Beraprost Sodium Group Research Articles

Beraprost Sodium Delays the Decline of Glomerular Filtration Rate in Patients with Diabetic Nephropathy: A Retrospective Study.

To investigate the reno-protective effect of beraprost sodium (BPS) in patients with diabetic nephropathy (DN). We retrospectively analyzed patients with DN hospitalized in China-Japan Friendship Hospital from January 2015 to December 2021 who received combination of conventional treatment and BPS (120ug/day) therapy. We selected patients with DN matched in age and estimated glomerular filtration rate (eGFR) as controls, who received only conventional therapy. Baseline information and clinical variables at each follow-up visit were collected from all patients. The changes of clinical variables were compared between the two groups before and after treatment. A total of 50 patients with DN met the inclusion and exclusion criteria, with 25 patients in each group. The baseline characteristics of the two groups have no significant difference (p > 0.05). Serum albumin levels after treatment were improved in both groups, but the improvement was statistically significant only in BPS group (35.5-39.8g/l, p < 0.001). The eGFR worsened significantly in both groups (p = 0.009 and p = 0.001). However, the decline of eGFR was less in BPS group than that in control group (- 9.8 vs. - 16.7ml/min/1.73m2, p = 0.037). In the subgroup analysis, 30 patients received 3-12months treatment and 20 patients received more than 12months treatment. During the 3-12months treatment period, serum creatinine and eGFR in the control group were significantly worsened compared with those before treatment (p = 0.019 and p = 0.03), but in the BPS group they were relatively stable (p > 0.05). After more than 12months treatment, although the serum creatinine and eGFR were significantly worsened in both groups (p < 0.05), the decline of eGFR was less in BPS group than that in control group (- 10.1 vs. - 25.9ml/min/1.73m2, p = 0.045). Combination of conventional treatment and BPS therapy delays the decline of eGFR in patients with DN in the long term.

Ruan Jian Qing Mai Recipe Inhibits the Inflammatory Response in Acute Lower Limb Ischemic Mice through the JAK2/STAT3 Pathway.

Ruan jian qing mai recipe (RJQM) is an empirical prescription for treating arteriosclerosis obliterans (ASO). However, the mechanism of RJQM recipe-mediated ASO attenuation has not yet been elucidated. Therefore, this study aimed to explore the mechanism by which the RJQM recipe relieves ASO in a mouse model of lower limb ischemia, which was established by ligating and breaking the femoral artery of the left lower limb. The surgical groups were divided into the ischemic group, beraprost sodium group, low-dose RJQM group, medium-dose RJQM group, and high-dose RJQM group. Normal mice were set as the control group. The blood flow of the lower limb was examined on days 7 and 14. At the end of animal procedures, blood samples were collected, and the rectus femoris of the left lower limb were harvested. Results revealed that mice in the ischemic group demonstrated low blood flow. Additionally, hematoxylin and eosin, and Masson staining results showed that inflammation of the rectus femoris was obvious in the ischemia group, and the level of fibrosis was increased. Blood flow was recovered in all treatment groups compared to the ischemic group, and the inflammatory infiltration and fibrosis of the rectus femoris were relieved after RJQM treatment. The serum levels of interleukin (IL)-17A and IL-21 were decreased, and the expression of JAK2/STAT3 proteins was inhibited in all RJQM treatment groups compared to the ischemia group. Furthermore, the improvement of IL-17A, IL-21, and rectus femoris fibrosis was more obvious with increasing treatment time. In conclusion, RJQM can effectively alleviate ASO and promote the recovery of lower limb blood flow by regulating the JAK2/STAT3 signaling pathway to reduce the inflammatory response.

