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Background: 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. Hypothesis/Objectives: To evaluate the efficacy and safety of BPS in the treatment of cats with CKD, as compared to placebo. Animals: Seventy‐four client‐owned cats with naturally occurring CKD. Methods: 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). Results: 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. Conclusions and Clinical Importance: 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. [ABSTRACT FROM AUTHOR]

A previously reported bioassay method for Spodoptera litura chitinase inhibitors has been improved by use of colloidal chitin powder witha uniform particle size. This improvement made the assay four times more sensitive. Detection of three active supernatants by screening of supernatants and cell extracts from 135 fermentation broths has proved the efficiency of this improved method. (C) 1999 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Objective: Endothelial dysfunction plays an important role in the pathogenesis of chronic kidney disease. Prostacyclin (PGI 2 ), an endothelial cell-produced endogenous prostaglandin, plays a crucial role in maintaining endothelial function. However, its effects on intestinal microcirculation and barrier function are not fully understood. We hypothesized that PGI 2 improves intestinal microcirculation and barrier function via endothelial protective effects., Methods: ICR and ICGN (a spontaneous nephrotic model) mice were used in this study. Intestinal microcirculation was visualized in vivo to investigate PGI 2 effects. Beraprost served as PGI 2 . PGI 2 administration spanned 4 weeks, following which we assessed its influence on intestinal endothelial, intestinal barrier, and renal functions., Results: We visualized intestinal microcirculation and endothelial glycocalyx in the intestinal blood vessels. Beraprost administration induced a 1.2-fold dilatation of the vascular diameter of the small intestine. Intestinal blood flow in ICGN mice was significantly reduced compared that in ICR mice but improved with beraprost administration. ICGN mice exhibited reduced serum albumin levels, decreased ambulation, an imbalance in intestinal reactive oxygen species (ROS)/nitric oxide (NO), and impaired tight junctions; all were ameliorated by beraprost administration., Conclusions: Beraprost improves intestinal microcirculation and barrier function by ameliorating ROS/NO imbalances, thereby reducing physical inactivity during renal failure., (© 2024 The Author(s). Microcirculation published by John Wiley & Sons Ltd.)

We conducted a multicenter, randomized, double-blind, placebo-controlled, phase IIb/III study (CASSIOPEIR) using a renal composite endpoint (i.e., doubling of SCr or end-stage renal disease) in seven Asian countries/region. CASSIOPEIR compared TRK-100STP (120 μg and 240 μg) with placebo in patients with non-diabetic CKD patients with primary glomerular disease or nephrosclerosis (n = 892). However, the superiority of TRK-100STP over placebo was not observed. A prior phase II study on which the Phase IIb/III study design was based included only Japanese patients. We therefore evaluated TRK-100STP efficacy and safety in a subgroup of Japanese patients using the CASSIOPEIR dataset. As the timing of treatment initiation is important in CKD, we conducted additional subgroup analyses based on the baseline serum creatinine (SCr) and eGFR. ITT analysis was performed in a Japanese subgroup (n = 339) in which the primary endpoint was the first occurrence of renal composite endpoint. Significant differences were observed for TRK-100STP 240 μg vs. placebo (P = 0.0493; HR 0.69 [95% CI: 0.47, 1.00]), but no significant difference was observed between TRK-100 120 μg and placebo (P = 0.3523; HR 0.85). More prominent improvement was observed with TRK-100STP 240 μg vs. placebo for baseline SCr  < 3.0 mg/dL (P = 0.0031; HR 0.43); SCr < 3.5 mg/dL (P = 0.0237, HR 0.59); and eGFR ≥ 10 mL/min/1.73 m 2 (P = 0.0339, HR0.67), respectively. No significant changes in urinary albumin/creatinine ratio and blood pressure were observed. TRK-100STP was generally well tolerated and most adverse drug reactions were mild or moderate in severity. In conclusion, in the Japanese subgroup of CASSIOPEIR, TRK-100STP 240 μg/day significantly improved the renal composite endpoint compared with placebo, with greater efficacy in subjects with SCr < 3.5 or eGFR ≥ 10 mL/min/1.73 m 2 ., (© 2020 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Background and Objectives: Beraprost sodium (BPS), an orally administrable prostaglandin I 2 derivative, is used for the treatment of chronic arterial occlusion and pulmonary arterial hypertension and has potential efficacy in nephropathy. Beraprost sustained release (beraprost SR) is an oral sustained-release formulation of BPS. To confirm the dose rationale reported in a multi-regional study of nephropathy patients in Asia, this open-label study evaluated ethnic differences in the pharmacokinetic profiles of BPS and its active diastereomer (BPS-314d) after beraprost SR administration among healthy Japanese, Chinese, and Korean adult males., Methods: Twelve healthy subjects in each ethnic group were enrolled. Subjects received a single oral dose of 120 μg beraprost SR under fasting conditions., Results: The geometric mean ratio (90% confidence interval) of the maximum plasma concentration (C max ) and area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration (AUC last ) of BPS was 1.12 (0.85-1.48) and 1.40 (1.05-1.86) in Chinese, and 1.18 (0.90-1.55) and 1.18 (0.89-1.58) in Korean compared to Japanese subjects. These differences were not clinically relevant. Similarly, differences in the C max and AUC last of BPS-314d were also small among the ethnic groups. Urinary excretion of BPS and BPS-314d was limited in all ethnic groups. Together, these findings indicate that the pharmacokinetics of beraprost SR are not affected by ethnic background., Conclusions: There were no clinically meaningful ethnic differences in the pharmacokinetics of BPS and BPS-314d following beraprost SR administration among Japanese, Chinese and Korean populations.

