beraprost and Chronic-Disease

Epoprostenol and the structurally related compounds treprostinil, iloprost, and beraprost are collectively referred to as prostanoids. The discovery of epoprostenol in 1976 and unequivocal demonstration of its efficacy in 1996 dramatically altered the approach to therapy for pulmonary arterial hypertension (PAH). Development of prostanoids available through multiple routes of administration and the discovery and development of other agents acting through alternative pathways continue to expand the array of therapeutic options. The use of prostanoids in combination with other PAH drugs and for treating pulmonary hypertensive disorders outside of the PAH classification are areas of ongoing research.

Topics: Antihypertensive Agents; Chronic Disease; Epoprostenol; Heart Defects, Congenital; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Prostaglandins; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome

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

To evaluate the clinical efficacy and safety of sequential treatment with alprostadil and beraprost sodium for chronic renal failure caused by chronic glomerulonephritis.. Sixty-three patients with chronic renal failure due to chronic glomerulonephritis, after receiving a 2-week-long conventional treatment, were randomly divided into alprostadil group (n=20, with alprostadil injection at 10 µg/d for 2 weeks), sequential treatment group (n=21, with alprostadil injection at 10 µg/d for 2 weeks and oral beraprost sodium at 20 µg three times a day for 12 weeks), and strengthened sequential treatment group (n=22, with alprostadil injection at 20 µg/d for 2 weeks and a double dose of oral beraprost sodium for 12 weeks). Urinary albumin excretion rate (UAER), cystatin C (Cys C), blood urea nitrogen, creatinine, fibrinogen, D-dimer, prothrombin time (PT), and platelets were tested before and after the treatment, and the changes in urinary albumin discharge rate, serum creatinine, and glomerular filtration rate were determined.. The patients in strengthened sequential treatment group showed a significantly decreased change rate of urinary albumin discharge rate (P<0.01) than those in the other two groups. In the two sequential treatment groups, especially the strengthened treatment group, the change rate of glomerular filtration rate increased significantly compared with that in alprostadil group (P<0.01). Strengthened sequential treatment resulted also in significantly decreased increment of serum creatinine compared that in the other 2 groups (P<0.01). After 14 weeks of treatment, fibrinogen and D-dimer were decreased in all the 3 groups (P<0.05) to a comparable level between the 3 groups (P>0.05), and prothrombin time (PT) or platelet showed no significant changes (P>0.05).. Sequential treatment with alprostadil and beraprost sodium can improve the glomerular filtration rate and decrease urine albumin excretion rate, serum creatinine increase rate, and lower blood fibrinogen and D-dimer levels, thus delaying the progression of chronic renal failure caused by chronic glomerulonephritis. This therapy shows a dose-related effect with good clinical safety.

Topics: Adolescent; Adult; Aged; Alprostadil; Blood Urea Nitrogen; Chronic Disease; Creatinine; Drug Therapy, Combination; Epoprostenol; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Glomerular Filtration Rate; Glomerulonephritis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Prothrombin Time; Urological Agents; Young Adult

Distal-type chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease for which a new therapeutic strategy needs to be developed. We examined the effects of percutaneous transluminal pulmonary angioplasty (PTPA).. We prospectively enrolled 12 patients with distal-type CTEPH. After stabilizing their condition with pulmonary vasodilators, we then performed PTPA, which markedly improved pulmonary hemodynamics and pulmonary artery structure, as confirmed by angiography and optical coherence tomography, and also significantly improved their long-term prognosis compared with 39 historical controls.. PTPA is a promising therapeutic option for distal-type CTEPH.

Topics: Aged; Angioplasty; Antihypertensive Agents; Bosentan; Chronic Disease; Combined Modality Therapy; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Prognosis; Prospective Studies; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

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.

Topics: Administration, Oral; Chronic Disease; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Embolism; Vasodilator Agents

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

Prostanoids are a well-established therapy for pulmonary arterial hypertension (PAH), and observational studies suggest their efficacy even in chronic thromboembolic pulmonary hypertension (CTEPH) patients.. To compare the effects of 6 months of treatment with beraprost, an orally-active prostacyclin analog, in patients with distal CTEPH and PAH.. Case-control study.. Sixteen patients with severe pulmonary hypertension (NYHA II-IV), eight with distal CTEPH matched with eight patients with idiopathic PAH for similar effort tolerance.. All patients were in stable clinical and hemodynamic condition for 3 months with maximal standard therapy. During the titration phase (4 weeks) beraprost was increased to maximal tolerated dose (mean daily dosage: CTEPH 275 +/- 47 microg, PAH 277 +/- 47 microg) in adjunction of standard therapy, patients were followed-up for 6 months.. World Heart Organization (WHO) functional class, exercise capacity measured by distance walked in 6 min, and systolic pulmonary pressure (echocardiography), were evaluated at baseline, and at 1-, 3- and 6-month interval.. At 6 months WHO class decreased significantly in both groups (CTEPH from 2.7 +/- 0.6 to 2.0 +/- 0.24, p < 0.05; PAH from 3.0 +/- 0.26 to 2.1 +/- 0.25, p < 0.05), similarly the 6-min walk distance increased significantly from baseline (CTEPH from 312 +/- 31 to 373 +/- 29 m, p < 0.003; PAH from 303 +/- 31 to 347 +/- 29, p < 0.0003). Systolic pulmonary artery pressure showed a trend toward lower value (CTEPH from 85 +/- 7 m to 81 +/- 6 mm Hg, p = NS; PAH from 89 +/- 7 to 82 +/- 5, p = NS). During the observation period we did not have any death. The drug was well-tolerated with minor side-effects.. In patients with CTEPH beraprost had similar mid-term clinical and hemodynamic improvements than in patients with PAH.

