Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension

OBJECTIVES: We sought to investigate the impact of adjunct sildenafil on exercise capacity and hemodynamic parameters in patients with pulmonary arterial hypertension (PAH) who fulfilled predefined criteria of deterioration despite ongoing treatment with inhaled iloprost. BACKGROUND: Inhaled iloprost is an effective therapy in PAH. The phosphodiesterase-5 inhibitor sildenafil exerts pulmonary vasodilation and may amplify prostanoid efficacy. METHODS: Of 73 PAH patients receiving long-term inhaled iloprost treatment, 14 fulfilled criteria of deterioration unresponsive to conventional treatment. These patients received adjunct oral sildenafil over a period of nine to 12 months, leaving the inhalative iloprost regimen unchanged. RESULTS: Before iloprost therapy, the baseline 6-min walking distance was 217 +/- 31 m (mean +/- SEM), with an improvement to 305 +/- 28 m within the first three months of iloprost treatment and a subsequent decline to 256 +/- 30 m after 18 +/- 4 months. Adjunct therapy with sildenafil reversed the deterioration and increased the 6-min walk distance to 346 +/- 26 m (p = 0.002, Wilcoxon test) at three months of combined therapy, with a sustained efficacy up to 12 months (349 +/- 32 m, p = 0.002). The distribution of New York Heart Association functional classes (IV/III/II) improved from September 9, 2000, before sildenafil, to January 8, 2003, after nine to 12 months with sildenafil. All hemodynamic variables changed favorably: pulmonary vascular resistance decreased from 2,494 +/- 256 before sildenafil to 1,950 +/- 128 dynes.s.cm(-5).m(2) after three months of adjunct sildenafil (p = 0.036). Two patients died of severe pneumonia during the period of combined therapy. No further serious adverse events occurred. CONCLUSIONS; In patients with severe PAH deteriorating despite ongoing prostanoid treatment, long-term adjunct oral sildenafil improves exercise capacity and pulmonary hemodynamics. A combination of prostanoids and sildenafil is an appealing concept for future treatment of pulmonary hypertension.     

西地那非在儿童先天性心脏病相关性肺动脉高压中的应用

目的:观察西地那非治疗先天性心脏病(CHD)相关性肺动脉高压(PAH)儿童患者的安全性和有效性。方法:选择13例年龄<18岁的CHD合并PAH的患者,口服西地那非每次0.25～1mg/kg,3次/d进行治疗。对比患者用药前后的6 min步行试验距离(6 MWT)、平均肺动脉压力(mPAP)、肺血管阻力指数(PVRI)、肺循环与体循环平均压比率(Pp/Ps)及肺循环与体循环阻力比率(Rp/Rs)的变化。结果:13例服药患者平均随访(9.5±6.2)个月,6 MWT平均增加(47.36±15.7)m,P<0.05。其中11例分别行用药前后的心导管检查,检查结果示mPAP从(87.1±8.4)mmHg(1 mmHg=0.133 kPa)降至(82.2±3.7)mmHg,P=0.1;PVRI从(24.5±7.4)Wood units m2降至(20.3±5.4)Wood units m2,P<0.05;Pp/Ps从(0.99±0.09)降至(0.89±0.05),P<0.05;Rp/Rs从(0.91±0.25)降至(0.86±0.17),P=0.5。所有患者服药期间无明显不良反应及肝肾功能异常。结论:西地那非在CHD相关性PAH儿童患者中应用是安全的,能显著改善患者的活动耐量,降低肺血管阻力。     

西地那非治疗肺动脉高压疗效和安全性的初步观察

目的 探讨西地那非治疗对肺动脉高压患者的临床疗效及耐受性,为西地那非治疗肺动脉高压提供依据.方法 连续入选2007年5月至2009年4月阜外心血管病医院收治的肺动脉高压患者56例,其中男11例,女45例,年龄(31±11)岁.给予西地那非25 mg口服,3次/d,记录治疗前和治疗12周后患者心功能和肺动脉高压功能分级、6 min步行距离、Borg呼吸困难指数、血流动力学改变及临床症状,同时监测患者血液循环及实验室检测指标及不良反应.结果 治疗12周后,患者心功能和肺动脉高压功能分级有明显改善(P<0.01),其中2例Ⅳ级升高至Ⅲ级;8例Ⅲ级改善为Ⅱ级,2例升高至Ⅰ级;5例Ⅱ级升高至Ⅰ级.无纽约心功能分级及世界卫生组织肺动脉高压功能分级恶化病例;6 min步行距离由(352±80)m增加至(396±78)m;差值为(44±70)m(P<0.01);肺动脉平均压降低(6±14)mm Hg(1 mm Hg=0.133 kPa)、肺血管阻力降低(490±832) Dys·s·cm-5(均P<0.01)心输出量增加(1.1±2.0) L/min,P<0.01;心指数增加(0.7±1.1) L·min-1·m-2(均P<0.01).患者无临床恶化情况,耐受性良好,无严重不良事件.结论 西地那非治疗可显著改善肺动脉高压患者功能分级,活动耐力及血流动力学.

