Prostacyclin analogs were the first class of drugs to be marketed for targeted treatment of pulmonary hypertension, and landmark changes in the poor prognosis of patients with pulmonary hypertension. These include intravenous epoprostenol (Epoprostenol), subcutaneous travoprost (Treprostinil), inhaled iloprost (Iloprost), and oral beraprost (Beraprost). Currently, all prostacyclin drugs require intravenous injection, subcutaneous injection or nebulized inhalation, except for Beraprost, which is administered orally. However, the hemodynamic performance of beraprost has been unsatisfactory due to absorption, steady-state time, and half-life. Currently, beprost is approved for the treatment of pulmonary hypertension in Japan and Korea. In this article, we review the history of research on beprostol. PGI2 is a metabolite of arachidonic acid released from membrane phospholipids and is mainly produced by vascular endothelial cells. PGI2 also inhibits collagen synthesis in vascular smooth muscle cells and lung fibroblasts. PGI2 is hydrolyzed to inactive 6-keto-PGF1α in normal pH and has a half-life of about 6 min in humans (37oC, pH 7.4). The plasma clearance of PGI2 after intravenous injection is high (93 ml/min/kg), with a small volume of distribution (357 ml/kg) and a short plasma half-life (2 min).1 Bepridocycline sodium is the first orally active prostacyclin analog. It is rapidly absorbed in fasting, reaches peak concentration after 30 min, and has a clearance half-life of 35-40 min2. II. Experimental studies Tanonaka3 et al. placed rabbits’ hearts in hypoxia for 20 min and then restored them for 45 min, and observed the cardiac function and metabolic changes in two groups of rabbits with and without beprostol under hypoxia. The results showed that the myocardium of the beprostatin-treated group significantly inhibited the increase in tissue calcium and reduced the production of creatine kinase and ATP metabolites under hypoxia. Beprost is beneficial for the recovery of myocardial function and metabolism after hypoxia. Tamaoki4 et al. studied the dog airway and found that beraprost not only effectively diaped airway smooth muscle by increasing cAMP production and stimulating Na+-K+ATPase, but also reduced the neurally mediated contractile effect by inhibiting the release of acetylcholine from cholinergic nerve endings. Saito5 et al. administered beraprost to chronically hypoxic and normoxic mice separately and showed that beraprost caused pulmonary vasodilation in both groups, but the vasodilatory effect was more sustained in the hypoxic group. Miyata et al6 administered oral beprostin to rats with wild lily soda-induced pulmonary hypertension and found that beprostin not only had pulmonary vasodilating and anti-platelet aggregation effects, but also reduced the production of inflammatory factors such as IL-1, IL-6 and TNF, effectively reducing the progression of the disease in PAH rats. inotropic effect, and its action was associated with TXA2 receptor mediation. Kaneshige et al8 found that beprost inhibited myocardial fibrosis in the endomyocardial layer of the ventricular myocardium thereby slowing down myocardial hypertrophy due to hypertension. Long-term use of beprost may maintain myocardial diastolic function and prevent myocardial interstitial fibrosis. Recent studies have also found that beraprost induces nitric oxide production and phosphorylation of nitric oxide synthase, mediated by the cAMP/protein kinase A pathway at position 1179-serine phosphorylation. It also upregulated the expression of several genes including angiogenesis, anti-atherosclerosis and endothelial function and downregulated the expression of atherosclerotic genes.9 III. Clinical studies Beraprost was started in Japan in 1995 for the treatment of pulmonary hypertension. An open study with a small sample size10 showed that beprost improved the hemodynamics of idiopathic pulmonary arterial hypertension (IPAH), with most patients showing improved cardiac function and a 26% reduction in pulmonary vascular resistance after a 2-month follow-up.11 Nagaya et al. conducted a prospective, open study showing that 24 patients with IPAH on beprost had a 3 Vizza12 et al. followed up 13 patients with severe pulmonary hypertension with oral beraprost treatment for 12 months. The study found that after 1 month of treatment, the mean cardiac function class decreased from 3.4 to 2.9 (p < 0.05) and the 6-minute walking distance (6MWD) increased from 213 to 276 m (p < 0.05), with no significant difference in pulmonary artery systolic pressure. At 12 months follow-up, cardiac function, exercise tolerance, and pulmonary artery systolic pressure continued to improve in 11 patients. Two prospective, double-blind, placebo-controlled, multicenter clinical studies were conducted in Europe and the United States in 2002 and 2003, respectively, to investigate the efficacy and safety of beprostol in the treatment of pulmonary hypertension. 2002 Galie13 et al. conducted a 12-week prospective, double-blind, randomized, placebo-controlled study comparing 130 patients with class II-III cardiac function Pulmonary hypertension patients randomized to treatment with either beraprost or placebo. Mean 80ug qid treatment in the beprost group showed a significant increase in exercise tolerance, with a 25 m increase in 6MWD, including a more significant 45 m increase in IPAH patients, and a significant decrease in Borg respiratory score. However, there were no significant differences in hemodynamic parameters and survival rates between the two groups. Adverse reactions due to beraprost are mostly related to vasodilatation of the body circulation and usually occur at the beginning of the drug administration, which may gradually diminish and disappear. In 2003, Barst14 studied the therapeutic effects of oral beraprost on pulmonary hypertension. 