Topics: Adult; Case-Control Studies; Chronic Disease; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Thromboembolism; Treatment Outcome

The inhibition of prostaglandin (PG) synthesis is at the center of current anti-inflammatory therapies. Because cyclooxygenase-2 (COX-2) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of multiple PGs, there is currently a strong focus on characterizing the role of the different PGs in the inflammation process and development of arthritis. Evidence to date suggests that both PGE(2) and PGI(2) act as mediators of pain and inflammation. Most of the data indicating a role for PGI(2) in this context have been generated in animal models of acute pain. Herein, we describe the role of PGI(2) in models of osteoarthritis (OA) and rheumatoid arthritis using a highly selective PGI(2) receptor (IP, Ptgir) antagonist and IP receptor-deficient mice. In the rat OA model using monoiodoacetate injection into the knee joint, the IP antagonist reduced pain with an efficacy approaching that of the NSAID diclofenac. In a chronic model of inflammatory arthritis, collagen-antibody induced arthritis model in mice, IP receptor-deficient mice displayed a 91% reduction in arthritis score. Interestingly, pretreatment with the IP [N-[4-(imidazolidin-2-ylideneamino)-benzyl]-4-methoxy-benzamide] antagonist in this model also caused a significant reduction of the symptoms, whereas administration of the compound after the initiation of arthritis had no detectable effect. Our data indicate that, in addition to its role in acute inflammation, PGI(2) is involved in the development of chronic inflammation. The results also suggest that the inhibition of PGI(2) synthesis by NSAIDs and COX-2 inhibitors, in addition to that of PGE(2), contributes to their efficacy in treating the signs of arthritis.

Topics: Animals; Arthritis, Experimental; Carrageenan; Chromatography, High Pressure Liquid; Chronic Disease; Collagen; Cyclooxygenase 2 Inhibitors; Edema; Epoprostenol; Hot Temperature; Hyperalgesia; Inflammation; Iodoacetates; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoarthritis; Ovalbumin; Pain; Prostaglandins I; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol

Inhaled PGI2 has been reported to elicit pulmonary vasodilation, but whether it is also effective in treating chronic hypoxic pulmonary hypertension is still uncertain. We designed this study to address the in vivo effectiveness of inhaled Beraprost, a stable PGI2 analogue, on pulmonary vascular tone during hypoxic exposure in normoxic (N) and chronically hypoxic (CH) rats. Pulmonary vasodilation was observed by low-dose inhaled Beraprost in N rats, but not in CH rats. It was not until higher doses of Beraprost were given that pulmonary vasodilation was obtained in CH rats. When the agent was continuously administered by an intravascular route at the inhaled dose, it elicited no vasodilation in N rats. On the contrary, it elicited profound vasodilation in CH rats, although a concomitant systemic hypotension was observed. The PGI2 receptor mRNA expression was unchanged in the lungs of CH rats compared with that of N rats. We conclude that low doses of aerosolized Beraprost may reduce pulmonary vascular tone in rats without preexisting lung diseases. In contrast, when hypoxic pulmonary hypertension is present, the threshold of Beraprost inhalation was elevated to provoke pulmonary vasodilation.

Topics: Administration, Inhalation; Animals; Chronic Disease; Epoprostenol; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol; Receptors, Prostaglandin; RNA, Messenger

Changes in blood flow after chronic compression were observed in 19 dogs after 10 mmHg compression for 1 week before and 1 hour after the intravenous administration of one of three doses of beraprost sodium (BPS; 30 ng x kg(-1) x min(-1), n = 7; 100 ng x kg(-1) x min(-1), n = 7; and 300 ng x kg(-1) x min(-1), n = 5). The speed of blood flow was calculated using a specially designed microscope equipped with a video camera. Dogs treated with BPS had lesser degrees of reduction in their nerve conduction velocity compared with controls. A vascular mechanism of injury likely explains why BPS-treated dogs had a lesser degree of reduction in their nerve conduction velocities compared with the control population.

Topics: Animals; Blood Flow Velocity; Cauda Equina; Chronic Disease; Dogs; Epoprostenol; Neural Conduction; Reference Values; Regional Blood Flow; Spinal Cord Compression; Time Factors; Vasodilator Agents