SUMMARY BackgroundProton pump inhibitors (PPIs) are widely used for the treatment of acidrelated diseases. Vonoprazan is a member of a new class of acid suppressants; potassium-competitive acid blockers. Vonoprazan may thus be an alternative to PPIs.

BackgroundTAK-438 (vonoprazan) is a potassium-competitive acid blocker that reversibly inhibits gastric H+, K+-ATPase.AimTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-438 in healthy Japanese and non-Japanese men.MethodsIn two Phase I, randomised, double-blind, placebo-controlled studies, healthy men (Japan N = 60; UK N = 48) received TAK-438 10–40 mg once daily at a fixed dose level for 7 consecutive days. Assessments included safety, tolerability, pharmacokinetics and pharmacodynamics (intragastric pH).ResultsPlasma concentration–time profiles of TAK-438 at all dose levels showed rapid absorption (median Tmax ≤2 h). Mean elimination half-life was up to 9 h. Exposure was slightly greater than dose proportional, with no apparent time-dependent inhibition of metabolism. There was no important difference between the two studies in AUC0-tau on Day 7. TAK-438 caused dose-dependent acid suppression. On Day 7, mean 24-h intragastric pH>4 holding time ratio (HTR) with 40 mg TAK-438 was 100% (Japan) and 93.2% (UK), and mean night-time pH>4 HTR was 100% (Japan) and 90.4% (UK). TAK-438 was well tolerated. The frequency of adverse events was similar at all dose levels and there were no serious adverse events. There were no important increases in serum alanine transaminase activity. Serum gastrin and pepsinogen I and II concentrations increased with TAK-438 dose.ConclusionsTAK-438 in multiple rising oral dose levels of 10–40 mg once daily for 7 days was safe and well tolerated in healthy men and caused rapid, profound and sustained suppression of gastric acid secretion throughout each 24-h dosing interval. Clinicaltrials.gov identifiers: NCT02123953 and NCT02141711.

OBJECTIVES:To evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-438 (vonoprazan, a potassium-competitive acid blocker) in healthy male subjects.METHODS:In two phase I, randomized, double-blind, placebo-controlled, single rising-dose studies, healthy male subjects (Japan N=84; UK N=63) received a single TAK-438 dose (1–120 mg in Japan and 1–40 mg in the UK). Assessments included safety, tolerability, pharmacokinetics, and pharmacodynamics (intragastric pH).RESULTS:Plasma concentration–time profiles of TAK-438 at all dose levels showed rapid absorption (median Tmax up to 2 h). Estimated mean elimination half-life was up to 9 h. Exposure was slightly greater than dose proportional. No clear difference in TAK-438 pharmacokinetics was observed between Japanese and non-Japanese subjects. Acid suppression was dose dependent and similar in both studies. The 24-h intragastric pH ≥4 holding time ratio with 40 mg TAK-438 was 92% in Japan and 87% in the UK. TAK-438 was well tolerated, with no adverse events reported in Japanese subjects; 10 of 63 UK subjects experienced 12 treatment-emergent adverse events (non-serious). Increases in serum gastrin and pepsinogen I and II concentrations were observed at doses ≥10 mg, but there were no changes in alanine aminotransferase concentrations.CONCLUSIONS:Single oral doses of TAK-438 20–120 mg caused rapid, profound, and 24-h suppression of gastric acid secretion in healthy male subjects, regardless of geographical region, and TAK-438 was well tolerated at all doses studied, making it a potential alternative to proton pump inhibitors for the treatment of acid-related disorders.

Background:Standard treatment for patients with erosive esophagitis (EE) is proton-pump inhibitors (PPIs), but some patients are resistant to PPIs. We aimed to evaluate the acid-inhibitory effects and efficacy of a novel potassium-competitive acid blocker (vonoprazan) in patients with PPI-resistant EE.MethodsThis randomized, double-blind, multicenter study of vonoprazan evaluated gastric and esophageal pH over a 24-hour period as the primary endpoint and EE healing rate as the secondary endpoint. Following a 7 to 14-day run-in period (lansoprazole 30 mg treatment), patients with endoscopically confirmed PPI-resistant EE received vonoprazan 20 mg or 40 mg for 8 weeks.ResultsPatients were randomized to receive vonoprazan 20 mg (n = 9) or 40 mg (n = 10). Over a 24-hour period; both groups showed a significant increase from baseline in the percentage of time gastric pH ≥ 4, referred to as pH 4 holding time ratio (HTR): an increase from 73.21% to 96.46% in the 20 mg group, and from 69.97% to 100.00% in the 40 mg group. Increases from baseline in esophageal pH 4 HTRs were not significant. The 40 mg group showed greater increases in gastric and esophageal pH 4 HTRs compared with the 20 mg group, but differences between groups were not significant. After 8 weeks’ treatment, the healing rate in subjects with baseline EE grades A–D was 60.0% (3/5 patients) in the 20 mg group and 71.4% (5/7 patients) in the 40 mg group. Vonoprazan was generally well tolerated. One patient (40 mg group) experienced four treatment-emergent adverse events (TEAEs) (unrelated to study drug), leading to study discontinuation.ConclusionsVonoprazan 20 mg and 40 mg effectively inhibited gastric acid secretion over a 24-hour period with significantly increased gastric pH 4 HTR, and resulted in an EE healing rate > 60.0% in this study. Vonoprazan treatment may be valuable for patients with PPI-resistant EE

