Gastroesophageal reflux disease (GERD) is characterized by the presence of reflux symptoms, such as heartburn and regurgitation, and/or esophageal mucosal injury caused by reflux of gastric contents into the esophagus.1,2 In recent decades, the prevalence of GERD has been increasing in Japan, likely due to the westernization of eating habits, as well as decreased
Proton pump inhibitors (PPIs) are often used as first-line treatment for GERD2 and have been shown to reduce the size of the acid pocket.12,13 Recently, vonoprazan, a new potassium-competitive acid blocker, has been approved as a treatment option for GERD in Japan.14 This drug has been shown to provide faster, steadier, and more potent acid reducing effects as compared to conventional PPIs.15,16 However, no known report regarding the effects of vonoprazan on the acid pocket have been presented.
In most previous studies of gastric acid pockets, measurements were performed by use of a pull-through technique with dual pH sensors.9,13,17 However, such a technique only provides information during a very brief period of time and changes over time cannot be observed. To address this issue, we developed a novel catheter equipped with 8 vertically arrayed pH sensors. The aim of this study is to evaluate the gastric acid pocket in healthy subjects during the postprandial period with this pH sensor catheter. In addition, we sought to determine postprandial changes of the gastric acid pocket following administration of vonoprazan as compared to rabeprazole, a conventional PPI, with our system.
Twelve healthy adult volunteers were recruited (7 males, 5 females; mean age 24.0 ± 2.6 years, range 21-32 years; mean body mass index 20.7 ± 1.9 kg/m2). All subjects were free of gastrointestinal symptoms. In addition, none had a previous history of upper gastrointestinal surgery, or were taking any drugs that might influence gastrointestinal motility or acid secretion. Each had negative results in a urine antibody test for
We developed a novel pH sensor catheter equipped with 8 vertically arrayed pH sensors in cooperation with Star Medical, Inc (Tokyo, Japan). This flexible catheter measures 2.35 mm in diameter and is equipped with 8 pH electrodes along the distal end (Fig. 1). The electrodes are arranged at intervals of 1 cm on the vertical axis and pH can be determined within a span of 7 cm. This multi-channel pH sensor catheter has been approved for medical use and is reusable. Eight-channel pH data can be simultaneously recorded by connecting the catheter to 4 portable digital recorders (Pocket Monitor GMMS-200pH; Star Medical, Inc). Prior to performing the present examinations, the probe was calibrated at room temperature using pH 4.0 and 7.0 buffer solutions.
After providing nasal anesthesia with xylocaine, the catheter was inserted transnasally into the esophagus and positioning was confirmed with fluoroscopic imaging to ensure that the sensor straddled the gastric fluid surface (Fig. 2). The external portion was tightly fixed to the cheek at a point 2 cm outside the nostril, then hung on an ear and attached to the skin of the neck with surgical tape. The subjects were instructed to remain in the same seated position without deep breathing during the observation period, and the catheter position was thoroughly checked before and after the meal by X-ray imaging.
The enrolled subjects participated in 2 study sessions (Fig. 3). All study sessions were performed after an overnight fast. For the first session (Fig. 3A) the pH sensor catheter was placed transnasally at 8 AM and pH measuring was started. Starting from 9 AM, the subject consumed a standardized meal, consisting of fried noodles (556 kcal; protein 9.4 g, fat 20.9 g, and carbohydrate 82.6 g) and stew (167 kcal; protein 5.9 g, lipid 7.1 g, and carbohydrate 19.7 g), and pH measurements were continued for 3 hours (period 1). Vonoprazan at 20 mg was given at 12 PM. At 3 PM, the subjects consumed the same standardized meal and then the catheter was removed at 6 PM after 3 hours of measurements (period 2).
PPIs are known to be slow to achieve steady-state inhibition of gastric acid secretion, typically requiring 2 days to 3 days to reach a therapeutic range.16 Therefore, in the second study session (Fig. 3B), rabeprazole was administered for 2 days prior to performing pH measurements. On the day of starting those measurements, the subject consumed breakfast at 7 AM and was given rabeprazole at 20 mg at 7:30 AM. The catheter was inserted at 10:30 AM and the standardized meal noted above was given 1:30 PM. After 3 hours of measurements (period 3), the catheter was removed. There was a washout period of at least 2 weeks between the study sessions. All sessions and testing were conducted by the same experienced investigator (S.S.).
Recorded data were analyzed using computer software (Eight Star; Star Medical, Inc). The acid pocket was defined as the distinct region just below the esophago-gastric junction in the proximal stomach, which is clearly more acidic (pH < 4) than the other parts of the esophagus and stomach.8 To assess its characteristics, the length, appearance time, lasting time, and mean pH of the most acidic channel were evaluated in each subject. The length of the acid pocket was expressed by positive numbers of pH channels. For example, 2 positive channels in the acid pocket indicated a range of 1 cm to 3 cm because of the spacing between the pH sensors. In addition, the effects of vonoprazan and rabeprazole on acid pocket formation were assessed. Values are expressed as the mean ± SD. Statistical analyses were performed using Fisher’s exact test, with
All subjects completed the first study session, though the acid pocket was not appropriately measured in 2 due to catheter position, thus they were excluded. The remaining 10 subjects proceeded to the second study session and all completed the testing. No apparent hiatal hernia was shown by X-ray imaging in any of the subjects. There were no adverse events during any of the sessions.