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 2 Derivative for Evaluating Improvement of Renal Function) was a randomized, double-blind, placebo-controlled study conducted at 160 sites in seven Asia-Pacific countries and regions. Eligible patients (n = 892) were randomized to TRK-100STP 120, 240 μg, or placebo for a treatment period of up to 4 years. The primary efficacy endpoint was time to first occurrence of a renal composite: doubling of serum creatinine or occurrence of end-stage renal disease. No significant differences were observed in composite endpoints between TRK-100STP and placebo (P = 0.5674). Hazard ratios (95% CI) in the TRK-100STP 120 and 240 μg vs. placebo groups were 0.98 (0.78, 1.22) and 0.91 (0.72, 1.14), respectively. The overall incidence of adverse events and adverse drug reactions was comparable between treatment arms., (© 2019 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Background: 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., Hypothesis/objectives: To evaluate the efficacy and safety of BPS in the treatment of cats with CKD, as compared to placebo., Animals: Seventy-four client-owned cats with naturally occurring CKD., Methods: 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)., Results: 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., Conclusions and Clinical Importance: 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., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

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 max 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 0-48h 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 max 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 0-48h 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 max and AUC 0-48h 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., (© 2016, The American College of Clinical Pharmacology.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., Trial Registration: NCT02480751. June 21, 2015.

Background: Chronic kidney disease (CKD) is public health concern even in Asian countries. TRK-100STP, a sustained release tablet of an orally-active prostacyclin analogue, beraprost sodium, is suggested to suppress worsening of some parameters of renal filtration function, containing in slope of 1/serum creatinine (1/SCr) vs. time in a phase II clinical trial., Methods/design: We describe the design of the phase IIb/III trial of TRK-100STP, CASSIOPEIR (CRF Asian Study with Oral PGI2 derivative for Evaluating Improvement of Renal function) conducted in approximately 160 centers in China, Hong Kong, Japan, Malaysia, Republic of Korea, Taiwan, and Thailand. A total of 750 patients (n = 250 per group) with primary glomerular disease or nephrosclerosis were planned to be enrolled. Patients were randomized into one of three treatment groups in a double-bind, placebo-controlled manner: TRK-100STP 60 μg b.i.d.; TRK-100STP 120 μg b.i.d.; or placebo. The treatment period is planned to last 2 to 4 years. The primary efficacy endpoint is the renal composite endpoint including doubling of SCr and ESRD (dialysis induction, renal transplantation, or increase in SCr to ≥ 6.0 mg/dL)., Discussion: This trial targeting CKD patients is designed to (a) demonstrate the superiority of TRK-100STP over placebo using renal composite endpoints, (b) determine the recommended clinical dose, and (c) assess the safety of TRK-100STP in this population and setting., Trial Registration: ClinicalTrials.gov Identifier: NCT01090037.