Effect of beraprost sodium on renal function and p38MAPK signaling pathway in rats with diabetic nephropathy

Purpose: To investigate the effect of beraprost sodium (BPS) on renal function and P38MAPK pathway in diabetic nephropathy (DN) rats.Methods: Sprague Dawley (SD) rats (n = 30) were randomly divided into three groups, viz, normal control (NC), diabetic nephropathy (DN) and beraprost sodium (BPS). Creatinine (Cr), blood urea nitrogen (BUN) and fasting blood glucose (FBG), were determined by Hitachi 7020 automatic biochemical analyzer, while low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and total cholesterol (TC) were measured by Olympus 400 automatic biochemical analyzer. Western blot analysis was performed to examine protein expression. Interleukin-6 (IL-6), hs-CRP, and TNF-α levels were evaluated using enzyme linked immunosorbent assay (ELISA).Results: After 8 weeks of treatment, renal function indices (urine output, KW/BW, UAlb/24 h, Cr and BUN), blood lipid indices (FBG, LDL-C, TG and TC) and inflammatory factors levels (IL-6, hs-CRP and TNF-α) in DN group were higher than NC group (p &lt; 0.05). In BPS group, renal function and blood lipid indices and inflammatory factor levels decreased when compared to DN group (p &lt; 0.05). Furthermore, BPS inhibited the protein expression of p-P38MAPK, TGF-β1 and COX-2.Conclusion: Beraprost sodium improves renal function in DN rats by inhibiting P38MAPK signalingpathway.

Inhibitory Effects of Beraprost Sodium in Murine Hepatic Sinusoidal Obstruction Syndrome.

In this study, the liver sinusoidal endothelial cells (LSECs)-protective effects of beraprost sodium (BPS) were investigated using mice with monocrotaline (MCT)-induced sinusoidal obstruction syndrome (SOS). The mice were divided into BPS, placebo and control groups. They were killed 48 h after MCT administration, and blood samples and liver tissues were evaluated. Immunostaining was performed using anti-SE-1 and anti-CD42b antibodies, whereas plasminogen activator inhibitor (PAI-1) and endothelial nitric oxide synthase (eNOS) levels were evaluated using western blot or real-time RT-PCR. On pathological examination, SOS-related findings were observed in zone 3 in the placebo group; however, these were significantly suppressed in the BPS group. SE-1 staining showed a consistent number of LSECs in the BPS group compared with that in the placebo group, while CD42b staining showed a significant decrease in the number of extravasated platelet aggregation (EPA) in the BPS group. PAI-1 expression was significantly lower in the BPS group than in the placebo group; however, eNOS expression was significantly higher in the BPS group than in the placebo group. Prophylactic administration of BPS is useful for suppressing the development of SOS through the protective effects of LSEC.

Short-Term Effects of Beraprost Sodium on the Markers for Cardiovascular Risk Prediction in Type 2 Diabetic Patients with Microalbuminuria.

BackgroundTo evaluate the changes in cardiovascular risk markers including pulse wave velocity (PWV), microalbuminuria, inflammatory cytokines, and adhesion molecules after treatment with beraprost sodium (BPS) in patients with diabetic nephropathy.MethodsThis was a multicenter, prospective, randomized, double-blind, placebo-controlled trial. Type 2 diabetes mellitus patients with microalbuminuria were included. The primary endpoints were changes in microalbuminuria in spot urine and PWV after BPS or placebo (PCB) treatment for 24 weeks. The secondary endpoints were changes in clinical and metabolic parameters.ResultsA total of 52 patients completed the 24-week trial. Changes in PWV were not different significantly in the BPS and PCB groups (right, P=0.16; left, P=0.11). Changes in microalbuminuria were 14.2±157.0 and 34.5±146.6 (µg/mg Cr) in the BPS and PCB groups, respectively (P=0.63). Subgroup analysis in the high blood pressure (BP) group (baseline systolic BP >120 mm Hg and diastolic BP >80 mm Hg), showed that microalbuminuria decreased by −47.6 in the BPS group compared with an increase by 116.4 (µg/mg Cr) in the PCB group (P=0.04). Also, in the large waist circumference group (>95 cm), microalbuminuria decreased significantly in the BPS group (P=0.04).ConclusionShort-term treatment of BPS for patients with diabetic nephropathy did not show significant improvement in various cardiovascular risk factors. However, BPS significantly decreased microalbuminuria in study subjects with higher cardiovascular risk such as high BP or large waist circumference.

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

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.

Effectiveness of beraprost sodium in maintaining vascular access patency in patients on hemodialysis.

