• J Ruth Wu-Wong, Megumi Kawai, Yung-wu Chen, Jerry L Wessale, Ching-jang Huang, Meng-ting Wu, and Masaki Nakane.
• Vidasym, Chicago, IL, USA. ruth.wuwong@prodigy.net
• Am. J. Nephrol. 2013 Jan 1; 37 (4): 310-9.

Background/AimsVitamin 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.MethodsTwo structurally similar VDRMs were tested in the 5/6 nephrectomized (NX) rats with elevated PTH, endothelial dysfunction and left ventricular hypertrophy.ResultsVS-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.ConclusionsStructurally 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.Copyright © 2013 S. Karger AG, Basel.

39 keywords...

hide…