Effect of beraprost sodium on pulmonaryvascular resistance in candidates for a Fontan procedure: A preliminarystudy

OBJECTIVE: Although long-term prostacyclin(PGI2) therapy in patients with severe pulmonary hypertension (PH)reduces pulmonary vascular resistance (PVR), there have been no reports on its therapeutic effects in patients with mild PH. We investigated the chronic effect of beraprost sodium (BPS), an oral PGI2 analog, in children with mild PH. METHODS: We studied 20 patients who were destined for a Fontan procedure with a mean pulmonary arterial pressure(PAP) of>20 mmHg and/or PVR of>3.0 Wood units. Both the PAP and the PVR in these cases were too high for patients to undergo a successful Fontan procedure. Seven patients received BPS (PG group) and 13 did not (control group). All patients underwent repeat cardiac catheterization to examine pulmonary hemodynamics. RESULTS: In the PG group, the pulmonary-to-systemic flow ratio (Qp/Qs) did not change after BPS administration(1.1 +/- 0.6 vs 1.3 +/- 0.9);however, the mean PAP decreased significantly (25.3 +/- 8.2 vs 19.9 +/- 6.5 mmHg; P < 0.05),as did PVR (3.7 +/- 1.3 vs 2.3 +/- 0.9 Wood units; P < 0.05), whereas the pulmonary artery (PA) index increased significantly (312 +/- 136 vs 375 +/- 165; P < 0.05). In the control group, the mean PAP decreased significantly (24.9 +/- 4.7 vs 19.8 +/- 6.3 mmHg; P < 0.05)and the PA index increased significantly (295 +/- 72 vs 362 +/- 114; P < 0.05). No significant changes in Qp/Qs (1.5 +/- 0.8 vs 1.4 +/- 0.6)or PVR (2.9 +/- 1.3 vs 2.5 +/- 0.8 Wood units) were observed. CONCLUSION: We conclude that long-term BPS administration probably reduces PVR in potential candidates for a Fontan procedure with mild PH. This treatment would reduce the risks associated with the Fontan procedure and would also improve its outcome.     

消渴保肾汤联合贝前列素钠治疗糖尿病肾病临床研究

目的：观察消渴保肾汤联合贝前列素钠治疗糖尿病肾病的临床疗效。方法：90例糖尿病肾病患者随机分为联合治疗组、贝前列素钠组、消渴保肾汤组,每组30例。贝前列素钠组采用贝前列素钠治疗;消渴保肾汤组采用消渴保肾汤治疗;联合治疗组采用贝前列素钠与消渴保肾汤联合治疗,3组治疗周期均为20周。比较治疗前后各组的24小时尿微量白蛋白、血清 C 反应蛋白（C-reactive protein,CRP）、肿瘤坏死因子-α（tumour necrosis factor-α,TNF-α）、血糖、糖化血红蛋白、血肌酐水平。结果：治疗前,3组之间的24小时尿微量白蛋白、血清 CRP 与 TNF-α比较,差异无统计学意义（P ＞0．05）;与治疗前比较,3组治疗后的24小时尿微量白蛋白、血清 CRP 与 TNF-α水平均显著降低,差异有统计学意义（P ＜0．05）;联合治疗组的24小时尿微量白蛋白、血清 CRP 与 TNF-α水平显著低于贝前列素钠组及消渴保肾汤组,差异有统计学意义（P ＜0．05）。治疗后,3组患者的血糖水平、糖化血红蛋白和血肌酐水平比较,差异无统计学意义（P ＞0．05）。结论：消渴保肾汤联合贝前列素钠治疗糖尿病肾病疗效较好,能够降低24小时尿微量白蛋白、血清 CRP 与 TNF-α水平,缓解糖尿病肾病患者微炎症反应。     

前列环素类药物治疗肺动脉高压的进展

研究显示前列环素减少和肺动脉高压的发生有关,前列环素类药物依前列醇、曲前列环素、贝前列环素、伊洛前列腺素均能降低肺动脉压力、肺血管阻力,增加心输出量、6min步行距离,同时无明显不良反应,从而改善肺动脉高压患者的症状和预后。     

Use of prostaglandin I2 analog in treatment of massive hepatic necrosis associated with endothelial cell injury and diffuse sinusoidal fibrin deposition

Endothelial cell damage causes massive hepatic necrosis as a result of fibrin deposition in the hepatic sinusoids. When a stable analog of prostaglandin I₂, beraprost sodium, was administered to rats given either dimethylnitrosamine, carbon tetrachloride, or endotoxin followingCorynebacterium parvum administration, the hepatic necrosis produced in each was attenuated, but to a greater extent in the dimethylnitrosamine and endotoxin/Corynebacterium parvum models, where fibrin deposition in the hepatic sinusoids occurs, as compared to the carbon tetrachloride model, where such fibrin deposition does not occur. Beraprost sodium reduced the expected increase of portal venous pressure in the endotoxin/Corynebacterium parvum model without affecting plasma thrombin-antithrombin III complex levels. Beraprost sodium also significantly reduced cell killing of both isolated rat hepatocytes and hepatic sinusoidal endothelial cells exposed totert-butyl hydroperoxide when compared to controls. Beraprost sodium could prove to be a therapeutic candidate for the treatment of hepatic necrosis, particularly in cases associated with fibrin deposition in the hepatic sinusoids because of its fibrin clot-clearning action.     

