Characterization of SNF472 pharmacokinetics and efficacy in uremic and non-uremic rats models of cardiovascular calcification

Autor: Ferrer, Miguel D., Ketteler, Markus, Tur, Fernando, Tur, Eva, Isem, Bernat, Salcedo, Carolina, Joubert, Pieter H., Behets, Geert, Neven, Ellen, d' Haese, Patrick C., Perelló, Joan, Isern, Bernet
Rok vydání: 2018
Předmět:
Physiology
humanos
030232 urology & nephrology
lcsh:Medicine
Organic chemistry
030204 cardiovascular system & hematology
Pharmacology
ratas
Biochemistry
chemistry.chemical_compound
0302 clinical medicine
Bolus (medicine)
Cardiovascular calcification
Chronic Kidney Disease
Medicine and Health Sciences
Medicine
Renal Insufficiency
Vitamin D
lcsh:Science
Cholecalciferol
Multidisciplinary
Pharmaceutics
Nucleotides
Soft tissue
Calcinosis
Heart
Vitamins
Physical sciences
Chemistry
Cardiovascular Diseases
Nephrology
Disease Progression
Anatomy
Engineering sciences. Technology
Research Article
insuficiencia renal
Vitamin
Drug Administration
colecalciferol
enfermedades cardiovasculares
Calcification
03 medical and health sciences
Chemical compounds
Pharmacokinetics
Drug Therapy
progresión de la enfermedad
Organic compounds
Vitamin D and neurology
Animals
Humans
Renal Insufficiency
Chronic
Biology
Uremia
business.industry
Adenine
lcsh:R
Biology and Life Sciences
Plasma levels
medicine.disease
equipment and supplies
Rats
Disease Models
Animal
chemistry
Cardiovascular Anatomy
animales
Kidney Failure
Chronic
lcsh:Q
Human medicine
business
Physiological Processes
Inositol
Zdroj: PLoS ONE
PLoS ONE, Vol 13, Iss 5, p e0197061 (2018)
ISSN: 1932-6203
Popis: End-stage renal disease is strongly associated with progressive cardiovascular calcification (CVC) and there is currently no therapy targeted to treat CVC. SNF472 is an experimental formulation under development for treatment of soft tissue calcification. We have investigated the pharmacokinetics of SNF472 administration in rats and its inhibitory effects on CVC. SNF472 was studied in three rat models: (1) prevention of vitamin D-3-induced CVC with an intravenous SNF472 bolus of 1 mg/kg SNF472, (2) inhibition of progression of vitamin D-3-induced CVC with a subcutaneous SNF472 bolus of 10 or 60 mg/kg SNF472, starting after calcification induction, (3) CVC in adenine-induced uremic rats treated with 50 mg/kg SNF472 via i.v. 4h -infusion. Uremic rats presented lower plasma levels of SNF472 than control animals after i.v. infusion. CVC in non-uremic rats was inhibited by 60-70% after treatment with SNF472 and progression of cardiac calcification completely blocked. Development of CVC in uremic rats was inhibited by up to 80% following i.v. infusion of SNF472. SNF472 inhibits the development and progression of CVC in uremic and non-uremic rats in the same range of SNF472 plasma levels but using in each case the required dose to obtain those levels. These results collectively support the development of SNF472 as a novel therapeutic option for treatment of CVC in humans.
This study was supported by a grant from Fundacion Genoma Espana/Centro para el Desarrollo Tecnologico Industrial (CDTI) through the INNOCASH program (IC10- 129) and from private funds of Laboratoris Sanifit. MF (PTQ-11-04860), ET (PTQ-09-01-00301) and CS (PTQ-11-04872) were co-funded by the INNCORPORA-Torres Quevedo subprogram of the Ministerio de Economia y Competitividad, Government of Spain. The funders (Fundacion Genoma Espana/CDTI, Ministerio de Economia y Competitividad, the investors of Laboratoris Sanifit) provided support in the form of salaries for authors [MF, FT, ET, BI, CS, PJ, JP], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.
Databáze: OpenAIRE
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