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。     

Addition of sildenafil in patients with pulmonary arterial hypertension with inadequate response to bosentan monotherapy

BACKGROUND:

Pulmonary arterial hypertension (PAH) remains a progressive disease despite improvement when using one of three medication classes: prostanoids, endothelin receptor antagonists or phosphodiesterase-5 inhibitors. Combination therapy has been proposed for patients with unsatisfactory response to monotherapy.

OBJECTIVES:

To examine the effect of adding sildenafil to bosentan on 6 min walk distance (6MWD) and New York Heart Association (NYHA) classification in patients with PAH who achieved inadequate improvement with bosentan monotherapy.

METHODS:

Patients with idiopathic PAH or connective tissue disease-associated PAH, and who had either self-reported inadequate improvement in exercise tolerance or a decline in 6MWD after initial improvement, were included in the study (n=10). Data on 6MWD and NYHA class at baseline (before initiation of bosentan), three and six months after baseline, second baseline (before initiation of combination therapy with sildenafil), and three and six months after second baseline were analyzed for any changes.

RESULTS:

Mean time from initiation of bosentan monotherapy to initiation of combination therapy was 558 days (range 150 to 900 days). Six months after initiation of bosentan, 6MWD increased by 57.2 m above the baseline of 314.4 m. Six months after combination therapy, 6MWD was 62.80 m higher than the baseline before initiation of combination therapy of 339 m (P<0.02). The overall increase in 6MWD six months after combination therapy was higher than the first baseline by 87.4 m (P not significant). NYHA functional class did not improve with combination therapy in all patients.

DISCUSSION:

Initiating combination therapy in patients who achieve an inadequate improvement in exercise tolerance with mono-therapy may result in further improvement in exercise tolerance.     

西地那非治疗肺动脉高压的研究进展

本文综述西地那非治疗肺动脉高压的临床应用进展.西地那非是一种选择性的磷酸二酯酶抑制剂,通过减少环鸟苷酸(cGMP)的降解发挥其治疗作用.研究表明西地那非和吸入一氧化氮一样可以用于急性血管舒张试验.西地那非单独应用或者和其它药物联合应用已经证明对于各种类型的肺动脉高压具有一定疗效,而且因其价格比前列环素类药物及内皮素受体拮抗剂便宜,因此其临床应用前景是引人注目的.然而在西地那非治疗肺动脉高压的临床应用方面目前尚缺乏多中心、大例数的研究资料.     

Successful treatment with sildenafil in systemic sclerosis patients with isolated pulmonary arterial hypertension: two case reports

We describe two systemic sclerosis (SSc) patients with isolated pulmonary arterial hypertension (PAH) who were given treatment with 50 mg oral sildenafil per day. We evaluated the efficacy of oral sildenafil for isolated PAH in SSc patients by direct assessment with cardiac catheterization before and 6 months after the initiation of sildenafil. Right-heart catheterization demonstrated decreased mean pulmonary artery pressure, decreased pulmonary vascular resistance, and increased cardiac output after treatment with sildenafil. Brain natriuretic peptide levels were gradually decreased. The 6-min walking distance was greatly extended. Moreover, the physical conditions of both patients were much improved. We recognized no adverse events. We propose that oral sildenafil may be beneficial as a selective pulmonary vasodilator and as long-term treatment in SSc patients with isolated PAH.     

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.     

西地那非联合辛伐他汀治疗女性肺动脉高压的临床研究

目的探讨西地那非联合辛伐他汀治疗女性肺动脉高压（PAH）的临床疗效。方法49例女性PAH患者分为氨氯地平治疗组（A组）16例、西地那非治疗组（B组）16例、西地那非联合辛伐他汀治疗组（C组）17例。A组给予氨氯地平片5mg,1次／d;B组给予西地那非片50mg,3次／d;C组给予西地那非片50mg,3次／d,联合辛伐他汀片80mg,1次／d,疗程均为12周。试验前、后进行生活质量问卷评分（QOL）并测量右室收缩压（RVSP）及6min步行距离（6-MWT）。结果A组治疗后QOL、RVSP和6-MWT分别为44．42±2．12、（69．12±3．23）mmHg和（312．12±5．13）m;B组治疗后分别为38．02±1．92、（59．72±2．42）mmHg和（331．78±5．62）m;C组治疗后分别为32．33±1．89、（50．86±2．27）mmHg和（355．22±6．76）m。三组治疗后QOL、RVSP及6-MWT较治疗前均有所改善,B组比A组明显（P〈0．05）,C组较B组明显（P〈0．05）,而C组较A组更为显著（P〈0．01）。结论西地那非联合辛伐他汀较西地那非单药更能有效降低女性PAH患者的肺动脉压,改善患者生活质量,提高其运动耐力。     

Current epoprostenol use in patients with severe idiopathic,heritable or anorexigen-associated pulmonary arterial hypertension: Data from the French pulmonary hypertension registry

Objectives

The current use of intravenous epoprostenol in patients with severe idiopathic, heritable or anorexigen-use associated pulmonary arterial hypertension (IHA-PAH) was investigated.