Abstract：

Objective To explore the safety and efficacy of oral sildenafil therapy for pulmonary arterial hypertension(PAH), and to provide evidence for sildenafil treatment for Chinese patients with PAH. Methods In this 12-week, prospective, open-label, uncontrolled study, 56 patients with PAH were given oral sildenafil (25 mg, tid). The primary end point was change from baseline to 12 weeks in exercise capacity assessed by 6 min walk (6MW) test. Secondary end points included changes in WHO class and cardiopulmonary hemodynamics. Clinical worsening was defined as death, transplantation, hospitalization for PAH, or initiation of additional therapies for PAH, such as intravenous epoprostenol or oral bosentan. Results After 12 weeks, the compliance was good in 56 patients. Significant improvement was seen in NYHA heart function class and WHO class as compared to baseline(P<0.01): from class Ⅳ to class Ⅲ in 2, from class Ⅲ to class Ⅱ in 8 and to class Ⅰ in 2 cases, and from class Ⅱ to class Ⅰ in 5 cases. No NYHA heart function class and WHO PAH function class deterioration were observed. Oral sidenafil increased 6MW distance, from (352±80) m to (396±78) m, with a change of (44±70) m(P<0.01). Significant improvement was seen in hemodynamics (mean pulmonary artery pressure, P<0.01; cardiac index, P<0.01; pulmonary vascular resistance, P<0.01) at week 12 as compared with baseline. Mean right atrial pressure decreased (3±11)mm Hg (1 mm Hg=0.133 kPa), mean pulmonary arterial pressure decreased (6±14) mm Hg, cardiac output increased (1.1±2.0)L/min, cardiac index increased (0.7±1.1)L·min-1·m-2, and total pulmonary resistance decreased (490±831) Dys·s·cm-5. Side effects were mild and consistent with those reported with sildenafil treatment. No statistically significant clinical worsening was observed with sildenafil therapy for PAH patients. Conclusions Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with pulmonary arterial hypertension.     

Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension.

For chronic thromboembolic pulmonary hypertension not amenable to pulmonary endarterectomy, effective medical therapy is desired. In an open-label uncontrolled clinical trial, 104 patients (mean +/- sem age 62 +/- 11 yrs) with inoperable chronic thromboembolic pulmonary hypertension were treated with 50 mg sildenafil t.i.d. At baseline, patients had severe pulmonary hypertension (pulmonary vascular resistance 863 +/- 38 dyn.s.cm(-5)) and a 6-min walking distance of 310 +/- 11 m. Eight patients were in World Health Organization functional class II, 76 in class III and 20 in class IV. After 3 months' treatment, there was significant haemodynamic improvement, with reduction of pulmonary vascular resistance to 759 +/- 62 dyn.s.cm(-5). The 6-min walking distance increased significantly to 361 +/- 15 m after 3 months' treatment, and to 366 +/- 18 m after 12 months' treatment. A subset of 67 patients received a single dose of 50 mg sildenafil during initial right heart catheterisation. The acute haemodynamic effect of this was not predictive of long-term outcome. In this large series of patients with inoperable chronic thromboembolic pulmonary hypertension, open-label treatment with sildenafil led to significant long-term functional improvement. The acute effect of sildenafil may not predict the long-term outcome of therapy.     

