Occurrence of nighttime gastroesophageal reflux in disturbed and normal sleepers.

BACKGROUND & AIMS: It is not uncommon in a sleep laboratory to encounter individuals who have complaints of disturbed sleep, but who do not meet the criteria for a sleep disorder when evaluated by polysomnography. Because gastroesophageal reflux is known to occur in many individuals without their awareness, it is possible that some of these individuals might be suffering from reflux that is disturbing their sleep. METHODS: Eighty-one individuals with complaints of disturbed or unrefreshing sleep, but no complaints of heartburn, were recruited. A comparison group of 39 individuals with neither sleep nor heartburn complaints also was studied. Both groups were studied on 2 separate occasions by simultaneous polysomnography and pH monitoring to detect the presence of nighttime gastroesophageal reflux and to determine sleep outcomes. RESULTS: In the disturbed-sleep group 27% of subjects had at least one reflux event compared with 33% in the normals. In the subjects who experienced reflux, the disturbed-sleep group had a significantly greater percentage of acid exposure time compared with the normals (9.5% vs 1.6%; P < .05). Participants in the disturbed-sleep group also had a longer sleep-onset latency (P < .05) and less total sleep time (P < .05) compared with the normal sleepers. CONCLUSIONS: Among individuals with complaints of disturbed sleep, there was a subset of individuals who had significant gastroesophageal reflux. We speculate that sleep-related gastroesophageal reflux may play a role in producing disturbed sleep in individuals without heartburn and otherwise unexplained sleep disturbance.

A randomized, comparative study of three doses of AZD0865 and esomeprazole for healing of reflux esophagitis.

BACKGROUND & AIMS: AZD0865 belongs to a new class of acid-suppressing agents with rapid onset of action and potent acid inhibition. We evaluated its effectiveness for healing reflux esophagitis. METHODS: One thousand five hundred twenty-one patients with Los Angeles A-D esophagitis and heartburn of moderate or severe intensity for > or = 4 days/week were randomized to AZD0865 25, 50, or 75 mg or esomeprazole 40 mg once daily for 4-8 weeks. The primary end point was esophagitis healing by AZD0865 at 4 weeks. Healing and control of heartburn were also assessed at 2, 4, and 8 weeks for AZD0865 and esomeprazole. RESULTS: After 4 weeks of treatment, healing rates were similar among AZD0865 doses (76.9%; confidence interval [CI], 72.4%-81.1%); 78.2% (CI, 73.7%-82.3%), and 81.1% (CI, 76.7%-84.9%) for 25, 50, and 75 mg, respectively). The healing rate with esomeprazole at 4 weeks was similar (81.9%; CI, 77.6%-88.7%), and healing rates also were comparable among all treatments at 2 and 8 weeks. There were no significant differences in heartburn control among treatments. AZD0865 and esomeprazole were well-tolerated, although reversible increases in transaminases occurred in a small number of patients receiving AZD0865, especially at the 75-mg dose. CONCLUSIONS: AZD0865 25, 50, and 75 mg provided similar efficacy to esomeprazole 40 mg in terms of esophagitis healing and heartburn control. These findings suggest that increasing the degree of acid inhibition beyond that already achieved by esomeprazole 40 mg (or AZD0865 25 mg) does not translate into increased clinical efficacy in esophagitis patients.

The effect of the area under the plasma concentration vs time curve and the maximum plasma concentration of esomeprazole on intragastric pH.

