BACKGROUND AND PURPOSE: Phosphate imbalance is often present in chronic kidney disease (CKD), and it contributes to a higher cardiovascular mortality rate. A phosphate binder is typically part of a treatment strategy for controlling phosphate imbalance. However, safety concerns and low compliance are two well-recognized disadvantages of on-market phosphate binders. This report describes the preclinical studies of VS-505, a non-absorbable, calcium- and aluminum-free, plant-derived polymer currently being evaluated in haemodialysis patients in Australia. EXPERIMENTAL APPROACH: Normal Sprague Dawley (SD) rats or uraemic SD rats induced by 5/6 nephrectomy fed a high-phosphate diet were treated with VS-505 or sevelamer (0.05-10% in food) for 5 and 28 days respectively. KEY RESULTS: Urinary and serum phosphate levels were significantly elevated in untreated rats, and were decreased by VS-505 and sevelamer. VS-505 increased faecal phosphate levels in a dose-dependent manner. High-phosphate diet also caused an increase in serum FGF-23 and parathyroid hormone in nephrectomized (NX) rats, effects prevented by VS-505 or sevelamer. Significant aortic calcification was observed in NX rats treated with 5% sevelamer, whereas VS-505 at all doses tested did not show effects. VS-505 had no effects on small intestine histomorphology and intestinal sodium-dependent phosphate cotransporter gene expression. In vitro characterizations showed that VS-505 has a relatively high density and low expansion volume when exposed to simulated gastric fluid. CONCLUSIONS AND IMPLICATIONS: VS-505 is a safe and effective phosphate binder and may offer the advantage of having a reduced pill burden and minimal GI side effects for CKD patients.
BACKGROUND AND PURPOSE:Phosphate imbalance is often present in chronic kidney disease (CKD), and it contributes to a higher cardiovascular mortality rate. A phosphate binder is typically part of a treatment strategy for controlling phosphate imbalance. However, safety concerns and low compliance are two well-recognized disadvantages of on-market phosphate binders. This report describes the preclinical studies of VS-505, a non-absorbable, calcium- and aluminum-free, plant-derived polymer currently being evaluated in haemodialysis patients in Australia. EXPERIMENTAL APPROACH: Normal Sprague Dawley (SD) rats or uraemic SD rats induced by 5/6 nephrectomy fed a high-phosphate diet were treated with VS-505 or sevelamer (0.05-10% in food) for 5 and 28 days respectively. KEY RESULTS: Urinary and serum phosphate levels were significantly elevated in untreated rats, and were decreased by VS-505 and sevelamer. VS-505 increased faecal phosphate levels in a dose-dependent manner. High-phosphate diet also caused an increase in serum FGF-23 and parathyroid hormone in nephrectomized (NX) rats, effects prevented by VS-505 or sevelamer. Significant aortic calcification was observed in NX rats treated with 5% sevelamer, whereas VS-505 at all doses tested did not show effects. VS-505 had no effects on small intestine histomorphology and intestinal sodium-dependent phosphate cotransporter gene expression. In vitro characterizations showed that VS-505 has a relatively high density and low expansion volume when exposed to simulated gastric fluid. CONCLUSIONS AND IMPLICATIONS: VS-505 is a safe and effective phosphate binder and may offer the advantage of having a reduced pill burden and minimal GI side effects for CKDpatients.
Authors: Michael J Curtis; Richard A Bond; Domenico Spina; Amrita Ahluwalia; Stephen P A Alexander; Mark A Giembycz; Annette Gilchrist; Daniel Hoyer; Paul A Insel; Angelo A Izzo; Andrew J Lawrence; David J MacEwan; Lawrence D F Moon; Sue Wonnacott; Arthur H Weston; John C McGrath Journal: Br J Pharmacol Date: 2015-07 Impact factor: 8.739
Authors: D P Rosenbaum; S R Holmes-Farley; W H Mandeville; M Pitruzzello; D I Goldberg Journal: Nephrol Dial Transplant Date: 1997-05 Impact factor: 5.992
Authors: Helen Eddington; Richard Hoefield; Smeeta Sinha; Constantina Chrysochou; Beverley Lane; Robert N Foley; Janet Hegarty; John New; Donal J O'Donoghue; Rachel J Middleton; Philip A Kalra Journal: Clin J Am Soc Nephrol Date: 2010-08-05 Impact factor: 8.237
Authors: Geert J Behets; Geert Dams; Stephen J Damment; Patrick Martin; Marc E De Broe; Patrick C D'Haese Journal: Am J Physiol Renal Physiol Date: 2013-11-06
Authors: Xiaojun Wang; Yanping Xu; Xiaohong Yu; Asim Dey; Hong Y Zhang; Charity M Zink; Derek Wodka; Gina Porter; William F Matter; Leah Porras; Charles A Reidy; Jeffrey A Peterson; Brian E Mattioni; Joseph V Haas; Mark C Kowala; John R Wetterau Journal: Pharmacol Res Perspect Date: 2022-04