beraprost and Arteriosclerosis-Obliterans

A novel prostaglandin I2 (PGI2) analogue, beraprost sodium, is the first launched drug as an orally active PGI2. PGI2 was discovered in 1976, and has attracted much attention as a medicine for cardiovascular diseases such as strokes and heart attacks because of its potent antiplatelet and vasodilating effect. However, PGI2 is extremely unstable for the use as practical medicines. Thus, stable PGI2 analogues have been explored by a large number of researchers in the world. Just after the discovery of PGI2, we started a research on chemically and metabolically stable PGI2 derivatives with longer duration of action and less adverse reaction. We invented a novel class of stable PGI2, 5,6,7-trinor-4,8-inter-m-phenylenePGI2 analogues that have the phenol moiety instead of the enolether moiety of PGI2. Further efforts were devoted to enhance the efficacy of the PGI2 analogues and to eliminate their side effects, and an orally active analogue, beraprost sodium, was obtained. In order to establish the synthetic route of beraprost sodium, various novel processes were invented, including ortho-selective metalation of bromoanisoles by means of Grignard reagents, copper-catalyzed SN2' cyclization to prepare cyclopenta[b]benzofuran, and stereo-selective elongation of the omega-side chain by Prins reaction. Beraprost sodium inhibit platelet aggregation induced by adenosine 5'-diphosphate (ADP), collagen and arachidonic acid. It was shown that the drug has a potent antiplatelet effect both in vitro and ex vivo in human and several animal species. In clinical studies, beraprost sodium exerted a marked effect to improve arteriosclerosis obliterans. No serious adverse effects related with the drug have been reported. It was highly evaluated as an orally active PGI2 by pharmaceutical companies overseas as well, and now clinical trials are under way in U.S.A. and Europe.

Topics: Animals; Arteriosclerosis Obliterans; Clinical Trials as Topic; Depression, Chemical; Epoprostenol; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Vasodilator Agents

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.

Topics: Aged; Arteriosclerosis Obliterans; Biomarkers; Creatinine; Cystatin C; Diabetic Nephropathies; Disease Progression; Epoprostenol; Female; Glomerular Filtration Rate; Humans; Japan; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renin-Angiotensin System; Time Factors; Treatment Outcome

This study aimed to evaluate the effect of oral beraprost sodium, a prostaglandin I2 analogue, on symptoms of intermittent claudication in patients with arteriosclerosis obliterans. The research design consisted of a before and after treatment study without comparison groups. The subjects comprised arteriosclerosis obliterans patients who experienced intermittent claudication. Furthermore, this study aimed to assess the mechanism of action of beraprost sodium via blood sampling and measurements of flow-mediated vasodilatation before and after treatment.. The study was performed prospectively in 7 patients with arteriosclerosis obliterans. Beraprost sodium (40 microg) was orally administered to 7 patients at study entry, followed by administration of 120 microg/day for 12 weeks. Blood sampling and measurements of flow-mediated vasodilatation were performed before and after treatment at study entry, 4 weeks, and 12 weeks after treatment. Treadmill exercise tests were performed three times at study entry, 4 weeks, and 12 weeks after treatment. The ankle-brachial index (ABI) was measured at rest and after exercise.. Pain-free walking distances increased by 138% at 12 weeks after treatment. Maximum walking distances increased by 133%. The ABI was significantly increased at 4 weeks and 12 weeks after treatment at rest. Endothelin-1 levels tended to be decreased at 1 h after administration of 40 microg beraprost sodium. N(G),N(G)-dimethyl-L-arginine, nitrate ions, and flow-mediated vasodilatation.. Beraprost sodium tended to decrease endothelin-1 levels and improved symptoms of intermittent claudication in patients with arteriosclerosis obliterans.

Topics: Administration, Oral; Aged; Ankle Brachial Index; Arginine; Arteriosclerosis Obliterans; Biomarkers; Endothelin-1; Epoprostenol; Exercise Test; Exercise Tolerance; Humans; Intermittent Claudication; Platelet Aggregation Inhibitors; Prospective Studies; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents; Walking