Hemodialysis vascular access dysfunction, mostly attributed to neointimal hyperplasia, is a major cause of morbidity and hospitalization in patients on hemodialysis. It has been reported that prostaglandin I2 has pleiotropic effects including anti-platelet, vasodilating, anti-inflammatory, and anti-atherogenic properties. In addition, several studies have shown that prostaglandin I2 can inhibit neointimal formation after vascular injury. This study aimed to investigate the effects of beraprost sodium, an oral synthetic analog of prostaglandin I2, on vascular access patency in patients on hemodialysis who experienced primary hemodialysis vascular access failure. Fifty-five patients with end-stage renal disease who were on hemodialysis were prospectively selected for this study. Twenty-three patients were assigned to be treated with 120µg/day of beraprost sodium, while remaining patients (n=32) were assigned to a control group. The primary outcome was primary unassisted vascular access patency at 2years. The incidence of primary unassisted patency at 2years was 83% in the beraprost sodium group and 38% in the control group (p=0.001). Analysis of covariables indicated that this effect occurred mainly as a result of beraprost sodium administration. No life-threatening adverse event or severe bleeding was recorded in any of the groups. Our data indicated that an oral prostaglandin I2 analog, beraprost sodium, is effective and safe for the maintenance of vascular access patency in patients on hemodialysis with primary vascular access failure.

UEG Week 2016 Poster Presentations

Contact E-mail Address: nakuraokura0922@yahoo.co.jp.IntroductionSinusoidal obstruction syndrome (SOS) is a drug-induced liver injury caused by anticancer treatments, such as oxaliplatin-based chemotherapy. Injury of sinusoidal endothelial cells (SECs) and subsequent extravasated platelet aggregation (EPA) initiate development of SOS. Beraprost sodium (BPS) has a protective effect on SECs and antiplatelet effect. The aim of this study was to examine the protective effect of BPS against SECs injury resulting from monocrotaline (MCT)-induced SOS in mice.Aims & MethodsSOS was induced in Crl:CD1 (ICR) mice by intraperitoneal administration of MCT (270 mg/kg). To evaluate the effect of BPS on SOS, the mice were divided into two groups. In the BPS group, BPS (200 μl/kg) was injected by intraperitoneal administration at 1 hour before, 3 hours after, and 9 hours after MCT administration. The control group received intraperitoneal injections of the same volume of saline at the same time points. All mice were sacrificed at 48 hours after MCT administration and the protective effect on SECs was assessed by determining blood cell count, serum biochemical findings and immunohistochemical stains of sinusoidal endothelial cell antibody (SEC-1) and CD62P (P-selectin). Western blot analysis and real-time polymerase chain reaction (RT-PCR) were also used to examine plasminogen activator inhibitor-1 (PAI-1) and endothelial nitric oxide synthase (eNOS) expression.ResultsPlatelet count was maintained in the BPS group compared to that in the MCT group (48.2 vs. 4.8 ´104/μl, P < 0.001). Serum transaminase levels and hyaluronic acid (HA) in the BPS group were significantly reduced compared to the levels in the MCT group (AST 129 vs. 1013 IU/L, P < 0.05; ALT 90 vs. 923 IU/L, P < 0.01; HA 670 vs. 2243 ng/mL, P < 0.01). In the MCT group, liver histology showed endothelial damage of the central venule, congestion and obstruction of the sinusoids, and necrosis of hepatocytes in zone 3. In the BPS group, these findings were suppressed. Immunohistochemistry showed a protective effect of SECs on SEC-1 and a decrease in platelet infiltration in the space of Disse on CD62P in the BPS group compared to that in the MCT group. Expression of PAI-1 was significantly lower and expression of eNOS was significantly higher in the BPS group.ConclusionBPS preserved SECs and suppressed the progression of MCT-induced SOS in mice, suggesting that BPS is useful for the prevention of SOS.Disclosure of InterestAll authors have declared no conflicts of interest.

