beraprost and Arterial-Occlusive-Diseases

Beraprost sodium (BPS) is a stable orally active prostacyclin analogue with vasodilatory and anti-platelet effects, and has been widely used as therapeutics for pulmonary artery hypertension and chronic arterial obstruction. In order to elucidate its effects on endothelium, we first examined the short-term effects of BPS on nitric oxide (NO) production and endothelial NO synthase (eNOS) activation using bovine aortic endothelial cells. Short-term treatment of BPS induced NO production as well as eNOS phosphorylation at Ser-1179 mediated via cAMP/protein kinase A (PKA) pathway. The effects of BPS on capillary-like tube formation were next determined using human umbilical vein ECs (HUVECs)/normal human dermal fibroblasts co-culture system. BPS was observed to induce capillary-like tube formation mediated via cAMP/PKA pathway, but not via NO generation. Finally, we performed DNA microarray analyses using RNA extracted from BPS treated HUVECs. Interestingly, BPS up-regulated several genes involved in angiogenesis, anti-atherosclerosis, and endothelial function, while down-regulated several genes involved in atherosclerosis. Our data therefore indicate that BPS may be useful not only for patients with pulmonary artery hypertension and chronic arterial obstruction, but also for general atherosclerotic patients complicated with endothelial dysfunction. Further studies are needed to clarify molecular mechanisms of these BPS effects including the involvement of peroxisome proliferator-activated receptor-delta.

Topics: Animals; Arterial Occlusive Diseases; Atherosclerosis; Cardiovascular Diseases; Endothelium, Vascular; Epoprostenol; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Neovascularization, Physiologic; Nitric Oxide; Nitric Oxide Synthase Type III; Platelet Aggregation Inhibitors; Signal Transduction; Vasodilator Agents

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.

Topics: Administration, Oral; Animals; Arterial Occlusive Diseases; Chronic Disease; Clinical Trials as Topic; Epoprostenol; Humans; Hypertension, Pulmonary; Platelet Aggregation Inhibitors; Vasodilator Agents

Selective right pulmonary arteriography and 3-dimensional computed tomography revealed multiple severe stenoses of the peripheral pulmonary artery associated with poststenotic aneurysms in a 65-year-old woman. She was referred to the hospital for evaluation of dry cough, gradually increasing dyspnea and multiple nodular shadows on a chest radiograph. Echocardiography and cardiac catheterization showed severe pulmonary hypertension, though other structural heart diseases or well-characterized congenital syndromes were ruled out. She was diagnosed as isolated peripheral pulmonary artery branch stenosis. Recent advances in CT technology enable a less-invasive assessment of pulmonary artery, and can be useful in the management of pulmonary arterial hypertension.

Topics: Aged; Aneurysm; Arterial Occlusive Diseases; Cardiac Catheterization; Constriction, Pathologic; Cough; Dyspnea; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Imaging, Three-Dimensional; Oxygen Inhalation Therapy; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Ultrasonography; Vasodilator Agents; Warfarin

Beraprost sodium (BPS), a chemically stable and orally active prostacyclin analogue used for the treatment of chronic occlusive disease and primary pulmonary hypertension, was investigated in terms of its drug-drug interaction mediated by cytochrome P450. In a metabolic enzyme characterization study using P450-expressing insect cell microsomes, beraprost (BP) was slightly metabolized in the presence of CYP2C8, but not metabolized by the other P450 isoforms (CYP1A2, [corrected] CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A11) at a concentration of 20 microM. These results suggest that none of the P450 isoforms is a major metabolic enzyme of BP. In a P450 induction study using human hepatocytes, BP did not induce any P450 isoform (CYP1A2, CYP2C9, CYP2C19, and CYP3A4) at concentrations of 1-100 microM. Furthermore, in a P450 inhibition study using human liver microsomes, BP did not inhibit any P450 isoform (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations of 0.05-1 microM. Therefore it is concluded that BP is not involved in drug-drug interaction mediated by P450 isoforms.

Topics: Antihypertensive Agents; Arterial Occlusive Diseases; Chronic Disease; Cytochrome P-450 Enzyme System; Drug Interactions; Epoprostenol; Humans; Hypertension, Pulmonary; In Vitro Techniques; Isoenzymes; Microsomes, Liver; Platelet Aggregation Inhibitors

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.