Arteriosclerosis obliterans (ASO) causes ischemic symptoms of the lower limbs, reducing quality of life (QOL), and has a poor prognosis. Early diagnosis and treatment are necessary. In this study, the effects of long-term administration of beraprost sodium (beraprost) to treat ASO were investigated.. One hundred and eighty eight patients treated with beraprost for ≥1 year were retrospectively identified. Outcomes were lower limb ischemic symptoms, carotid intima/media thickness (IMT), and cardiovascular events. Patients reported visual analog scale scores for major symptoms at baseline and after 3, 6, and 12 months of treatment.. Overall, 188 patients (mean age 70.8 ± 10.15 years, Fontaine classification: grade I 14.4%, grade II 85.6%) treated with beraprost for 2.4-10.7 years (mean 6.5 years) were included in this study. Administration of beraprost significantly reduced patient-reported severity of lower limb ischemic symptoms in all patients at 12 months, including those with diabetes, hypertension, or dyslipidemia. IMT decreased from 1.09 ± 0.09 mm at baseline to 1.04 ± 0.11 mm at 12 months (P < 0.001). Decreases in IMT were similar in patients with diabetes, hypertension, or dyslipidemia. Overall, 26 (13.8%) events occurred during a mean follow-up of 6.5 years, including 23 cardiovascular events (unstable angina in three patients, myocardial infarction in six patients, cerebral infarction in eight patients, and transient cerebral ischemic attack in six patients) and non-cardiovascular death in three patients. Beraprost at 120 μg/day significantly reduced the risk of ischemic symptoms compared with <120 μg/day (adjusted hazard ratio: 0.17; 95% confidence interval: 0.06, 0.45; P < 0.001). No severe adverse events or adverse events requiring dose reductions/discontinuation occurred during long-term administration of beraprost.. Beraprost reduced lower limb ischemic symptoms, IMT, and the incidence of cardiovascular events in patients with ASO.

Topics: Aged; Aged, 80 and over; Arteriosclerosis Obliterans; Carotid Intima-Media Thickness; Epoprostenol; Female; Humans; Intermittent Claudication; Japan; Male; Middle Aged; Quality of Life; Retrospective Studies; Treatment Outcome; Vasodilator Agents

Although conventional bypass grafting is commonly used to treat ischemia in lower extremities, graft failure often occurs. This study retrospectively analyzed the factors that affect graft patency to help establish more effective treatment of obstructive arterial disease of the lower limbs. Kaplan-Meier analysis was used to estimate graft patency in 90 legs of 80 patients who underwent femoropopliteal bypass (28 vein grafts and 62 expanded polytetrafluoroethylene grafts) between 1984 and 2003. Patients were randomly selected for graft materials in sequential surgical treatment order. After initial analysis, several risk factors and postoperative medication regimens were analyzed to ascertain any association with graft failure. The overall mean patency period for femoropopliteal bypass was 10.5 +/- 0.7 years. Graft occlusion occurred in 20 limbs. Neither the materials composing the grafts nor the position of distal anastmosis had any influence on patency maintenance. Graft occlusion rates were significantly greater in patients with either diabetes (p = 0.0049) or rest pain before surgery (p = 0.0011). Postoperative administration of beraprost sodium significantly increased the patency period (p = 0.0082). Diabetes and rest pain before surgery are important factors for late graft failure after femoropopliteal bypass. Our data also suggest that administration of beraprost sodium increases the graft patency period.

Topics: Aged; Arteriosclerosis Obliterans; Blood Vessel Prosthesis Implantation; Diabetic Angiopathies; Epoprostenol; Female; Femoral Artery; Graft Occlusion, Vascular; Humans; Leg; Male; Middle Aged; Platelet Aggregation Inhibitors; Popliteal Artery; Postoperative Period; Retrospective Studies; Vascular Patency

1. The effect of the potassium channel opener KRN4884 on the peripheral arterial occlusion model induced by laurate was examined and compared with that of beraprost sodium and nilvadipine. 2. KRN4884 or beraprost sodium prevented macroscopic changes in the paw after the injection of laurate. In contrast, nilvadipine did not improve the lesions. 3. KRN4884 produced a dose-dependent increase in gastrocnemius blood flow in the chronic femoral artery-ligated rats. The effect of KRN4884 on the blood flow was stronger in the hypoxic muscle than in the normal muscle. 4. KRN4884 did not have a direct antiplatelet aggregation activity. 5. These findings suggest that KRN4884 is useful for the therapy of peripheral arterial occlusive disease and that the effect of KRN4884 is associated with an increase in blood flow in ischemic skeletal muscle.

Topics: Animals; Arterial Occlusive Diseases; Arteriosclerosis Obliterans; Constriction; Disease Models, Animal; Epoprostenol; Femoral Artery; Male; Muscle, Skeletal; Potassium Channels; Pyridines; Rats; Rats, Wistar; Regional Blood Flow; Thromboangiitis Obliterans