Nonclinical Model for Assessing Gastric Effects of Bisphosphonates

摘要: Gastrointestinal intolerance has been associatedwith amino bisphosphonate therapy in the clinic. Theobjective of this study was to develop a model forassessing bisphosphonateinduced gastric damage that may aid development futurebisphosphonate therapies. Rats were dosed concomitantlywith indomethacin (40 mg/kg, subcutaneously) and anamino or pyridinyl (orally at 150, 225 300 mg/kg). The bisphosphonates studied werepamidronate alendronate (primary aminobisphosphonates) risedronate NE-97221 (pyridinylbisphosphonates). Macroscopically, inducedsignificantly (P < 0.05) more antral (both lesionlength number) than pamidronate at225 mg/kg.NE-97221 induced significantly (lesion length) mg/kgand greater number lesions compared pamidronateand mg/kg. wasvalidated histologically, macroscopic findings correlated with histologic evidence antralmucosal necrosis inflammatory infiltration thelamina propria. calcium chelators EGTA EDTA didnot induce when according same protocol as thenitrogen-containing bisphosphonates. This suggests thatcalcium chelation does not account for gastriceffects model. fasted, indomethacin-treatedrat provides novel nonclinical assessgastric effects bisphosphonates, which thedevelopment future Thesedata suggest expressed on an actual anticipated clinical dose basis forosteoporosis (pamidronate, 150 mg; alendronate, 5-10 mg;risedronate NE-97221, 5 mg), primary aminobisphosphonates have potential forinducing do pyridinylbisphosphonates.