Effects of oral beraprost sodium, a prostaglandin I2 analogue, on endothelium dependent vasodilatation in the forearm of patients with coronary artery disease

1. Previous clinical studies with prostaglandin I(2) (PGI(2)) analogue beraprost sodium suggested the potential effects on protection of cardiovascular events in patients with peripheral artery disease. Although the mechanism is not well known, experimental studies have shown protective effects of endothelial cells. This study was designed to examine the effects of beraprost sodium on vascular endothelial function in the forearm of patients with coronary artery disease. 2. Beraprost sodium (120 microg/day) was orally administered to 14 coronary artery disease patients for 4 weeks and then stopped for 4 weeks. Eleven control patients did not receive beraprost sodium treatment. Reactive hyperemia was induced in the forearm, endothelium-dependent vasodilatation was assessed by plethysmography, and urinary 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) was measured at baseline, 4 weeks and 8 weeks. 3. Both groups had similar reactive hyperemic responses at baseline. In the control group, reactive hyperemic response and urinary 8-iso-PGF(2alpha) remained unchanged for 8 weeks. In the beraprost group, maximum forearm blood flow increased significantly (P = 0.01) after 4 weeks of treatment and returned to baseline at 8 weeks. Duration of hyperemia increased significantly (P = 0.003) after 4 weeks, and remained greater than baseline at 8 weeks (P = 0.02). Urinary 8-iso-PGF(2alpha) decreased significantly (P = 0.03) after 4 weeks, and tended to be lower at 8 weeks (P = 0.07). Changes in reactive hyperemia correlated weakly but significantly with changes in 8-iso-PGF(2alpha) (P < 0.001). 4. Beraprost sodium decreased oxidative stress and improved forearm endothelium-dependent vasodilatation in coronary artery disease patients. The favorable effects on vascular endothelium could potentially lead to a decrease in vascular events.     

贝前列素联合西地那非对COPD合并肺动脉高压的临床研究

目的 探究患有慢性阻塞性肺疾病(COPD)合并肺动脉高压的患者使用贝前列素与西地那非联合治疗方案的临床效果.方法 选取2014年6月至2015年12月收集住院的COPD合并肺动脉高压的患者80例,采用随机分组法分为对照组、贝前列素组、西地那非组、贝前列素与西地那非联合用药组,每组20例;对比分析4组患者接受治疗后1、3、6个月的治疗效果.结果 贝前列素组、西地那非组与联合治疗组患者经过治疗运动耐力显著提高,患者的血气分析、血液流变性指标、心肌酶指标、血浆脑钠素(BNP)、左心室射血分数(LVEF)、右心房压、左右心室大小、PAP、6 min步行距离、肺功能检查均有明显改善.结论 通过使用两种联合药物作用的疗效的评估,可以一定程度降低COPD合并肺动脉高压患者的发病次数,降低其病死率,提高生活质量,具有较好的社会经济效应.     

Neuroprotective properties of prostaglandin I2 IP receptor in focal cerebral ischemia

We and others have identified that inhibition of cyclooxygenase might not be the optimal approach to limiting brain damage after stroke. Now we are investigating the unique properties of the various prostaglandin receptors to determine whether blocking those that mediate toxicity or stimulating those that reduce toxicity will improve neurological outcomes. Here, we determined the respective contribution of the prostaglandin I₂ (PGI₂) receptor in transient middle cerebral artery (MCA) occlusion (tMCAO) and permanent MCAO (pMCAO) preclinical stroke models by using male wildtype (WT) and IP receptor knockout (IP^−/−) C57Bl/6 mice. In addition, we investigated the putative preventive and therapeutic effects of the IP receptor agonist beraprost. The infarct volumes and neurological deficit scores (NDS) were significantly greater in IP^−/− than in WT mice after both tMCAO and pMCAO. Interestingly, beraprost pretreatment (50 or 100 μg/kg p.o.) 30 min before tMCAO and post-treatment (100 μg/kg p.o.) at 2 or 4.5 h of reperfusion significantly reduced the neurological deficit score and infarct volume in WT mice. Post-treatment with beraprost (100 μg/kg p.o.) 4.5 h after pMCAO also significantly decreased neurological deficits and infarct volume in WT mice. Together, these novel findings suggest for the first time that PGI₂ IP receptor activation can attenuate anatomical and functional damage following ischemic stroke.     

