The GABA(B) receptor agonist AZD9343 inhibits transient lower oesophageal sphincter relaxations and acid reflux in healthy volunteers: a phase I study.

BACKGROUND: Transient lower oesophageal sphincter relaxations (TLESRs) represent an interesting target for the treatment of gastro-oesophageal reflux. Baclofen reduces TLESRs and reflux episodes, but is not optimal for clinical application because of its central side effects. Therefore, new agents are required. AIM: To study the effect of AZD9343, a new selective GABA(B) receptor agonist, in healthy volunteers. METHODS: A total of 27 subjects participated in a placebo-controlled, randomized, two-centre phase I study. Subjects underwent oesophageal manometry and pH-metry for 3 h postprandially. Before meal ingestion, a single oral dose of placebo, 60 and 320 mg AZD9343 or 40 mg baclofen was given on four separate days. RESULTS: Somnolence was reported after 320 mg AZD9343 and baclofen. Reversible short-lasting paraesthesia was reported after AZD9343. AZD9343 320 mg and baclofen significantly reduced the number of TLESRs with 32% and 40% respectively. Acid reflux was significantly decreased by AZD9343 and baclofen. Like baclofen, AZD9343 increased LES pressure before meal intake. AZD9343 320 mg and baclofen significantly reduced the swallowing rate. CONCLUSIONS: Like baclofen, AZD9343 dose-dependently decreases the number of TLESRs and acid reflux episodes, increases LES pressure and reduces swallowing, extending the concept that GABA(B) agonists are potent reflux inhibitors. However, discovery of analogues with an improved side effect profile is warranted.

The gastro-oesophageal common cavity revisited.

The manometric common cavity phenomenon has been used as indicator of gastro-oesophageal reflux of liquid or gaseous substances. Using combined pH and impedance recording as reference standard the value of a common cavity as indicator of gastro-oesophageal reflux was tested. Ten healthy male subjects underwent combined stationary pressure, pH and impedance recording for 4.5 h. After 1.15 h of recording, a reflux-eliciting meal was consumed. The chi-squared and Kolmogorov-Smirnov tests were used for the statistical analysis. A common cavity was found in 95 (43%) of the 223 reflux events detected by impedance, while seven common cavities were unrelated to a reflux episode. In 54% of the reflux events detected by impedance without a common cavity, a possible common cavity was obscured by either contractile activity or artefacts of various origin. The types of reflux associated with a common cavity (liquid 60%, mixed 31%, gas 9%) and without a common cavity (liquid 59%, mixed 29%, gas 12%) did not differ, or did the acidity of the reflux episodes (with common cavity: acid 67%; without common cavity: acid 58%). The common cavity is a specific but not a sensitive marker of gastro-oesophageal reflux. Furthermore, common cavities are not specific for a particular type of reflux.

Diagnostic value of the proton pump inhibitor test for gastro-oesophageal reflux disease in primary care.

AIM: To assess the diagnostic accuracy of the proton pump inhibitor test in a primary care population as well as its additional value over reflux history, using the symptom association probability outcome during 24-h oesophageal pH recording as reference test for gastro-oesophageal reflux disease. METHODS: Subjects with symptoms suggestive of gastro-oesophageal reflux disease were recruited from primary care. After a 24-h pH recording with calculation of the symptom association probability, subjects started using 40 mg esomeprazole once daily for 13 days. The proton pump inhibitor test was considered positive when the subjects reported adequate symptom suppression. Data are presented as means with 95% confidence intervals. RESULTS: Successful 24-h pH recording was accomplished in 84 of the 90 subjects, while the symptom association probability was calculable in 74. The symptom association probability was positive in 70% of the subjects. The sensitivity of the proton pump inhibitor test was 0.91 (CI 0.78-0.96) and the specificity was 0.26 (CI 0.10-0.49). The mean likelihood ratio was 1.2 (CI 0.9-1.6) with little variation over the 13 consecutive proton pump inhibitor test days. The likelihood ratios of gastro-oesophageal reflux disease symptoms were comparable, ranging around 1. CONCLUSIONS: In primary care patients with reflux symptoms gastro-oesophageal reflux disease is highly prevalent. Under these conditions the additional value of short-term treatment with a proton pump inhibitor for diagnosing gastro-oesophageal reflux disease is limited.

Diagnostic value of the Reflux Disease Questionnaire in general practice.

OBJECTIVES: This study determined the diagnostic and therapeutic response of the Reflux Disease Questionnaire (RDQ) using the symptom association probability (SAP) as reference. In addition, the RDQ's construct validity and its relationship to quality of life (QOL) were ascertained. METHODS: Seventy-four patients with GORD symptoms (age 51 years (22-78); male 62%) derived from primary care completed the RDQ, GSRS and QOLRAD before and after a 2 weeks' course of esomeprazole 40 mg daily. The SAP was determined by a 24-hour pH recording before PPI treatment. The diagnostic abilities of the RDQ (total and 4 dimensions scores) were assessed with the area under the curve (AUC) of a receiver operating curve. RDQ scores before and after PPI treatment were compared with Wilcoxon tests. Multiple linear regressions assessed the RDQ's construct validity (GSRS) and relationship to QOL (QOLRAD). RESULTS: The AUCs were low for all RDQ dimensions (AUC <0.6). In the SAP-positive patients all RDQ dimensions improved (p < 0.0001) while the scores of the SAP negatives did not (heartburn p < 0.01; GORD and total score p < 0.05; regurgitation and dyspepsia n.s.). The RDQ was related to the total and reflux GSRS dimensions while the food and drink QOL dimension was linearly associated with the RDQ. CONCLUSIONS: The RDQ is a valid and reliable questionnaire with excellent construct validity and a good relationship to QOL. The diagnostic value of the RDQ in primary care is limited, but combination with an additional PPI treatment course might improve the RDQ's ability to discriminate GORD patients according to their SAP outcome.