Characterization of microminipig as a laboratory animal for safety pharmacology study by analyzing fluvoxamine-induced cardiovascular and dermatological adverse reactions
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Fluvoxamine is a selective serotonin-reuptake inhibitor, of which IC50 values for serotonin- and noradrenaline-uptake process were reported to be 3.8 and 620 nmol/L, respectively, also known to directly inhibit cardiac Na+, Ca2+, and K+ channels. We characterized microminipig as a laboratory animal by analyzing fluvoxamine-induced cardiovascular and dermatological responses under halothane anesthesia. Fluvoxamine maleate was infused in doses of 0.1, 1, and 10 mg/kg over 10 min with a pause of 20 min (n = 4). The peak plasma concentrations were 35, 320, and 1906 ng/mL, of which free plasma concentrations were estimated as 20, 187, and 1108 nmol/L, respectively. The low and middle doses did not alter any cardiovascular variable. The high dose increased heart rate and mean blood pressure, prolonged QRS width, but shortened QT interval, whereas no significant change was detected in PR interval or QTcF. Moreover, it induced systemic erythema on the skin. Pretreatment of H1/5-HT2A antagonist cyproheptadine hydrochloride sesquihydrate in a dose of 0.3 mg/kg significantly attenuated the fluvoxamine-induced pressor response; but tended to further enhance sinus automaticity, atrioventricular nodal conduction; and ventricular repolarization in addition to intraventricular conduction delay; whereas it markedly suppressed onset of systemic erythema (n = 4). In microminipigs, cardiovascular adverse effects of the high dose may be manifested as a sum of its inhibitory action on the cardiac ionic channels and its stimulatory effects on serotonergic and adrenergic systems, whereas dermatologic reaction can be induced primarily through H1/5-HT2A receptor-dependent mechanism. Thus, microminipigs may be used for analyzing such multifarious adverse events of clinical serotonergic pharmacotherapy.
KeywordsFluvoxamine Microminipig Hypertension Tachycardia Systemic erythema
The authors thank Dr. Keith G. Lurie, Dr. Yoshikiyo Akasaka, Dr. Yuji Nakamura, Dr. Takeshi Wada, Dr. Kentaro Ando, and Dr. Yasuki Akie for their scientific advice, and for Mr. Yoshinori Kondo, Mr. Makoto Shinozaki, and Mrs. Yuri Ichikawa for their technical assistances.
This study was supported in part by Japan agency for medical research and development (AMED Grant #AS2116907E and #JP18mk0104117j0001) and Japan society for the promotion of science (JSPS KAKENHI Grant #JP16K08559).
Compliance with Ethical Standards
Conflict of interest
The authors indicated no potential conflict of interest.
All experiments were approved by the Toho University Animal Care and User Committee (No. 15-52-275, 16-53-275, 17-54-275, 18-51-394) and performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of Toho University.
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