Beraprost Sodium Protects Against Diabetic Nephropathy in Patients with Arteriosclerosis Obliterans: A Prospective, Randomized, Open-label Study

Inhibition of the renin-angiotensin system (RAS) has been used to treat diabetic nephropathy. However, RAS inhibition increases the risk of renal complications. In this study, we evaluated the effect of combining RAS inhibitor treatment with beraprost sodium (BPS), a prostaglandin I2 analog, in diabetic nephropathy with arteriosclerosis obliterans. This study was a prospective, randomized, open-label study. Twenty-six Japanese patients (age >30 years) with diabetic nephropathy and arteriosclerosis obliterans were randomly assigned to the BPS group (n=13), which received the combination of an RAS inhibitor and BPS (120 μg/day) therapy, or the control group (n=13), which received only an RAS inhibitor. Patients were followed up for 1 year. The primary endpoint was the effect of BPS on renal function. In the control group, serum creatinine (1.64±0.87 to 2.34±1.53 mg/dL, p<0.001), 1/creatinine (0.82±0.47 to 0.65±0.47, p=0.003) cystatin C (1.77±0.61 to 2.18±0.86 mg/L, p<0.001), and the estimated glomerular filtration rate (43.9±26.1 to 34.0±24.6 mL/min/1.73 m(2), p=0.004) were significantly worsened 48 weeks after the start of treatment. Conversely, in the BPS group, serum creatinine (1.71±0.75 to 1.66±0.81 mg/dL, p=0.850), 1/creatinine (0.66±0.19 to 0.71±0.25, p=0.577), cystatin C (1.79±0.55 to 1.80±0.57 mg/L, p=0.999), and the estimated glomerular filtration rate (35.8±10.8 to 38.7±14.4 mL/min/1.73 m(2), p=0.613) were unchanged. Combination treatment with BPS and an RAS inhibitor prevented the progression of diabetic nephropathy. These observations should be confirmed in large-scale studies with long-term follow-up.

Effects of beraprost sodium on renal function and inflammatory factors of rats with diabetic nephropathy.

Beraprost sodium (BPS) is a prostaglandin analogue. We investigated its effects on rats with diabetic nephropathy. There were 20 rats each in the normal control group (NC), the diabetic nephropathy group (DN), and the BPS treatment group. The rats in DN and BPS groups were given a high-fat diet combined with low-dose streptozotocin intraperitoneal injections. The rats in the BPS group were given daily 0.6 mg/kg intraperitoneal injections of this drug. After 8 weeks, blood glucose, 24-h UAlb, Cr, BUN, hs-CRP, and IL-6 levels increased significantly in the DN group compared with the NC group; however, the body mass was significantly reduced in the DN group compared with the NC group. Blood glucose, urine output, 24-h UAlb, Cr, hs-CRP, and IL-6 levels were significantly lower in the BPS group than in the DN group; the body mass was significantly greater in the DN group. Therefore, we concluded that BPS can improve renal function and protect the kidneys of DN rats by reducing oxidative stress and generation of inflammatory cytokines; it also decreases urinary protein excretion of rats with diabetic nephropathy.

The Protective Effect of Beraprost Sodium on Diabetic Cardiomyopathy through the Inhibition of the p38 MAPK Signaling Pathway in High-Fat-Induced SD Rats.

Objective. To investigate the effect of beraprost sodium (BPS) on diabetic cardiomyopathy and the underlying mechanism. Methods. A total of 40 Sprague Dawley rats were randomly divided into the normal control group (N = 10) and the model group (N = 30). The model group was fed a high-fat diet followed by a one-time dose of streptozotocin (STZ) to establish the diabetes mellitus model. After that, rats were randomly divided into two groups with or without BPS intervention. After 8 weeks, we explored the role of the p38 MAPK signaling pathway in inflammation, oxidative stress, cardiac morphology, and myocardial apoptosis. Results. Compared with control, the ratio of heart-weight to body-weight and the serum levels of SOD and GSH in the BPS group significantly increased, the expression of p38 MAPK, the serum levels of MDA, TGF-β1, TNF-α, HIF-1α, MMP-9, caspase-3, BNP, ANP, and heart Bax expression significantly decreased, and heart Bcl-2 expression significantly increased. H&E staining in diabetic rats showed the cardiac muscle fibers derangement, the widening gap, the pyknotic and fragmented nuclei, and more apoptosis. Conclusions. BPS effectively showed protective effects on diabetic myocardial cells, possibly through the inhibition of p38 MAPK signaling pathway.

