Objectives: Remimazolam, an ultra-short-acting benzodiazepine, has been used for procedural sedation in the United States. We conducted an investigator-initiated clinical trial to determine the appropriate dose of remimazolam required for sedation during gastrointestinal endoscopy in Japanese subjects.
Methods:In this single-center, open-label, uncontrolled, phase II trial, a three-stage cohort investigated the appropriate initial and additional doses of remimazolam required for gastrointestinal endoscopy. This study was designed with advice from the Pharmaceuticals and Medical Devices Agency. The initial and additional doses were 2 mg and 1 mg/dose, 3 mg and 1 mg/dose, and 5 mg and 2 mg/dose in cohorts 1, 2, and 3, respectively. Each cohort included 10 cases of upper gastrointestinal endoscopy and colonoscopy. The primary end-point was the success rate of sedation during gastrointestinal endoscopy.Results: Sedation was successful in all gastrointestinal endoscopies in cohorts 1 and 2. In cohort 1, sedation was achieved in five (25.0%) and 10 (50.0%) participants with the initial dose and total dose (initial dose + additional dose ≤ the initial dose of the next cohort), respectively, before endoscopy. In cohort 2, sedation was achieved in 11 (55.0%) and 18 (90.0%) participants with the initial dose and total dose, respectively, before endoscopy. No patient in either cohort lost consciousness or required flumazenil or manual ventilation.
Conclusion:Initial and additional doses of 3 mg and 1 mg/dose of remimazolam, respectively, were shown to be effective and safe for sedation during gastrointestinal endoscopy in Japanese patients.
Background: High mobility group box 1 (HMGB1) is a chromatin structural protein expressed ubiquitously in the nuclei of mammalian cells. Increasing evidence suggests that inflammatory responses are involved in the progression of systemic injuries induced by a diverse range of insults, including stroke, trauma, tumors, and degenerative diseases. Whether HMGB1 expression in systemic organs is associated with transient ischemic attack (TIA) remains unclear. We hypothesized that HMGB1 expression after TIA would exacerbate systemic symptoms due to acute inflammation.Material and Methods: We performed transient bilateral and unilateral common carotid artery occlusion (2VO and 1VO) on Sprague-Dawley (SD) male rats. Rats were randomized to the sham, 1VO, and 2VO groups. The sham group underwent no procedure that involved common carotid artery occlusion. Common carotid arteries were clamped for 30 minutes and, subsequently, reperfused for 24 hours. Brain, heart, liver, lung, spleen, kidney and intestine tissue samples were collected for biochemical and histopathological analysis. Protein and mRNA expression were determined by western blot analysis and polymerase chain reaction (PCR).Results: HMGB1 expression increased in the brain, liver, spleen and intestine of the rat 1VO and 2VO models. In vivo results indicated high expression of HMGB1 in TIA, and the expression of MMP-9 and PKCδ in the cerebral cortex and hippocampus was regulated by HMGB1. In the 2VO model, the expression of CD11b and GFAP in the cerebral cortex was significantly increased compared with that in the control group (P < 0.001). HMGB1 was translocated from the nucleus to the cytoplasm at early stages after TIA and then localized to the cytoplasm of phagocytic microglia at later stages.Conclusion: HMGB1 expression increased in the systemic organs after TIA. HMGB1 promotes systemic inflammation, which mediates the immune response and tissue damage in the brain after TIA. Targeting HMGB1 signaling may be a promising therapeutic approach for the treatment of TIA.
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