Methods

This observational study evaluated newly diagnosed (≤ 1 year) patients with IHA-PAH, enrolled in the French pulmonary hypertension (PH) registry between 2006 and 2010 and treated with epoprostenol. Among 209 consecutive patients receiving epoprostenol for the treatment of severe PH, 78 had IHA-PAH, including 43 patients naïve of previous PAH-specific treatment.

Results

After 4 months of epoprostenol therapy, improvement was observed for treatment naïve patients (n = 43) and for patients who had received previous PAH-specific therapy (n = 35): NYHA functional class improved in 79% and 44% of these patients, respectively, 6-minute walk distance increased by 146 (p < 0.0001) and 41 m (p = 0.03), cardiac index increased by 1.2 (p < 0.0001) and 0.5 L·min^− 1·m^− 2 (p = 0.006), and pulmonary vascular resistance decreased by 700 (p < 0.0001) and 299 dyn·s·cm^− 5 (p = 0.009). In the treatment-naïve patient group, upfront combination of epoprostenol and oral PAH therapy tended to be more beneficial compared with epoprostenol monotherapy and was associated with improvement in cardiac index (p = 0.03).The observed 1- and 3-year survival estimates from epoprostenol initiation were 84% and 69%, respectively. The highest survival rates were observed for treatment-naïve patients receiving upfront combination of epoprostenol and oral PAH therapy (92% and 88% at 1 and 3 years, respectively).

Conclusions

First-line therapy with epoprostenol, especially when combined with oral PAH treatment, was associated with a substantial improvement in clinical and hemodynamic status and favorable survival estimates in patients with severe IHA-PAH.     

Intravenous epoprostenol treatment of patients with connective tissue disease and pulmonary arterial hypertension at a single center

Objective

To assess the efficacy of epoprostenol treatment in Japanese patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD).

Methods

Sixteen patients with PAH–CTD treated with continuous intravenous epoprostenol at a single center between 2000 and 2009 were enrolled. Baseline characteristics, short-term and long-term outcomes, predictors of mortality, and safety profiles were evaluated. For survival analysis, 16 controls were selected who matched the underlying CTD, World Health Organization functional class, and use of PAH drugs, except for epoprostenol.

Results

Six patients had systemic lupus erythematosus, five had mixed CTD, four had systemic sclerosis, and one had primary Sjögren’s syndrome. The mean pulmonary arterial pressure (mPAP), cardiac index (CI), pulmonary vascular resistance, and functional class were significantly improved during the first 6 months of epoprostenol treatment. Cumulative survival rates at 1, 2, and 3 years in epoprostenol-treated patients were 69, 69, and 55 %, respectively, and were significantly better than those of the controls. Functional class, CI at baseline, and reduction of mPAP at 6 months were identified as predictors of survival. Adverse events, including flushing and catheter-related infection, were frequent, but all patients tolerated the treatment.

Conclusion

Based on the improvements in both short-term and long-term outcomes among our patient cohort, epoprostenol is an effective treatment for CTD patients with advanced PAH.     

Short term effects of sildenafil citrate therapy in secondary pulmonary hypertension

ObjectivesTo study the short term effects of sildenafil citrate therapy in patients with secondary pulmonary hypertension.MethodsForty patients with known symptomatic secondary pulmonary hypertension due to valvular heart disease, chronic thromboembolic disease, chronic obstructive pulmonary disease, interstitial pulmonary fibrosis, and idiopathic dilated cardiomyopathy were included in this phase II study. Patients were allocated in a randomized, placebo controlled design to either sildenafil or placebo for 6 weeks. Baseline and 6 week follow up included assessment of hemodynamic parameters, functional class using the NYHA classification, echocardiographic measurements of pulmonary artery systolic pressure and left ventricular ejection fraction.ResultsThe mean NYHA class at 6 weeks was 2.05 ± 0.4 in the sildenafil group versus 2.6 ± 0.6 in the placebo group, p = 0.02. The mean systolic pulmonary artery pressure significantly decreased in the sildenafil group at 6 weeks (43 ± 4 mmHg), compared to placebo patients (53 ± 7 mmHg), p = 0.02. Ejection fraction was higher in the sildenafil group, 59 ± 12% versus 54 ± 14% in the placebo group, but did not reach statistically significant difference. Sildenafil was well tolerated with minimal side effects.ConclusionOur data suggest that sildenafil therapy may provide benefits to selected patients with pulmonary hypertension secondary to cardiac or pulmonary diseases.     

一氧化氮及一氧化氮合酶在低氧性肺动脉高压中的研究进展

一氧化氮可调节肺血管张力,维持肺血管正常结构和肺循环的低阻力状态,在低氧性肺动脉高压的发生机制中起重要作用.由于一氧化氮具有独特的理化性质和生物学活性,因此目前研究主要集中在对其合成的关键酶一氧化氮合酶.下面就一氧化氮、一氧化氮合酶在低氧性肺动脉高压发病中的作用机制及临床应用的研究作一简单综述.     