Randomized Pilot Trial Between Prostaglandin I2 Analog and Anti‐Platelet Drugs on Peripheral Arterial Disease in Hemodialysis Patients

The effect of the prostaglandin I2 analog, beraprost sodium (BPS), on hemodialysis (HD) patients with peripheral arterial disease (PAD) has not been fully elucidated. The effect of BPS was compared to that of PAD drugs in HD patients with PAD in a multicenter randomized prospective interventional pilot study (J-PADD). Seventy-two PAD patients on HD were entered and randomly divided into two groups; that is, BPS group (Group A: n = 35) and PAD drug (cilostazol or sarpogrelate) group (Group B: n = 37). Primary endpoint was changes in skin perfusion pressure (SPP). Kidney Disease Quality of Life (KDQOL) score, cardiovascular events, PAD events, and adverse events were also evaluated. SPP increased significantly in both groups at 24 weeks from their basal levels. The absolute increase of SPP in Group A and Group B were 15.4 ± 30.0 mm Hg (P < 0.0001) and 20.2 ± 22.1 mm Hg (P = 0.025) (instep), and 13.8 ± 19.3 mm Hg (P < 0.0001) and 9.2 ± 16.3 mm Hg (P = 0.041) (sole), respectively. Changes of KDQOL score showed significantly better result in the role of physical score in Group A compared with Group B. Although heart rate was unchanged in Group A, 9.3/min increase was seen in Group B patients who received cilostazol. There was no intergroup difference in cardiovascular events and/or PAD events between the two groups during the study period. This exploratory pilot study suggested BPS was as effective as anti-platelet drugs in improving microcirculation in HD patients.

The effect of oral prostaglandin analogue on painful diabetic neuropathy: a double‐blind, randomized, controlled trial

This study was performed to assess the efficacy of beraprost sodium (BPS) in painful diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients. In this randomized clinical trial, 99 T2DM patients (41% male, age 60 ± 6 years) with DPN but without evidence of peripheral artery disease were randomized to receive either BPS (40 µg, tid) or placebo for 8 weeks. The primary end point was the improvement of the total symptom score (TSS), temperature rebound (TR) and nadir to peak (NP) above baseline. After 8 weeks treatment, the change of TSS in the BPS group showed a significant improvement compared to the placebo group (2.80 ± 2.48 vs. 1.60 ± 1.94 points, p = 0.009). Furthermore, the number of patients who showed signs of improvement in TSS and the proportion of patients with 50% relief of symptom was also significantly greater in the BPS group than in the placebo group (83.7 vs. 62%, p = 0.015, 36.2 vs. 14%, p = 0.009, respectively). In conclusion, treatment with BPS significantly improved TSS over an 8-week period.

Beraprost Sodium, an Orally Active Prostaglandin I2 Analog, Improves Renal Anemia in Hemodialysis Patients With Peripheral Arterial Disease

Beraprost sodium (BPS) is a stable, orally active prostaglandin I(2) (PGI(2) ) analog with antiplatelet and vasodilating properties. It has been reported that PGI(2) has pleiotropic effects that are anti-inflammatory and anti-atherogenic. In this study, we aim to determine the relationship between PGI(2) and renal anemia. We conducted a prospective randomized trial including 20 hemodialysis patients. Ten patients were assigned to be treated with 120 µg/day of BPS and the other patients were assigned to a control group. After six months, the titer of hemoglobin had significantly increased in the BPS group compared to the baseline (11.1 ± 0.3 g/dL vs. 10.3 ± 1.4 g/dL, respectively), and there was a significant difference between the BPS group and the control group. The level of ferritin was lower in the BPS group compared to the control group, but the average dose of erythropoietin did not significantly change. These findings suggest that BPS may improve renal anemia in hemodialysis patients.

Effect of beraprost sodium (BPS) in a new rat partial unilateral ureteral obstruction model

Unilateral ureteral obstruction (UUO) is a representative model for investigating the common mechanism of decreasing renal function in chronic renal failure. In this study, we present a new partial UUO model in adult rats and evaluated the effect of beraprost sodium (BPS: stable prostaglandin I 2 (PGI 2) analog). We could make reproductive and uniform partial UUO by ligating the left ureter together with a 0.5 mm diameter stainless steel wire with nylon thread, and withdrawing the stainless wire. One week later, the ureteral obstruction was released. After 3 weeks from the release of UUO, all animals of control group, without BPS administration, developed basophilic degeneration of tubular epithelium, tubular dilatation and interstitial fibrosis. The areas of tubular degeneration and fibrosis were significantly reduced in the BPS group, orally administered BPS 300 μg/kg twice a day from the next day of the release of obstruction, than in control group. In conclusion, we can established the adult rat partial UUO-release model and revealed that BPS can inhibit renal tubular damage and tubulointerstitial fibrosis.

