Combinations for reducing serum phosphates in patients
A phosphate binder and phosphate technology, which can be used in drug combinations, medical preparations containing active ingredients, pharmaceutical formulations, etc., can solve the problems of reducing serum phosphate, not adhering to phosphate binders, and inability to absorb
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Embodiment 1
[0481] Cell-based activity under prompt conditions. Rat or human NHE3-mediated Na was measured using a modification of the pH-sensitive dye method originally reported by Paradiso (PNAS USA. + Dependent H + reverse transport. Opossum kidney (OK) cells were obtained from ATCC and propagated according to their instructions. The rat NHE3 gene (GenBank M85300) or human NHE3 gene (GenBank NM — 004174.1) was introduced into OK cells by electroporation, and the cells were seeded into 96-well plates and grown overnight. Aspirate the medium from the well, and the cells were washed with NaCl-HEPES buffer (100mM NaCl, 50mM HEPES, 10mM glucose, 5mM KCl, 2mM CaCl 2 , 1mM MgCl 2, pH 7.4) and washed twice at room temperature with 5 μM bis(acetoxymethyl)3,3'-(3',6'-bis(acetoxymethoxy)-5-((acetyl Oxymethoxy)carbonyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-2',7'-diyl)dipropionate (BCECF-AM) NH 4 Cl-HEPES buffer (20mM NH 4 Cl, 80mM NaCl, 50mM HEPES, 5mM KCl, 2mM CaCl 2 , 1mM MgCl 2...
Embodiment 2
[0487] The role in the rat model of uremia-associated vascular calcification
[0488] Chronic kidney disease (CKD) has multiple pathogenic mechanisms, and advanced CKD is often characterized by disordered mineral metabolism (eg, hyperphosphatemia, hypercalcemia) and vascular calcification. Therefore, a study was performed to test the effectiveness of Cpd 002 in a uremic rat model of CKD characterized by vascular calcification. The model is characterized by renal insufficiency and regular active vitamin D 3 Administration to promote hyperphosphatemia and vascular calcification (see Lopez et al., J. Am. Soc. Nephrol. 17:795-804, 2006). The study utilized Spraque-Dawley rats treated as follows: 5 / 6 by resection th Nephrectomy; regular intraperitoneal (i.p.) administration of calcitriol (active vitamin D 3 ) 80ng / kg, 3 times a week; and fed a purified 0.9% P diet (inorganic phosphorus).
[0489] Rats were stratified into two experimental groups based on serum creatinine levels...
Embodiment 3
[0497] Effects in adenine-induced uremia rat model
[0498] The effect of Cpd 002 was tested in the adenine-induced uremic rat model. During the nephritis induction period, rats were fed a diet containing 0.75% adenine and 1.2% phosphorus. The basic diet during the treatment period was normal food containing 0.3% adenine and 0.6% phosphorus for 2 weeks. Rats were pair-fed (Groups 1 and 2 to 3, 4 days apart) for the first 5 days and then had free access to food. Treatment groups were as follows: Vehicle, n=10; Cpd 002, 2 mg / kg / day drug in food, n=10; and Cpd 002, 5 mg / kg / day drug in food, n=12. Obtain weekly measurements of serum markers and renal function.
[0499] Cpd 002 reduced serum phosphorus and serum creatinine at early time points. Here, this adenine-induced model is considered to be acute kidney injury characterized by progressive recovery of renal function. Therefore, the effect at earlier time points was significant.
[0500] Data from the organ weight collect...
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