肺动脉高压治疗新视野

随着肺动脉高压发病机制研究的突破性进展,针对不同信号通路的关键作用靶点逐渐被认识。至今已有10多种新型肺动脉高压靶向药物陆续上市,目前治疗肺动脉高压的靶向药物主要有作用于内皮素通路的药物,作用于一氧化氮通路的药物和作用于前列环素通路的药物。上述药物主要用于治疗动脉性肺动脉高压和慢性血栓栓塞性肺动脉高压,其在临床中的应用极大地改善了肺动脉高压患者的预后。     

前列环素治疗肺动脉高压(续一)

肺动脉高压时,肺血管收缩,肺循环阻力增加,右心室泵血负荷加重。前列环素是内源性花生四烯酸通过环氧酶途径代谢产生的一种前列腺素类物质,可强有力地舒张血管,因而被认为是治疗肺动脉高压最有效的药物之一。近来,前列环素及其类似物已广泛应用于临床治疗肺动脉高压。但是,过去5年内,肺动脉高压相关的死亡率并没有明显降低,因此临床上需要更有效的治疗方法。本文简要回顾当前肺动脉高压的治疗方法并阐述与目前治疗相关的问题,此外,重点关注新兴的技术包括前列环素合成酶基因疗法、采用自体干细胞的细胞疗法以及提高前列环素产能的干细胞工程。通过使用当前的先进技术,以及在分子水平上了解前列环素的合成,期望在肺动脉高压的治疗上取得重大进展。     

肺动脉高压药物治疗进展

肺动脉高压(pulmonary artery hypertension,PAH)是指静息时平均肺动脉压>25 mm Hg,且肺毛细血管压或左房压<15 mm Hg [1].血管扩张剂是治疗肺动脉高压的一类重要药物,能降低肺动脉压力,改善患者血流动力学及肺通气/灌注比值,提高肺动脉高压患者的生活质量,运动耐力以及存活率.其理论基础是肺动脉高压时存在肺动脉的痉挛.当前主要的肺血管扩张剂主要有钙离子拮抗剂、前列环素类药物、内皮素受体拮抗剂、磷酸二酯酶-5抑制剂和一氧化氮.现就肺动脉高压治疗中肺血管扩张剂的应用及部分药物治疗进展进行综述.     

胶原血管病合并肺动脉高压

在胶原血管病的并发症中,肺动脉高压是相当严重的,但是经常被忽略.去年,对于肺动脉高压发展的认识已经有明显的提高.肺血管的细胞异常增生目前被认为是导致肺血管管腔闭塞的主要原因.对于几种胶原血管病和肺动脉高压患者医学方面治疗主要集中于前列环素的使用,通过改善运动能力和血液动力学的变化.持续性静脉内使用前列环素仍作为继发性肺动脉高压治疗的标准,但是更少入侵性替代药物如口服贝前列素贝拉普罗(局部缺血改善药),雾化吸入依洛前列环素前列腺素类药、内皮素受体兑换物受到此类患者的青睐.     

用伊洛前列素吸入治疗心脏病患者围术期肺动脉高压

目前肺动脉高压的治疗仍然是一个棘手的问题,前列环素类似物伊洛前列素是近年来应用较多的肺动脉高压治疗药物,由于其具有高度肺血管选择性、能调节肺血管内皮功能、抑制血管重塑和微血栓形成等药物学特点,因此可明显改善血流动力学和临床症状。本文主要综述吸入伊洛前列素在成人心脏手术围术期肺动脉高压的应用。     

肺动脉高压的药物治疗进展

肺动脉高压是以肺小动脉的血管痉挛、内膜增生、重构为主要特征的一种疾病。肺小动脉的血管增生、重构导致肺血管阻力进行性增加,最终导致右心衰竭和死亡。在过去的20多年,随着我们对肺动脉高压病理机制的认识增加,该病的治疗也获得了很大的进步。除了传统的吸氧、利尿、强心、钙离子拮抗剂、抗凝等治疗,靶向药物治疗的研发与推广使用使肺动脉高压患者的预后得到了明显的改善,目前主要的靶向药物治疗包括：前列环素类似物、内皮素受体拮抗剂、磷酸二酯酶-5抑制剂,且一些新型的药物及联合治疗方案也在研究中。现就肺动脉高压的药物治疗进展简要地做一综述。     

