Mark Sostek

Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study

OBJECTIVES:Proton pump inhibitors owe their clinical efficacy to their ability to suppress gastric acid production. The objective of this study was to evaluate and compare intragastric pH following standard doses of esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole.METHODS:This randomized, open-label, comparative five-way crossover study evaluated the 24-h intragastric pH profile of oral esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg, and rabeprazole 20 mg once daily in 34 Helicobacter pylori–negative patients aged 18–60 yr with symptoms of gastroesophageal reflux disease. Patients were randomly assigned to one of five treatment sequences and study drug was taken on 5 consecutive mornings 30 minutes prior to a standardized breakfast. A washout period of at least 10 days separated each treatment phase.RESULTS:Thirty-four patients provided evaluable data for all five comparators. The mean number of hours of evaluable pH data was ≥23.75 hours. On day 5, intragastric pH was maintained above 4.0 for a mean of 14.0 h with esomeprazole, 12.1 h with rabeprazole, 11.8 h with omeprazole, 11.5 h with lansoprazole, and 10.1 h with pantoprazole (p ≤ 0.001 for differences between esomeprazole and all other comparators). Esomeprazole also provided a significantly higher percentage of patients with an intragastric pH greater than 4.0 for more than 12 h relative to the other proton pump inhibitors (p < 0.05). The frequency of adverse events was similar between treatment groups.CONCLUSIONS:Esomeprazole at the standard dose of 40 mg once daily provided more effective control of gastric acid at steady state than standard doses of lansoprazole, omeprazole, pantoprazole, and rabeprazole in patients with symptoms of gastroesophageal reflux disease.

Treatment of chronic posterior laryngitis with esomeprazole

Objective: To evaluate the efficacy of acid‐suppressive therapy with the proton pump inhibitor esomeprazole on the signs and symptoms of chronic posterior laryngitis (CPL) in patients with suspected reflux laryngitis.

Naloxegol for opioid-induced constipation in patients with noncancer pain.

BACKGROUND Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety of naloxegol, an oral, peripherally acting, μ-opioid receptor antagonist, for the treatment of opioid-induced constipation. METHODS In two identical phase 3, double-blind studies (study 04, 652 participants; study 05, 700 participants), outpatients with noncancer pain and opioid-induced constipation were randomly assigned to receive a daily dose of 12.5 or 25 mg of naloxegol or placebo. The primary end point was the 12-week response rate (≥3 spontaneous bowel movements per week and an increase from baseline of ≥1 spontaneous bowel movements for ≥9 of 12 weeks and for ≥3 of the final 4 weeks) in the intention-to-treat population. The key secondary end points were the response rate in the subpopulation of patients with an inadequate response to laxatives before enrollment, time to first postdose spontaneous bowel movement, and mean number of days per week with one or more spontaneous bowel movements. RESULTS Response rates were significantly higher with 25 mg of naloxegol than with placebo (intention-to-treat population: study 04, 44.4% vs. 29.4%, P=0.001; study 05, 39.7% vs. 29.3%, P=0.02; patients with an inadequate response to laxatives: study 04, 48.7% vs. 28.8%, P=0.002; study 05, 46.8% vs. 31.4%, P=0.01); in study 04, response rates were also higher in the group treated with 12.5 mg of naloxegol (intention-to-treat population, 40.8% vs. 29.4%, P=0.02; patients with an inadequate response to laxatives, 42.6% vs. 28.8%, P=0.03). A shorter time to the first postdose spontaneous bowel movement and a higher mean number of days per week with one or more spontaneous bowel movements were observed with 25 mg of naloxegol versus placebo in both studies (P<0.001) and with 12.5 mg of naloxegol in study 04 (P<0.001). Pain scores and daily opioid dose were similar among the three groups. Adverse events (primarily gastrointestinal) occurred most frequently in the groups treated with 25 mg of naloxegol. CONCLUSIONS Treatment with naloxegol, as compared with placebo, resulted in a significantly higher rate of treatment response, without reducing opioid-mediated analgesia. (Funded by AstraZeneca; KODIAC-04 and KODIAC-05 ClinicalTrials.gov numbers, NCT01309841 and NCT01323790, respectively.).

