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 [(3)H] pyrilamine was performed using recombinant human histamine H(1) receptors (rhH(1)R). 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 H(1) receptors, pentobarbital-induced sleeping time, passive cutaneous anaphylaxis (PCA) reaction, and antigen-induced itch-scratch responses (ISRs).
Results: TAK-427 inhibited ligand binding to rhH(1)R with an IC(50) value of 17.3 nmol/l. TAK-427 inhibited histamine-induced skin reactions in guinea pigs and mice with an ID(50) 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 H(1) 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.