Changes in right ventricular structure and function assessed using cardiac magnetic resonance imaging in bosentan-treated patients with pulmonary arterial hypertension

Patients with pulmonary arterial hypertension (PAH) usually show improvements in symptoms, exercise capacity, and hemodynamics after treatment with approved medical therapies. This study sought to determine whether improvement in right-sided cardiac function measured using cardiac magnetic resonance imaging would also be seen and whether these changes would correlate with improvement in exercise capacity. Sixteen patients with PAH underwent evaluation at baseline and after 12 months of treatment with bosentan. After treatment, cardiac index, pulmonary vascular resistance, and 6-minute walk distance improved, and there was a trend toward improvement in right ventricular (RV) stroke volume (70 +/- 27 to 81 +/- 30 ml; p = 0.08), but no change in RV ejection fraction (RVEF) or RV end-diastolic volume. Six-minute walk distance improved by 59 m (p <0.05) in the overall cohort and improved more in patients in whom RVEF increased compared with those with stable or decreased RVEF (+98 vs -37 m, respectively; p = 0.01). Three patients died during follow-up, and these patients had significantly lower RVEF and left ventricular end-diastolic volume indexes than surviving patients. In conclusion, these results suggest that cardiac magnetic resonance imaging may have value in determining response to therapy and prognosis in patients with PAH.     

Clinical efficacy of sitaxsentan,an endothelin-A receptor antagonist,in patients with pulmonary arterial hypertension: open-label pilot study

STUDY OBJECTIVES: To evaluate the safety and efficacy of sitaxsentan, an endothelin-A receptor antagonist, in a 12-week, open-label trial of patients with pulmonary arterial hypertension (PAH). PATIENTS: Six children and 14 adults with New York Heart Association (NYHA) functional class II, III, or IV primary pulmonary hypertension or PAH associated with either congenital systemic-to-pulmonary shunts or collagen vascular disease were enrolled. MEASUREMENTS: Sitaxsentan was administered orally at 100 to 500 mg bid for 12 weeks. Cardiopulmonary hemodynamics via cardiac catheterization were obtained at baseline and week 12. Six-minute walk test distance was measured at baseline, week 6, and week 12. RESULTS: Sitaxsentan treatment resulted in significant improvement in exercise capacity as assessed by the 6-min walk distance (baseline [mean +/- SD], 466 +/- 132 m; week 12, 515 +/- 141 m, n = 20, p = 0.006). Mean pulmonary artery pressure and pulmonary vascular resistance index also improved (63 +/- 20 to 52 +/- 22 mm Hg, n = 17, p = 0.0002; and 20 +/- 11 to 14 +/- 13 U x m(2), n = 17, p = 0.008, respectively). Serious adverse events included two cases of acute hepatitis (fatal in one patient). CONCLUSIONS: Patients with NYHA functional class II, III, or IV PAH showed a significant improvement in exercise capacity and cardiopulmonary hemodynamics over a 12-week period of treatment with sitaxsentan, an endothelin-A receptor antagonist. Further investigation is warranted to evaluate the safety and efficacy of sitaxsentan in patients with PAH.     

Sildenafil for Chronic Obstructive Pulmonary Disease: A Randomized Crossover Trial

Abstract

Rationale: Pulmonary hypertension with exercise is common in chronic obstructive pulmonary disease (COPD) and may contribute to exercise limitation in this disease. We aimed to determine the effects of treatment with sildenafil on exercise capacity in patients with COPD and emphysema. Methods: We performed a randomized, double-blind, placebo-controlled 2-period crossover trial of sildenafil thrice daily in ten adults with COPD and emphysema on CT scan without pulmonary hypertension. We randomized study participants to 4 weeks of sildenafil (or placebo) followed by a 1-week washout and then 4 weeks of placebo (or sildenafil). The 2 primary outcomes were the 6-minute walk distance and oxygen consumption at peak exercise. Results: Sildenafil had no effect on 6-minute walk distance (placebo-corrected difference = -7.8 m, 95% confidence interval, -23.2 to 7.5 m, p = 0.35) or oxygen consumption at peak exercise (placebo-corrected difference = -0.1 ml/kg/min, 95% confidence interval -2.1 to 1.8 ml/kg/min, p = 0.89). Sildenafil increased the alveolar-arterial oxygen gradient (p = 0.02), worsened symptoms (p = 0.04), and decreased quality-of-life (p = 0.03). Adverse events were more frequent while receiving sildenafil (p = 0.005). Conclusions: Routine sildenafil administration did not have a beneficial effect on exercise capacity in patients with COPD and emphysema without pulmonary hypertension. Sildenafil significantly worsened gas exchange at rest and quality of life. (clinicaltrials.gov NCT00104637).     

