Characterization of microminipig as a laboratory animal for safety pharmacology study by analyzing fluvoxamine-induced cardiovascular and dermatological adverse reactions

  • Yoichi Tanikawa
  • Mihoko Hagiwara-Nagasawa
  • Ryuichi Kambayashi
  • Ai Goto
  • Koki Chiba
  • Kumiko Kitta
  • Kiyotaka Hoshiai
  • Hiroko Izumi-Nakaseko
  • Atsuhiko T. Naito
  • Atsushi SugiyamaEmail author


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.


Fluvoxamine 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.

Ethical Approval

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.


  1. 1.
    Hyttel, J. (1994). Pharmacological characterization of selective serotonin reuptake inhibitors (SSRIs). International Clinical Psychopharmacology, 9(Suppl 1), 19–26.CrossRefGoogle Scholar
  2. 2.
    Yamazaki-Hashimoto, Y., Nakamura, Y., Ohara, H., Cao, X., Kitahara, K., Izumi-Nakaseko, H., et al. (2015). Fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations. The Journal of Toxicological Sciences, 40, 33–42.CrossRefGoogle Scholar
  3. 3.
    Milnes, J. T., Crociani, O., Archangeli, A., Hancox, J. C., & Witchel, H. J. (2003). Blockade of HERG potassium currents by fluvoxamine: Incomplete attenuation by 6 mutations at F656 or Y652. British Journal of Pharmacology, 139, 887–898.CrossRefGoogle Scholar
  4. 4.
    Stirnimann, G., Petitprez, S., Abriel, H., & Schwick, N. G. (2010). Brugada syndrome ECG provoked by the selective serotonin reuptake inhibitor fluvoxamine. Europace, 12, 282–283.CrossRefGoogle Scholar
  5. 5.
    Haberzettl, R., Bert, B., Fink, H., & Fox, M. A. (2013). Animal models of the serotonin syndrome: A systematic review. Behavioural Brain Research, 256, 328–345.CrossRefGoogle Scholar
  6. 6.
    Kaneko, N., Itoh, K., Sugiyama, A., & Izumi, Y. (2011). Microminipig, a non-rodent experimental animal optimized for life science research: Preface. Journal of Pharmacological Sciences, 115, 112–114.CrossRefGoogle Scholar
  7. 7.
    Matsukura, S., Nakamura, Y., Cao, X., Wada, T., Izumi-Nakaseko, H., Ando, K., et al. (2017). Characterization of microminipigs as an in vivo experimental model for cardiac safety pharmacology. Journal of Pharmacological Sciences, 133, 103–109.CrossRefGoogle Scholar
  8. 8.
    Yokoyama, H., Nakamura, Y., Saito, H., Nagayama, Y., Hoshiai, K., Wada, T., et al. (2017). Pharmacological characterization of microminipig as a model to assess the drug-induced cardiovascular responses for non-clinical toxicity and/or safety pharmacology studies. The Journal of Toxicological Sciences, 42, 93–101.CrossRefGoogle Scholar
  9. 9.
    Cao, X., Wada, T., Nakamura, Y., Matsukura, S., Izumi-Nakaseko, H., Ando, K., et al. (2017). Sensitivity and reliability of halothane-anaesthetized microminipigs to assess risk for drug-induced long QT syndrome. Basic & Clinical Pharmacology & Toxicology, 121, 465–470.CrossRefGoogle Scholar
  10. 10.
    Ando, K., Takahara, A., Nakamura, Y., Wada, T., Chiba, K., Goto, A., et al. (2018). Changes of electrocardiogram and hemodynamics in response to dipyridamole: In vivo comparative analyses using anesthetized beagle dogs and microminipigs. Journal of Pharmacological Sciences, 136, 86–92.CrossRefGoogle Scholar
  11. 11.
    Lubna, N. J., Nakamura, Y., Hagiwara-Nagasawa, M., Goto, A., Chiba, K., Kitta, K., et al. (2018). Electropharmacological characterization of microminipigs as a laboratory animal using anti-influenza virus drug oseltamivir. The Journal of Toxicological Sciences, 43, 507–512.CrossRefGoogle Scholar
  12. 12.
    Wada, T., Ohara, H., Nakamura, Y., Cao, X., Izumi-Nakaseko, H., Ando, K., et al. (2017). Efficacy of precordial percussion pacing assessed in a cardiac standstill microminipig model. Circulation Journal, 81, 1137–1143.CrossRefGoogle Scholar
  13. 13.
    Sugiyama, A. (2008). Sensitive and reliable proarrhythmia in vivo animal models for predicting drug-induced torsades de pointes in patients with remodelled hearts. British Journal of Pharmacology, 154, 1528–1537.CrossRefGoogle Scholar
  14. 14.
