糖皮质激素性骨质疏松症课件_2.ppt

* * * 这张图展示的是所有双膦酸药物的作用机制，通过与骨表面的羟基磷灰石结合而进一步对破骨细胞发挥作用。 首先，药物进入体内后直接与骨表面结合，并且主要在骨吸收活跃部位的骨表面浓集，当破骨细胞侵蚀骨组织的时候，会将骨表面的双膦酸盐吸收入破骨细胞体内，使细胞功能丧失，最终凋亡。 * * Functional Domains of Bisphosphonates Bisphosphonates have several functional domains and different molecular structures. As a class, all bisphosphonates work by binding their phosphonate groups to hydroxyapatite. All approved bisphosphonates have and OH group in R1; this creates a triple hook and enhances binding to bone. Varying the R2 substituents can result in differences in antiresorptive potency of several orders of magnitude. Pamidronate and alendronate have an R2 side chain that contains a basic primary nitrogen atom in an alkyl chain and have greater antiresorptive potency than either etidronate or clodronate. Ibandronate has a more highly substituted nitrogen moiety in R2 and shows greater antiresorptive potency than pamidronate or alendronate. The most potent antiresorptive bisphosphonates are risedronate and zoledronic acid, which both contain a nitrogen atom within a heterocyclic ring in the R2 position. Enhancements in antiresorptive potency resulting from differences in the R2 groups appear to be particularly linked to inhibition of the farnesyl pyrophosphate synthase enzyme within the mevalonate pathway in osteoclasts. Reference Nancollas GH, Tang R, Phipps RJ, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006;38:617-627. * IC50是指“反应”被抑制一半时抑制剂的浓度，这里的反应可以是酶催化反应，抗原抗体反应等。在凋亡方面，可以理解为一定浓度的某种药物诱导肿瘤细胞凋亡50%，该浓度称为50%抑制浓度，即凋亡细胞与全部细胞数之比等于50%时所对应的浓度，IC50值可以用来衡量药物诱导凋亡的能力，即诱导能力越强，该数值越低,当然也可以反向说明某种细胞对药物的耐受程度。 Zoledronic Acid Has a High Therapeutic Ratio for Inhibition of Resorption to Mineralization Bisphosphonates have the potential to impair bone mineralization. This side effect has been reported for a number of earlier bisphosphonates administered at high therapeutic doses.1,2 When selecting new compounds for clinical use, it is obviously impo