beraprost and Renal-Insufficiency--Chronic

TRK-100STP, a sustained-release preparation of the orally active prostacyclin analogue beraprost sodium, targets renal hypoxia. This study aimed to show the superiority of TRK-100STP over placebos in patients with chronic kidney disease (with either primary glomerular disease or nephrosclerosis) to determine the recommended dose. CASSIOPEIR (Chronic Renal Failure Asian Study with Oral PGI

Topics: Adult; Aged; Creatinine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Epoprostenol; Female; Humans; Male; Middle Aged; Nephrosclerosis; Renal Insufficiency, Chronic; Vasodilator Agents; Young Adult

Chronic kidney disease (CKD) is a common progressive and irreversible disease in cats. The efficacy and safety of beraprost sodium (BPS) in cats with CKD have not been evaluated.. To evaluate the efficacy and safety of BPS in the treatment of cats with CKD, as compared to placebo.. Seventy-four client-owned cats with naturally occurring CKD.. Double-blind, placebo-controlled, multicenter, prospective, randomized trial. The cats received BPS (55 μg/cat) or a placebo PO q12 h for 180 days. The primary endpoint was prospectively defined as a change in the serum creatinine (sCr), serum phosphorus-to-calcium ratio or urine specific gravity (USG).. The sCr increased significantly (P = 0.0030) in the placebo group (mean ± SD: 2.8 ± 0.7 to 3.2 ± 1.3 mg/dL) but not in the BPS group (2.4 ± 0.7 to 2.5 ± 0.7 mg/dL). The difference between the groups at day 180 was significant (0.8 mg/dL, 95% CI: 0.2 to 1.3 mg/dL, P = 0.0071). The serum phosphorus-to-calcium ratio was significantly (P = 0.0037) increased in the placebo group (0.46 ± 0.10 to 0.52 ± 0.21 mg/dL) but not in the BPS group (0.50 ± 0.08 to 0.51 ± 0.11 mg/dL). There was no significant change in the USG in either group. An adverse event judged as being treatment-related included vomiting that occurred in 1 case in the placebo group. No clinically relevant change was observed in the CBC and other blood chemistry tests.. Beraprost sodium treatment was well tolerated and safe in cats with CKD. BPS inhibited the reduction in renal filtration function as measured by sCr increase.

Topics: Animals; Cat Diseases; Cats; Double-Blind Method; Epoprostenol; Female; Male; Prospective Studies; Renal Insufficiency, Chronic; Treatment Outcome; Vasodilator Agents

Evidence increasingly points to the importance of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal disease (ESRD). Beraprost sodium (BPS) is an orally active prostacyclin (PGI2) analogue demonstrating prevention of the progression of chronic kidney disease (CKD) in various animal models by maintaining renal blood flow and attenuating renal ischemic condition.. This multicenter, randomized, double-blind, placebo-controlled, phase II trial was designed to determine the recommended dose of the sustained-release form of BPS (TRK-100STP 120 μg/day or 240 μg/day) in Japanese patients with CKD. TRK-100STP was administered to a total of 112 patients. The primary efficacy endpoint was the difference in the slope of the regression line of reciprocal of serum creatinine (1/SCr) over time, obtained by the least-squares method.. Regarding the primary endpoint, statistical superiority of TRK-100STP 240 μg over placebo was not confirmed and so a recommended dose was not determined. Compared to placebo, however, the slope of regression line of 1/SCr, elevation of SCr and serum cystatin C during the treatment period revealed greater improvement at 120 μg, at both doses, and at 240 μg, respectively. In terms of safety, both TRK-100STP treatment groups were well tolerated.. Although the study failed to meet the primary endpoint, results indicate that TRK-100STP may potentially prevent the decline in renal function of CKD patients independent of blood pressure or urinary protein levels.. NCT02480751. June 21, 2015.