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。     

肺动脉高压联合治疗方案效价研究

目的：探讨吸入型伊洛前列素和西地那非2种药物联合应用及单独用药在治疗重度肺动脉高压患者中的效价。方法：29例肺动脉高压患者随机分为单独应用伊洛前列素组（I组）、西地那非组（S组）和伊洛前列素续减合并西地那非递增的联合治疗组（I＋S组）,观察治疗4、12、24周时3组的临床疗效和经费。结果：治疗12周时,I组及I＋S组较S组在心排出量、6min步行距离和心功能WHO分级的改善方面均有明显差异（P〈0．05）;但I组与I＋S组相比疗效无显著差异：治疗24周时,3组疗效均无显著差异（P〉0．05）。12周及24周时I＋S组治疗费用较I组明显减少,分别节省32％及64％,S组治疗费用最低。结论：吸入伊洛前列素合并口服西地那非的续减递增联合治疗是重度肺动脉高压患者高效价的治疗方案。     

枸橼酸西地那非治疗心脏手术后肺动脉高压的临床研究

目的研究枸橼酸西地那非对心脏手术后重度肺动脉高压的影响。方法自2002年9月至2005年1月共使用枸橼酸西地那非治疗心脏手术后重度肺动脉高压共27例,其中10例小儿,17例成人。男17例,女10例,年龄1～63岁(平均37岁),体重6～67kg(平均40kg)。所有病例均在术前行超声心动图检查确诊为重度肺动脉高压。27例患者中14例先天性心脏病,其中9例为室间隔缺损;1例为右室双出口;1例为房间隔缺损;1例为完全性肺静脉异位引流;1例为动脉导管未闭;1例为三房心。上述先心病患者均行心内畸形矫治术。另外13例为风湿性心脏病,其中11例重度二尖瓣狭窄,2例重度二尖瓣关闭不全,13例患者均合并有三尖瓣关闭不全,均行二尖瓣人工瓣膜置换术、三尖瓣整形术;其中2例合并有主动脉瓣病变同期行主动脉瓣人工瓣膜置换术,1例因合并有冠心病同期行冠状动脉旁路移植术。所有病例术后均予持续镇静和镇痛,保持适度的过度通气,维持轻度呼碱状态,同时积极地纠正各种水、电解质紊乱及代谢性酸中毒。给予多巴胺3～10μg.kg-1.min-1,米力农0.5μg.kg-1.min-1强心治疗,NO吸入(10～70)×10-6及前列腺素E1(PGE1)10～40ng.kg-1.min-1维持肺血管扩张,降低肺动脉压力。经上述处理后,27例患者术后72小时内尚反复出现肺动脉压升高,血氧饱和度、血氧分压下降,肺氧合功能下降,其中7例患者出现肺动脉高压危象。给予高浓度吸氧,增加NO吸入浓度及PGE1用量,肺动脉压仍无明显下降,肺氧合功能无进一步改善,即给予枸橼酸西地那非(辉瑞制药公司,商品名万艾可),1～2mg/kg,每8小时一次。观察患者肺动脉压、动脉血压、血氧饱和度、动脉氧分压、动脉二氧化碳分压、吸氧浓度、NO吸入浓度的变化。结果服用枸橼酸西地那非1小时以后,25例患者血氧饱和度、血氧分压渐上升,肺动脉压开始下降,体循环血压稳定或稍增高。1～2天后,吸氧浓度下降,渐降低或停用NO吸入,以及减量使用PGE1,肺动脉压基本稳定,无进一步上升,肺氧合功能改善,并顺利停用呼吸机。使用枸橼酸西地那非期间无一例患者再次出现肺动脉高压危象,血流动力学平稳。25例患者顺利出院,2例患者因术后低心排综合征而出现多器官功能衰竭死亡。结论枸橼酸西地那非是一种新型的、高选择性降低心脏手术后严重肺动脉高压的药物。     

粉防己碱与硝苯地平对大鼠肺动脉高压影响对比的实验研究

目的:通过粉防己碱与硝苯地平对比实验研究,探讨粉防己碱与硝苯地平对肺动脉高压的治疗作用及其机制。方法:40只,雄性,Wistar大鼠,随机分为4组,即:模型组、粉防己碱治疗组、硝苯地平治疗组和对照组。采用左全肺切除复合腹腔注射野百合碱建立大鼠肺动脉高压模型,分别应用粉防己碱和硝苯地平按最低安全剂量进行灌胃干预、治疗组。测定大鼠血液中一氧化氮(NO)的含量,血流动力学指标,右心指数,光镜下观察肺小动脉病理变化。结果:两个治疗组肺动脉压力及右心指数均降低,均能够改善肺血管重构,但两者相比差异无统计学意义;血中NO含量粉防己碱组明显高于硝苯地平组,且对大鼠体循环压力影响小,两者相比较差异有统计学意义。结论:粉防已碱和硝苯地平均能够逆转野百合碱所致的大鼠肺动脉高压模型肺血管重建,降低肺动脉压力,但综合比较,前者对于降低肺动脉高压更有优势,可能与NO相关。