Beraprost
Beraprost (Kaken’s Procylin, Yamanouchi’s Dorner) was the first orally active prostacyclin analogue to reach the market. It has been used to treat pulmonary arterial hypertension in Japan since 1995, but it is not licensed in the United States or Europe. Toray manufactures the agent under the brand name Dorner to treat peripheral arterial disease (PAD). Beraprost is rapidly absorbed and has a half-life of 35-40 minutes. It mediates vasodilation and inhibition of platelet activation via the mechanism of action previously outlined for prostacyclin analogues.
Two large, randomized, double-blind, placebo-controlled studies investigated the effects of beraprost therapy in pulmonary arterial hypertension patients. The first involved 130 pulmonary arterial hypertension patients randomized to receive beraprost (80 micrograms four times daily) or placebo for 12 weeks. The primary end point was the 6MWD. Results showed that patients treated with beraprost demonstrated an improvement in exercise capacity and symptoms. The difference in the 6MWD was 25.1 m between the beraprost and placebo groups (95% confidence interval = 1.8-48.3; p = 0.036) and 45 m for the patients with pulmonary arterial hypertension. Hemodynamics showed no statistically significant change, and there was no change in survival benefit in either group.
The second study involved 116 pulmonary arterial hypertension (pulmonary arterial hypertension and pulmonary arterial hypertension associated with connective tissue disease or congenital heart defects) patients considered NYHA classes III and IV. The median dose of beraprost was 120 micrograms four times daily, and the follow-up period was 12 months. This study’s primary end point was disease progression (death, need for transplantation, epoprostenol rescue, or a greater than 25% reduction in peak oxygen consumption). Results showed that patients treated with beraprost exhibited less evidence of disease progression at six months (p = 0.002), although this effect was not evident at either shorter or longer follow-up intervals. The 6MWD improved at 3 months (22 m improvement) and 6 months (31m improvement) when compared with placebo but not at 9 or 12 months.
These results are disappointing given that an earlier, small study involving 24 pulmonary arterial hypertension patients showed an improvement in three-year survival on treatment with beraprost (76% survived) compared with patients receiving conventional therapy for pulmonary arterial hypertension (44% survived).
Side effects experienced with beraprost were related to systemic vasodilation; they were particularly frequent during the study’s dose-finding stage.
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