Effect of Long-term Administration of a Prostacyclin Analogue (Beraprost Sodium) on Myocardial Fibrosis in Dahl Rats

Beraprost sodium (BPS) is an orally active prostacyclin analogue. The effects of BPS on the heart, including coronary circulation improvement, myocardial and vascular protection and anti-fibrosis effect on myocardium interstitium, have previously been demonstrated. However, the effects of BPS on hemodynamics, cardiac function and myocardial contractility in patients in the hypertrophic phase have not been clarified. Therefore, in the present study, the effects of BPS under long-term administration were investigated using the hypertension model of salt-sensitive Dahl rats. Six-week-old Dahl rats were divided into three groups, an 8% high salt diet group treated with BPS (BPS group), an untreated 8% high salt diet group (HHF group) and an untreated 0.3% low salt diet group (Control group), and observations were conducted until 17 weeks of age. In the BPS and HHF groups, the survival rates after 11 weeks of high salt diet intake were 87.5% and 47.1%, respectively (p<0.05). At 17 weeks of age, the atrial systolic peak velocity/early diastolic peak velocity and heart weight index of the BPS group decreased significantly compared with the HHF group (p<0.05). The HHF group exhibited significantly more severe myocardial fibrosis mainly in the endocardial layer of the left and right ventricles compared with the BPS and Control groups (p<0.05). In the present study, long-term BPS administration preserved diastolic function and prevented myocardial interstitial fibrosis in the non-compensatory phase. The results of the present study suggest that BPS is effective for treatment of hypertensive cardiac hypertrophy.

The Prostacyclin Analog Beraprost Sodium Augments the Efficacy of Therapeutic Angiogenesis Induced by Autologous Bone Marrow Cells

Implantation of autologous bone marrow (BM) mononuclear cells (MNCs) has been shown to augment neovascular formation in ischemic tissues in experimental animals and in humans. Prostaglandin derivatives improve the symptoms of patients with critical limb ischemia, possibly by their vasodilating and antiplatelet actions. We therefore examined whether therapeutic angiogenesis by implantation of autologous BM-MNCs would be enhanced by beraprost sodium (BPS), using a rabbit ischemic hindlimb model. Ischemia was induced by surgical resection of the left femoral artery. Twenty-five New Zealand white rabbits were divided into four groups. The first group (BM group, n = 4) received autologous BM-MNCs (2 x 10(6)/animal) implanted into the ischemic tissue 1 week after limb ischemia. The second group (BM+BPS group, n = 8) received BPS injected into the dorsal skin (300 microg/kg daily) starting 1 week before limb surgery. This group received BM-MNC implantation 1 week after surgery. Daily injection of BPS was continued until the end of the protocol. The third group (BPS group, n = 8) received BPS injected into the dorsal skin (600 microg/kg daily) starting 1 week before limb surgery. The fourth group received saline as a control (n = 4). The extent of angiogenesis in the ischemic hindlimb was assessed using the angiographic score (AS), ischemic/normal limb calf blood pressure ratio (CBPR), and tissue capillary density. Four weeks after limb ischemia, the ischemic/normal CBPR was highest in the BM+BPS group, followed by the BPS, BM, and control groups (0.56 +/- 0.16, 0.51 +/- 0.25, 0.44 +/- 0.15, and 0.30 +/- 0.10, respectively). The AS was also the greatest in the BM+BP group, followed by the BM, BP, and S group (1.63 +/-0.21, 1.31 +/- 0.25, 1.26 +/- 0.21 and 0.80 +/- 0.10, respectively). The TCD was greatest in the BM+BP group, followed in by the BM, BP, and S group? (46 +/- 4.1, 34 +/- 0.7, 33 +/- 6.9, and 19 +/- 1.8 per field, respectively). BP treatment is an effective means to enhance the efficacy of therapeutic angiogenesis induced by autologous BM-MNCs implantation in ischemic hindlimb tissues.

