Kurt Brown

Effect of esomeprazole on nighttime heartburn and sleep quality in patients with GERD : A randomized, placebo-controlled trial

OBJECTIVES:Sleep disturbances are common in patients with gastroesophageal reflux disease (GERD). This study examined the effects of esomeprazole on nighttime heartburn, GERD-related sleep disturbances, sleep quality, work productivity, and regular activities.METHODS:This multicenter, randomized, double-blind, placebo-controlled trial included adults with GERD-associated sleep disturbances and moderate-to-severe nighttime heartburn (recorded by patient diary during screening). Patients received oral esomeprazole 40 mg (n = 220) or 20 mg (n = 226) or placebo (n = 229) once daily for 4 wk. The primary outcome was relief of nighttime heartburn. Secondary outcomes included resolution of sleep disturbances, sleep quality measured by the Pittsburgh Sleep Quality Index (PSQI) questionnaire, and work productivity measured by the Work Productivity and Activity Impairment Questionnaire.RESULTS:Nighttime heartburn was relieved in 53.1% (111/209), 50.5% (111/220), and 12.7% (28/221) of patients who received esomeprazole 40 mg, esomeprazole 20 mg, and placebo, respectively. Differences (95% CI) versus placebo were 40.5% (32.4%, 48.5%) and 37.8% (29.9%, 45.7%) and were highly significant (p < 0.0001). GERD-related sleep disturbances resolved in significantly more (p < 0.0001) patients who received esomeprazole 40 (73.7%) or 20 mg (73.2%) than in those who received placebo (41.2%). Both esomeprazole groups had greater PSQI global score changes from baseline (p < 0.0001 vs placebo) and more (p < 0.0001 vs placebo) work hours saved per week per patient compared with baseline (esomeprazole 40 mg, 11.6 h; esomeprazole 20 mg, 12.3 h; placebo, 6.2 h).CONCLUSIONS:Esomeprazole reduced nighttime heartburn and GERD-related sleep disturbances and improved sleep quality and work productivity.

NSAID-Associated Adverse Effects and Acid Control Aids to Prevent Them A Review of Current Treatment Options

NSAIDs are central to the clinical management of a wide range of conditions. However, NSAIDs in combination with gastric acid, which has been shown to play a central role in upper gastrointestinal (GI) events, can damage the gastroduodenal mucosa and result in dyspeptic symptoms and peptic lesions such as ulceration.

Clinical trial: healing of NSAID-associated gastric ulcers in patients continuing NSAID therapy – a randomized study comparing ranitidine with esomeprazole

Background  The use of non‐steroidal anti‐inflammatory drugs (NSAID) is associated with an increased risk of gastric ulcer (GU) development.

Healing of Gastric Ulcers with Esomeprazole Versus Ranitidine in Patients Who Continued to Receive NSAID Therapy: A Randomized Trial

OBJECTIVE:To compare orally administered esomeprazole 40 mg once daily and 20 mg once daily with ranitidine 150 mg twice daily for the healing of gastric ulcers (GUs) during 8 wks in patients who continued to receive daily nonsteroidal anti-inflammatory drug (NSAID) therapy.METHODS:This multicenter, randomized, double-blind, parallel-group trial included patients who were receiving nonselective or cyclo-oxygenase-2 (COX-2)–selective NSAIDs and had at least one GU ≥5 mm but no gastric or duodenal ulcer >25 mm in diameter at the baseline esophagogastroduodenoscopy (EGD). After 4 and 8 wks of treatment, ulcer-healing status was confirmed by EGD. The primary outcome was the percentage of patients in each treatment group who had no GUs (GU healing rate) at week 8.RESULTS:A total of 406 patients were randomized to treatment. At week 8, GU healing rates with esomeprazole 40 and 20 mg were 91.5% (118/129; 95% CI, 86.7–96.3%) and 88.4% (122/138; 95% CI, 83.1–93.7%), respectively, and were significantly higher than the 74.2% rate (98/132; 95% CI, 66.8–81.7%) with ranitidine (p < 0.01 for both comparisons). GU healing rates at 4 wks (78.3%[101/129] and 79.0%[109/138] in the esomeprazole 40- and 20-mg groups, respectively) were also significantly higher (p < 0.05) than in the ranitidine group (66.7%[88/132]). All treatments were well tolerated.CONCLUSIONS:Esomeprazole 40 and 20 mg once daily are effective and well-tolerated therapies compared with ranitidine 150 mg twice daily for healing GUs in patients who need to continue NSAID therapy.

