Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial

Kôyama, Akio; Fujita, Toshiro; Gejyo, Fumitake; Origasa, Hideki; Isono, Masanao; Kurumatani, Hajimu; Okada, Kiyonobu; Kanoh, Hideo; Kiriyama, T; Yamada, S.

doi:10.1186/s12882-015-0130-5

Cited by 19 publications

(24 citation statements)

References 38 publications

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“…On the other hand, regarding safety, no relationship was observed between the incidence of adverse events and the severity of impaired kidney function following the single oral administration of 120 μg of BPS, and the tolerability was confirmed in subjects with impaired kidney function. Because the tolerability was also confirmed in patients with impaired kidney function in a phase 2 trial (120 μg BID for 26 weeks), the safety in subjects with impaired kidney function in the present study was no problem. Furthermore, in the phase 2 trial, a significant improvement in the ratio of SCr was achieved in the 120‐μg group (60 μg BID) as well as in the 240‐μg group (120 μg BID), independent of blood pressure or urinary protein levels .…”

Section: Discussionsupporting

confidence: 54%

“…Because the tolerability was also confirmed in patients with impaired kidney function in a phase 2 trial (120 μg BID for 26 weeks), the safety in subjects with impaired kidney function in the present study was no problem. Furthermore, in the phase 2 trial, a significant improvement in the ratio of SCr was achieved in the 120‐μg group (60 μg BID) as well as in the 240‐μg group (120 μg BID), independent of blood pressure or urinary protein levels . Therefore, we consider that the pharmacokinetics changes of BPS and BPS‐314 d accompanied with impaired kidney function are not clinically relevant, and the dose adjustment is not necessary in patients with impaired kidney function.…”

Section: Discussionsupporting

confidence: 54%

“…Among various chronic kidney disease (CKD) models, BPS has been shown to inhibit increases in serum creatinine levels and to improve survival rates in 2 different rat models, anti–glomerular basement membrane glomerulonephritis and 5/6 nephrectomized CKD rats, thereby demonstrating its potential to suppress the progression of renal failure . In clinical settings BPS has been administered to patients with CKD, and the findings obtained suggest that BPS also suppresses declines in kidney function in humans.…”

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confidence: 99%

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The Pharmacokinetics of Beraprost Sodium Following Single Oral Administration to Subjects With Impaired Kidney Function

Shimamura

Miyakawa

Doi

et al. 2016

The Journal of Clinical Pharma

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The purpose of the present study was to evaluate the pharmacokinetics of beraprost sodium (BPS) and its active enantiomer, BPS-314d, in Japanese subjects with impaired kidney function. The plasma and urine concentrations of BPS and BPS-314d were measured following the single oral administration of 120 μg of BPS as the sustained-release tablet, TRK-100STP, under fasting conditions to 18 subjects with impaired kidney function (stage 2, 3, and 4 chronic kidney disease [CKD] as categorized by the estimated glomerular filtration rate) and to 6 age-, body weight-, and gender-matched subjects with normal kidney function (stage 1 CKD). The C values (mean ± SD) of BPS in stage 1, 2, 3, and 4 CKD, respectively, were 84.9 ± 22.9, 119.8 ± 36.4, 190.6 ± 137.3, and 240.2 ± 110.5 pg/mL; its AUC were 978 ± 226, 1252 ± 427, 1862 ± 964, and 1766 ± 806 pg·h/mL, respectively, and its cumulative urinary excretion rates were 0.704 ± 0.351%, 0.638 ± 0.292%, 0.485 ± 0.294%, and 0.159 ± 0.136%. The C values of BPS-314d were 22.4 ± 6.4, 30.8 ± 8.5, 46.7 ± 30.6, and 54.4 ± 25.2 pg/mL, its AUC were 155 ± 56, 226 ± 67, 341 ± 176, and 329 ± 143 pg·h/mL, and its cumulative urinary excretion rates were 0.428 ± 0.242%, 0.349 ± 0.179%, 0.356 ± 0.270%, and 0.096 ± 0.099%, respectively. Adverse events were reported in 2 subjects with stage 2 CKD and 1 subject with stage 4 CKD. The C and AUC of BPS and BPS-314d were higher based on the severity of impaired kidney function. No relationship was observed between the incidence of adverse events and the severity, and tolerability was confirmed. We consider that dose adjustment is not necessary, but BPS is more carefully treated in patients with impaired kidney function.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionsupporting

confidence: 54%

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confidence: 99%

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The Pharmacokinetics of Beraprost Sodium Following Single Oral Administration to Subjects With Impaired Kidney Function

Shimamura

Miyakawa

Doi

et al. 2016

The Journal of Clinical Pharma

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“…Moreover, we estimated the 55 μg/body dose in this study would not have acute action to reduce the blood pressure; in a study using healthy cats, we had confirmed BPS at doses up to 100 μg/kg had no influence on the blood pressure . Furthermore, a human study also suggests that BPS inhibits increase in the sCr without lowering the blood pressure . Thus, it is unlikely that reduced blood pressure might be involved in the mechanism of action of BPS.…”

Section: Discussionmentioning

confidence: 99%

A Double‐blind, Placebo‐controlled, Multicenter, Prospective, Randomized Study of Beraprost Sodium Treatment for Cats with Chronic Kidney Disease

Takenaka¹,

Iio

Sato

et al. 2017

Veterinary Internal Medicne

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BackgroundChronic 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.Hypothesis/ObjectivesTo evaluate the efficacy and safety of BPS in the treatment of cats with CKD, as compared to placebo.AnimalsSeventy‐four client‐owned cats with naturally occurring CKD.MethodsDouble‐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).ResultsThe 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.Conclusions and Clinical ImportanceBeraprost sodium treatment was well tolerated and safe in cats with CKD. BPS inhibited the reduction in renal filtration function as measured by sCr increase.

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“…Patients suffering from CRF could be more susceptible to other conditions, such as coronary artery diseases, ultimately leading to a decrease in quality of life and even death [15]. Recently, Koyama et al revealed that BPS served as a therapeutic treatment for chronic kidney disease (CKD) in several animal models [16]. Hence, based on this evidence, we hypothesized that BPS, as a stable analogue of PGI2, could influence the local RAS in rats with CRF.…”

Section: Discussionmentioning

confidence: 99%

Beraprost Sodium, a Stable Analogue of PGI2, Inhibits the Renin-Angiotensin System in the Renal Tissues of Rats with Chronic Renal Failure

Wang¹,

Zhang²,

Lu³

et al. 2018

Kidney Blood Press Res

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Background/Aims: 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. Methods: 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. Results: 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. Conclusion: 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.

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Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial

Cited by 19 publications

References 38 publications

The Pharmacokinetics of Beraprost Sodium Following Single Oral Administration to Subjects With Impaired Kidney Function

The Pharmacokinetics of Beraprost Sodium Following Single Oral Administration to Subjects With Impaired Kidney Function

A Double‐blind, Placebo‐controlled, Multicenter, Prospective, Randomized Study of Beraprost Sodium Treatment for Cats with Chronic Kidney Disease

Beraprost Sodium, a Stable Analogue of PGI2, Inhibits the Renin-Angiotensin System in the Renal Tissues of Rats with Chronic Renal Failure

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