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Inflammation Research

, Volume 52, Issue 5, pp 206–214 | Cite as

Characteristics of the antihistamine effect of TAK-427, a novel imidazopyridazine derivative

  • S. Fukuda
  • K. Midoro
  • M. Yamasaki
  • M. Gyoten
  • Y. Kawano
  • H. Fukui
  • Y. Ashida
  • H. Nagaya
Regular paper

Abstract:

Objective and Design: The characteristics of the antihistamine effect of the new antiallergic compound TAK-427 were investigated. Materials and methods: In vitro binding assay of [3H] pyrilamine was performed using recombinant human histamine H1 receptors (rhH1R). In vivo studies were performed in male ICR mice or Hartley guinea pigs. Drugs were administered orally 1 h before examinations. Determinations were made of histamine-induced skin reaction, ex vivo measured radioligand binding to brain and lung H1 receptors, pentobarbital-induced sleeping time, passive cutaneous anaphylaxis (PCA) reaction, and antigen-induced itch-scratch responses (ISRs). Results: TAK-427 inhibited ligand binding to rhH1R with an IC50 value of 17.3 nmol/l. TAK-427 inhibited histamine-induced skin reactions in guinea pigs and mice with an ID50 value of 0.884 and 0.450 mg/kg, p.o., respectively; significant inhibition associated with 10 mg/kg of TAK-427 was still observed 24 h after dosing in guinea pigs. TAK-427 showed as high selectivity for peripheral H1 receptors as terfenadine and epinastine did, which was evaluated by ex vivo measured radioligand binding. Even at 300 mg/kg, TAK-427 did not affect pentobarbital-induced sleeping time in mice. TAK-427 significantly inhibited PCA in mice and guinea pigs, and also inhibited antigen-induced ISRs in guinea pigs. Conclusions: These results suggest that TAK-427 may have a long-lasting antihistamine activity with minimum sedative side effect and suppress acute phase allergic reactions.

Key words:TAK-427 – Antihistamine activity – Sedation 

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Copyright information

© Birkhäuser Verlag, 2003

Authors and Affiliations

  • S. Fukuda
    • 1
  • K. Midoro
    • 1
  • M. Yamasaki
    • 1
  • M. Gyoten
    • 1
  • Y. Kawano
    • 1
  • H. Fukui
    • 2
  • Y. Ashida
    • 1
  • H. Nagaya
    • 1
  1. 1.Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Juso-Honmachi, Yodogawa-ku, Osaka, 532-8686, Japan, Fax: ++81 6 6300 6306, e-mail: Fukuda_Shigeru@takeda.co.jp JP
  2. 2.Department of Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokushima, 1-78, Shoumachi, Tokushima 770-8505, Japan JP

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