Clinical trial: esomeprazole for moderate‐to‐severe nighttime heartburn and gastro‐oesophageal reflux disease‐related sleep disturbances

Aliment Pharmacol Ther 2010; 32: 182–190

Incidence of Peptic Ulcer Bleeding in the US Pediatric Population

Objectives: The aim of the present study was to determine the incidence of peptic ulcer bleeding (PUB) in pediatric patients. Methods: A hospital inpatient database, Premier Perspective, and an insurance claims database, MarketScan, were analyzed to estimate upper and lower limits for the annual incidence of PUB in the US pediatric population. Results: Using data from the Premier Perspective database and database-specific projection methodology, the total number of cases of hospitalization of pediatric patients for PUB in the United States in 2008 was estimated to be between 378 and 652. This translated to an incidence of 0.5 to 0.9/100,000 individuals in the pediatric population. Using data from the MarketScan database, the incidence of PUB in the insured pediatric population was estimated to be 4.4/100,000 individuals. Overall, 17.4% of insured pediatric patients diagnosed as having any upper gastrointestinal ulcer in 2008 were reported to have developed PUB. Conclusions: The estimated incidence of PUB in the US pediatric population in 2008 ranged from 0.5 to 4.4/100,000 individuals. The total number of cases of PUB in pediatric patients in the United States each year was thus estimated to be between 378 and 3250. Such estimates provide a likely lower and upper limit for the total number of cases of the condition annually.

Phase I, Multicenter, Randomized, Open-Label Study Evaluating the Pharmacokinetics and Safety Profile of Repeated Once-Daily Doses of Intravenous Esomeprazole in Children 0 to 17 Years of Age

BACKGROUND Several oral proton pump inhibitors (PPIs) are currently approved for use in pediatric patients in North America and Europe. However, when use of oral therapy is not possible or appropriate, intravenous formulations of PPIs may be helpful. Intravenous esomeprazole is approved in the United States for the short-term treatment of gastroesophageal reflux disease (GERD) with erosive esophagitis in adults and in pediatric patients 1 month to 17 years of age (inclusive) as an alternative to oral therapy. Four open-label, randomized, 2-way crossover studies in adults with GERD found no clinically relevant differences in acid suppression between repeated doses of oral and intravenous esomeprazole. However, the pharmacokinetics of intravenous esomeprazole has not been studied extensively in children. OBJECTIVE The aim of this study was to evaluate steady-state pharmacokinetics and tolerability of repeated doses of intravenous esomeprazole in children. METHODS In this multicenter, open-label study, hospitalized patients (0-17 years of age) considered for acid suppression therapy received once-daily intravenous esomeprazole sodium for injection at 0.5 mg/kg (0-1 month of age), 1.0 mg/kg (1-11 months of age), 10 mg (1-5 years of age), 10 or 20 mg (6-11 years of age), or 20 or 40 mg (12-17 years of age) for 4 days. Children 6 to 11 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 10 or 20 mg, and adolescents 12 to 17 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 20 or 40 mg. Blood samples were drawn pre- and post-dose. Plasma esomeprazole was measured using reversed-phase liquid chromatography and mass spectrometry. Pharmacokinetic variables were derived using mixed-effects modeling. Adverse events (AEs) were assessed. RESULTS Fifty-nine patients were randomized and 57 received the study drug. A majority of patients were white (44 white, 5 black/African American, 3 Asian, 5 other) and male (35/57). Fifty patients were eligible for pharmacokinetic analysis, including 6 to 8 patients in each age group. Esomeprazole pharmacokinetics was dose proportional and related to weight and age. Clearance increased with increasing weight and age. The mean AUC(τ) ranged from 6.9 μmol · h/L (10 mg, 6-11 years) to 17.6 μmol · h/L (40 mg, 12-17 years). The mean C(ss,max) ranged from 3.7 μmol/L (0.5 mg/kg, 0-1 month) to 10.5 μmol/L (40 mg, 12-17 years). Thirty-one patients experienced 1 or more AEs; 6 patients experienced 1 or more treatment-unrelated serious AEs. CONCLUSIONS Intravenous esomeprazole at doses resulting in targeted AUC(τ) and C(ss,max) similar to therapeutic exposure in adults appeared to be reasonably well tolerated in this small, select pediatric population. ClinicalTrials.gov identifier: NCT00474019.

Safety, pharmacokinetic and pharmacodynamic properties of TV-1106, a long-acting GH treatment for GH deficiency