OBJECTIVE: The aim of this study was to create a useful model of the effect of the area under the plasma concentration vs time curve (AUC) and the maximum plasma concentration (C(max)) of esomeprazole on intragastric pH, measured as the percentage of total time with intragastric pH above 4 (%pH>4) during a 24-h period. METHODS: The evaluation is based on esomeprazole data from two crossover studies. In the first study ( n=36), intragastric pH and plasma concentrations were measured on day 5 of repeated once-daily 20-mg and 40-mg doses of esomeprazole during fasting conditions. In the second study ( n=24), measurements were made on days 1 and 5 of repeated once-daily dosing with 40 mg of esomeprazole under fasting and fed conditions. A model was applied in which the logistic function of %pH>4 was assumed to be linearly dependent on log-transformed AUC and C(max). The effects of repeated dosing and of fed relative to fasting conditions were included in the model, and the interindividual variation in %pH>4 was accounted for. RESULTS: The effect of the pharmacokinetic variables AUC and C(max) of esomeprazole on %pH>4 can be adequately described by a model using a logistic function for %pH>4 and a normally distributed error. In this model, log-transformed AUC and C(max) were both statistically significant. The model showed that for a fixed AUC, a decrease in C(max) gives an increase in %pH>4. A decrease in AUC, keeping C(max) fixed, gives a decrease in %pH>4, but a simultaneous decrease in C(max) and AUC will result in a less pronounced decrease in %pH>4. The model may be used for predicting differences in %pH>4 between two formulations, based on assessments of AUC and C(max). Repeated dosing gave an increased %pH>4, where approximately half of the increase stemmed from increased AUC and C(max), and the rest could be attributable to the persistent blockade of the proton pumps. Food intake reduced AUC and C(max) but had no obvious effect on %pH>4, which is explained by a prolonged time period with quantifiable plasma concentrations. CONCLUSION: The effect of the pharmacokinetic variables AUC and C(max) of esomeprazole on %pH>4 can be adequately described by a model using a logistic function for %pH>4 and a normally distributed error.

Pharmacokinetics of omeprazole given by continuous intravenous infusion to patients with varying degrees of hepatic dysfunction.

OBJECTIVE: To examine the pharmacokinetics of omeprazole during intravenous infusion in patients with varying degrees of liver dysfunction (Child-Pugh categories A to C). DESIGN: Nonblinded single-period study. PATIENTS: Thirteen patients, five males and eight females with a mean age of 59 years and proven hepatic cirrhosis, classified according to Child-Pugh criteria as A (n = 5), B (n = 4) or C (n = 4). METHODS: Each patient received an 80mg bolus of omeprazole over 30 minutes followed by a continuous infusion of 8 mg/h for 47.5 hours. Blood samples were taken frequently throughout the infusion and during the subsequent 24-hour washout period for determination of omeprazole and its metabolites. Laboratory screening was also performed at the start of the study, after 72 hours and at the 14 day follow-up visit. RESULTS: Data were evaluable for 12 patients. For omeprazole, the mean total area under the plasma concentration-time curve (AUC) was 286.5 micromol x h/L, peak plasma concentration was 14.9 micromol/L and terminal elimination half-life was 4.1 hours; these values were higher than those observed historically in control patient populations. Concentrations of the metabolite omeprazole sulphone were also increased, but there was a decrease in concentrations of hydroxy-omeprazole. Deviations from normal values increased with increasing disease severity for all parameters. For example, in patients with liver dysfunction of Child-Pugh categories A, B and C, AUC(48 )was 240.8, 280.4 and 323.3 micromol x h/L compared with 151.3 micromol x h/L in the historical control population. Despite its altered pharmacokinetics, omeprazole was not associated with any serious or untoward effects. CONCLUSION: Exposure to omeprazole following intravenous administration was higher in patients with liver dysfunction than in the normal population. However, even in patients with severely impaired liver function, the omeprazole plasma concentration did not change by more than 100% and the drug was well tolerated.

Esomeprazole 40 mg and 20 mg is efficacious in the long-term management of patients with endoscopy-negative gastro-oesophageal reflux disease: a placebo-controlled trial of on-demand therapy for 6 months.