依洛前列环素吸入治疗对高原肺动脉高压患者血流动力学的影响

目的探讨吸入依洛前列环素对高原肺动脉高压（PAH）患者血流动力学的影响。方法12例重度PAH患者行吸入依洛前列环素治疗,观察吸入药物前后各血流动力学参数的变化。结果吸入依洛前列环素后PAH患者的肺动脉收缩压、肺动脉舒张压、肺动脉平均压、肺血管阻力下降,外周动脉血血氧饱和度、周围动脉氧分压、体循环血流量、肺循环血流量、心脏指数（C I）增加;肺小动脉嵌顿压、心率无明显变化。结论吸入依洛前列环素治疗PAH患者安全有效。     

伊洛前列素吸入治疗严重肺动脉高压

前列环素是最早用于原发性肺动脉高压的急救药物。然而 ,由于不能选择性扩张肺血管及继发的全身性副作用限制了该药在临床上的应用。伊洛前列素 (Ｉｌｏｐｒｏｓｔ)是一种具有稳定结构的前列环素类似物 ,其喷雾剂可选择性扩张肺血管 ,而无明显体循环血压降低和通气 血流比例失衡的副作用。本研究采用伊洛前列素吸入治疗 1 9例严重原发或继发性肺动脉高压患者 ,评价其对有生命危险的肺动脉高压的疗效。方法　研究对象为 1 995～ 1 998年期间 ,在德国 6所大学医院登记的 1 9例经用常规治疗仍有进行性右心衰竭的严重肺动脉高压患者 ,平均年龄 (…     

欧美肺动脉高压诊疗指南解读

肺动脉高压是一大类以肺动脉压力进行性增高,伴或不伴有小肺动脉病变为特征的恶性肺血管疾病,往往可引起右心功能衰竭甚至死亡。在前列环素等药物应用前,肺动脉高压患者预后极差,从被诊断至死亡的存活时间中位数仅2.8年,因此肺动脉高压是一类严重威胁人类身心健康的常见疾病。     

肺动脉高压的药物治疗进展

肺动脉高压是以小肺动脉的血管增生和重构为主要特征,导致肺血管阻力进行性增加,最终引起右心衰和死亡的一种疾病。以前治疗肺动脉高压的药物包括钙离子拮抗剂、抗凝剂和对严重患者持续静脉注射依前列醇。最近,前列环素类似物treprostinil、贝拉普罗、伊洛前列素和内皮素受体拮抗剂波生坦已用于临床试验。因此,在过去的20年间,对肺动脉高压治疗取得的进展有助于延长病人的生存时间和提高他们的生活质量。     

Combination therapy with prostacyclin and tadalafil for severe pulmonary arterial hypertension: a pilot study

Despite the introduction of new drugs that have changed the course of pulmonary arterial hypertension (PAH), some patients are still refractory to treatment and deteriorate rapidly. Long-acting phosphodiesterase-5 inhibitors are a new class of drugs that are effective in PAH. This prospective study assessed the potential of combination therapy with prostacyclin and tadalafil for treatment of severe PAH. We report four cases of severe PAH that deteriorated despite prostacyclin therapy. Two patients had Eisenmenger syndrome, one had pulmonary hypertension associated with scleroderma and one had histiocytosis X. All were treated with tadalafil, 10-20 mg once daily, in addition to prostacyclin. After 3 months of treatment, all patients improved clinically, with an increase in mean 6MWD from 214 to 272 m. In three patients, the New York Heart Association functional class decreased from IV to III. Echocardiograms showed no significant changes in pulmonary arterial pressure. Although this study was limited by the small sample size, it suggests that tadalafil in combination with prostacyclin is an effective treatment for severe PAH. Tadalafil may be beneficial for the treatment of patients with advanced disease.     

Pharmacologically induced pulmonary vasodilatation in children and young adults with primary pulmonary hypertension

To evaluate pulmonary vasoreactivity in children and young adults with primary pulmonary hypertension, we performed cardiac catheterizations on nine patients with primary pulmonary hypertension (nine months to 23 years old) and made hemodynamic measurements: before and after infusing prostacyclin, and before and after administering sublingual nifedipine. Based upon the response to prostacyclin, patients were divided into responders and nonresponders using the following criteria: 20 percent or greater decrease in mean pulmonary arterial pressure; an increase in cardiac index; and no change, or a decrease in the pulmonary vascular resistance to systemic vascular resistance ratio. By these criteria, five of the nine patients had a reactive pulmonary vascular bed and responded to prostacyclin administration. In addition, they all responded to nifedipine. The remaining four did not respond to either drug. There was a close correlation (r = 0.85, p less than 0.01) between the magnitude of the pulmonary vasodilator response to treatment with prostacyclin and nifedipine. There was also a significant inverse correlation between the age of the patient at the time of the study and the pulmonary vasodilator response to administration of prostacyclin (r = 0.91, p less than 0.01) and nifedipine (r = 0.82, p less than 0.01); ie, both drugs produced a greater fall in pulmonary arterial pressure in younger patients with primary pulmonary hypertension than in older ones.     

