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  • Title: Development of polyethylene glycol-conjugated alendronate, a novel nitrogen-containing bisphosphonate derivative: evaluation of absorption, safety, and effects after intrapulmonary administration in rats.
    Author: Katsumi H, Takashima M, Sano J, Nishiyama K, Kitamura N, Sakane T, Hibi T, Yamamoto A.
    Journal: J Pharm Sci; 2011 Sep; 100(9):3783-92. PubMed ID: 21567410.
    Abstract:
    Bisphosphonates are widely used for the treatment of bone diseases, including hypercalcemia and osteoporosis. However, the bioavailability (BA) of orally administered bisphosphonates is low, at approximately 0.9%-1.8%. In addition, the oral administration of bisphosphonates is associated with mucosal damage, including gastritis, gastric ulcer, and erosive esophagitis. Here, to develop a new delivery system for bisphosphonates that improve their BA and safety, we developed polyethylene glycol (PEG)-conjugated alendronate, a novel nitrogen-containing bisphosphonate derivative. We evaluated the absorption and safety of PEG-alendronate in rats following intrapulmonary administration. The BA of PEG-alendronate after intrapulmonary administration was approximately 44 ± 10% in rats, which was similar to that of alendronate (54 ± 3.9%). Alendronate significantly increased total protein concentration and lactate dehydrogenase activity in bronchoalveolar lavage fluid, suggesting that pulmonary epithelium was locally damaged by intrapulmonary administration of alendronate. In marked contrast, PEG-alendronate did not significantly increase the markers following intrapulmonary administration. In an osteoporosis model in rats, intrapulmonary administration of PEG-alendronate effectively inhibited decreases in the width of the growth plate to a level similar to that achieved by intrapulmonary administration of alendronate. These results indicate that pulmonary delivery of PEG-alendronate is a promising approach for the treatment of bone diseases.
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