00 hours on the day of the baseline (day −1). Subjects took each dose of revaprazan at 8.00 hours, after fasting overnight, and continued fasting until 4 h after administration of revaprazan on days 1 and 7. Each dose of revaprazan was wrapped in an opaque envelope and was given to the subject by a study coordinator who witnessed the emptying of the revaprazan into the subject’s mouth and the swallowing of the dose. On days 2–6, subjects received the dose once daily at the same time as on day 1, and continued fasting for 2 h after administration of revaprazan. A standardized meal buy Hydroxychloroquine was provided to the

subjects 4 h and 8 h after the 8.00 hours administration of revaprazan at baseline Fulvestrant ic50 and on days 1 and 7. Subjects were dismissed from the clinic after they had been observed eating the meal at baseline and on days 1 and 7. Each administration period was separated by a washout period of 7 days, during which no revaprazan was taken (Fig. 1). Drugs other than revaprazan were not allowed during the study period. Ambulatory 24-h intragastric pH monitoring was performed at baseline and on days 1 and 7 of each administration period (Fig. 1). After induction of anesthesia using a 1% lidocaine spray administered via the nose, a calibrated bipolar glass pH electrode catheter (Medtronic Synectics AB, Stockholm, Sweden) was inserted

into the stomach via the nose and positioned approximately 5 cm below the manometrically located lower esophageal sphincter.13 The catheter was connected to a portable digital data recorder (MicroDigitrapper 4 Mb, Medtronic Synectics AB), and intragastric pH was recorded every 8 s. Revaprazan was administrated after probe placement.

Data were analyzed after completion of the recording. Mean intragastric Digestive enzyme pH–time profile, 24-h median intragastric pH and mean percentage time of pH > 4 were calculated. Serum gastrin levels were measured under fasting conditions and 1 and 2 h postprandially (5 h and 6 h after administration of revaprazan) at baseline and on days 1 and 7 of each cross-over period (Fig. 1) using a commercial, validated radioimmunoassay (ALPCO, Salem, NH, USA). Blood samples for pharmacokinetic assessment of revaprazan were taken at set times on days 1 and 7 (Fig. 1). Blood samples (8 mL) were obtained via an indwelling cannula inserted into a forearm vein. Blood was sampled at baseline (pre-dose) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h after drug administration. The blood samples were centrifuged at 1200 × g for 10 min at 4°C, and the plasma was immediately stored in polypropylene tubes at −20°C or lower until required for analysis. The plasma concentration of revaprazan was determined by liquid chromatography/mass spectrometry.