We have previously demonstrated that renoprotective effects of a prostacyclin analog, beraprost sodium, on the kidney of anti-glomerular basement membrane glomerulonephritis (GN) rats. The aim of this study is to address the renoprotection mechanism of beraprost sodium, especially in the terminal stage of GN. Beraprost sodium was orally administrated from 2 to 7 weeks after induction of GN, and renal function, morphology, protein and mRNA levels were analyzed. We found the beraprost sodium treatment suppressed the structural regression of renal microvascular network and decline of renal blood flow occurred in the kidney of GN rats. To address the mechanism of the structural maintenance, we focused on apoptosis because the increased number of apoptotic renal microvascular endothelial cells and tubular epithelial cells was observed in the kidneys of GN rats as compared with normal and beraprost sodium treated rats. Protein and mRNA analyses demonstrated that mitochondria-dependent apoptotic pathway was activated in the kidneys of GN rats, and beraprost sodium suppressed the activation by modulating the expression patterns of pro- and anti-apoptotic factors. These results suggest that inhibition of mitochondria-dependent apoptosis of renal cells in GN kidney and consequent maintenance of renal functional structures, including microvascular network might contribute to the renoprotective effect of beraprost sodium in GN., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (© 2013 Elsevier B.V. All rights reserved.)

A 47-year-old woman was diagnosed as advanced gastric cancer of cardia(poorly-differentiated adenocarcionoma), with multiple para-aortic lymph node and liver metastasis, in March, 2005. We attempted neo-adjuvant chemotherapy with docetaxel(DOC), cisplatin(CDDP), and S-1(DCS). After 3 courses of DCS, we confirmed that the para-aortic lymph nodes and liver metastasis became small. Then, we were able to perform total gastrectomy, splenectomy, and D2 lymph node dissection. Additionally, we performed an intraoperative radiofrequency ablation to the scar of the liver metastasis. Histopathologically, we identified lymph node metastases in #1 and #16b1 pre. S-1 and DOC were administered as adjuvant chemotherapy. At seven years since the operation, the patient has shown no signs of recurrence. Combined modality therapy for advanced gastric cancer diagnosed with stage IV can be an effective treatment, so we hope that it will be established as a standard therapy.

Objective: The prostacyclin analog, beraprost sodium (BPS), was examined for its potential to improve the symptoms of obesity-type diabetes (i.e., hyperglycemia, hyperinsulinemia, dyslipidemia, histopathologic changes, and diabetic complications)., Research Design and Methods: Obese Zucker rats, an experimental model of genetic obesity-induced type 2 diabetes, were repeatedly administered BPS at oral doses of 0.2 or 0.6 mg x kg(-1) x day(-1) b.i.d. for 12 weeks, and serum chemistry, urinalysis, and histopathologic examination were performed., Results: BPS dose-dependently suppressed serum glucose, insulin, triglyceride, and cholesterol levels in obese animals. In oral glucose tolerance test, BPS suppressed the post-glucose-loading elevation of serum glucose in a dose-dependent manner. Urinary N-acetyl-beta-D-glucosaminidase was significantly lower in BPS-treated obese animals compared with control animals, although no significant differences were observed in urinary protein levels between the BPS-treated groups and the control group. In addition, histopathologic examination revealed significant protective effects of BPS against renal disorder in obese animals. Histopathologically, BPS also inhibited the progression of hepatic steatosis, hypertrophy of adipose tissue, and pancreatic fibrosis. Furthermore, thermographic analysis of the hind limb sole skin surface indicated a significant increase in temperature in BPS-treated animals, compared with control animals, which was likely due to improved blood circulation by administration of BPS., Conclusions: BPS suppressed the pathogenesis and development of diabetes and its complication, nephropathy, which was presumably accompanied by improving glucose intolerance and insulin resistance in obese Zucker rats.

Little data are available on the role of blood rheology in atherosclerosis in hemodialysis (HD) patients. This study sought to assess the relationship between leukocytes conjugated with platelets (leukocyte aggregates [LA]) and atherosclerosis in patients with HD. The present study included 118 patients on HD. As surrogate markers of atherosclerosis, aortic stiffness measured by brachial-ankle pulse wave velocity, and carotid intima-media thickness (IMT) were measured. As an assessment of LA, a method, microchannel array flow analyzer, which makes it possible to directly observe the flow of blood cell elements through the microchannel, was used. We measured a number of LA during 50 microL flow of whole blood through microchannels. In 12 age-matched healthy individuals, a number of LA during 50 microL flow of whole blood was 25.7+/-5.4, whereas in HD patients it was significantly increased up to 48.2+/-16.4 (P<0.001). Flow cytometry demonstrated that LA were predominantly monocytes. Leukocyte aggregates were positively associated with plasma levels of fibrinogen (P<0.01), or serum high-sensitive C-reactive protein (P<0.01). Moreover, LA had highly significant associations with brachial-ankle pulse wave velocity (P<0.001) and IMT (P<0.001). In conclusion, we demonstrated hemorheologically that monocyte-platelet conjugates play an important role in aortic stiffness and IMT in HD patients.

