PDF(Pubmed)
Abstract：
Duchenne muscular dystrophy (DMD) is a progressive disabling X-linked recessive disorder that causes gradual and irreversible loss of muscle, resulting in early death. The corticosteroids prednisone/prednisolone and deflazacort are used to treat DMD as the standard of care; however, only deflazacort is FDA approved for DMD. The novel atypical corticosteroid vamorolone is being investigated for treatment of DMD. We compared the pharmaceutical properties as well as the efficacy and safety of the three corticosteroids across multiple doses in the B10-mdx DMD mouse model. Pharmacokinetic studies in the mouse and evaluation of p-glycoprotein (P-gP) efflux in a cellular system demonstrated that vamorolone is not a strong P-gp substrate resulting in measurable central nervous system (CNS) exposure in the mouse. In contrast, deflazacort and prednisolone are strong P-gp substrates. All three corticosteroids showed efficacy, but also side effects at efficacious doses. After dosing mdx mice for two weeks, all three corticosteroids induced changes in gene expression in the liver and the muscle, but prednisolone and vamorolone induced more changes in the brain than did deflazacort. Both prednisolone and vamorolone induced depression-like behavior. All three corticosteroids reduced endogenous corticosterone levels, increased glucose levels, and reduced osteocalcin levels. Using micro-computed tomography, femur bone density was decreased, reaching significance with prednisolone. The results of these studies indicate that efficacious doses of vamorolone, are associated with similar side effects as seen with other corticosteroids. Further, because vamorolone is not a strong P-gp substrate, vamorolone distributes into the CNS increasing the potential CNS side-effects.
摘要：
Duchenne肌营养不良症（DMD）是一种进行性致残X连锁隐性疾病，可导致肌肉逐渐和不可逆转的损失，导致早期死亡。皮质类固醇泼尼松/泼尼松龙和deflazacort用于治疗DMD作为护理标准;然而，只有defrazacort被FDA批准用于DMD。正在研究用于治疗DMD的新型非典型皮质类固醇瓦莫罗酮。我们比较了B10-mdxDMD小鼠模型中三种皮质类固醇在多个剂量中的药物特性以及功效和安全性。小鼠中的药代动力学研究和细胞系统中p-糖蛋白（P-gP）流出的评估表明，vamorolone不是强P-gp底物，导致小鼠可测量的中枢神经系统（CNS）暴露。相比之下,deflazacort和泼尼松龙是强P-gp底物。所有三种皮质类固醇都显示出疗效，但在有效剂量下也有副作用。给药mdx小鼠两周后，所有三种皮质类固醇都诱导肝脏和肌肉中基因表达的变化，但是泼尼松龙和vamorolone比defriazacort引起的大脑变化更多。泼尼松龙和瓦莫罗龙均可诱发抑郁样行为。所有三种皮质类固醇均降低内源性皮质酮水平，葡萄糖水平升高，和降低骨钙蛋白水平。用微型计算机断层扫描,股骨骨密度降低，使用泼尼松龙达到意义。这些研究的结果表明有效剂量的沃莫罗酮，与其他皮质类固醇相似的副作用。Further,因为vamorolone不是一个强的P-gp底物,vamorolone分布到CNS中，增加了潜在的CNS副作用。
