{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T10:34:20Z","timestamp":1760783660844,"version":"3.40.4"},"reference-count":51,"publisher":"S. Karger AG","issue":"4","license":[{"start":{"date-parts":[[2013,1,1]],"date-time":"2013-01-01T00:00:00Z","timestamp":1356998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2013,1,1]],"date-time":"2013-01-01T00:00:00Z","timestamp":1356998400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Am J Nephrol"],"published-print":{"date-parts":[[2013]]},"abstract":"<jats:p>&lt;b&gt;&lt;i&gt;Background\/Aims:&lt;\/i&gt;&lt;\/b&gt; 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. &lt;b&gt;&lt;i&gt;Methods:&lt;\/i&gt;&lt;\/b&gt; Two structurally similar VDRMs were tested in the 5\/6 nephrectomized (NX) rats with elevated PTH, endothelial dysfunction and left ventricular hypertrophy. &lt;b&gt;&lt;i&gt;Results:&lt;\/i&gt;&lt;\/b&gt; VS-110 and VS-411 at 0.01-1 \u03bcg\/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 \u03bcg\/kg (therapeutic index = \u223c1-fold), while VS-110 did not raise serum Ca even at 1 \u03bcg\/kg (therapeutic index &gt;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&lt;sub&gt;50&lt;\/sub&gt; &lt;0.1 n&lt;smlcap&gt;M&lt;\/smlcap&gt;. &lt;b&gt;&lt;i&gt;Conclusions:&lt;\/i&gt;&lt;\/b&gt; 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.<\/jats:p>","DOI":"10.1159\/000348755","type":"journal-article","created":{"date-parts":[[2013,3,21]],"date-time":"2013-03-21T13:44:48Z","timestamp":1363873488000},"page":"310-319","source":"Crossref","is-referenced-by-count":11,"title":["Two Novel Vitamin D Receptor Modulators with Similar Structures Exhibit Different Hypercalcemic Effects in 5\/6 Nephrectomized Uremic Rats"],"prefix":"10.1159","volume":"37","author":[{"given":"J. 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