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 1beta (IL-1beta) 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 microg/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-1beta 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.