Treatment of Patients With Persistent Heartburn Symptoms: A Double-Blind, Randomized Trial

BACKGROUND & AIMS Common treatment practices in patients who continue to be symptomatic on proton pump inhibitor once-daily treatment include either increasing the dosage or the use of supplemental medication. This trials purpose was to compare 2 therapeutic strategies, increasing the proton pump inhibitor dosage to twice daily versus switching to another proton pump inhibitor, in patients with persistent heartburn while receiving standard-dose proton pump inhibitor therapy. METHODS This multicenter, randomized, double-blind, double-dummy trial included patients with persistent heartburn symptoms while receiving therapy with lansoprazole 30 mg once daily. Patients were randomly assigned to treatment for 8 weeks with either single-dose esomeprazole (40 mg once daily) (n = 138) or lansoprazole 30 mg twice daily (n = 144). The primary efficacy variable was the percentage of heartburn-free days from day 8 to the end of treatment. RESULTS Single-dose esomeprazole was at least as effective as twice-daily lansoprazole for the primary end point of percentage of heartburn-free days during the study period (54.4% and 57.5%, respectively). Symptom scores improved from baseline in similar numbers of patients for heartburn (83.3% of patients in each group), acid regurgitation (76.8% vs 72.9%, P = .58), and epigastric pain (67.4% vs 61.1%, P = .32), and rescue antacid use was also similar (0.4 tablets/day vs 0.5 tablets/day, P = .50). CONCLUSIONS Switching patients with persistent heartburn on a standard-dose proton pump inhibitor to a different proton pump inhibitor was as effective as increasing the proton pump inhibitor dosage to twice daily for controlling heartburn symptoms.

A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation.

Summary Oral naloxegol was well tolerated and increased the frequency of spontaneous bowel movements in patients with opioid‐induced constipation without compromising analgesia or inducing opioid withdrawal. ABSTRACT Naloxegol (previously known as NKTR‐118) is a peripherally acting &mgr;‐opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once‐daily agent for the treatment of opioid‐induced constipation (OIC). Eligible patients with OIC (n = 207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30–1000 mg/day morphine equivalents for ≥2 weeks were randomized to receive 4 weeks of double‐blind placebo or naloxegol (5, 25, or 50 mg) once daily in sequential cohorts after a 1‐week placebo run‐in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25‐ and 50‐mg naloxegol cohorts vs placebo (2.9 vs 1.0 [P = 0.0020] and 3.3 vs 0.5 [P = 0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25 mg (3.0 vs 0.8 [P = 0.0022]) and 50 mg (3.5 vs 1.0 [P < 0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25 mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50‐mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25‐ and 50‐mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once‐daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC.

Efficacy of esomeprazole 40 mg vs. lansoprazole 30 mg for healing moderate to severe erosive oesophagitis.

Background : Secondary analyses from previous studies indicated that esomeprazole was more effective than lansoprazole and omeprazole in healing moderate or severe (Los Angeles grades C or D) erosive oesophagitis (EE).

Clinical trial: the incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone

Aliment Pharmacol Ther 2010; 32: 401–413

Relationship between intragastric acid control and healing status in the treatment of moderate to severe erosive oesophagitis

Aim  To assess the relationship between the percentage of time intragastric pH >4.0 and healing of erosive oesophagitis.

Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation

Opioid‐induced constipation (OIC) is a common adverse effect of opioid therapy.

Intragastric acid suppression and pharmacokinetics of twice‐daily esomeprazole: a randomized, three‐way crossover study

Background : Patients with refractory gastro‐oesophageal reflux disease, extra‐oesophageal reflux symptoms, Barretts oesophagus, or Zollinger–Ellison syndrome may require greater acid suppression than that obtained with once‐daily esomeprazole.