Oral sildenafil therapy improves health-related quality of life and functional status in pulmonary arterial hypertension

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase-5 inhibitor, has shown promising results as a novel oral monotherapy in the treatment of pulmonary arterial hypertension (PAH). We conducted a cross-sectional survey of 19 consecutive PAH patients, aged 16-75 years, with WHO functional class II or worse over 3 months of oral sildenafil. Improvement in exercise capacity was achieved in 15/19 (79%) patients. 6-minute walk test distance increased from 299+/-118 m to 360+/-127 m, p=0.016, and WHO functional class decreased significantly. Both PASP and CI showed a non-significant trend toward improvement. Patients also reported significant improvement in physical (p=0.002) and social (p<0.001) functioning, and general health (p=0.01) of Rand SF-36 questionnaire. There was improvement in domains of role limitation due to physical health (p=0.16), emotion (p=0.14), and energy level (p=0.4). Our study suggests that oral sildenafil monotherapy is effective in improving exercise capacity and health-related quality of life amongst PAH patients.     

Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and mid-term effects.

AIM: The treatment of patients with pulmonary arterial hypertension remains a challenge. We set out to investigate the use of sildenafil, a selective inhibitor of phosphodiesterase type 5, in patients with this disease. METHODS AND RESULTS: Ten patients (8 females, mean age 34.5+/-3.3 years) with pulmonary hypertension underwent right heart catheterisation with vasodilator testing using incremental doses of intravenous sildenafil without adverse events. All patients were subsequently commenced on oral sildenafil 50 mg t.d.s. Nine patients had repeat right heart catheterisation 3 months after the commencement of oral therapy. There was a significant reduction in mean pulmonary artery pressure (from 55.8+/-5.9 to 50.4+/-6.1 mmHg, p=0.038 ) and pulmonary vascular resistance (from 10.1+/-1.7 to 8.6+/-1.5 Wood units, p=0.009 ), and an increase in cardiac output (from 4.7+/-0.3 to 5.0+/-0.4 l/min, p=0.15 ). Furthermore, there was a significant increase in the 6-minute walk test, a mean of 112 m. In response to a quality-of-life questionnaire, patients indicated marked clinical improvement on sildenafil. Sildenafil was discontinued in 1 patient due to a transient visual disturbance. The only patient previously awaiting transplantation was removed from the active transplantation list. CONCLUSIONS: Sildenafil is well tolerated in its intravenous and oral forms and appears to improve both pulmonary haemodynamics and the clinical status of patients with pulmonary hypertension after 3 months of oral therapy.     

Effects of the endothelin receptor antagonist bosentan on hemodynamics, symptoms and functional capacity in Japanese patients with severe pulmonary hypertension.

BACKGROUND: Endothelin (ET)-1 has a pathogenic role in pulmonary arterial hypertension (PAH). Recent clinical studies carried out in Western populations showed that blockade of the ET receptors by bosentan improves pulmonary hemodynamics and exercise capacity. In the present study, the efficacy of bosentan was assessed in Japanese patients with PAH. METHOD AND RESULTS: Because the pharmacokinetics of bosentan and its metabolites are similar in Japanese and Caucasian subjects, the same dose of bosentan, 125 mg twice daily, was administered in the Japanese open-label clinical trial. In 18 patients, mean pulmonary arterial pressure decreased from 52.4+/-13.8 to 46.8+/-13.8 mmHg (p=0.003) and cardiac index increased from 2.20+/-0.74 to 2.61 +/-0.72 L.min(-1).m(-2) (p=0.002). The 6-min walking distance increased from 410+/-89.5 to 494+/-86.0 m (p<0.0001). The dyspnea index (Borg scale) decreased from 3.2+/-2.4 to 2.2+/-1.7 (p=0.02). The specific activity scale (SAS) gradually increased throughout the study period from 2.9+/-0.8 to 4.6+/-1.9 METs (p=0.0005). WHO Class improved in 10 patients. CONCLUSION: Bosentan was well tolerated and improved the hemodynamics, symptoms, exercise capacity, and quality of life of Japanese patients with PAH. Thus, bosentan can be a valuable therapeutic option in Japanese patients.     

Repetitive hemodilution in chronic obstructive pulmonary disease and pulmonary hypertension: effects on pulmonary hemodynamics, gas exchange, and exercise capacity.