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 microg/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.

In rats receiving bilateral femoral arteries ligation (day 0), repeated oral administration of the prostacyclin derivative beraprost sodium (50 microg/kg, b.i.d.) from day 1 to day 5 resulted in a significant prolongation in walking time in rotarod walking exercise performed on day 5. Similarly, results were obtained in rats with bilateral femoral arterial thrombosis induced by application of FeCl(3)/HCl. In the ligation model, a significant increase was observed in femoral/carotid arterial blood pressure ratio even on day 2. These results indicated that beraprost sodium improves blood flow and walking disturbances associated with arterial occlusion in rats.

Effects of beraprost sodium, a chemically stable prostacyclin analogue, on renal dysfunction in an experimental rat model of glomerulonephritis were investigated. Beraprost sodium (30, 100 and 300 microg/kg) was orally given twice daily from the late stage of nephritis in which renal dysfunction was already developed. Beraprost sodium treatment inhibited the increase in urinary protein, serum creatinine and blood urea nitrogen, and the decrease in creatinine clearance. The elevation of serum creatinine was also inhibited by predonisolone (1 mg/kg). However, captopril (25, 50 and 100 mg/kg) and dipyridamole (20 and 60 mg/kg) failed to inhibit the elevation of serum creatinine. In the beraprost sodium-treated nephritic rats, the increase in mRNA levels for monocyte chemoattractant protein-1 (MCP-1) and collagen in the kidney was inhibited. These results suggest that beraprost sodium ameliorates developed renal dysfunction and is possibly an effective agent for the treatment of human glomerulonephritis.

Prostacyclin is an endogeneous eicosanoid synthesized by vascular endothelial cells, and has potent inhibitory effects on platelet adhesion/aggregation and vasoconstriction. However, its therapeutic use is restricted by its extremely short half-life. Beraprost sodium (beraprost) is the first orally active prostacyclin analogue developed by TORAY Industries, Inc. Beraprost possesses a phenol moiety instead of the exo-enol ether moiety, which is the cause of the instability of prostacyclin, and has a modified omega-side chain that contributes to dissociating antiplatelet action from adverse reactions. In 1992, beraprost was approved as a drug for chronic arterial occlusion. Beraprost is now widely used clinically as "Dorner" or "Procylin". The indication for "primary pulmonary hypertension" was also approved in 1999. Recently in Europe, a placebo controlled trial named "Beraprost et Claudication Intermittent-2 (BERCI-2)" was performed, and it was reported that beraprost improved the walking distances of the patients. Beraprost has a variety of biological activities such as antiplatelet effects, vasodilation effects, antiproliferative effects on vascular smooth muscle cells, cytoprotective effects on endothelial cells and inhibitory effects on the production of inflammatory cytokines. On the basis of basic and clinical research, it has been suggested that beraprost is also effective for many intractable diseases. We expect that the relationship between reduced prostacyclin level and these diseases would be clarified and the beneficial effects of beraprost would be demonstrated by controlled clinical trials in the future.

Direct detection of nitric oxide (NO) is essential for understanding the precise mechanism of its production from endothelial cells. Previously, we developed an NO detection system based on the chemiluminescence reaction between NO and luminol-H2O2. Here, we have applied this system to cultured endothelial cells for the direct and on-time measurement of NO. The perfusate from cultured endothelial cells was continuously mixed with luminol-H2O2. N(G)-monomethyl-L-arginine (L-NMMA) (10(-4) M) decreased the chemiluminescence signal of NO, suggesting the existence of basal NO release. Bradykinin (10(-8) M-10(-6) M) increased the NO signal (10(-6) M; 5.1+/-0.4 fmol/min, corresponding to 1.7 pM in the perfusate), and this was inhibited by 10(-4) M L-NMMA (1.8+/-0.3 fmol/min). These results corresponded to the changes in cGMP levels in RFL-6 cells, which provide an NO bioassay system. We conclude that the luminol-H2O2 system is useful for the direct and continuous measurement of NO from cultured endothelial cells.

Transesophageal echocardiography (TEE) has enabled detection of the cardiac source of systemic emboli. We report the case of a patient who manifested systemic, multiple embolization in the kidney, skin, and upper gastrointestinal tract following coronary angiography. TEE allowed visualization of the atherosclerotic debris in the thoracic aorta. The clinical picture of the patient was consistent with that of cholesterol embolism. We recommend that patients with extensive atherosclerotic disease should undergo TEE before cardiac catheterization or other invasive procedures involving the aorta are carried out.

