Usefulness of Continuous Low-Dose Fentanyl in Combination with Dexmedetomidine and Midazolam for Intravenous Sedation: A Randomised Controlled Trial.

Intravenous dexmedetomidine (DEX) and midazolam (MZ) are currently used to achieve sedation in dental surgery under local anaesthesia. However, the efficacy of low-dose fentanyl (FEN) in combination with DEX and MZ sedation remains unclear. Therefore, we implemented a prospective randomised controlled trial to investigate the intra- and postoperative analgesic effects, intraoperative respiratory and circulatory dynamics, and frequency of intra- and postoperative adverse events of continuous low-dose fentanyl administration with DEX and MZ sedation. Patients aged 20-64 years scheduled for dental surgery under sedation were randomly assigned to the DEX+MZ (DM) or DEX+MZ+FEN (DMF) group. DEX was administered at 4 µg/kg/h for 10 min and then reduced to 0.7 µg/kg/h until the end of surgery. MZ was administered at 0.04 mg/kg upon the initial administration of DEX and 0.02 mg/kg every hour thereafter. In the DMF group, FEN infusion was administered at 2 µg/kg/h during the initial administration of DEX and then reduced to 1 µg/kg/h after 10 min until the end of surgery. Primary outcomes were intra- and postoperative analgesic efficacies, whereas secondary outcomes were intraoperative respiratory and circulatory dynamics. The total amount of intraoperative local anaesthetic administered and the heart rate were significantly lower in the DMF group than in the DM group (P = 0.044 and P < 0.01, respectively). No significant difference was observed in the frequency of postoperative administration of analgesics and intra- and postoperative adverse events. These findings demonstrated that low-dose FEN infusion in combination with DEX and MZ sedation in dental surgery provides intraoperative analgesia and suppresses tachycardia with little effect on blood pressure and respiratory dynamics and without effect on postoperative analgesia.

Downregulation of stanniocalcin 1 is responsible for sorafenib-induced cardiotoxicity.

Sorafenib is associated with adverse cardiac effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish and human cardiomyocytes. Fluorescent cardiac imaging using pigmentless zebrafish with green fluorescent protein hearts revealed that the ventricular dimensions of the longitudinal axis with sorafenib were significantly shorter than those of the control group. Transcriptome analysis of their hearts revealed that stanniocalcin 1 (stc1) was downregulated by sorafenib. stc1 knockdown in zebrafish revealed that reduction of stc1 decreased the longitudinal dimensions of zebrafish ventricles, similar to that which occurs during sorafenib treatment. STC1 downregulation and cytotoxicity were also seen in human cardiomyocytes exposed to sorafenib. To clarify the molecular function of stc1 in sorafenib-induced cardiotoxicity, we focused on oxidative stress in cardiomyocytes treated with sorafenib. Reactive oxygen species (ROS) production significantly increased in both species of human cardiomyocytes and zebrafish exposed to sorafenib and STC1 knockdown compared with the controls. Finally, we found that forced expression of stc1 normalized impairment, decreasing the longitudinal dimensions in zebrafish treated with sorafenib. Our study demonstrated that STC1 plays a protective role against ventricular dysfunction and ROS overproduction, which are induced by sorafenib treatment. We discovered for the first time that STC1 downregulation is responsible for sorafenib-induced cardiotoxicity through activated ROS generation.

Identification of a novel indoline derivative for in vivo fluorescent imaging of blood-brain barrier disruption in animal models.

Disruption of the blood-brain barrier (BBB) can occur in various pathophysiological conditions. Administration of extraneous tracers that can pass the disrupted, but not the intact, BBB and detection of the extravasation have been widely used to assess BBB disruption in animal models. Although several fluorescent tracers have been successfully used, the administration of these tracers basically requires intravascular injection, which can be laborious when using small animals such as zebrafish. To identify fluorescent tracers that could be easily administered into various animal models and visualize the BBB disruption in vivo, we prepared nine structurally related indoline derivatives (IDs) as a minimum set of diverse fluorescent compounds. We found that one ID, ZMB741, had the highest affinity for serum albumin and emitted the strongest fluorescence in the presence of serum albumin of the nine IDs tested. The affinity to serum albumin and the fluorescence intensity was superior to those of Evans blue and indocyanine green that have been conventionally used to assess the BBB disruption. We showed that ZMB741 could be administered into zebrafish by static immersion or mice by intraperitoneal injection and visualizes the active disruption of their BBB. These results suggest that ZMB741 can be a convenient and versatile tool for in vivo fluorescent imaging of BBB disruption in various animal models. The strategy used in this study can also be applied to diversity-oriented libraries to identify novel fluorescent tracers that may be superior to ZMB741.