Hans Rydholm

The effect of baclofen on gastro-oesophageal reflux, lower oesophageal sphincter function and reflux symptoms in patients with reflux disease.

Background : Baclofen decreases gastro‐oesophageal reflux episodes in healthy subjects by reducing the incidence of transient lower oesophageal sphincter relaxations.

Baclofen-mediated gastro-oesophageal acid reflux control in patients with established reflux disease

To explore the effect of baclofen on oesophageal acid exposure in patients with gastro‐oesophageal reflux disease.

Effect of lesogaberan, a novel GABA(B)-receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects.

Aliment Pharmacol Ther 31, 1208–1217

Rapid initial gastric emptying and hypersensitivity to gastric filling in functional dyspepsia: effects of duodenal lipids.

Objective. Impaired distension-induced gastric accommodation and hypersensitivity to distension have been demonstrated by gastric barostat in patients with functional dyspepsia (FD). In this study we investigated distension-induced responses to gastric filling with water in healthy volunteers and FD patients, using non-invasive ultrasonography. Material and methods. Eighteen healthy volunteers and 18 FD patients were given infusions of 10 ml saline or lipid (3 kcal/ml) through a nasoduodenal tube. After tube retraction, the stomach was filled with 1000 ml water during 10 min. Intragastric volume was monitored by 3D ultrasonography, and fullness, pain and nausea were assessed. Results. Compared with healthy volunteers, patients with FD had faster gastric emptying at 5 min (p=0.0008) and reported more fullness (p=0.006) during gastric filling with water. Prior duodenal lipid exposure reduced initial gastric emptying rate in FD patients to the level seen in healthy volunteers. However, despite similar gastric volumes, the patients still reported greater fullness (p=0.002) and nausea (p=0.01). Conclusions. Patients with FD had abnormally rapid initial gastric emptying of water and hypersensitivity to gastric filling. Though normalizing gastric emptying rate and volumes, duodenal lipid exposure did not improve hypersensitivity. Rapid initial gastric emptying of water might be a sign of impaired distension-induced gastric accommodation.

Esomeprazole 40 mg provides more effective acid control than omeprazole 40 mg

Purpose: Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor developed as an optical isomer to be available for clinical use. The aim of this study was to compare the effect on intragastric pH of esomeprazole 40 mg vs omeprazole 40 mg in patients with symptomatic gastroesophageal reflux disease (GERD).

Reproducibility of meal‐induced transient lower oesophageal sphincter relaxations in patients with gastro‐oesophageal reflux disease

Abstract Aim:  To calculate the number of subjects required in trials investigating drugs reducing the number of transient lower oesophageal sphincter relaxations (TLOSRs), the inter‐ and intra‐individual variability of TLOSRs were determined, using meal ingestion as a trigger of TLOSRs and reflux.

Baclofen-mediated gastro-esophageal acid-reflux control in patients with established reflux disease

AIM To explore the effect of baclofen on oesophageal acid exposure in patients with gastro-oesophageal reflux disease. METHODS AND MATERIALS Twenty patients with established reflux disease were included in this double-blind, randomized, crossover study. Baclofen, 40 mg, or placebo was given as a single dose with a washout period of 4 weeks. Symptoms were assessed by a visual analogue scale. Oesophageal pH was registered for 12 h and analysed for the whole period and for the 0-4-h, 4-8-h, 8-12-h and 2-h post-prandial periods. RESULTS Baclofen significantly reduced the number of reflux episodes during the 0-4-h (7.9 vs. 16.5, P < 0.0001; post-prandially: 6.0 vs. 11.2, P < 0.0001) and 0-12-h (46.5 vs. 73, P=0.0001; post-prandially: 18.8 vs. 29.3, P < 0.0001) periods. The fraction of time with pH < 4 was significantly lowered during the 0-4-h period (9.3 vs. 15.6, P=0.0019; post-prandially: 16.1 vs. 23.5, P=0.0083). Similar results were also obtained in patients with a hiatus hernia (n=13). Belching was significantly reduced (32 vs. 69 episodes, P < 0.01). CONCLUSIONS A single oral dose of 40 mg baclofen significantly reduced both the number of reflux episodes and the fraction of time with pH < 4, an effect primarily found during the first 4 h after dosing.

Reducing Adverse Effects During Drug Development: The Example of Lesogaberan and Paresthesia

PURPOSE Lesogaberan, a γ-aminobutyric acid (GABA)B receptor agonist, was developed for the treatment of gastroesophageal reflux disease in patients with a partial response to proton pump inhibitor therapy. A high prevalence of paresthesia was observed in healthy individuals after dosing with lesogaberan in early-phase clinical trials. The aim of this review was to gain further insight into paresthesia caused by lesogaberan by summarizing the relevant preclinical and clinical data. METHODS This study was a narrative review of the literature and unpublished data. FINDINGS The occurrence of paresthesia may depend on the route or rate of drug administration; several studies were conducted to test this hypothesis, and formulations were developed to minimize the occurrence of paresthesia. Phase I clinical studies showed that, in healthy individuals, paresthesia occurred soon after administration of lesogaberan in a dose-dependent manner regardless of the route of administration. The occurrence of paresthesia could be decreased by fractionating the dose or reducing the rate of administration. These findings suggest that the initial rate of absorption plays an important part in the development of paresthesia. Modified-release formulations minimize the occurrence of paresthesia while retaining the anti-reflux activity of the drug, as measured by esophageal pH and the number of transient lower esophageal sphincter relaxations. IMPLICATIONS The development of lesogaberan was halted because the effect on gastroesophageal reflux disease symptoms observed in Phase II studies was not considered clinically meaningful in the target patient population. Nevertheless, it is an example of successful formulation development designed to minimize the occurrence of a compounds adverse effect while retaining its pharmacodynamic action.

Prevention of upper gastrointestinal bleeding in critically ill Chinese patients: a randomized, double-blind study evaluating esomeprazole and cimetidine

Abstract Objective: To assess the efficacy and safety of esomeprazole in preventing upper gastrointestinal (GI) bleeding in critically ill Chinese patients, using cimetidine as an active comparator. Methods: A pre-specified non-inferiority limit (5%) was used to compare rates of significant upper GI bleeding in this randomized, double-blind, parallel-group, phase 3 study across 27 intensive care units in China. Secondary endpoints included safety and tolerability measures. Patients required mechanical ventilation and had at least one additional risk factor for stress ulcer bleeding. Patients were randomized to receive either active esomeprazole 40 mg, as a 30-min intravenous (IV) infusion twice daily, and an IV placebo cimetidine infusion or active cimetidine 50 mg/h, as a continuous infusion following an initial bolus of 300 mg, and placebo esomeprazole injections, given up to 14 days. Patients were blinded using this double-dummy technique. Results: Of 274 patients, 2.7% with esomeprazole and 4.6% with cimetidine had significant upper GI bleeding (bright red blood in the gastric tube not clearing after lavage or persistent Gastroccult-positive “coffee grounds” material). Non-inferiority of esomeprazole to cimetidine was demonstrated. The safety profiles of both drugs were similar and as expected in critically ill patients. Conclusions: Esomeprazole is effective in preventing upper GI bleeding in critically ill Chinese patients, as demonstrated by the non-inferiority analysis using cimetidine as an active control. Trial registration: ClinicalTrials.gov identifier NCT02157376.