Inhaled prostanoids in the therapy of pulmonary hypertension
Inhaled prostanoids in the therapy of pulmonary hypertension
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DOI：
10.1089/jamp.2007.0657
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发表时间：
2008-03-01
影响因子：
3.4
通讯作者：
Schmehl, Thomas
中科院分区：
文献类型：
--
作者：
Gessler, Tobias;Seeger, Werner;Schmehl, Thomas
前列环素和前列环素类似物是有效的血管扩张剂，具有抗血栓形成、抗炎和抗增殖特性。这些特性使它们成为治疗肺动脉高压的有效药物，肺动脉高压是一种以肺循环中动脉压和血管阻力增加为特征的危及生命的疾病。肺动脉粥样硬化的肺血管表现为内膜纤维化、中膜肥大、外膜增厚等特异性重塑，以及以血管收缩和原位血栓形成为特征的功能性改变。前列环素静脉给药是重度肺动脉高压的公认治疗选择。然而，缺乏肺和肺内选择性可导致危及生命的肺和全身副作用。因此，提出了前列腺素类药物的吸入给药途径。几项吸入性伊洛前列素（一种稳定的前列环素类似物）的研究表明，在肺循环中具有优先和有效的血管舒张作用。一项在203例肺动脉高压患者中开展的随机、双盲、安慰剂对照、多中心研究显示，吸入伊洛前列素可显著改善运动能力和肺血流动力学，且耐受性和安全性极佳。因此，吸入性伊洛前列素已在许多国家被批准用于治疗重度肺动脉高压。然而，吸入伊洛前列素的主要缺点是半衰期短和血流动力学效应（30至60分钟），需要每日多次吸入给药（最多9次）。进一步改善吸入前列腺素类治疗的策略包括使用具有较长半衰期的前列环素类似物（例如，曲前列环素），与口服药物的组合（例如，磷酸二酯酶抑制剂或内皮素受体拮抗剂）和气雾化控释制剂如脂质体和纳米颗粒的开发。前列环素及其类似物的治疗是肺动脉高压治疗的主要支柱，给许多患有这种可怕疾病的患者带来了新的希望。随着吸入性伊洛前列素，一种新药扩大了气雾剂治疗肺部和全身性疾病的范围。
Prostacyclin and prostacyclin analogues are potent vasodilators and possess antithrombotic, anti-inflammatory and antiproliferative properties. These properties qualify them as efficient drugs for the treatment of pulmonary hypertension, a life-threatening illness characterized by an increase in artery pressure and vascular zresistance in the pulmonary circulation. Diseased pulmonary vessels show specificremodeling with intimal fibrosis, medial hypertrophy, and adventitial thickening, as well as functional changes characterized by vasoconstriction and in situ thrombosis. The intravenous administration of prostacyclin is a well-established therapy option in severe pulmonary hypertension. However, lack of pulmonary and intrapulmonary selectivity can lead to life-threatening pulmonary and systemic side effects. Therefore, the application,of prostanoids by inhalation had been proposed. Several studies with inhaled iloprost, a stable prostacyclin analogue, demonstrated preferential and potent vasorelaxation in the pulmonary circulation. In a randomized, double-blind, placebo controlled, multicenter study in 203 patients with pulmonary hypertension inhaled iloprost showed significant improvement of exercise capacity and pulmon ry hemodynamics with excellent tolerability and safety. Consequently, inhaled iloprost has been approved in many countries for treatment of severe pulmonary hypertension. A major drawback of inhaled iloprost, however, is the short half-life and hemodynamic effect (30 to 60 min) demanding multiple daily inhalation manoe*uvres (up to nine times). Strategies for further improvement of inhaled prostanoid therapy include use of prostacyclin analogues with longer half-life (e.g., treprostinil), combinations with oral drugs (e.g., phosphodiesterase inhibitors or endothelin receptor antagonists) and development of aerosolized controlled release formulations such as liposomes and nanoparticles. The therapy with prostacyclin and its analogues is a main, pillar in the treatment of pulmonary hypertension, giving new hope to many patients suffering from this terrible disease. With inhaled iloprost, a new drug has enlarged the scope of aerosol therapies for treatment of pulmonary and systemic diseases.