oxadiazoles and Renal-Insufficiency--Chronic

Angiotensin receptor blockers (ARBs) are preferably used in hypertensive patients with CKD. Azilsartan is a strong antihypertensive ARB, but its antiproteinuric effects are not well understood. We compared the antiproteinuric effect of azilsartan and candesartan in CKD patients in an open-label, randomized, crossover trial.. A total of 111 patients were treated with 20 mg of azilsartan daily for 2 months as a run-in period. After the run-in period, patients were randomized into 2 arms and received either 20 mg of azilsartan or 8 mg of candesartan daily for 3 months in a crossover trial. The primary outcome was the percent change in urinary protein-to-Cr ratio (UPCR).. Ninety-five patients completed the trial. The mean age was 64.3 years. The estimated glomerular filtration rate (eGFR) and UPCR were 41.5 mL/min/1.73 m2 and 1.8 g/gCr, respectively. The baseline systolic and diastolic blood pressures were 131.4 and 71.0 mm Hg, respectively. The mean percent change in the UPCR was -3.8% in the azilsartan group and 30.8% in the candesartan group at the 1st endpoint (p = 0.0004), and 6.1% in the azilsartan group and 25.8% in the candesartan group at the 2nd (final) endpoint (p = 0.029). The incidence of adverse events, including eGFR levels and serum potassium levels, was not significantly different between the groups.. A 20 mg azilsartan dose had potent antiproteinuric effects compared with an 8 mg candesartan dose, without an increase in adverse events. Azilsartan may provide renal protection in addition to antihypertensive effects in CKD patients.

Topics: Angiotensin II Type 1 Receptor Blockers; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biphenyl Compounds; Cross-Over Studies; Female; Humans; Male; Middle Aged; Oxadiazoles; Proteinuria; Renal Insufficiency, Chronic; Tetrazoles

An open-label, long-term study evaluated safety and tolerability of azilsartan medoxomil/chlorthalidone (AZL-M/CLD) vs olmesartan/hydrochlorothiazide (OLM/HCTZ) in hypertensive participants with stage 3 chronic kidney disease. Initial therapy was AZL-M/CLD 20/12.5 mg (n = 77) or OLM/HCTZ 20/12.5 mg (n = 76), but could be up-titrated (AZL-M/CLD to 40/25 mg; OLM/HCTZ to 40/25 mg [US] or 20/25 mg [Europe]) with other agents added during weeks 4-52. Primary endpoint was proportion of participants with ≥ 1 adverse event (AE) through week 52. Baseline demographics were similar. AEs did not differ between groups (88.3%, AZL-M/CLD vs 76.3%, OLM/HCTZ; P = .058). AZL-M/CLD showed greater systolic BP reductions after initial dosing (P = .037) but not during long-term follow-up (P = .588). A greater proportion of participants up-titrated to the highest dose with OLM/HCTZ (48.7%) vs AZL-M/CLD (29.9%) (P = .021) and were taking additional antihypertensive medications (26.3% vs 16.9%). Both AZL-M/CLD and OLM/HCTZ showed similar efficacy and tolerability.

Topics: Aged; Benzimidazoles; Chlorthalidone; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Olmesartan Medoxomil; Oxadiazoles; Renal Insufficiency, Chronic; Treatment Outcome

Kidney fibrosis is a histological hallmark of chronic kidney disease (CKD) and is believed to be involved in the progression of CKD. Therefore, inhibition of kidney fibrosis is a potential strategy for slowing CKD progression. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated by interleukin-6 and is reported to be involved in fibrosis. Previously, S3I-201, an inhibitor of STAT3 phosphorylation, was shown to inhibit renal fibrosis in a mouse model, but its mechanism was not clarified completely. In this study, we investigated whether STX-0119, a new inhibitor of STAT3 dimerization, suppressed kidney fibrotic gene expression using a mouse model of kidney fibrosis and examined the underlying mechanisms. Kidney fibrosis was induced by unilateral ureteral obstruction (UUO), which was accompanied by upregulation of STAT3 target genes. STX-0119 administration suppressed the expression of fibrotic genes in UUO kidneys without affecting STAT3 phosphorylation. STX-0119 decreased Cxcr4 mRNA in cultured rat kidney fibroblasts and Ccr1 mRNA in blood cells from UUO mice, both of which are reported to be involved in the progression of kidney fibrosis. These results suggest that STX-0119 inhibits fibrotic gene expression in kidney by suppressing Cxcr4 and Ccr1 expression. This is the first report to indicate a part of the mechanism of the antifibrotic effects of a STAT3 inhibitor and suggests that STX-0119 may be a lead compound for the treatment of kidney fibrosis.

Topics: Animals; Fibroblasts; Fibrosis; Kidney; Mice; Mice, Inbred C57BL; Oxadiazoles; Quinolines; Rats; RAW 264.7 Cells; Receptors, CCR1; Receptors, CXCR4; Renal Insufficiency, Chronic; STAT3 Transcription Factor

The concentrations of several d-amino acids have been reported to significantly increase in the plasma of patients with chronic kidney disease (CKD). However, the amounts of these d-amino acids are low (around 1% of the l-form or lower), and their analyses were complicated by various interfering compounds in many clinical samples. A highly selective analytical method is thus required to perform the accurate and precise determination of these d-amino acids in the plasma of CKD patients. In the present study, a selective 3D-HPLC system equipped with reversed-phase, anion-exchange, and enantioselective columns has been designed and developed for the determination of the asparagine, serine, alanine and proline enantiomers. For the sensitive analysis, amino acids were precolumn derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole and detected by their fluorescence. The system was validated by using human plasma in addition to the standard amino acids, and results with a sufficient linearity, precision, and accuracy were obtained. The 3D-HPLC system was applied to the plasma of patients with different stages of CKD and all of the target d-amino acids were clearly observed without interferences for all 25 tested patients. Good correlations were shown between the kidney function of the patients and the %d values of the target analytes, especially d-Asn and d-Ser, indicating that the present 3D-HPLC method is useful for the sensitive diagnosis of CKD.

Topics: Amino Acids; Chromatography, High Pressure Liquid; Fluorescent Dyes; Humans; Oxadiazoles; Renal Insufficiency, Chronic; Stereoisomerism

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Benzimidazoles; Blood Pressure; Creatinine; Kidney; Male; Natriuresis; Oxadiazoles; Peptidyl-Dipeptidase A; Rats; Rats, Inbred WKY; Renal Insufficiency, Chronic; Sodium; Sympatholytics

Topics: Antihypertensive Agents; Benzimidazoles; Chlorthalidone; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Olmesartan Medoxomil; Oxadiazoles; Renal Insufficiency, Chronic; Tetrazoles