The authors have designed small diameter vascular prostheses with incorporated matrices that can be absorbed into a growing anastomotic neointima. First, a gelatin-heparin complex was coated on the inner surface of tubular ultrafine polyester fabrics presealed with heat denatured albumin. Second, to control the bioabsorption rate, the prepared grafts were cross-linked with polyepoxy compounds for 3 days (Group I; n = 14) or 5 days (Group II; n = 4). These grafts, 3 mm in diameter and 4 cm long, replaced the carotid arteries of nine mongrel dogs weighing 9.5-14 kg. Six of eight (75%) grafts in Group I were patent when the animals were killed 4 weeks after surgery. Doppler sound examination revealed that the remaining six were patent for 16 weeks. In Group II, three of four (75%) grafts were patent when the animals were killed 8 weeks after surgery. In both groups, scanning electron microscopic study showed neither platelet aggregation nor fibrin formation on the midportion. However, these two groups significantly differed in histology. In Group I, thin anastomotic neointima advanced over the mostly absorbed gelatin-heparin complex layer. Connective tissue was well formed around the polyester scaffold. In contrast, thick neointima advanced over the gelatin-heparin complex layer that still remained on the luminal surface in Group II. These results suggest that the gelatin-heparin complex, when cross-linked adequately, could simultaneously function as a temporary antithrombogenic surface and as an excellent substructure of an anastomotic neointima.

A cardiac wall substitute made of non-woven ultrafine fibers was developed. It consists of a basal knitted scrim with strongly entangled ultrafine polyester fibers, lined with a fine velour of entangled ultrafine fibers that provide high ravel and tear resistance, a perfect matrix for preclotting, and an anchor for cell adhesion. Six of the new patches and all control patches (a polytetrafluorethylene patch, woven Dacron patch, and glutaraldehyde-treated equine pericardium) were implanted in the right ventricular outflow tracts in 24 dogs. Animal experiments showed that the new patch was easy to handle and suture without fraying or tearing through the edge.

The purpose of the study is to investigate the role of the serotonergic nervous system in centrally administrated angiotensin II (A-II) mediated hemodynamic as well as vasopressin (AVP) responses. Eight-week-old male SHR and age-matched Wistar Kyoto rats (WKY) were used and the experiment was performed in the conscious state. In protocol 1, after resting observation of 30 minutes 10ng of A-II was given intracerebroventricularly (i.c.v.). This was followed by i.c.v. injection of 1 microgram of 5-HT2 receptor antagonist, xylamidine, 50 minutes later; then 10ng of i.c.v. A-II was repeated after 10 minutes (SHR: n = 7, WKY: n = 10). In protocol 2, plasma vasopressin (AVP) was measured in the following groups. In one group, 1.3ml of blood was sampled from the carotid cannula after resting observation, and the same amount of blood from an age-matched donor rat of the same strain was transfused immediately. Two hours later, 10ng of A-II was given i.c.v., and blood was sampled again after 1 minute (SHR: n = 7, WKY: n = 12). In another group, 1 microgram of xylamidine was given i.c.v. and was followed by 10ng of A-II 10 minutes later; then blood was collected after 1 minute (SHR: n = 8, WKY: n = 13). In protocol 1, resting MAP were 144 +/- 6mmHg in SHR and 99 +/- 2mmHg in WKY. I.c.v. A-II elicited a consistent pressor response in both SHR and WKY, but the response was significantly larger in SHR than that in WKY, +45 +/- 3 and +37 +/- 1mmHg, respectively. Xylamidine had no effect on MAP, and repeated A-II produced significant pressor responses. However, the responses were significantly smaller in both SHR (+36 +/- 3mmHg) and WKY (+25 +/- 1mmHg) as compared with those to initial A-II injection. In protocol 2, resting AVP were similar in SHR (1.5 +/- 0.2pg/ml) and in WKY (1.6 +/- 0.1pg/ml). However, after i.c.v. A-II injection, AVP became higher in SHR (131 +/- 14pg/ml) than in WKY (64 +/- 6pg/ml). AVP after A-II injection with xylamidine pretreatment were similar in SHR (48 +/- 6pg/ml) and in WKY (45 +/- 4pg/ml). Since the responses of both MAP and AVP to i.c.v. A-II were larger in SHR, and the responses were effectively suppressed by S2 receptor antagonists, the central serotonergic nervous system may play an important role in the hemodynamic as well as AVP responses to i.c.v. A-II administration.