BACKGROUND: In cor pulmonale associated with severe chronic obstructive pulmonary disease (COPD), disturbances of pulmonary microcirculation may contribute significantly to hypoxemia, pulmonary hypertension, and exercise intolerance. OBJECTIVE: It was tested whether reduction of blood viscosity induced by repetitive hemodilution might improve pulmonary hemodynamics and oxygen uptake. METHODS: Seven patients with stable COPD (forced expiratory volume in 1 s 33 +/- 3 % of predicted, means +/- SE) and pulmonary hypertension were phlebotomized 5-6 times over a period of 3 months with substitution of 6% hydroxyethyl starch (molecular weight 40, 000). This resulted in a stepwise reduction of the hematocrit from 53.3 +/- 2.6 to 45.8 +/- 3.1% and a reduction of whole blood viscosity from 9.8 +/- 0.6 to 8.8 +/- 0.7 mPa x s at a shear rate of 2.0 s-1. Before and after the treatment period, patients underwent cardiopulmonary exercise testing and right heart catheterization. RESULTS: Mean pulmonary artery pressure (PAm) decreased from 30 +/- 3 to 22 +/- 2 mm Hg and arterial oxygen partial pressure (PaO2) increased from 63.2 +/- 2.2 to 71.8 +/- 3.7 mm Hg at rest. During peak exercise, PAm decreased from 59 +/- 7 to 53 +/- 7 mm Hg and PaO2 increased from 54.0 +/- 5.7 to 63.2 +/- 2.4 mm Hg after hemodilution. Peak oxygen consumption rose from 573 +/- 84 to 750 +/- 59 ml x min-1, corresponding to an increase in cardiac index from 4.25 +/- 0.5 to 5.88 +/- 0.76 liters x min-1 x m-2. Pulmonary vascular resistance fell from 345 +/- 53 to 194 +/- 32 dyn x s x cm-5. The patients' peak exercise capacity increased from 9.2 +/- 2. 0 before to 13.5 +/- 3.2 kJ at the end of the study (p < 0.05 for all differences, paired t test). CONCLUSION: The findings suggest that a prolonged improvement of pulmonary microcirculation by reducing blood viscosity may improve pulmonary gas exchange, central hemodynamics, and exercise tolerance in patients with severe COPD and pulmonary hypertension.     

Pulmonary artery pressure-flow relations after prostacyclin in primary pulmonary hypertension

Exercise tolerance improves within a few weeks after prostacyclin initiation in patients with primary pulmonary hypertension even in the absence of significant changes in resting pulmonary vascular resistance and/or in patients who fail to respond to an acute vasodilator challenge. We tested the hypothesis that this early effect of prostacyclin may be ascribable to an improved pressure-flow response of the pulmonary circulation to exercise. Pulmonary hemodynamic variables at rest and during exercise and the 6-min walking distance were determined before and after 6 wk of continuous intravenous prostacyclin treatment (11 +/- 1.5 ng/kg/min) in seven patients unresponsive to an acute nitric oxide vasodilator test. Mean pulmonary arterial pressure/cardiac index coordinates obtained during exercise were pooled, and the slopes of these plots were compared using covariance analysis. All hemodynamic variables at rest were unchanged after prostacyclin. By contrast, the 6-min walking distance improved in all patients (mean increase, 81 m) and the slope of the mean pulmonary artery pressures/cardiac indexes plot decreased with prostacyclin, from 18.2 to 13.1 mm Hg/L/min/m(2) (p < 0.01). These results suggest that the improvement in exercise tolerance seen after 6 wk of prostacyclin therapy may be ascribable to a decrease in incremental pulmonary vascular resistance during exercise.     

Long-term pulmonary hemodynamic effects of ambrisentan in pulmonary arterial hypertension

The long-term effects of endothelin receptor antagonists on pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) are not well studied. This post hoc analysis examined changes in pulmonary hemodynamics in a cohort of patients with PAH who underwent follow-up right heart catheterization (RHC) in a long-term ambrisentan study (ARIES-E). A retrospective review was conducted of patients who underwent RHC after >3 months of ambrisentan therapy. Changes from baseline in mean PAP, mean right atrial pressure, cardiac index, and PVR were assessed and correlations between these hemodynamic changes and exercise capacity were examined. Sixty-eight patients who received ambrisentan in the ARIES studies had ≥1 follow-up RHC while receiving ambrisentan. Fifty-eight patients were on ambrisentan alone at the time of the first RHC. Median time from initiation of ambrisentan therapy to follow-up RHC was 60 weeks (range 14 to 158). Significant improvements compared to baseline were observed for mean PAP (-7.6 mm Hg, 95% confidence interval [CI] -10.0 to -5.1), PVR (-266 dyne × s/cm(5), 95% CI -350 to -180), and cardiac index (0.4 L/min/m(2), 95% CI 0.2 to 0.6 L/min/m(2)); for patients on ambrisentan alone, changes in mean PAP and PVR were inversely correlated with change from baseline 6-minute walking distance (r = -0.41 and -0.43, respectively, p <0.001 for the 2 comparisons) at time of follow-up RHC. In conclusion, ambrisentan may provide sustained improvements in pulmonary hemodynamics in patients with PAH who receive long-term treatment and these changes correlate with improvements in exercise capacity.     

Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study

RATIONALE: Phosphodiesterase type 5 (PDE5) inhibition has been proposed for the treatment for pulmonary arterial hypertension (PAH). OBJECTIVE: This study compared adding sildenafil, a PDE5 inhibitor, to conventional treatment with the current practice of adding bosentan, an endothelin receptor antagonist. METHODS: Twenty-six patients with PAH, idiopathic or associated with connective tissue disease, World Health Organization (WHO) functional class III, were randomized in a double-blind fashion to receive sildenafil (50 mg twice daily for 4 weeks, then 50 mg three times daily) or bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily) over 16 weeks. MEASUREMENTS: Changes in right ventricular (RV) mass (using cardiovascular magnetic resonance), 6-minute walk distance, cardiac function, brain natriuretic peptide, and Borg dyspnea index. MAIN RESULTS: When analyzed by intention to treat, there were no significant differences between the two treatment groups. One patient on sildenafil died suddenly. Patients on sildenafil who completed the protocol showed significant changes from baseline, namely, reductions in RV mass (-8.8 g; 95% confidence interval [CI], -2, -16; n = 13, p = 0.015) and plasma brain natriuretic peptide levels (-19.4 fmol x ml(-1); 95% CI, -5, -34; p = 0.014) and improvements in 6-minute walk distance (114 m; 95% CI, 67, 160; p = 0.0002), cardiac index (0.3 L x min(-1) x m(-2); 95% CI, 0.1, 0.4; p = 0.008), and systolic left ventricular eccentricity index (-0.2; 95% CI, -0.02, -0.37; p = 0.031). Bosentan improved 6-minute walk distance (59 m; 95% CI, 29, 89; n = 12, p = 0.001) and cardiac index (0.3; 95% CI, 0.1, 0.4; p = 0.008). CONCLUSIONS: Sildenafil added to conventional treatment reduces RV mass and improves cardiac function and exercise capacity in patients with PAH, WHO functional class III. Safety monitoring is important until more experience is obtained.     

贝前列素钠联合西地那非治疗肺动脉高压的临床观察

目的:评价在西地那非基础上加用贝前列素钠治疗第一大类肺动脉高压患者的随机对照研究,探讨贝前列素钠及西地那非单药及联合治疗的疗效及安全性。方法:连续收集符合标准的肺动脉高压患者30例,随机分成两组,分别给予西地那非、西地那非加贝前列素钠治疗,疗程12周。对入组患者进行基线评估,包括右心漂浮导管,超声心动图,WHO肺动脉高压功能分级(WHO-FC)、6分钟步行距离(6MWT)等检查,治疗随访12周后重复上述检查,评价两组的疗效和安全性。结果:两组肺动脉高压患者经治疗12周后运动耐力均改善,6MWT提高,WHO-FC改善,超声心动图肺动脉收缩压、右心导管肺动脉平均压及全肺循环阻力均降低,贝前列素钠加西地那非组疗效明显优于单独西地那非组,差异有统计学意义。药物不良反应:联合治疗组有30%患者早期出现轻度头晕,面色潮红、头痛及腹泻等,2~3w后可以耐受。西地那非组有26%的患者出现头痛、脸红消化不良及鼻出血,经1周后均耐受,不良反应发生率差异无统计学意义。结论:贝前列素钠与西地那非联合用药组较单独用药组能更有效的降低肺动脉压力,改善临床症状且安全。     

Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study

OBJECTIVES: In a randomized, double-blind, crossover design, we compared the efficacy of sildenafil with placebo in patients with primary pulmonary hypertension (PPH). The primary end point was the change in exercise time on treadmill using the Naughton protocol. Secondary end points were change in cardiac index and pulmonary artery systolic pressure as assessed by Doppler echocardiography and quality of life (QOL) as assessed by a questionnaire. BACKGROUND: Primary pulmonary hypertension is a disorder with limited treatment options. Uncontrolled studies had shown sildenafil to be beneficial in the treatment of PPH. METHODS: After initial clinical evaluation, including Doppler echocardiography and treadmill exercise test, patients were randomized to placebo or sildenafil with dosages ranging from 25 to 100 mg thrice daily on the basis of body weight. The evaluation was repeated after six weeks. Then patients were crossed over to alternate therapy. Final evaluation was performed after another six weeks of treatment. RESULTS: Twenty-two patients completed the study. Exercise time increased by 44% from 475 +/- 168 s at the end of placebo phase to 686 +/- 224 s at the end of sildenafil phase (p < 0.0001). With sildenafil, cardiac index improved from 2.80 +/- 0.9 l/m2 to 3.45 +/- 1.1 l/m(2) (p < 0.0001), whereas pulmonary artery systolic pressure decreased insignificantly from 105.23 +/- 17.82 mm Hg to 98.50 +/- 24.38 mm Hg. There was significant improvement in the dyspnea and fatigue components of the QOL questionnaire. During the placebo phase, one patient died and another had syncope. There were no serious side effects with sildenafil. CONCLUSIONS: Sildenafil significantly improves exercise tolerance, cardiac index, and QOL in patients with PPH.     

Safety of sapropterin dihydrochloride (6r-bh4) in patients with pulmonary hypertension

The authors investigated the safety of oral tetrahydrobiopterin (BH4), a cofactor for nitric oxide synthesis, as a novel treatment for pulmonary hypertension (PH). Eighteen patients with pulmonary arterial hypertension or inoperable chronic thromboembolic PH received sapropterin dihydrochloride (6R-BH4), the optically active form of BH4, in addition to treatment with sildenafil and/or endothelin receptor antagonists in an open-label, dose-escalation study. 6R-BH4 was administered starting at a dose of 2.5 mg/kg and increasing to 20 mg/kg over 8 weeks. Changes in markers of nitric oxide synthesis, inflammation and oxidant stress, as well as exercise capacity and cardiac function were measured. 6R-BH4 was well tolerated at all doses without systemic hypotension, even when given in combination with sildenafil. There was a small but significant reduction in plasma monocyte chemoattractant protein (MCP)-1 levels on 5 mg/kg. No significant changes in measures of nitric oxide synthesis or oxidant stress were observed. There was improvement in 6-minute walk distance, most significant at a dose of 5 mg/kg, from 379 ± 61 to 413 ± 57 m 414 ± 57 m (P = .002). Oral 6R-BH4 can be administered safely in doses up to 20 mg/kg daily to patients with PH. Further studies are needed to explore its therapeutic potential.     

The effects of pulmonary rehabilitation with chronic obstructive pulmonary disease (COPD)]

It is controversial whether pulmonary rehabilitation is effective in patients with chronic obstructive pulmonary disease (COPD). To test the effect of pulmonary rehabilitation, 7 patients with COPD (aged 76.0 +/- 2.6 years) were enrolled in pulmonary rehabilitation program for 6 weeks. The program consisted of relaxation, pursed lip breathing, diaphragmatic breathing, panic control, muscle stretch gymnastics, and exercise training. The distance of the 6-minute walking test increased significantly from 246.4 +/- 38.0 (m) to 304.3 +/- 28.4 (m) (p < 0.05). The minimum SpO2 during the 6-minute walking test increased from 86.0 +/- 2.8 (%) to 90.1 +/- 1.3 (%) and dyspnea as measured with Borg scale decreased from 5.6 +/- 1.1 to 4.6 +/- 0.5, although they were not significantly different. These results suggest that pulmonary rehabilitation might improve exercise tolerance in elderly patients with COPD.     