The prostacyclin analogue beraprost sodium prevents development of arterial stiffness in elderly patients with cerebral infarction

Prostacyclin (PGI 2) inhibits platelet aggregation, smooth muscle cell proliferation, and vasoconstriction. Arterial stiffness assessed by pulse wave velocity (PWV) predicts mortality in various cardiovascular diseases. To study the preventive effects of a prostacyclin analogue, beraprost sodium, on arterial PWV values in elderly patients with cerebral infarction. Forty-four patients with a history of cerebral infarction received beraprost sodium (120 μg/day p.o.) or no beraprost sodium (control) for 3 months. Arterial PWV and ankle brachial indices (ABI) were determined prior to starting the medication and after 3 months of medication. Initially, there were no differences in age, blood pressure, and body mass index. Further, PWV or ABI did not differ between the beraprost sodium group ( n=22) and the control group ( n=22). After 3 months, PWV in beraprost sodium group was significantly reduced (−123±282) when compared with the control group (147±274)( P=0.006). ABI was not significantly different when comparing the two groups at 3 months. Long-term administration of beraprost sodium prevents the decline in arterials biomechanics in elderly patients with cerebral infarction.

Effect of Beraprost Sodium in Patients with Chronic Obstructive Pulmonary Disease

Background : Pulmonary vascular changes which occur early in the course of chronic obstructive pulmonary disease (COPD) are prevalent manifestation and later cause pulmonary hypertension, which is a bad prognostic factor in COPD. Beraprost sodium (BPS), an orally active prostacyclin analogue, has been shown to improve survival in patients with primary pulmonary hypertension. This study investigated the effect of BPS in the patients with COPD. Methods : This is a double-blind randomized placebo-controlled, two center clinical trial. Twenty one consecutive patients with COPD were enrolled from June 2003 to June 2004 (patients treated with BPS for 3 months, BPS group, n=11; those with placebo, placebo group, n=10). The baseline demographic, pulmonary function and hemodynamic data were not significantly different between two groups. Results : On echocardiographic examination, trans tricuspid valve pressure gradient has decreased significantly after 3 months with beraprost in the BPS group [17.7(±11.4) to 8.2(±8.9) mm Hg, p-value<0.05], while there was no significant change in the control group. Six-minute walking distance has decreased in the control group and increased in the BPS group, but there was no statistical significance. Conclusion : In patients with COPD oral administration of BPS reduced the pulmonary arterial pressure. The clinical significance of this finding, that is improving symptoms and natural course of the disease, needs further study. (Tuberc Respir Dis 2004; 57:320-328)

Effect of Orally Active Prostacyclin Analogue on Survival in Patients With Chronic Thromboembolic Pulmonary Hypertension Without Major Vessel Obstruction

This study investigated whether treatment with beraprost sodium (BPS), an orally active prostacyclin analog, improves hemodynamics and survival in patients with peripheral-vessel chronic thromboembolic pulmonary hypertension (CTEPH), for which there is no surgical option. Oral administration of BPS has been shown to improve the hemodynamics and prognosis in patients with primary pulmonary hypertension; however, whether BPS has beneficial effects in CTEPH remains unknown. Forty-three patients with peripheral-vessel CTEPH were classified into two groups: patients treated with BPS (BPS group, n = 20) and those without BPS (conventional group, n = 23). Baseline demographic and hemodynamic data did not significantly differ between the two groups. BPS therapy improved New York Heart Association functional class in 10 patients (50%) and significantly decreased total pulmonary resistance from 18 +/- 6 to 15 +/- 8 Wood units (p < 0.05) [mean +/- SD]. Sixteen patients died of cardiopulmonary causes in the conventional group during a mean follow-up period of 58 +/- 45 months. In contrast, only three patients died of cardiopulmonary causes in the BPS group during a mean follow-up period of 44 +/- 30 months. The absence of BPS therapy, elevated total pulmonary resistance, heart rate, and age were independently related to the mortality by Cox proportional hazard analysis. The 1-year, 3-year, and 5-year survival rates for the BPS group were 100%, 85%, and 76%, respectively, compared to 87%, 60%, and 46% in the conventional group. This preliminary study suggests that oral administration of BPS may improve hemodynamics and survival in patients with peripheral-vessel CTEPH, for which there is no surgical option.