Hong Eunchong, Gu Sun Mi, Kim Jin Mook, Yoon Kyung Sik, Lee Jin-Moo, Kim Young-Hoon, Suh Soo Kyung, Lee Dohyun, Eom Heejong, Yun Jaesuk, Cha Hye Jin
College of Pharmacy, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28160, Republic of Korea.
Pharmacological Research Division, National Institute of Food and Drug Safety Evaluation (NIFDS), Ministry of Food and Drug Safety (MFDS), 187 Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28159, Republic of Korea.
Toxicol Res (Camb). 2022 Jul 8;11(4):644-653. doi: 10.1093/toxres/tfac039. eCollection 2022 Aug.
The use of many benzodiazepines is controlled worldwide due to their high likelihood of abuse and potential adverse effects. Flubromazepam-a designer benzodiazepine-is a long-acting gamma-aminobutyric acid subtype A receptor agonist. There is currently a lack of scientific evidence regarding the potential for flubromazepam dependence or other adverse effects. This study aimed to evaluate the dependence potential, and cardiotoxicity via confirmation of the QT and RR intervals which are the factors on the electrical properties of the heart of flubromazepam in rodents. Using a conditioned place preference test, we discovered that mice treated intraperitoneally with flubromazepam (0.1 mg/kg) exhibited a significant preference for the flubromazepam-paired compartment, suggesting a potential for flubromazepam dependence. In addition, we observed several cardiotoxic effects of flubromazepam; 100-μM flubromazepam reduced cell viability, increased RR intervals but not QT intervals in the electrocardiography measurements, and considerably inhibited potassium channels in a human ether-à-go-go-related gene assay. Collectively, these findings suggest that flubromazepam may have adverse effects on psychological and cardiovascular health, laying the foundation for further efforts to list flubromazepam as a controlled substance at both national and international levels.
由于许多苯二氮䓬类药物极易被滥用且存在潜在的不良反应,因此其使用在全球范围内受到管制。氟溴西泮——一种设计型苯二氮䓬类药物——是一种长效的γ-氨基丁酸A亚型受体激动剂。目前,关于氟溴西泮产生依赖性或其他不良反应的可能性,缺乏科学证据。本研究旨在通过确认QT和RR间期来评估氟溴西泮在啮齿动物体内的依赖性潜力和心脏毒性,这两个间期是反映心脏电特性的因素。通过条件性位置偏爱试验,我们发现腹腔注射氟溴西泮(0.1毫克/千克)的小鼠对与氟溴西泮配对的隔室表现出显著偏爱,这表明氟溴西泮具有产生依赖性的可能性。此外,我们观察到了氟溴西泮的几种心脏毒性作用;在心电图测量中,100微摩尔的氟溴西泮降低了细胞活力,增加了RR间期,但未改变QT间期,并且在一项人类醚-à-去相关基因试验中显著抑制了钾通道。总体而言,这些发现表明氟溴西泮可能对心理和心血管健康产生不利影响,为在国家和国际层面进一步努力将氟溴西泮列为管制物质奠定了基础。