Topics: Administration, Oral; Adult; Aged; Creatinine; Cystatin C; Delayed-Action Preparations; Disease Progression; Double-Blind Method; Epoprostenol; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Vasodilator Agents

Chronic renal failure (CRF) is a prolonged kidney condition characterized by decreased kidney function that can eventually develop into total kidney failure. The renin-angiotensin system (RAS) helps to regulate the balance between human bodily fluids and electrolytes. The aim of the present study was to investigate the effects of a prostacyclin analogue (beraprost sodium [BPS]) on the expression of key factors associated with local RAS activities in the renal tissues of rats with CRF.. After a CRF rat model was successfully established, the levels of BUN, SCr, phosphorus, and calcium were detected by an automatic biochemistry analyzer. Furthermore, the activities of malondialdehyde (MDA) and superoxide dismutase (SOD) in rat renal tissues were measured using a colorimetric method, while the activity of angiotensin-converting enzyme (ACE) was determined by ultraviolet (UV) spectrophotometry. In situ hybridization was employed to determine the expression of angiotensin II type 1 receptor (AT). Finally, the positive expression rates of cells expressing important apoptotic proteins (Bax and Bcl-2) were determined, and the protein and mRNA levels of phosphatidylinositol 3-kinase (AKT) and key factors involved in the RAS (AT1, AT2, angiotensin ACE and angiotensinogen [AGT]) were evaluated by RT-qPCR and western blot analysis.. Initial observations revealed that treatment with BPS decreased the levels of BUN, SCr and phosphorus but increased calcium levels in the renal tissues of CRF rats. Additionally, BPS reduced the levels of MDA while increasing the levels of SOD, ACE activity, and AT1 expression in the renal tissues of CRF rats. BPS inhibited glomerular hypertension and hyperfiltration; increased the mRNA and protein levels of AKT and AT2; and decreased the mRNA and protein levels of AT1, AGT, and ACE in the renal tissues of CRF rats.. The results of this study demonstrate that BPS, a PGI2 analogue, inhibits the expression of key factors involved in the local RAS, resulting in a delay in the occurrence and development of CRF. The key findings of the present study ultimately highlight the potential of this PGI2 analogue as a promising therapeutic strategy for treating CRF.

Topics: Animals; Blood Chemical Analysis; Epoprostenol; Kidney; Rats; Renal Insufficiency, Chronic; Renin-Angiotensin System

Beraprost sodium, a stable prostacyclin analog, was showed to improve survival rates in two different rat models, anti-glomerular basement membrane (GBM) glomerulonephritis (GN) and 5/6 nephrectomized (Nx) chronic kidney disease (CKD) rats. In the anti-GBM rat, beraprost sodium (0.2 and 0.6 mg/kg/day) improved survival rate (hazard ratio for beraprost sodium 0.6 mg/kg/day group, 0.10; 95% confidence interval, 0.01 to 0.68). Subsequently, in the 5/6 Nx CKD rat, beraprost sodium (0.6 mg/kg/day) improved survival rate (hazard ratio for beraprost sodium, 0.46; 95% confidence interval, 0.23 to 0.92), serum creatinine doubling time and the slope of the reciprocal of serum creatinine. In the anti-GBM GN rats, beraprost sodium suppressed the serum accumulation of representative uremic toxins such as indoxyl sulfate. Furthermore, beraprost sodium inhibited human aortic endothelial cell (HAEC) injury induced by indoxyl sulfate, indicating that beraprost sodium might have a protective effect against cardiovascular damage due to CKD. These results show that beraprost sodium can improve the survival rates in two rat models of anti-GBM GN and 5/6 Nx CKD rats by protecting endothelial cells and thereby ameliorating decreased renal function. Therefore, clinical studies are needed in patients with chronic kidney failure to determine whether beraprost sodium will become a useful medication in CKD.

Topics: Animals; Aorta; Cyclic AMP; Endothelial Cells; Epoprostenol; Glomerular Basement Membrane; Glomerulonephritis; Humans; Indican; Male; Nephrectomy; Rats; Renal Insufficiency, Chronic; Survival Analysis