Effects of YM175, a New-Generation Bisphosphonate, on Hypercalcemia Induced by Tumor-Derived Bone Resorbing Factors in Rats

The Japanese Journal of Pharmacology

Kyoko Teramura²  Koichiro Takahashi¹  Atsushi Shirahata²  Shinji Fukushima²  Satoshi Kokubo²  Shinji Usuda² 

[1]Present address for correspondence: Applied Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

[2]Applied Pharmacology Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

关键词: Bisphosphonate;    Hypercalcemia;    Parathyroid hormone-related protein;    Interleukin 1β;    Bone resorbing factor;   

DOI  :  10.1254/jjp.76.155

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(23)Cited-By(7)YM175 (disodium cycloheptylaminomethylenediphosphonate monohydrate) is a new-generation bisphosphonate with stronger inhibitory activity on bone resorption than first-generation bisphosphonates. In the present study, the effect of YM175 on hypercalcemia induced in rats by single administration of either parathyroid hormone-related protein (PTHrP) or concomitant administration of PTHrP and interleukin 1β (IL-1β) was investigated. YM175 (0.01 – 1 mg/kg, i.v.) inhibited the increase in serum free calcium concentration induced by continuous administration of PTHrP alone (3 μg/rat/day, s.c., 7 days) dose-dependently. The inhibitory effect of YM175 appeared the day after administration and remained 3 days after administration. The effect of YM175 reached a maximum 2 days after administration, at which time the ED50 value of YM175 was calculated to be 0.041 mg/kg, i.v., revealing a potency approximately 50- and 10-fold stronger than those of either pamidronate or alendronate, respectively. In contrast, elcatonin (1 – 10 units/kg, s.c.) only transiently inhibited PTHrP-induced free calcium increase. YM175 (0.1 – 3 mg/kg, i.v.) also inhibited the increase in the serum free calcium concentration induced by continuous concomitant administration of both PTHrP and IL-1β in a dose-dependent manner. These results indicated that YM175 is expected to be a useful drug for hypercalcemia associated with malignant tumors due to its efficacy and range of effect.

【 授权许可】

Unknown