Topics: Animals; Arterial Occlusive Diseases; Epoprostenol; Femoral Artery; Intermittent Claudication; Male; Rats; Rats, Wistar; Regional Blood Flow; Walking

A 20-year-old woman was admitted with increasing breathlessness on exertion. A diagnosis of isolated peripheral pulmonary artery stenosis (PPS) was confirmed by right-sided cardiac catheterization and pulmonary angiography. We tried treatment with a newly developed oral prostacyclin analogue, beraprost sodium. Her symptoms gradually improved 1 month after treatment. After 1 year, we observed a decrease in pulmonary arterial pressure (from 118/16 [mean 59] to 87/13 [mean 40] mmHg) and systolic right ventricular pressure (from 125 to 90 mmHg). This is the first report to describe the chronic effect of oral prostacyclin analogue on isolated peripheral pulmonary artery stenosis.

Topics: Adult; Arterial Occlusive Diseases; Blood Pressure; Epoprostenol; Female; Humans; Pulmonary Artery; Radiography; Treatment Outcome; Vasodilator Agents

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

Intimal thickening and luminal narrowing of the coronary arteries are insidious complications of cardiac allograft. However, the pathogenesis of cardiac allograft vasculopathy (CAV) remains to be clarified. In this study, the protective effect of a prostacyclin analogue (beraprost sodium; BPS) on CAV was evaluated after heterotopic cardiac transplantation in rat. All recipients were treated with cyclosporine A (10 mg/kg/day intramuscularly). Eight rats received oral therapy with BPS of 50 micrograms/kg/day (BPS group) and another 8 rats received vehicle only (control group). All surviving cardiac grafts were removed on the 60th postoperative day and were examined to determine the severities of cellular rejection and CAV (> 50 microns in diameter). Additionally, 6-keto-prostagrandin F1 alpha and thromboxane B2 were compared between the two groups. There was no significant difference in the grading score for cellular rejection based on the ISHLT grading system (2.31 +/- 0.75 vs 2.47 +/- 0.65, p = 0.81). Although the endothelial cells were preserved in both groups, a deposition of fibrin-like dense materials was recognized in the subendothelial layers of the control group, but not in the BPS group. Intimal thickening was inhibited significantly in the BPS group. The intimal ratio (intimal area/sectional area of artery) was significantly lower in the BPS group than in the control group (0.134 +/- 0.03 vs 0.205 +/- 0.047; p < 0.01), without any difference in the medial ratio (medial area/sectional area of artery). alpha-actin positive smooth muscle cells (SMC) in intima were fewer in number in the BPS group than in the control group. The plasma thromboxane B2 level was significantly lower in the BPS group than in the control group (270 +/- 116 pg/ml vs 585 +/- 258 pg/mg; p < 0.01). It was concluded that BPS suppressed CAV development after heterotopic allogenic cardiac transplantation in rats.

Topics: Animals; Arterial Occlusive Diseases; Coronary Vessels; Epoprostenol; Heart Transplantation; Male; Rats; Rats, Inbred Lew; Transplantation, Heterotopic; Transplantation, Homologous; Vasodilator Agents

Beraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2- hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H- cyclopenta[b]benzofuran-5-butyrate, TRK-100) is a chemically and biologically stable epoprostenol analogue which possesses both potent antiplatelet and peripheral vasodilating actions. Its effect on obstruction of the peripheral artery was studied in three different models: 1. acute thrombosis induced by electrical-stimulation of the femoral artery in rabbits, 2. occlusion induced by intra-arterial injection of sodium laurate in rats and 3. tail gangrene induced by subcutaneous injections of both ergotamine and epinephrine in rats. Oral administration of beraprost sodium resulted in suppression of thrombus formation in the acute thrombosis model, marked improvement of macroscopic and histological observations in the laurate-occlusion model and inhibition of tail gangrene extension. In contrast, ticlopidine improved thrombus formation in the acute thrombosis model and slightly improved histological observation in the laurate-occlusion model, but not in the tail gangrene model. Cilostazol suppressed lesions in the acute thrombosis model, but not in the tail gangrene model. These findings suggest that beraprost sodium may be very useful clinically for the therapy of peripheral circulation insufficiency diseases such as Buerger's disease and Raynaud's disease.

Topics: Acute Disease; Animals; Arterial Occlusive Diseases; Electric Stimulation; Epinephrine; Epoprostenol; Ergotamine; Female; Gangrene; Lauric Acids; Male; Platelet Aggregation Inhibitors; Rabbits; Rats; Rats, Inbred Strains; Regional Blood Flow; Tail; Thrombosis