The control of cellular responses on substrate surfaces is essential for logical surface design aiming at endothelialized, vital implant devices. In this paper, the surface property that alters cell adhesion, spreading, migration, and proliferation processes is shown to be a determinant of endothelial cell assembly or angiogenesis in vitro. This was clearly demonstrated on slightly hydrophobic cellulosic surfaces, which induced organized three-dimensional cellular assemblies of bovine thoracic endothelial cells. The results indicated that this was driven by enhanced migratory response and/or retraction or involution of two-dimensional adherent cells, in which cell-cell interaction was enforced in a time dependent fashion. The present study strongly suggests that the mechanism leading to in vitro angiogenesis is primarily due to a weak cell-substrate interaction relative to cell-cell interaction.

Although autologous connective tissue grafts (ACTG) are an ideal vascular substitute, they have not yet been used as small diameter vascular grafts because of thrombogenicity. We reported on ACTGs in which mesh tubes were fabricated from ultra-fine polyester fibers (UFPF) and used as a framework. Antithrombogenicity was established using an original heparinization method, with a 50% patency 1 month postimplantation. Early failure of these grafts was caused mainly by loss of antithrombogenicity before development of endothelialization on the inner surface. In this study, higher concentrations of heparin were used for in situ heparinization of the grafts before implantation in combination with antiplatelet therapy (cilostazol, OPC-13013 for the first month after substitution for canine carotid arteries. As a result, more complete healing of the grafts was attained, with a patency rate of 63% at 1 month, when small doses of antiplatelet agents were used. More intensive antiplatelet therapy resulted in impairment of graft healing, causing hematomas around the grafts. Thus, optimal doses of antiplatelet agents remain uncertain.

The authors previously showed that a vascular prosthesis made of ultrafine polyester fibers (UFPF) had high healing ability even when of low porosity. In this study, new highly porous vascular grafts fabricated from UFPF (water porosity: 3,600 ml/min/cm2, 8 mm in inner diameter and 5 cm in length), were developed and implanted in the thoracic descending aorta of dogs to evaluate their endothelialization capability. Two weeks after implantation, many colonies of endothelial cells with openings of capillary blood vessels were noted, even in the middle portion of the grafts. Numerous fibroblasts and capillary blood vessels were also observed in the synthetic walls. These results suggest that UFPF vascular grafts provide a suitable microenvironment for infiltration and proliferation of fibroblasts, which are accompanied by the capillary formation as nutrient supply; these capillaries provide multiple sources of endothelial coverage on the luminal surface. It is expected that the new, highly porous vascular grafts may have rich endothelialization capability and stable healing properties in humans.

Unlabelled: Recently, the serotonergic nervous system has been receiving attention as part of the blood pressure regulating mechanism of the central nervous system, and it has been postulated that the system may participate in the pathogenesis of hypertension. The purpose of this experiment is to investigate the mechanism of hemodynamic change after i.c.v. administration of 5-HT in SHR and in normotensive Wistar Rats (WR)., Materials and Methods: Twenty-week-old male SHR (n = 11) and age-matched WR (n = 14) were used. On the day before the experiments, the unilateral carotid artery and jugular vein were cannulated. Also, a cannula was inserted stereotaxically into the anterior horn of the lateral cerebral ventricle. Experiments were performed under the conscious and minimum restrained state. Experiment I: After observation of resting mean arterial pressure (MAP) and heart rate (HR) for 20 minutes, 5-HT (5 micrograms/5 microliter saline) was administrated i.c.v., and MAP and HR were observed for 90 minutes. Then, 200 micrograms of phenoxybenzamine (POB) was given from the jugular cannula. Thirty minutes after the POB administration when MAP was stabilized, 5 micrograms of 5-HT was again given i.c.v., and MAP and HR were recorded for 30 minutes. Experiment II: Plasma norepinephrine (PNE) was measured before and 2 minutes after 5-HT i.c.v. administration. The control sample (1.5 ml) was withdrawn at least 30 minutes before the 5-HT injection, and immediately after the blood sampling, the same amount of blood which was obtained from the age-matched donor rat of the same strain was transfused., Results: Experiment I: Resting MAP was 136.4 +/- 5.1 mmHg in SHR and 99.1 +/- 3.0 mmHg in WR. I.c.v. administration of 5-HT elicited consistent pressor response in SHR and in WR.(ABSTRACT TRUNCATED AT 250 WORDS)