著者

Nobuyuki Suzuki Ryuichi Kambayashi Ai Goto Hiroko Izumi-Nakaseko Yoshinori Takei Atsuhiko T Naito Atsushi Sugiyama

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.48, no.12, pp.645-654, 2023 (Released:2023-12-01)

参考文献数

27

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Antiparasitic ivermectin has been reported to induce cardiovascular adverse events, including orthostatic hypotension, tachycardia and cardiopulmonary arrest, of which the underlying pathophysiology remains unknown. Since its drug repurposing as an antiviral agent is underway at higher doses than those for antiparasitic, we evaluated the cardiovascular safety pharmacology of ivermectin using isoflurane-anesthetized beagle dogs (n=4). Ivermectin in doses of 0.1 followed by 1 mg/kg was intravenously infused over 10 min with an interval of 20 min, attaining peak plasma concentrations of 0.94 ± 0.04 and 8.82 ± 1.25 μg/mL, which were 29-31 and 276-288 times higher than those observed after its antiparasitic oral dose of 12 mg/body, respectively. The latter peak concentration was > 2 times greater than those inhibiting proliferation of dengue virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hepatitis B virus in vitro. Ivermectin decreased heart rate without altering mean blood pressure, suggesting that ivermectin does not cause hypotension or tachycardia directly. Ivermectin hardly altered atrioventricular nodal or intraventricular conduction, indicating a lack of inhibitory action on Ca2+ or Na+ channel in vivo. Ivermectin prolonged QT interval/QTcV in a dose-related manner and tended to slow the repolarization speed in a reverse frequency-dependent manner, supporting previously described its IKr inhibition, which would explain Tpeak-Tend prolongation and heart-rate reduction in this study. Meanwhile, ivermectin did not significantly prolong J-Tpeakc or terminal repolarization period, indicating torsadogenic potential of ivermectin leading to the onset of cardiopulmonary arrest would be small. Thus, ivermectin has a broad range of cardiovascular safety profiles, which will help facilitate its drug repurposing.

著者

Masashi Uehara Shota Ikegami Takashi Takizawa Hiroki Oba Noriaki Yokogawa Takeshi Sasagawa Kei Ando Hiroaki Nakashima Naoki Segi Toru Funayama Fumihiko Eto Akihiro Yamaji Kota Watanabe Satoshi Nori Kazuki Takeda Takeo Furuya Sumihisa Orita Hideaki Nakajima Tomohiro Yamada Tomohiko Hasegawa Yoshinori Terashima Ryosuke Hirota Hidenori Suzuki Yasuaki Imajo Hitoshi Tonomura Munehiro Sakata Ko Hashimoto Yoshito Onoda Kenichi Kawaguchi Yohei Haruta Nobuyuki Suzuki Kenji Kato Hiroshi Uei Hirokatsu Sawada Kazuo Nakanishi Kosuke Misaki Hidetomi Terai Koji Tamai Eiki Shirasawa Gen Inoue Kenichiro Kakutani Yuji Kakiuchi Katsuhito Kiyasu Hiroyuki Tominaga Hiroto Tokumoto Yoichi Iizuka Eiji Takasawa Koji Akeda Norihiko Takegami Haruki Funao Yasushi Oshima Takashi Kaito Daisuke Sakai Toshitaka Yoshii Tetsuro Ohba Bungo Otsuki Shoji Seki Masashi Miyazaki Masayuki Ishihara Seiji Okada Yasuchika Aoki Katsumi Harimaya Hideki Murakami Ken Ishii Seiji Ohtori Shiro Imagama Satoshi Kato

出版者

The Japanese Society for Spine Surgery and Related Research

雑誌

Spine Surgery and Related Research (ISSN:2432261X)

巻号頁・発行日

pp.2021-0183, (Released:2021-12-27)

被引用文献数

2

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Background: In elderly patients with cervical spinal cord injury, comorbidities such as cardiovascular and cerebrovascular diseases are common, with frequent administration of antiplatelet/anticoagulant (APAC) drugs. Such patients may bleed easily or unexpectedly during surgery despite prior withdrawal of APAC medication. Few reports have examined the precise relationship between intraoperative blood loss and history of APAC use regarding surgery for cervical spine injury in the elderly.The presentmulticenter database survey aimed to answer the question of whether the use of APAC drugs affected the amount of intraoperative blood loss in elderly patients with cervical spinal cord trauma.Methods: The case histories of 1512 patients with cervical spine injury at 33 institutes were retrospectively reviewed. After excluding cases without spinal surgery or known blood loss volume, 797 patients were enrolled. Blood volume loss was the outcome of interest. We calculated propensity scores using the inverse probability of treatment weighting (IPTW) method. As an alternative sensitivity analysis, linear mixed model analyses were conducted as well.Results: Of the 776 patients (mean age: 75.1 ± 6.4 years) eligible for IPTW calculation, 157 (20.2%) were taking APAC medications before the injury. After weighting, mean estimated blood loss was 204 mL for non-APAC patients and 215 mL for APAC patients. APAC use in elderly patients was not significantly associated with surgical blood loss according to the IPTW method with propensity scoring or linear mixed model analyses. Thus, it appeared possible to perform surgery expecting comparable blood loss in APAC and non-APAC cases.Conclusions: This multicenter study revealed no significant increase in surgical blood loss in elderly patients with cervical trauma taking APAC drugs. Surgeons may be able to prioritize patient background, complications, and preexisting conditions over APAC use before injury when examining the surgical indications for cervical spine trauma in the elderly.