In the first study session, length, appearance time, lasting time, and average pH were assessed for postprandial acid pockets in the subjects (Fig. 3, period 1). In Figure 4, a representative image of a postprandial acid pocket is shown, in which the vertical axis shows the electrodes as part of the pH sensor catheter (channel 1, proximal end, to channel 8, distal end), while the horizontal axis shows time and pH is displayed by pH metry color surface contour plots. In this representative case, at 16 minutes after completion of a meal, the gastric acid pocket, with a pH level of 2 or less, was clearly visualized, and shown to be located at around channels 2 and 3. The lasting time of this acid pocket was 156 minutes and the length gradually broadened. An acid pocket was observed in all 10 cases that were appropriately measured, with a mean length of 2.2 ± 0.4 channels. The mean appearance time of an acid pocket after completion of a meal was 19.4 ± 6.8 minutes, mean lasting time was 145.5 ± 17.9 minutes, and mean pH was 2.4 ± 0.4 (Table 1).
Next, the effects of vonoprazan on postprandial gastric acid pocket development was evaluated (Fig. 3, period 2). A representative case is shown in Figure 5, in which an acid suppression effect began to appear approximately 152 minutes after administration, while the pH increased to approximately 7 or 8 after the second meal and no subsequent acid pocket formation was seen. The acid pocket was completely eliminated in all cases after administration of vonoprazan. The mean onset time for apparent acid inhibition by vonoprazan was 133.9 ± 34.2 minutes. In addition, the mean pH after administration was 7.6 ± 0.4, which was neutralized within 3 hours in all cases.
Finally, the effects of rabeprazole on postprandial gastric acid pocket formation was evaluated (Fig. 3, period 3). Similar to treatment with vonoprazan, the acid pocket was eliminated in 7 of 10 cases. In the 3 cases with a remaining postprandial acid pocket, the length was reduced and mean pH was greater as compared to that before administration (Fig. 6 and Table 2). These results suggest that an acid pocket in the present subjects had a higher incidence of elimination with vonoprazan as compared to rabeprazole, though there was no significant difference between those administrations (
In the present study, formation of a gastric acid pocket in healthy Japanese adults without
The gastric acid pocket forms due to secretion of acid from parietal cells located in secretory glands in the proximal stomach. That secretion is affected by various factors, including ethnicity, gender, age, and
This study is the first known to show the effects of vonoprazan on the gastric acid pocket. This drug has been consistently found to provide quicker and stronger acid inhibition than PPIs,16 while the present results indicate that the postprandial acid pocket was completely eliminated and gastric pH neutralized within 3 hours after a single administration of a standard dose (20 mg). In contrast, the acid pocket remained observable in 3 of 10 subjects for 3 days following rabeprazole administration. Although PPIs remain as first-line treatment for GERD,1,2 up to 40% of those patients remain symptomatic despite continuous PPI use.31 Other disadvantages of PPIs include several days before reaching the maximal effect32 and GERD symptoms are not sufficiently relieved after the first dose in two-thirds of administered patients due to the slow onset of action. In addition, accumulating evidence suggests that long-term PPI administration is associated with increased risk of enteric infection,
The present study has some limitations, including a limited number of subjects and non-inclusion of patients with GERD. It is difficult to directly compare the effects of vonoprazan and rabeprazole on the acid pockets due to the different mechanisms for acid inhibition. Additionally, 2 subjects were subsequently excluded because of inappropriate catheter positioning. With our method, the catheter is not fixed to the esophagus using hemostatic metal clips to reduce the burden caused by endoscopy,20,22 thus vertical movement of the catheter may have influenced the accuracy of obtained data regarding the gastric acid pocket. A future study that includes GERD patients with and without hiatal hernia is needed to clarify whether formation of a gastric acid pocket differs as compared to healthy subjects.
In summary, we successfully examined postprandial gastric acid pocket formation in healthy adults in Japan using our novel vertically arrayed 8-channel pH sensor catheter. Acid pocket development was strikingly suppressed following administration of vonoprazan or rabeprazole. Moreover, a single administration of vonoprazan completely eliminated the acid pocket within a short period, suggesting its effectiveness as treatment for GERD.
Norihisa Ishimura has received research funding from EA Pharma Co, Ltd, Daiichi-Sankyo Co, Ltd, Otsuka Pharmaceutical Co, Ltd; Shunji Ishihara has received research funding from Takeda Pharmaceutical Co, Ltd, Astellas Pharma Inc, EA Pharma Co, Ltd, Janssen Pharmaceutical K.K., ZERIA Pharmaceutical Co, Ltd, and lecture fees from Takeda Pharmaceutical Co, Ltd; Yoshikazu Kinoshita has received research funding from EA Pharma Co, Ltd, ZERIA Pharmaceutical Co, Ltd, and honorarium from EA Pharma Co, Ltd, Astellas Pharma Inc, AstraZeneca K.K., Mylan N.V., ZERIA Pharmaceutical Co, Ltd, Otsuka Pharmaceutical Co, Ltd, Takeda Pharmaceutical Co, Ltd, and Daiichi-Sankyo Co, Ltd. Shohei Sumi, Hironobu Mikami, Eiko Okimoto, Yuji Tamagawa, and Tsuyoshi Mishiro have no conflict of interest.
Shohei Sumi, Norihisa Ishimura, and Yoshikazu Kinoshita designed the study; Shohei Sumi, Hironobu Mikami, and Eiko Okimoto collected the data; Shohei Sumi and Yuji Tamagawa analyzed the data and wrote the draft; and Norihisa Ishimura, Tsuyoshi Mishiro, and Shunji Ishihara made critical revisions. All authors reviewed and approved the final version of the article before submission.