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Urine output
Published in Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor, Manual of Neuroanesthesia, 2017
ADH receptor antagonists, such as conivaptan and lixivaptan, inhibit the binding of ADH to renal receptors. They have been shown to be effective in small clinical trials by inducing aquaresis, the electrolyte-sparing excretion of free water.
Vasopressin receptor antagonists: a patent summary (2018-2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Ferenc Baska, Éva Bozó, Tamás Patócs
In parallel to the V1a and V1b antagonists, Sanofi has also developed V2 antagonist compounds. One of their most promising results was satavaptan (9, Figure 3), which is based on the well-known oxindole scaffold [46]. Satavaptan was investigated first as a treatment option for patients with SIADH-related hyponatremia but later a clinical study was initiated for the potential treatment of ascites, as well [47,48]. Another candidate with selectivity for V2 receptors and oral bioavailability was in development against symptomatic hypervolemic and euvolemic hyponatremia. Lixivaptan (VPA-985, 10, Figure 3), a tricyclic benzodiazepine derivative developed by Palladio Biosciences, Inc. was recently investigated in a phase 3 clinical trial in patients with ADPKD, but the study was stopped after reevaluating its commercial potential as a best-in-class therapeutic possibility [49,50]. Although both 9 and 10 were promising compounds with remarkable in vitro and in vivo profiles, none of these molecules received approval from the FDA.
Current and emerging treatment options to prevent renal failure due to autosomal dominant polycystic kidney disease
Published in Expert Opinion on Orphan Drugs, 2020
Gopala K. Rangan, Aarya Raghubanshi, Alissa Chaitarvornkit, Ashley N. Chandra, Robert Gardos, Alexandra Munt, Mark N. Read, Sayanthooran Saravanabavan, Jennifer Q.J. Zhang, Annette T.Y. Wong
At least eight SMDs (lixivaptan, tesevatinib, venglustat, bardoxolone, pravastatin, hydralazine, pioglitazone, metformin) are currently under evaluation in clinical trials [133] (Table 6). Lixivaptan is an orally active and selective V2 receptor antagonist that has pharmacological effects identical to tolvaptan but predicted to have a lower risk for hepatotoxicity [134]. Preclinical studies in the pck rat demonstrate that lixivaptan reduces renal cyst growth [135] and a 1-year double-blind randomized clinical trial to evaluate safety and efficacy in human ADPKD is anticipated to start in April 2021 and finish in 2024 (NCT04064346) [136]. (or KD019) is an orally active novel kinase inhibitor that suppresses multiple signal pathways regulating mitosis (tyrosine kinase, EGFR) and angiogenesis (VEGF-2) and under investigation for the treatment of cancer [137]. Preclinical studies in the pck rat and bpk mice support the efficacy of tesevatinib in PKD [138], and presently in Phase 2 randomized controlled clinical trial (50 mg vs. placebo n = 80) with Ht-TKV as the primary endpoint with the final data expected in 2022 (NCT03203642) [139].
New insights into targeting hepatic cystogenesis in autosomal dominant polycystic liver and kidney disease
Published in Expert Opinion on Therapeutic Targets, 2020
Thijs R. M. Barten, Lucas H. P. Bernts, Joost P. H. Drenth, Tom J. G. Gevers
In addition to polyuria, another limiting factor of using V2 R antagonists for PLD patients in clinical practice is hepatotoxicity. Tolvaptan is estimated to induce liver failure in 1/4000 ADPKD patients on long-term tolvaptan therapy, occurring between 3 and 18 months [43]. In addition, tolvaptan has been associated with idiosyncratic elevations of blood alanine and aspartate aminotransferases with infrequent cases of concomitant elevations in bilirubin. While these elevations were reversible with discontinuation of tolvaptan, they represent a potential for significant liver injury. While PLD is considered a benign condition that does not cause liver damage, pathology evaluation of 125 liver samples (obtained after either transplantation or partial hepatectomy) showed several abnormalities including fibrosis [44]. Although the pathophysiological mechanism of this fibrosis remains unknown, this challenges the paradigm that PLD does not affect non-cystic liver parenchyma. Therefore, clinicians should exercise caution when administering potentially hepatotoxic drugs such as tolvaptan in severe PLD. At present, lixivaptan has been evaluated insufficiently to draw valid conclusions on hepatotoxicity.