The potential for inhaled treprostinil in the treatment of pulmonary arterial hypertension

Inhaled treprostinil is a safe and well-tolerated approved pharmaceutical for the treatment of pulmonary arterial hypertension. In a series of open-label studies and in the pivotal trial with 253 patients, this long-acting prostacyclin analogue demonstrated pronounced pulmonary selectivity of vasodilatory effects, improved physical capacity and excellent tolerability and safety following aerosol administration. For efficient treatment, only four daily inhalations of treprostinil are necessary compared with six to nine in iloprost aerosol therapy. This review describes in detail the development of inhaled treprostinil, starting with intravenous epoprostenol followed by inhaled iloprost and subcutaneous treprostinil, all three representing well-established and widely approved prostanoid therapies for pulmonary hypertension. In order to circumvent the drawbacks of intravenous epoprostenol, stable prostacyclin analogues with similar pharmacological properties have been investigated. In addition, alternative routes of administration have been proposed and evaluated, mainly inhaled and subcutaneous delivery. The concept of inhaled treprostinil was to combine the pulmonary selectivity of an aerosolized vasodilator with the long-acting effects of a stable prostacyclin analogue. Pulmonary arterial hypertension remains, however, a severe, life-threatening disease, in spite of the enormous progress in specific drug therapy over the last decade. Therefore, further improvement of drug therapy will be essential, with clear potential for inhaled treprostinil: a reduction of inhalation frequency and duration would markedly improve quality of life and compliance, and a longer-lasting local prostanoid effect might further enhance the efficacy of inhaled treprostinil. The advantageous pharmacological properties of treprostinil offer the opportunity to establish a convenient metered dose inhaler as a delivery system, to combine inhaled treprostinil with available or future drugs for pulmonary arterial hypertension, or to develop sustained release formulations of treprostinil suitable for inhalation based on liposomes or biodegradable nanoparticles.     

Use of the Prostacyclin Receptor Agonist Selexipag in Patients With Pulmonary Arterial Hypertension Associated With Eisenmenger Syndrome

Eisenmenger syndrome is a multisystem disorder and the most severe form of pulmonary arterial hypertension in adult congenital heart disease. Pulmonary arterial hypertension represents a fatal disease, characterized by increased pulmonary vascular resistance, right heart failure, and death. Although therapeutic management has rapidly advanced in recent years, these patients were not included in randomized controlled trials for specific pulmonary arterial hypertension drugs, except for bosentan. However, in clinical practice we apply treatment strategies combining drugs targeting multiple pathobiological pathways. We present 3 patients with Eisenmenger syndrome and their improvement after starting treatment with selexipag, an oral selective IP prostacyclin receptor agonist.     

New Insights in the Treatment Strategy for Pulmonary Arterial Hypertension

Introduction Recent advances in our understanding of the pathophysiological and molecular mechanisms involved in pulmonary arterial hypertension have led to the development of novel and rational pharmacological therapies. In addition to conventional therapy (i.e., supplemental oxygen and calcium channel blockers), prostacyclin or endothelin receptor antagonists have been recommended as a first-line therapy for pulmonary arterial hypertension. However, these treatments have potential limitations with regard to their long-term efficacy and improvement in survival. Furthermore, intravenous prostacyclin (epoprostenol) therapy, which is recommended by most experts for patients with New York Heart Association (NYHA) functional class IV, is complicated, uncomfortable for patients, and expensive because of the cumbersome administration system. Considering these circumstances, it is necessary to develop additional novel therapeutic approaches that target the various components of this multifactorial disease. Case report In this short review, we present an overview of the current treatment options for pulmonary arterial hypertension and describe a case report with primary pulmonary hypertension. A male patient with NYHA functional class IV and showing no response to calcium channel blockers and prostacyclin exhibited significantly improved exercise tolerance and hemodynamics and long-term survival for more than 2.5 years after receiving an oral combination therapy of a phosphodiesterase type 5 inhibitor (sildenafil), phosphodiesterase type 3 inhibitor (pimobendan), and nicorandil. Future perspective We also discuss the background and plausible potential mechanisms involved in this case, as well as future perspectives in the treatment of pulmonary arterial hypertension.     

