OBJECTIVEY-25510 was administered by means of an intravenous drip infusion to healthy adult male volunteers at a dose of 40, 80 or 160 mg in a single-dose study, and at a dose of 160 mg once a day for 7 days in a multiple-dose study.RESULTSSerum levels of interleukin (IL)-1beta, IL-6 and IL-10 were significantly increased, but there was no change in leukocyte and platelet counts. The peak serum concentration of IL-1beta was nearly maximum at the single doses of 40 and 80 mg, and at the multiple dose of 160 mg per day. The peak serum concentration of IL-6 increased in a dose-dependent manner at a dose of 40 mg or more. For the multiple-dose study, the serum level of IL-10, which remained unchanged in the placebo group, began to increase in the Y-25510 group following the maximum serum level of IL-1beta and IL-6. There were no clinically relevant differences in body temperature and blood pressure after the administration of Y-25510.CONCLUSIONThese findings that leukocyte and platelet counts never increased, despite the increment of the IL-1beta and IL-6 production after the administration of Y-25510, may be explained in part by the negative feedback mechanism induced by IL-10.

01 Dec 1996·International Journal of Immunopharmacology

(±)-3-[4-(2-dimethylamino-1-methylethoxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-1-acetic acid (Y-25510) stimulates production of IL-1β and IL-6 at the level of messenger RNA expression in cultured human monocytes

Article

Author: Hidenobu Kusuhara ; Hirotsugu Komatsu ; Yoshifumi Ikeda ; Masao Hisadome

(+/-)-3-[4-(2-Dimethylamino-1-methylethoxy)phenyl]-1H-pyrazolo[3, 4-b]pyridine-1-acetic acid (Y-25510) stimulated the mRNA expression for interleukin-1 beta (IL-1 beta), and enhanced the expression induced by lipopolysaccharide (LPS) in cultured human peripheral blood mononuclear cells (PBMC) and THP-1 cells, a cell-line derived from human monocytic leukemia. Y-25510 also stimulated the mRNA expression for IL-6 in both types of the cells, however, the stimulation required the presence of LPS. In THP-1 cells, the stimulation of IL-1 beta mRNA expression by Y-25510 was suppressed by cycloheximide, an inhibitor of protein synthesis. This phenomenon indicates that the stimulation requires de norv protein synthesis. In contrast, the stimulation of mRNA expression for IL-6 by Y-25510 was not suppressed by cycloheximide but suppressed by N alpha-p-tosyl-L-phenylalanine chloromethyl ketone (TPCK), an inhibitor of nuclear transcription factor-kappa B (NF-kappa B) activation, in the presence of LPS, suggesting that the stimulation requires NF-kappa activation. These results demonstrate that Y-25510 stimulates the mRNA expression for IL-1 beta and IL-6 by different mechanisms. Dexamethasone suppressed the LPS-induced expression of mRNA for IL-1 beta and IL-6 in THP-1 cells, whereas the drug never suppressed the mRNA expression for these cytokines in the presence of Y-25510. The result indicates that Y-25510 stimulates the mRNA expression for IL-1 beta and IL-6 by different mechanisms from those of LPS.

01 Jun 1996·International Journal of Immunopharmacology

Enhancement of in vivo production of IL-1α and IL-6 in mice by Y-25510, a 1H-pyrazolo[3,4-b]pyridine-1-acetic acid derivative

Article

Author: Hirofumi Matsuyuki ; Tetsuko Fukuda ; Kikuo Nomoto ; Masao Hisadome ; Yoshifumi Ikeda

The serum concentrations of interleukin(IL)-1 alpha and IL-6 in C57BL/6 and C3H/HeN mice reached the maximum at 12-16 h after the intravenous treatment with (+/-)-3-[4-(2-dimethylamino-1-methylethoxy)- phenyl]-1H-pyrazolo[3,4-b]pyridine-1-acetic acid (Y-25510) at a dose of 3 mg/kg, and the concentration of IL-10 did at 20 h after the treatment. By repeated treatments with Y-25510 to C57BL/6 mice for 14 days, the maximal values of IL-1 alpha and IL-6 at day 14 were respectively 6.6 times and 5.7 times relative to those on day 1. Neither the counts of peripheral leukocytes nor those of platelets were, however, increased until day 15. The repeated treatment with Y-25510 followed by anti-IL-10 antibody for 14 days was significantly more effective than that with Y-25510 alone in increasing the concentrations of IL-1 alpha and IL-6 in C3H/HeN mice. In addition, both the counts of peripheral leukocytes and platelets were significantly increased at day 18. In conclusion, Y-25510 enhanced not only the production of endogenous IL-1 alpha and IL-6 but also that of IL-10 in healthy mice. As a result, in normal conditions, both the counts of peripheral leukocytes and platelets were never increased because of the inhibitory effect of endogenously produced IL-10.

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Indication	Highest Phase	Country/Location	Organization	Date
Leukopenia	Phase 1	-	Mitsubishi Tanabe Pharma Corp.	-
Leukopenia	Phase 1	JP	Mitsubishi Pharma Corp.	-
Thrombocytopenia	Phase 1	-	Mitsubishi Tanabe Pharma Corp.	-
Thrombocytopenia	Phase 1	JP	Mitsubishi Pharma Corp.	-

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