BACKGROUND: On-demand therapy may offer an effective approach to the long-term management of gastro-oesophageal reflux disease (GORD) without oesophagitis. AIM: To examine the efficacy of the novel proton pump inhibitor esomeprazole as on-demand therapy in endoscopy-negative GORD. PATIENTS AND METHODS: Endoscopy-negative GORD patients who achieved complete resolution of heartburn after short-term esomeprazole or omeprazole treatment (n = 721) were randomized to esomeprazole 20 mg (n = 282), 40 mg (n = 293) or placebo (n = 146) on demand (maximum one dose/day) for 6 months. The primary and secondary efficacy endpoints were time to study discontinuation due to (i) unwillingness to continue and (ii) inadequate control of heartburn, respectively. RESULTS: Both doses of esomeprazole were more effective than placebo. During the 6-month period, 42% of placebo recipients discontinued treatment due to unwillingness to continue, compared with 8% and 11% of esomeprazole 20 mg and 40 mg recipients, respectively. Overall, more patients treated with esomeprazole were free from gastrointestinal symptoms after 6 months of on-demand therapy. CONCLUSIONS: Esomeprazole 20 mg was superior to placebo for on-demand treatment of GORD; a higher dose did not confer additional clinical benefit. Over 90% of patients were willing to continue on-demand treatment with esomeprazole 20 mg over a 6-month period.

Effect of esomeprazole 40 mg vs omeprazole 40 mg on 24-hour intragastric pH in patients with symptoms of gastroesophageal reflux disease.

Maintenance of intragastric pH > 4 is vital for effective management of gastroesophageal reflux disease (GERD). Esomeprazole 40 mg, the first proton pump inhibitor developed as an optical isomer, demonstrates improved acid inhibition over omeprazole 20 mg. Our aim was to compare esomeprazole 40 mg with omeprazole 40 mg, once-daily, on intragastric acidity in patients with symptoms of GERD. In this open-label, crossover study, 130 patients with symptoms of GERD received esomeprazole 40 mg or omeprazole 40 mg once-daily for five days. The 24-hr intragastric pH was monitored on days 1 and 5 of each treatment period. The mean percentage of the 24-hr period with intragastric pH > 4 was significantly greater (P < 0.001) with esomeprazole 40 mg than with omeprazole 40 mg on days 1 (48.6% vs 40.6%) and 5 (68.4% vs 62.0%). Interpatient variability was significantly less with esomeprazole than omeprazole. Esomeprazole was well tolerated. In conclusion, esomeprazole 40 mg provides more effective acid control than twice the standard dose of omeprazole.

Pharmacokinetic study of esomeprazole in patients with hepatic impairment.

OBJECTIVE: To evaluate the pharmacokinetics and safety of esomeprazole (Nexium), the S-isomer of omeprazole, after repeated oral dosing in patients with hepatic impairment. DESIGN: Single-centre, open-label one-way study. METHODS: Twelve patients (aged 40-60 years) with mild to severe hepatic impairment received once-daily oral esomeprazole 40 mg for 5 days. Serial blood samples were drawn up to 24 h post-dose on day 5 to determine plasma levels of esomeprazole and its metabolites. Pharmacokinetic parameters were compared with an historical control group of 36 gastro-oesophageal reflux disease (GORD) patients (aged 29-58 years) with normal hepatic function. RESULTS: Esomeprazole was absorbed rapidly (mean maximum plasma concentration (Cmax) 6.1 micromol/l, mean time to Cmax (tmax) 1.9 h) and eliminated rapidly (mean plasma elimination half-life (t1/2) 2.1 h). Elimination of its pharmacologically inactive sulphone and hydroxy metabolites was more gradual. Patients with mild hepatic impairment had area under the plasma concentration-time curve during the dosage interval (AUCtau) and t1/2 values largely within the range of the control group. In patients with moderate hepatic impairment, t1/2 values were similar and AUCtau was slightly higher than in controls, whereas both parameters were increased in patients with severe hepatic impairment. The mean ratios of esomeprazole AUCtau, Cmax and t1/2 values in patients with and without hepatic impairment were 1.8, 1.3 and 1.3, respectively. CONCLUSIONS: The steady-state pharmacokinetics of esomeprazole were not altered substantially by mild or moderate hepatic impairment; however, plasma levels of esomeprazole were elevated in severe cases. Thus, dose adjustment appears unwarranted in mild or moderate hepatic impairment, but may be required in some severely impaired patients. Esomeprazole was tolerated well across the spectrum of hepatic impairment.