两种结构相似的新型维生素 D 受体调节剂在 5/6 肾切除尿毒症大鼠中表现出不同的高钙血症效应。
Two novel vitamin D receptor modulators with similar structures exhibit different hypercalcemic effects in 5/6 nephrectomized uremic rats.
机构信息
Vidasym, Chicago, IL, USA.
出版信息
Am J Nephrol. 2013;37(4):310-9. doi: 10.1159/000348755. Epub 2013 Mar 20.
BACKGROUND/AIMS: Vitamin D receptor modulators (VDRMs) are indicated for secondary hyperparathyroidism in chronic kidney disease (CKD). Clinical observations demonstrate that VDRM therapy provides cardiovascular (CV) benefit in CKD. Current on-market VDRMs have a narrow therapeutic index at 1- to 4-fold [hypercalcemic toxicity vs. parathyroid hormone (PTH)-suppressing efficacy]. Hypercalcemia leads to the need for frequent drug dose titration and serum calcium (Ca) monitoring. A VDRM with a wider therapeutic index and beneficial CV effects will be clinically useful.
METHODS
Two structurally similar VDRMs were tested in the 5/6 nephrectomized (NX) rats with elevated PTH, endothelial dysfunction and left ventricular hypertrophy.
RESULTS
VS-110 and VS-411 at 0.01-1 μg/kg (i.p. 3 times/week for 2 weeks) suppressed serum PTH effectively. VS-411 raised serum Ca with an 11% increase at 0.01 μg/kg (therapeutic index = ~1-fold), while VS-110 did not raise serum Ca even at 1 μg/kg (therapeutic index >50-fold). VS-110 improved endothelium-dependent aortic relaxation in a dose-dependent manner and significantly reduced left ventricular fibrosis without affecting serum Ca. VS-411 also exhibited effects on the CV parameters, but was less potent at the high doses with severe hypercalcemia. VS-110 and VS-411 specifically activated the reporter gene via a chimeric receptor containing the VDR ligand binding domain with EC(50) <0.1 nM.
CONCLUSIONS
Structurally similar VDRMs can exhibit distinctly different hypercalcemic effects in 5/6 NX uremic rats. While differences exist for the Ca and CV effects of VS-110 and VS-411, the clinical implications are unclear. VS-110's results are promising but clinical outcome studies need to be performed.
背景/目的：维生素 D 受体调节剂（VDRM）用于治疗慢性肾脏病（CKD）中的继发性甲状旁腺功能亢进症。临床观察表明，VDRM 治疗可提供 CKD 的心血管（CV）获益。目前市场上的 VDRM 的治疗指数狭窄，为 1-4 倍[高钙毒性与甲状旁腺激素（PTH）抑制作用]。高钙血症导致需要频繁调整药物剂量和监测血清钙（Ca）。具有更宽治疗指数和有益 CV 作用的 VDRM 将具有临床意义。
方法
在 5/6 肾切除（NX）大鼠中测试了两种结构相似的 VDRM，这些大鼠伴有升高的 PTH、内皮功能障碍和左心室肥厚。
结果
VS-110 和 VS-411 在 0.01-1μg/kg（每周腹腔注射 3 次，持续 2 周）有效抑制血清 PTH。VS-411 使血清 Ca 升高 11%，在 0.01μg/kg 时（治疗指数=~1 倍），而 VS-110 甚至在 1μg/kg 时也未升高血清 Ca（治疗指数>50 倍）。VS-110 以剂量依赖性方式改善内皮依赖性主动脉松弛，并显著减少左心室纤维化，而不影响血清 Ca。VS-411 也对 CV 参数产生影响，但在高剂量时效果较差，伴有严重高钙血症。VS-110 和 VS-411 通过含有 VDR 配体结合域的嵌合受体特异性激活报告基因，EC50<0.1 nM。
结论
结构相似的 VDRM 在 5/6 NX 尿毒症大鼠中可表现出明显不同的高钙血症效应。虽然 VS-110 和 VS-411 的 Ca 和 CV 效应存在差异，但临床意义尚不清楚。VS-110 的结果很有希望，但需要进行临床结局研究。
Zotero 插件