    Deardorff, O. G., Khan, T., Kulkarni, G., Doisy, R., & Loehr, C. (2016). Serotonin syndrome: Prophylactic treatment with cyproheptadine. The Primary Care Companion for CNS Disorders. Scholar
  15. 15.
    Boyer, E. W., & Shannon, M. (2005). The serotonin syndrome. New England Journal of Medicine, 352, 1112–1120.CrossRefGoogle Scholar
  16. 16.
    Graudins, A., Stearman, A., & Chan, B. (1998). Treatment of the serotonin syndrome with cyproheptadine. The Journal of Emergency Medicine, 16, 615–619.CrossRefGoogle Scholar
  17. 17.
    Kobayashi, K., Omuro, N., & Takahara, A. (2014). The conventional antihistamine drug cyproheptadine lacks QT-interval-prolonging action in halothane-anesthetized guinea pigs: Comparison with hydroxyzine. Journal of Pharmacological Sciences, 124, 92–98.CrossRefGoogle Scholar
  18. 18.
    Katzung, B. G.. Histamine (2018). Serotonin, & the Ergot Alkaloids. In B. G. Katzung (Ed.), Basic & clinical pharmacology (14th edn., pp. 277–299). New York: McGraw Hill Education.Google Scholar
  19. 19.
    DeBattista, C. (2018). Antidepressant Agents. In B. G. Katzung (Ed.), Basic & clinical pharmacology (14th edn., pp. 532–552). New York: McGraw Hill Education.Google Scholar
  20. 20.
    Fridericia, L. S. (1920). Die sytolendauer in elektrokardiogramm bei normalen menschen und bei herzkranken. Acta Medica Scandinavica, 53, 469–486.CrossRefGoogle Scholar
  21. 21.
    Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy, 7, 27–31.CrossRefGoogle Scholar
  22. 22.
    Ishigooka, J., Wakatabe, H., Shimada, E., Suzuki, M., Fukuyama, Y., & Murasaki, M., et al. (1993). Phase I trial on the serotonin reuptake inhibitor SME3110 (fluvoxamine maleate). Clinical Evaluation, 21, 441–490.Google Scholar
  23. 23.
    Norris, C. R., Boothe, D. M., Esparza, T., Gray, C., & Ragsdale, M. (1998). Disposition of cyproheptadine in cats after intravenous or oral administration of a single dose. American Journal of Veterinary Research, 59, 79–81.Google Scholar
  24. 24.
    Sato, N., Takata, H., Tsukui, M., Tatebayashi, T., Fuji, K., Hiranuma, T., et al. (1995). Studies on the pharmacokinetics of fluvoxamine maleate: Plasma concentration profile and brain distribution in rats. Japanese Pharmacology Therapy, 23, 637–643.Google Scholar
  25. 25.
    Miura, M., & Ohkubo, T. (2007). Identification of human cytochrome P450 enzymes involved in the major metabolic pathway of fluvoxamine. Xenobiotica, 37, 169–179.CrossRefGoogle Scholar
  26. 26.
    Murayama, N., Kaneko, N., Horiuchi, K., Ohyama, K., Shimizu, M., Ito, K., et al. (2009). Cytochrome P450-dependent drug oxidation activity of liver microsomes from Microminipigs, a possible new animal model for humans in non-clinical studies. Drug Metabolism and Pharmacokinetics, 24, 404–408.CrossRefGoogle Scholar
  27. 27.
    Sugiyama, A., Motomura, S., & Hashimoto, K. (1994). Utilization of isolated, blood-perfused canine papillary muscle preparation as a model to assess efficacy and adversity of class I antiarrhythmic drugs. The Japanese Journal of Pharmacology, 66, 303–316.CrossRefGoogle Scholar
  28. 28.
    Mcgregor, M., Davenport, H. T., Jegier, W., Sekelj, P., Gibbons, J. E., & Demers, P. P. (1958). The cardiovascular effects of halothane in normal children. British Journal of Anaesthesia, 30, 398–408.CrossRefGoogle Scholar
  29. 29.
    Mckinney, M. S., Fee, J. P. H., & Clarke, R. S. J. (1993). Cardiovascular effects of isoflurane and halothane in young and elderly adult patients. British Journal of Anaesthesia, 71, 696–701.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yoichi Tanikawa
    • 1
  • Mihoko Hagiwara-Nagasawa
    • 2
  • Ryuichi Kambayashi
    • 2
  • Ai Goto
    • 1
  • Koki Chiba
    • 1
  • Kumiko Kitta
    • 3
  • Kiyotaka Hoshiai
    • 3
  • Hiroko Izumi-Nakaseko
    • 1
    • 2
  • Atsuhiko T. Naito
    • 1
    • 2
  • Atsushi Sugiyama
    • 1
    • 2
    Email author
  1. 1.Department of PharmacologyToho University Graduate School of MedicineTokyoJapan
  2. 2.Department of Pharmacology, Faculty of MedicineToho UniversityTokyoJapan
  3. 3.Bioresearch CenterCMIC Pharma Science Co., LtdHokutoJapan

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