Background TV-1106 (Teva Pharmaceuticals) is a genetically fused recombinant protein of human GH (hGH) and human serum albumin, in development for treatment of GH deficiency (GHD). TV-1106 is expected to have an extended duration of action compared to daily GH treatment and may enable a reduction in the frequency of injections and improve compliance and quality of life for adults and children requiring GHD therapy. Objective To assess the safety, local tolerability, pharmacokinetics and pharmacodynamics of TV-1106 following single s.c. injections in healthy male volunteers. Methods Subjects (n=56) were assigned to one of seven ascending dose groups (3–100 mg) and received either a single dose of TV-1106 (n=6) or placebo (n=2) by s.c. injection. Results Eighteen subjects reported 43 adverse effects (AEs), which were mild to moderate; no serious AEs (SAEs) occurred. In 50, 70 and 100 mg groups there were mild to moderate increases in heart rate and systolic blood pressure that significantly correlated with higher levels of IGF1. TV-1106 showed pharmacokinetic characteristics of a long-acting hGH as demonstrated by a terminal elimination half-life of 23–35 h, delayed time of peak concentration, and systemic levels seen up to 7 days after dosing. IGF1 levels increased in a dose-dependent manner, before reaching a plateau, with levels above baseline extending beyond 7 days post dose. Conclusion Single administration of TV-1106 up to 100 mg was safe in healthy volunteers. Pharmacokinetics and pharmacodynamics support once-weekly administration in patients with GHD.

M1868 Esomeprazole for the Relief of Nighttime Heartburn in Patients with Gastroesophageal Reflux Disease (GERD)-Related Sleep Disturbances

test and comparison to placebo by Wilcoxon Rank Sum test. Results. In the placebo group reflux episodes increased from D-1 to D6. This effect was reduced in the ADX10059 treatment groups. A significant treatment effect was seen for total acid exposure % (p=0.048) and number of weakly acidic reflux episodes (p = 0.0411). Significant differences from placebo were seen for 125mg b.i.d for various reflux measures. Trends were also seen for the 250mg b.i.d. dose which did not appear more effective than 125mg b.i.d. The 50mg b.i.d dose was not significantly superior to placebo. Twice daily administration of ADX10059 gave satisfactory 24 hour plasma concentrations. All 3 doses were well tolerated. Adverse event frequency was 50 mg : n=3 ; 125 mg : n=8 ; 250 mg : n=9. All were mild or moderate. Themost commonwere insomnia (n=4), constipation (n=2) and flatulence (n=2). Conclusion. Compared to placebo, ADX10059 dose dependently decreased gastro-esophageal reflux events in healthy subjects. The tolerability of the MR formulation is suitable for longer term treatment to evaluate clinical symptom control in GERD patients. Median and 95% CI of changes Day -1 to Day 6 for 5 hour pH-impedance monitoring period

417 Effect of Esomeprazole On Sleep Quality in Patients with Gastroesophageal Reflux Disease (GERD)-Related Sleep Disturbances

Small intestinal bacterial overgrowth occurs often in patients treated with PPI, because of profound acid suppression, but its clinical significance, particularly after long-term treatment, needs yet to be clarified. Glucose H-breath test (GHBT) is the most accurate non invasive tool to diagnose SIBO. AIM: To clarify clinical significance and risk factors for SIBO in patients treated with PPI for long-term. MATERIAL AND METHOD: 450 patients were studied: 200 on PPI for at least 2 months (mean age 39±18 y;M 120;median treatment: 36 months, at full dose for at least 3⁄4 of the time); 200 with IBS, as “pathologic” controls (IBSc), in absence of PPI treatment for at least 3 years (mean age 37±19 y; M 102); 50 “normal” controls (N-c), in absence of PPI for at least 10 years (mean age 35±16 y; M 29). Patients on antibiotics in the last 6 months, on eucinetics or submitted to colonoscopy or barium enema in the last month before test were excluded. Neoplasia, malabsorption diseases, previous G-I surgery, metabolic/hormonal disturbances were also excluded. Each patient was submitted to GHBT (Gastrolyzer, Bedfont Sc. Ldt, England). Symptoms Index (S.I.) was rated as mild (0-5), moderate (6-10) or severe (11-15) on the basis of frequency, duration and severity of pain, constipation /diarrhoea, and “gassy bowel” symptom (by simply adding all parameter scores, each from 0 to 3). Patients affected by SIBO were treated with Rifaximin 400 mg tid for 2 wks. RESULTS: GHBT POSITIVE FOR SIBO: Pts on PPI: 50%. IBS-c:24.5% . N-c:6% (P<0.001) PREVALENCE OF SYMPTOMS SIBO-RELATED in PPI and IBS group respectively:1)Gassy bowel:64% VS 35%; 2)Diarrhoea:41% VS 30%; 3)Constipation:26% VS 19% HEALING OF SIBO: in PPI group: 87%. In IBS group:91%. HEALING OF SIBO IN RELATION TO PPI TREATMENT DURATION: Months 2-12: 93%;More than 13 months: 86%. CONCLUSIONS:1)SIBO is more frequent in patients on long term treatment with PPI than in healthy controls and in IBS controls, in a statistically significant way. 2) Prevalence and Severity of PPI-related SIBO increases with the duration of therapy. 3) “Gassy bowel” is more frequent and more severe in PPI-SIBO than in IBS-SIBO. 4) Healing of SIBO with Rifaximin is satisfactory, being more successful in patients on PPI less than 12 months. Severity of SIBO in relation to PPI-therapy duration