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

Takeshi Wada Mihoko Hagiwara-Nagasawa Ryuichi Kambayashi Ai Goto Koki Chiba Yoshio Nunoi Hiroko Izumi-Nakaseko Tadashi Koga Akio Matsumoto Yuji Nakazato Keith G. Lurie Atsushi Sugiyama

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.85, no.10, pp.1885-1891, 2021-09-24 (Released:2021-09-24)

参考文献数

29

被引用文献数

1

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Background:Effects of rapid electrical defibrillation and β-blockade on coronary ischemia/reperfusion-induced ventricular fibrillation (VF) during cardiopulmonary resuscitation (CPR) remain unknown.Methods and Results:After induction of VF by 30 min of ischemia followed by reperfusion, animals were treated with defibrillation alone (Group A, n=13), 2 min of open-chest cardiac massage followed by defibrillation (Group B, n=11), or the same therapy to Group B with propranolol (1 mg/kg, i.v.) treatment before ischemia/reperfusion (Group C, n=11). If return of spontaneous circulation (ROSC) was not attained, each therapy was repeated ≤3 times (Set-1). When ROSC was not obtained within Set-1, cardiac massage was applied to all animals followed by defibrillation, which was repeated ≤3 times (Set-2). ROSC after Set-1 was 8% in Group A, 82% in Group B and 82% in Group C, whereas that after Set-2 was 62% in Group A, 100% in Group B and 82% in Group C. Each animal with ROSC in Groups A (n=8) and B (n=11) showed sinus rhythm, whereas those in Group C (n=9) had sinus rhythm (n=5), atrial fibrillation (n=1), accelerated idioventricular rhythm (n=2) and atrioventricular block (n=1). Post ROSC heart rate and mean arterial pressure were significantly lower in Group C.Conclusions:Cardiac massage increased the likelihood of ROSC vs. rapid defibrillation, but β-blocker pretreatment may worsen hemodynamics and electrical stability after ROSC.

著者

Akihiro MORI Ai GOTO Ryoko KIBE Hitomi ODA Yasushi KATAOKA Toshinori SAKO

出版者

JAPANESE SOCIETY OF VETERINARY SCIENCE

雑誌

Journal of Veterinary Medical Science (ISSN:09167250)

巻号頁・発行日

vol.81, no.12, pp.1783-1790, 2019 (Released:2019-12-26)

参考文献数

48

被引用文献数

12

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The effects of prescription diets on canine intestinal microbiota are unknown. In this study, we used next generation sequencing to investigate the impact of four commercially available prescription diet regimens on the fecal microbiome in six healthy dogs. The diet regimens used were as follows: weight-loss diet, low-fat diet, renal diet, and anallergenic diet. We found a significantly decreased proportion of phylum Actinobacteria with the weight-loss diet compared to the anallergenic diet. There were no significant differences in the proportion of phylum Bacteroidetes between the four diets. The proportion of phylum Firmicutes was significantly decreased with the weight-loss diet compared to the anallergenic diet. The proportion of phylum Fusobacteria was significantly increased with the weight-loss diet compared to the anallergenic diet. There were no significant differences in the proportion of phylum Proteobacteria after consumption of the four diets. We therefore demonstrated that commercial prescription diet influences the fecal microbiome in healthy dogs. These results might be useful when choosing a prescription diet for targeting a disease.