贝前列素对心肌成纤维细胞胶原交联的影响及机制研究

目的 :观察贝前列素对血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)刺激下心肌成纤维细胞胶原交联的影响并初步探讨其机制。方法:体外培养新生大鼠心肌成纤维细胞,给予贝前列素预处理后,AngⅡ(100 nmol/L)再刺激24 h,测定细胞培养基中胶原含量和交联程度,实时荧光定量PCR和Western blot法测定赖氨酰氧化酶(lysyl oxidase,LOX)m RNA和蛋白表达。结果:贝前列素可剂量依赖性地抑制AngⅡ刺激下心肌成纤维细胞胶原分泌,其中10μmol/L作用最强。贝前列素(10μmol/L)预处理4 h后再给予AngⅡ刺激,心肌成纤维细胞胶原分泌明显减少,交联胶原水平下降,交联与非交联胶原比例变低;LOX m RNA和蛋白表达亦明显下降。结论:贝前列素抑制AngⅡ刺激下心肌成纤维细胞胶原交联,机制可能与下调LOX表达有关。     

Long term treatment of pulmonary arterial hypertension with beraprost,an oral prostacyclin analogue

OBJECTIVE—To evaluate the effects of one year''s treatment with beraprost, an orally active prostacyclin analogue, in patients with severe pulmonary hypertension.PATIENTS—13 patients with severe pulmonary hypertension. This was primary in nine, thromboembolic in three, and caused by Eisenmenger syndrome in one.METHODS—All patients underwent right heart catheterisation. Mean (SD) right atrial pressure was 5 (3) mm Hg, mean pulmonary artery pressure was 48 (12) mm Hg, cardiac index was 2.6 (0.8) l/min/m², and mixed venous oxygen saturation was 68 (7)%. Beraprost was started at the dose of 20 µg three to four times a day (1 µg/kg/day), increasing after one month to 40 µg three to four times a day (2 µg/kg/day), with further increases of 20 µg three to four times a day in case of clinical deterioration.MAIN OUTCOME MEASURES—New York Heart Association (NYHA) functional class, exercise capacity measured by distance walked in six minutes, and systolic pulmonary pressure (by echocardiography) were evaluated at baseline, after one month''s treatment, and then every three months for a year.RESULTS—After the first month of treatment, NYHA class decreased from 3.4 (0.7) to 2.9 (0.7) (p < 0.05), the six minute walking distance increased from 213 (64) to 276 (101) m (p < 0.05), and systolic pulmonary artery pressure decreased from 93 (15) to 85 (18) mm Hg (NS). One patient died after 40 days from refractory right heart failure, and another was lost for follow up at six months. The 11 remaining patients had persistent improvements in functional class and exercise capacity and a significant decrease in systolic pulmonary artery pressure in the period from 1-12 months. Side effects were minor.CONCLUSIONS—Oral administration of beraprost may result in long lasting clinical and haemodynamic improvements in patients with severe pulmonary hypertension.     

氨氯地平联合贝前列素钠治疗高血压早期肾损害临床研究

目的探讨氨氯地平联合贝前列素钠治疗高血压早期肾损害的疗效,以及对患者β2微球蛋白(β2-MG)、胱抑素C(CysC)、同型半胱氨酸(HCY)和尿微量白蛋白(m ALB)的影响。方法选取医院2017年5月至2018年5月接诊的高血压合并早期肾损害患者98例,按治疗方式不同分为治疗组和对照组,各49例。两组患者均给予常规基础治疗及苯磺酸氨氯地平片治疗,在此基础上,治疗组患者给予贝前列素钠片治疗。两组患者均治疗2个月。结果治疗后,两组患者的收缩压(DBP)和舒张压(SBP)均下降,且治疗组明显低于对照组(P <0. 05);两组患者的β2-MG,CysC,m ALB,HCY均下降,且治疗组显著低于对照组(P <0. 05);两组患者的白细胞介素6(IL-6)、肿瘤坏死因子-α(TNF-α)和超敏C反应蛋白(hs-CRP)水平均下降,且治疗组显著低于对照组(P <0. 05);治疗组不良反应发生率为6. 12%,与对照组的12. 24%相当(P> 0. 05)。结论氨氯地平联合贝前列素钠对高血压合并早期肾损害患者的肾脏保护作用更显著,其机制可能与稳定血压和抑制炎性反应有关,且安全性较高。