116 patients with pulmonary hypertension were randomized to receive the maximum tolerated dose of beraprost and placebo for a period of 12 months. The results showed that 6MWD increased by 22 m at 3 months and 31 m at 6 months compared to baseline in the treatment group compared to the placebo group, but did not change at 9 or 12 months. 1-year survival did not differ significantly between the two groups. The results of this study suggest that the efficacy of beraprost in treating pulmonary hypertension may diminish with time. Based on the results of this study, no indications have been approved for the treatment of pulmonary hypertension with beprostol in Europe or the United States. In a controlled study completed by Ono15 in 2003, oral beprost was shown to be effective in reducing pulmonary artery pressure and total pulmonary resistance in patients with chronic thromboembolic pulmonary hypertension (CTEPH) compared to the conventional treatment group, but did not show an increase in cardiac output, with approximately 50% of beprost-treated patients having improved functional status. In 2006, Vizza16 et al. treated eight patients with CTEPH and eight patients with IPAH with oral beraprost, and after 6 months the patients' cardiac functional class improved, decreasing from 2.7±0.6 to 2.0±0.24 in the CTEPH group and from 3.0±0.26 to 2.1±0.25 in the IPAH group. 6MWD increased significantly from 312±31m to 373±29m in the CTEPH group and from 303±31m to 347±39m in the IPAH group. Due to its short half-life, beraprost sodium requires multiple doses, which may lead to unstable blood levels and affect patient compliance with the drug. The long-acting formulation of oral beraprost (TRK-100STP) is currently undergoing relevant clinical studies.17,18 Kunieda18 et al. conducted an open, multicenter study of TRK-100STP in the treatment of pulmonary hypertension. 46 patients with pulmonary hypertension were treated with oral TRK-100STP for 12 weeks and found a significant increase in 6MWD of 33.4 ±TRK-100STP is expected to be the new representative drug of the oral prostacyclin class. Combination therapy The combination of several studies mentioned above shows that the short-term efficacy of beraprost alone in the treatment of pulmonary hypertension is positive, but the long-term efficacy is poor. Combination therapy may take advantage of the different mechanisms of action of the drugs to maximize clinical utility. Ueno19 et al. reported the efficacy of endothelin A receptor antagonist TA-0201 combined with beraprost in the treatment of pulmonary hypertension in a group of mice. The study divided mice with wild lily soda-induced pulmonary hypertension (PH) into five groups: normal control group, placebo-treated PH group, TA-0201-treated group, beraprost-treated group, and combination-treated group. The results showed that right ventricular systolic pressure and right ventricular weight index were lower in the beraprost-treated and ET-A receptor antagonist groups than in the placebo-treated group, and the reduction was more pronounced in the combination-treated group. Therefore, combination therapy was superior to monotherapy. Itoh20 et al. reported the effect of sildenafil combined with beraprost in the treatment of pulmonary hypertension in a group of mice. The study randomly divided the mice into control group, sildenafil treated group, beraprost treated group and sildenafil combined with beraprost treated group, 10 mice in each group were treated for 3 weeks. The results showed that the right ventricular systolic pressure, right ventricular weight index, and ventricular wall thickening rates were significantly lower in the combination treatment group than in the monotherapy group. 6 weeks later, the survival rates of mice in the sildenafil, beraprost, and combination treatment groups were significantly higher, 30% in the control group, 90% in the sildenafil group, 80% in the beraprost group, and 100% in the combination treatment group. Sildenafil dilates the pulmonary vasculature by increasing endothelial cGMP, while beraprost dilates the pulmonary vasculature by increasing cAMP. And it was found that the combination of both drugs increased intracellular cGMP levels more than sildenafil alone and increased intracellular cAMP levels more than beraprost alone. Thus the two drugs synergistically reduced dilated pulmonary vasculature and treated pulmonary hypertension. Ikeda21 et al. observed hemodynamic changes in six patients with moderate to severe pulmonary hypertension with oral beraprost and oral beraprost and sildenafil in the immediate post-dose period. Hemodynamic parameters showed a significant reduction in mean pulmonary artery pressure and pulmonary vascular resistance in the combination group compared to the beprost alone group, and the reduction in these parameters lasted longer with the combination therapy than with beprost alone. Case reports of successful treatment of severe pulmonary hypertension with beprostol in combination with sildenafil are not uncommon22-24 , but there is a lack of large-scale clinical trials to confirm its long-term efficacy and safety. V. CONCLUSION Beprost is an orally active prostacyclin analogue that may improve exercise tolerance with short-term use but has poor long-term efficacy. It may improve prognosis in patients with CTEPH. Combination therapy is expected to be an effective, safe and economical treatment option.