SP636SNF472 INHIBITS THE PROGRESSION OF VITAMIN D INDUCED CARDIOVASCULAR CALCIFICATION IN RATS

Abstract

SNF472 INHIBITS THE PROGRESSION OF VITAMIN D INDUCED CARDIOVASCULAR CALCIFICATION IN RATS J. Perelló1,2, C. Salcedo1, M. Ketteler3, F. Tur2, B. Isern1, P.H. Joubert1, M.D. Ferrer1 1 Laboratoris Sanifit SL., 07121 Palma de Mallorca, Spain. 2 Laboratory of Renal Lithiasis Research, IUNICS, University of the Balearic Islands, 07122 Palma, Spain. 3 Division of Nephrology, Klinikum Coburg GmbH, 33, D-96450 Coburg, Germany Introduction and aims: Cardiovascular calcification (VC) has been shown to be an independent predictor of cardiovascular events in CKD patients. We investigated the effects of subcutaneous SNF472, a formulation of phytate, on vitamin D induced VC progression, after setting up a new model for the rapid induction of VC with subcutaneous (s.c.) vitamin D3 in rats. Methods: Ninety male Sprague Dawley rats were used in this study. Of these 48 were used to evaluate the dose-response of vitamin D in producing VC. Calcification was induced through daily (day 1 to day 3) s.c. administration of 3, 10, 30, 100 or 300 kIU/kg of vitamin D3. A subset of 3 animals from each group was sacrificed and evaluated on days 3, 4 and 5. The remaining 42 animals were administered 100 kIU/kg vitamin D and divided into 5 groups, each group receiving daily s.c. vehicle or SNF472 for up to 5 days. One group received daily vehicle and 3 animals were sacrificed every day to evaluate VC progression up to day 5. Four more groups were dosed with SNF472 at 100 mg/kg, starting on day 1, 2, 3 or 4. Results: VC was induced in rats when vitamin D3 was administered at doses above 30 kIU/kg. The time course of calcification was similar in aorta and heart, where calcification became evident during the fourth day of study and continued increasing by day 5. There was a relationship between dose-regimen and the response relationship to SNF472. The group that received 4 doses showed a reduction of aorta calcification progression of 95%. The group that received a single dose on day 4 showed a reduction of calcification progression of 51%. The groups in between had intermediate effects. Therefore, SNF472 had a significant effect even when administered on the last days of progression. Conclusions: These results suggest a potential for the possible use of SNF472 in the treatment of VC in ESRD patients.