophagogastroduodenoscopy), and heartburn episodes for 2 days or more per week during the last week of the observation period while taking antacids. Ambulatory 24-h intraesophageal pH was monitored on the day before treatment and on the last day of treatment. The occurrence of a heartburn episode was recorded during pH monitoring. The primary endpoint was the change in the percentage of time with intraesophageal pH < 4 during the 24-h period before and after omeprazole treatment. RESULTS: Both omeprazole 10 mg and omeprazole 20 mg once daily reduced the percentage of time with intraesophageal pH < 4. The percentage reduction in time with intraesophageal pH < 4 after treatment with omeprazole was associated with a reduced number of heartburn episodes. Patients with grade M or grade N esophagus had similar pH profiles and NERD characteristics (e.g., pH holding time, symptom index) and comparable responses to omeprazole. No serious, drug-related adverse events were reported. CONCLUSIONS: Omeprazole 10 mg or 20 mg reduces the percentage of time with intraesophageal pH < 4, is efficacious, and is well tolerated in patients with NERD in Japan, regardless of the patient's endoscopic classification.

Acid-suppressive effects of rabeprazole, omeprazole, and lansoprazole at reduced and standard doses: a crossover comparative study in homozygous extensive metabolizers of cytochrome P450 2C19.

BACKGROUND AND OBJECTIVES: To improve clinical outcomes of the initial therapy for gastroesophageal reflux disease, intragastric pH should be above 4.0 for more than 20 hours a day (83.3%) and nocturnal gastric acid breakthrough, defined as 60 continuous minutes of intragastric pH below 4.0 at night, should be inhibited. A "step-down" therapy sometimes fails because of insufficient acid suppression. Therefore we compared the acid-suppressive effects of proton pump inhibitors. METHODS: This was a prospective, randomized, open-label, 8-way crossover study. In 9 healthy Helicobacter pylori-negative cytochrome P450 (CYP) 2C19 homozygous extensive metabolizers, intragastric pH was measured for 24 hours on day 7 of treatment with rabeprazole, omeprazole, and lansoprazole orally administered once daily at reduced and standard doses. RESULTS: Compared with baseline data (7% [range, 5%-20%]), the median values of the 24-hour percent of time that intragastric pH was above 4.0 significantly increased but did not exceed 83.3% under any of the 7 regimens, which were as follows: 10 mg rabeprazole (51% [range, 28%-78%], P < .01), 20 mg rabeprazole (59% [range, 36%-83%], P < .01), 10 mg omeprazole (26% [range, 4%-33%], P < .05), 20 mg omeprazole (48% [range, 31%-73%], P < .01), 40 mg omeprazole (62% [range, 47%-87%], P < .01), 15 mg lansoprazole (34% [range, 5%-51%], P < .05), and 30 mg lansoprazole (56% [range, 20%-76%], P < .05). Significant differences were observed among 10, 20, and 40 mg omeprazole (10 mg versus 20 mg, P < .01; 10 mg versus 40 mg, P < .01; and 20 mg versus 40 mg, P < .05) and between 15 and 30 mg lansoprazole (P < .01), whereas no significant difference was observed between 10 and 20 mg rabeprazole. Nocturnal gastric acid breakthrough was observed under all regimens. CONCLUSIONS: Rabeprazole, omeprazole, and lansoprazole, given once daily at standard doses, cannot be expected to achieve ideal acid suppression for the initial therapy for gastroesophageal reflux disease in Helicobacter-negative CYP2C19 homozygous extensive metabolizers. Rabeprazole 10 mg may be appropriate for step-down therapy.