Delirium risk of histamine-2 receptor antagonists and proton pump inhibitors: A study based on the adverse drug event reporting database in Japan.

OBJECTIVE: Although histamine-2 receptor antagonists (H2RAs) have been shown to be more likely to cause delirium than proton pump inhibitors (PPIs), these results were not adjusted for potential confounding factors. Accordingly, we investigated whether H2RAs and PPIs are risk factors for delirium, even when adjusting for other risk factors by analyzing adverse drug event reports compiled in the post-marketing stages of drugs provided by the Japanese regulatory authorities. METHOD: We analyzed 577,431 reports in the Japanese Adverse Drug Event Report database from April 2004 to July 2020. RESULTS: Of all reports analyzed, 2532 described delirium, and 574,899 described other adverse events. Delirium was associated with H2RAs (crude reporting odds ratio, ROR, 4.17; 95% CI, 3.34-5.22) but not PPIs (crude ROR 0.62; 95% CI 0.43-0.90). Even with adjustment for age, sex, history of dementia or depression, and concomitant drugs reported as risk factors for delirium, the use of H2RAs showed a significantly higher adjusted ROR than that of PPIs (H2RAs: adjusted ROR 3.99; 95% CI 3.18-5.01 and PPIs: adjusted ROR 0.58; 95%CI 0.40-0.84). CONCLUSIONS: These results suggest that, from a cognitive perspective, PPIs may be preferable to H2RAs for patients with or at risk for delirium.

Chloride intracellular channel protein 2 in cancer and non-cancer human tissues: relationship with tight junctions.

Chloride intracellular channel protein 2 (CLIC2) belongs to the CLIC family of conserved metazoan proteins. Although CLICs have been identified as chloride channels, they are currently considered multifunctional proteins. CLIC2 is the least studied family member. We investigated CLIC2 expression and localization in human hepatocellular carcinoma, metastatic colorectal cancer in the liver, and colorectal cancer. Significant expression of mRNAs encoding CLIC1, 2, 4, and 5 were found in the human tissues, but only CLIC2 was predominantly expressed in non-cancer tissues surrounding cancer masses. Fibrotic or dysfunctional (aspartate aminotransferase ≥40) non-cancer liver tissues and advanced stage HCC tissues expressed low levels of CLIC2. Endothelial cells lining blood vessels but not lymphatic vessels in non-cancer tissues expressed CLIC2 as well as high levels of the tight junction proteins claudins 1 and 5, occludin, and ZO-1. Most endothelial cells in blood vessels in cancer tissues had very low expressions of CLIC2 and tight junction proteins. CD31+/CD45- endothelial cells isolated from non-cancer tissues expressed mRNAs encoding CLIC2, claudin 1, occludin and ZO-1, while similar cell fractions from cancer tissues had very low expressions of these molecules. Knockdown of CLIC2 expression in human umbilical vein endothelial cells (HUVECs) allowed human cancer cells to transmigrate through a HUVEC monolayer. These results suggest that CLIC2 may be involved in the formation and/or maintenance of tight junctions and that cancer tissue vasculature lacks CLIC2 and tight junctions, which allows the intravasation of cancer cells necessary for hematogenous metastasis.