Treatment of pulmonary arterial hypertension: the role of prostacyclin and prostaglandin analogs

Pulmonary arterial hypertension is a progressive, fatal disease characterized by elevated pulmonary arterial pressure ≥25 mm Hg and normal pulmonary capillary wedge pressure ≤ 5 mm Hg. Physiological features of pulmonary arterial hypertension are characterized clinically by the presence of pre-capillary pulmonary hypertension not caused by other conditions such as lung diseases or chronic thromboembolic pulmonary hypertension. There are several therapies currently available that have been shown to improve hemodynamics and improve outcomes in patients with pulmonary arterial hypertension. These therapies include synthetic prostacyclin and prostaglandin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Multiple prostacyclin and prostaglandin analog formulations are currently in use (both branded and generic), available for parenteral, inhaled, or oral administration. This review discusses the pharmacology, clinical effects, and routes of administration of prostacyclin and prostaglandin analogs, emphasizing the advantages and disadvantages of each from the clinical perspective.     

Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to pulmonary fibrosis

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation-perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I2 caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 +/- 4.2 to 31.6 +/- 3.1 mmHg, and pulmonary vascular resistance (RL) from 810 +/- 226 to 386 +/- 69 dyn.s.cm-5 (p < 0.005, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left-shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with RL decreasing from 726 +/- 217 to 458 +/- 81 dyn.s.cm-5. In contrast, both intravenous PGI2 and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition PGI2 infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI2 analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI2 or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.     

A comparison of the acute hemodynamic effects of prostacyclin and hydralazine in primary pulmonary hypertension

In patients with primary pulmonary hypertension the administration of a vasodilating drug is often used to test pulmonary vasoreactivity. Hydralazine has been employed as a test drug, but because of its long duration of action there is a risk of sustained systemic arterial hypotension in patients with a fixed pulmonary vascular resistance. In this study we compared the acute hemodynamic effects of intravenous prostacyclin, a potent, short-acting vasodilator, with the effects of oral or intravenous hydralazine. Both prostacyclin and hydralazine increased cardiac output and decreased systemic pressure without changing pulmonary arterial pressure in seven patients with primary pulmonary hypertension. The average decrease in total pulmonary resistance with prostacyclin (-46% +/- 5%) was more than that with hydralazine (-32% +/- 6%). The respective decreases in total systemic resistance were -50% +/- 4% vs -43% +/- 6%. The percent changes in individual responses to the two agents were correlated (p less than 0.05) for pulmonary arterial pressure, systemic arterial pressure, total pulmonary resistance, and total systemic resistance. We concluded that the pulmonary hemodynamic effects of prostacyclin resembled those of hydralazine. Prostacyclin may predict the acute pulmonary hemodynamic effects of hydralazine in primary pulmonary hypertension and because of its prompt, brief action may provide greater patient safety.     

Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis.

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation-perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I(2) caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 +/- 4.2 to 31.6 +/- 3.1 mm Hg, and pulmonary vascular resistance (RL) from 810 +/- 226 to 386 +/- 69 dyn. s. cm(-)(5) (p < 0.05, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with RL decreasing from 726 +/- 217 to 458 +/- 81 dyn. s. cm(-)(5). In contrast, both intravenous PGI(2) and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition, PGI(2) infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI(2) analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI(2) or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.     

Treatments for pulmonary arterial hypertension

PURPOSE: Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction, in situ thrombosis and vascular remodeling of small pulmonary arteries inducing a fixed pulmonary arterial obstruction and persistent elevation of pulmonary arterial resistance. Conventional treatment is based on simple measures (exercise limitation) and non-specific drugs (warfarine, diuretics, oxygen). CURRENT KNOWLEDGE AND KEY POINTS: Pure vasodilators like calcium channel antagonists have little or no effect on the vast majority of patients, presumably because fixed pulmonary arteriopathy predominate over vasoconstriction. Intravenous prostacyclin (epoprostenol) and endothelin receptor antagonists have vasodilator and antiproliferative properties. Epoprostenol therapy has resulted in significant improvements in prognosis of this disease and this drug remains the first-line treatment of the most severe patients. Bosentan is an interesting first-line treatment for NYHA functional class III patients. Availability of novel specific drugs (endothelin receptor type A antagonists, prostacyclin analogues, type 5 phosphodiesterase inhibitors) open new perspectives in treatment of PAH. The long-term benefit of these drugs remains to be evaluated and their respective place in treatment of these patients is still uncertain. We here present the different therapeutic alternatives available in the PAH and propose an algorithm for treatment of these patients. FUTURE PROSPECTS AND PROJECTS: The evolution of therapy from vasodilators to antiproliferative agents reflects the advancement in our understanding of the mechanisms mediating pulmonary arterial hypertension.