Beraprost

Beraprost sodium (beraprost) is a stable, orally active prostacyclin analogue with vasodilatory, antiplatelet and cytoprotective effects. Beraprost acts by binding to prostacyclin membrane receptors ultimately inhibiting the release of Ca²⁺ from intracellular storage sites. This reduction in the influx of Ca²⁺has been postulated to cause relaxation of the smooth muscle cells and vasodilation.

Data from a large, randomised, double-blind, multicentre study indicated that beraprost was as efficacious as ticlopidine in the treatment of patients with peripheral arterial disease (Buerger’s disease and arteriosclerosis obliterans). Most patients receiving beraprost exhibited reduction of ulcer size, reported improvement of granulation appearance of the tissue and showed improvement of pain at rest and sensation of cold in the extremities.

In a large pivotal clinical trial in patients with intermittent claudication, beraprost treatment was associated with statistically significant increases in pain-free and absolute walking distances compared with those in patients receiving placebo. Statistically significant differences in the incidence of critical cardiovascular events among both treatment groups were not observed but patients receiving beraprost were more likely to be satisfied with changes in their quality of life. However, while preliminary unpublished data from a large, phase III, placebo-controlled study in the US suggested a trend toward fewer critical cardiovascular events (no specific data presented), this study did not confirm the positive results from the European phase III trial and statistical significance was not achieved in the study’s endpoints relating to exercise.

A series of small, noncomparative clinical trials of patients with the rare condition of pulmonary arterial hypertension (PAH) demonstrated that substantial reductions of pulmonary arterial pressure and resistance, increase of cardiac output, and increase of exercise capacity appeared to be associated with beraprost therapy; however, these data are very limited and in most instances are not fully published.

Beraprost is a well tolerated agent. Overall, the main adverse events include headache, hot flushes, diarrhoea and nausea. However, patients with PAH showed higher incidence of adverse events than those with peripheral arterial disease.

Conclusion: Beraprost, an orally administered PGI₂ analogue, is generally well tolerated and appears to be an effective agent in the treatment of patients with Buerger’s disease and arteriosclerosis obliterans. Comparative data from a large randomised trial indicated that the drug appears as effective as ticlopidine in patients with these conditions. In patients with intermittent claudication, significant benefits of beraprost compared with placebo were reported in a randomised clinical trial; however, the use of beraprost in these patients is not supported by recent preliminary unpublished data from a large, phase III, placebo-controlled study. Limited data suggest some efficacy with long-term beraprost treatment of patients with PAH, where options are few and where oral administration of the drug could be a considerable advantage over intravenous prosta-cyclin (PGI₂) therapy. Additional well-designed and, where possible, large trials with active comparators are necessary to define more precisely the place of beraprost in the treatment of patients with PAH, Buerger’s disease and arteriosclerosis obliterans.

Beraprost sodium (beraprost) is a stable, orally active prostacyclin (PGI₂) analogue with pharmacodynamic properties similar to those of PGI₂. The mechanisms of action of beraprost are currently under investigation and are likely to involve relaxation of vascular smooth cells, inhibition of platelet aggregation, dispersion of existing platelet aggregates, inhibition of chemotaxis and cell proliferation and cytoprotective effects.

Beraprost binds to PGI₂ membrane receptors linked to adenylate cyclase which induces the production of cyclic adenosine and guanosine monophosphates (cAMP and cGMP, respectively). It has been postulated that this effect of beraprost on cAMP and cGMP inhibits the release of Ca₂₊ from intracellular storage sites reducing the transmembrane influx of Ca₂₊. This reduction is believed to cause relaxation of the smooth muscle cells and to induce vasodilation.

Beraprost exhibited strong antiplatelet action in vitro and in animal and human studies. In vitro, this effect was present in human, rabbit, guinea-pig, rat, dog and cat platelet rich plasma and was between 0.2 and 0.5 as potent as that of PGI₂. In animal models, beraprost improved arterial lesions induced by sodium laureate. In humans, multiple doses of beraprost appeared to inhibit platelet aggregation caused by adenosine diphosphate, collagen and epinephrine.

