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

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.

Antitumor effects of 5'-deoxy-5-fluorouridine in combination with recombinant human interleukin 2 on murine colon carcinoma 26.

The antitumor activity of recombinant human interleukin 2 (rIL-2) in combination with 5'-deoxy-5-fluorouridine (doxifluridine; 5'-DFUR) against marine colon carcinoma 26 (Colon 26) was studied. BALB/c mice were treated daily for 15 days with 5'-DFUR, rIL-2 or both, beginning on day 7 after subcutaneous transplantation of Colon 26. While mice treated with 5'-DFUR or rIL-2 alone died of tumor growth with pulmonary metastases within 9 weeks posttransplantation, the survival time was significantly prolonged in mice treated with both 5'-DFUR and rIL-2. Most of the combination-treated animals showed the regression of local tumors and the inhibition of pulmonary metastasis. Histopathologically, many tumor cells were degenerated and necrotized, with marked infiltration of mononuclear cells including large granular lymphocytes (LGLs) with periodic acid-Schiff-positive cytoplasmic granules. The cells were positive for CD3 epsilon, asialo GM1 and NK1.1. Spleen cells from the combination-treated mice showed high activities of natural killer (NK) cytotoxicity as well as growth inhibition of Colon 26 and Meth A fibrosarcoma in mice. The results suggest that the combination therapy of 5'-DFUR plus rIL-2 enhanced non-specific cytotoxicity of LGL/NK cells for Colon 26 in tumor-bearing mice and was effective in the inhibition of tumor growth.

Immunopathology of chronic progressive hepatitis in nude mice infected with low-virulent mouse hepatitis virus.

Progressive hepatitis in athymic nude (nu/nu) mice due to a low-virulent mouse hepatitis virus, MHV-2 cc, was examined for involvement of immunocytes and serum antibodies. At 3 to 6 weeks postinoculation (p.i.) a considerable number of Mac 1- and asialo GM1-positive cells were accumulated in the affected liver and spleen. There were also some Thy-1-positive cells. Later than 2 weeks p.i., serum IgG and IgM antibodies were detected in parallel with virus-neutralizing activity, while the IgG levels were lower than those of infected euthymic (nu/+) littermates. By transfer of the infected nu/nu mouse serum, the recipient euthymic mice acquired resistance to lethal challenge infection with a virulent virus, MHV-2.