Effects of long-term treatment with prostacyclin on plasma adrenomedullin in patients with primary pulmonary hypertension]

OBJECTIVES: This study investigated whether plasma levels of adrenomedullin, a potent vasodilating endogenous neurohumoral mediator, are useful for assessing the severity of primary pulmonary hypertension. METHODS: Seventeen pediatric patients with primary pulmonary hypertension (eight girls, nine boys, mean age 12 +/- 4 years) were enrolled in this study. Thirteen patients in New York Heart Association (NYHA) classes III and IV had been treated with long-term continuous intravenous prostacyclin (PGI2) infusion therapy, and four patients in classes I and II had received beraprost sodium, an oral PGI2 analogue. Blood samples were taken from all patients at the first visit. Plasma levels of atrial and brain natriuretic peptide (ANP, BNP) and endothelin-1, and mature-type adrenomedullin were measured. The relationships were investigated between neurohumoral mediator levels and NYHA class, pulmonary hemodynamics, and exercise capacity assessed by 6-minute walk test. The changes in neurohumoral mediator levels at 1 month, 3 months, and 6 to 12 months were also evaluated in 11 survivors with long-term PGI2 treatment. RESULTS: All neurohumoral mediator levels were positively correlated with severity of NYHA class. Patients in class IV demonstrated significantly elevated neurohumoral mediator levels, except endothelin-1, in comparison with patients in classes I-III. Neurohumoral mediator levels had a significant negative correlation with exercise capacity. Stepwise regression analysis revealed that the BNP to ANP ratio (BNP/ANP) was the most powerful independent factor for total pulmonary resistance (r = 0.85, p = 0.0071) and cardiac index (r = 0.84, p = 0.009). Adrenomedullin was significantly correlated with BNP (r = 0.53, p = 0.03), endothelin-1 (r = 0.66, p = 0.006), and BNP/ANP (r = 0.73, p = 0.0009). ANP and BNP decreased from 196 +/- 213 and 494 +/- 361 pg/ml at baseline to 74 +/- 47 and 153 +/- 133 pg/ml at 1 month, respectively. There was an apparent re-increase in both ANP (187 +/- 194 pg/ml) and BNP (466 +/- 621 pg/ml) at 3 months, regardless of improvement in NYHA class and exercise capacity after long-term PGI2 treatment. In contrast, adrenomedullin decreased from 3.0 +/- 2.2 (baseline) to 1.7 +/- 0.7 fmol/ml at 1 month and 1.6 +/- 0.5 fmol/ml at 3 months. Adrenomedullin was slightly increased at 6-12 months (2.1 +/- 0.9 fmol/ml) without statistical significance. There was a significant relationship between the changes in adrenomedullin at 3 months compared to values at initiation of PGI2 therapy and the changes in mean pulmonary arterial pressure (r = 0.97, p = 0.0041). CONCLUSIONS: Plasma levels of neurohumoral mediators are useful for assessing the severity of primary pulmonary hypertension. In particular, adrenomedullin was valuable for evaluating both cardiac performance and pulmonary hemodynamics after long-term treatment with PGI2 in patients with primary pulmonary hypertension.     

Efficacy of oral sildenafil as rescue therapy in patients with severe pulmonary arterial hypertension chronically treated with prostacyclin. Long-term results

INTRODUCTION AND OBJECTIVE: Prostacyclin therapy is an effective treatment for severe pulmonary hypertension. Sildenafil, a selective phosphodiesterase type 5 inhibitor, induces selective vasodilatation of the pulmonary vessels. A synergistic effect has been described for these two drugs. The aim of this study was to evaluate the efficacy and safety of sildenafil as rescue therapy in patients with severe pulmonary hypertension on chronic treatment with prostacyclin whose clinical or functional course was unsatisfactory. PATIENTS AND METHOD: Observational study of 11 patients (7 men, 4 women, mean age 42 [8] years) diagnosed as having severe idiopathic pulmonary hypertension, who were receiving chronic prostacyclin therapy. Sildenafil was started after a worsening of their clinical or functional status. Baseline, 3-month and 12-month follow-up evaluations were based on functional status (NYHA functional class and 6-minute walking test), the presence of decompensated right heart failure and echocardiogram. RESULTS: Seven of the 11 patients showed significant improvements in exercise capacity (distance walked in 6 minutes) at 3 (+25 m) and 12 months' follow-up (+36 m). Improvements in functional class were seen, and heart failure disappeared. No significant adverse effects of sildenafil were detected. The echocardiographic parameters showed a significant reduction in right ventricular end-diastolic diameter and left ventricular diastolic eccentricity index. One patient died after 4 months of follow-up from sudden cardiac death. CONCLUSIONS: The addition of oral sildenafil to chronic prostacyclin treatment in patients with severe pulmonary hypertension improved functional capacity and reduced episodes of decompensated right heart failure, with good tolerance and no significant adverse effects.