In animal models, beraprost significantly inhibited the formation of fibrinous thrombosis, perivascularity, fibrosis and thinning of the arterial wall and increased blood flow in electrically occluded arteries. This antithrombotic effect of beraprost was 700- and 2700-fold more potent than that of ticlopidine and cilostazol, respectively. In humans, beraprost is associated with reductions of pulmonary arterial pressure and resistance and with increases of cardiac output. Beraprost also produced vasodilation in different arterial beds in animal studies via a mechanism similar to that of PGI₂ and improved red blood cell deformability in vitro and in vivo.

In vitro, beraprost inhibited the production of the cytokines interleukin-1, interleukin-6 and tumour necrosis factor in alveolar macrophages. Moreover, beraprost inhibited in a dose-dependent manner the production of cytotoxic oxygen metabolites responsible for endothelial cell damage and reduction of endogenous PGI₂ production.

In human studies, administration of single or multiple doses of beraprost produced peak plasma concentrations (C_max) of the unchanged drug within 30 to 60 minutes. C_max and area under the concentration curve (AUC) values ranging from 53 to 345 ng/L and 46.7 to 455.4 μg/L · h, respectively, were obtained after beraprost administration to healthy volunteers. Moreover, accumulation of beraprost and its metabolites was not observed after repeated administration. In animal studies, beraprost was primarily detected in the liver, kidney and gastrointestinal tract and to a lesser extent in the lung, blood and heart. Beraprost was excreted mainly as its main metabolite (free acid 2,3-dino-beraprost), rapidly (<72 hours) and through the faeces (73 to 82%) and urine (13 to 15%).

Data from a large (n = 422), randomised, double-blind, placebo-controlled, multicentre study of patients with intermittent claudication indicated that at treatment endpoint (6 months) more patients receiving beraprost showed an improvement of >50% in pain-free walking distance (91 vs 71, p < 0.05). Also, patients receiving beraprost showed a greater increase from baseline of pain-free (81.5 vs 52.5%, p < 0.01) and absolute walking distance (60.1 vs 35%, p < 0.01) although, a comparable incidence of critical cardiovascular events (4.8 vs 8.9%; all comparisons vs placebo). However, patients in the beraprost group were more likely to be satisfied with changes in their quality of life (p < 0.05). It is important to note, however, that recent preliminary unpublished data from a large (n ≈ 750), phase III, placebo-controlled study do not support the use of beraprost in patients with intermittent claudication.

Beraprost is generally a well tolerated agent. Combined data of 7515 patients with peripheral arterial disease indicated that adverse reactions were reported in 4.9% of patients. The main adverse events (incidence ≤1.2% in each case) were headache, facial hot flushes, hot flushes, diarrhoea and nausea. In a placebo-controlled clinical trial of patients with intermittent claudication (n = 422), the incidence of adverse events in beraprost recipients was 16.7%, with headache (6.2%) and vasodilation (5.3%) being the most commonly reported adverse events. In this study, 8.6 and 14.5% of patients receiving beraprost and placebo, respectively, discontinued treatment.

Combined data from clinical studies in patients with pulmonary arterial hypertension receiving beraprost therapy showed a higher incidence (60% of patients) of adverse events than in patients with peripheral arterial disease, although tolerability data are only available for 40 patients. Headache (22.5%), increased lactate dehydrogenase (12.5%), increased bilirubin (10%), hot flushes, diarrhoea, nausea and increased triglycerides (all 7.5%) were the most commonly reported adverse events.

The dosage recommendations outlined in this section focus on the use of beraprost in Japan, South Korea, The Philippines and Thailand, where beraprost has been approved for use in patients with peripheral arterial disease and pulmonary arterial hypertension (not approved for pulmonary arterial hypertension in The Philippines).

Beraprost is administered orally and should be taken after meals. In adult patients with peripheral arterial diseases beraprost 40μg three times a day is usually recommended. For adult patients with pulmonary arterial hypertension beraprost treatment starts at 60μg a day divided in three doses and can be increased gradually under careful observation up to a maximum of 180μg daily divided in three or four doses. However, in a recent 12-week clinical trial patients were administered higher beraprost dosages. In elderly patients beraprost should be prescribed with caution and it should be administered to pregnant women only if therapeutic benefits outweigh the risk of beraprost treatment. Beraprost is con-traindicated in nursing women and its safety has not been defined in children.

Beraprost should be administered with care in patients receiving anticoagulant, antiplatelet or fibrinolytic agents and may also increase bleeding in menstruating patients or those with bleeding tendency. In combination with other PGI₂ preparations, beraprost may further reduce blood pressure.