An Occupational Health Study of E m e r g e n c y P h y s i c i a n s i n J a p a n : H e a l t h Assessment by Immune Variables (CD4, CD8, CD56, and NK cell activity) at the Beginning of Work: Hiroteru OKAMOTO, et al. Department of Preventive Medicine and Public Health, School of Medicine, Kyorin University-This study was conducted to evaluate the occupational health of Japanese physicians in emergency medicine. Subjects participating in this study were eighty-nine physicians working at 12 medical facilities (10 critical care emergency centers) in Japan. Participants were asked to complete a questionnaire of work conditions and to provide blood samples for immune variable measurements (CD4, CD8, CD56 and natural killer cell (NK cell) activity) before commencing their work. The data collected from seventy-four of 89 participating physicians were analyzed. The traditional work group comprised of 39 emergency physicians, who were significantly overworked compared to other two groups: the shift work group and the day work group. Among these three groups, no immune variable was significantly different except lymphocyte, number of CD4, and NK cell activity; and the NK cell activity of the shift work group was significantly lower than those of the traditional work group (p<0.01) and the day work group (p<0.01) in terms of Bonferroni's multiple comparison, probably due to circadian rhythm. It was indicated that NK cell activity was significantly lower in samples collected at night versus in the morning (OR=8.34, 95%CI: 1.95-35.6, p<0.01) through multiple logistic regression analyses. NK cell activity was significantly lower in individuals taking 0-3 days off per month, as compared to those taking 4 or more days off (OR=4.65, 95%CI: 1.27-17.0, p=0.02), according to multiple logistic regression analyses. Therefore, the low NK cell activity appears to have reflected the extent of fatigue arising from physicians' overwork. Overwork would have been a potential risk for the physicians' health, resulting in a lower quality of Japanese emergency medical services than that which could have been achieved otherwise. This study suggests that it would be better for the Japanese emergency physicians to take 4 or more days off per month for their health and the quality of their services. (J Occup Health 2008; 50: 136-146)

mediates lymphocyte trafficking to gastrointestinal mucosa and gut-associated lymphoid tissue through mucosal addressin cell adhesion molecule-1 (MAdCAM 1). 1 The novel mechanism of action of vedolizumab allows it to bind exclusively to the α 4 β 7 integrin, antagonizing its adherence to MAdCAM-1 and thereby impairing the migration of leukocytes into gastrointestinal mucosa. 1 The gut-selective, anti-inflammatory activity of vedolizumab enables targeted therapy without generalized immunosuppression. Vedolizumab intravenous (IV), a lyophilized formulation of vedolizumab intended for IV infu

We evaluated the antioxidative effects of astaxanthin through the changes in superoxide scavenging activity, levels of hydrogen peroxide and total hydroperoxides in human aqueous humor. The study subjects were 35 patients who underwent bilateral cataract surgery on one side before and the other side after intake of astaxanthin (6 mg/day for 2 weeks). Their aqueous humor was taken during the surgery and subjected to measurements of the three parameters. After astaxanthin intake, the superoxide scavenging activity was significantly (p<0.05) elevated, while the level of total hydroperoxides was significantly (p<0.05) lowered. There was a significant negative correlation between the superoxide scavenging activity and the level of total hydroperoxides (r = −0.485, p<0.01), but no correlations between the hydrogen peroxide level and the other two parameters. Astaxanthin intake clearly enhanced the superoxide scavenging activity and suppressed the total hydroperoxides production in human aqueous humor, indicating the possibility that astaxanthin has suppressive effects on various oxidative stress-related diseases.

JapicCTI-153102.