肺動脈高壓藥物治療

前言
　　肺動脈高壓是一種進行性肺血管阻力增加，導致右心室衰竭的疾病 (1,2) 。此疾病的病理機轉包含肺內皮功能障礙 (pulmonary endothelial dysfunction)，導致一氧化氮(nitric oxide)和前列腺素(prostacyclin)等血管擴張劑的產生受損，以及內皮素-1 (endothelin-1)等血管收縮劑的過度表現 (3,4)。肺動脈高壓全球盛行率約佔1%，而大於65 歲以上的盛行率則高達5-10% (5,6)。肺動脈高壓的發生率約為每百萬人口10-52人（7），未經有效治療的肺動脈高壓患者，預後非常差，病人之存活期中位數(median survival)只有2.8年（8,9）。在過去20年裡，肺動脈高壓的治療已獲得顯著進展。儘管這些有效藥物的治療，一些藥物治療可能對某些患者無效，而使患者需要考慮進行肺移植 (10)。

Sildenafil於肺動脈高壓的療效
　　目前肺動脈高壓治療有五種不同類別藥物：endothelin 受體拮抗劑、PDE-5 抑制劑、soluble guanylate cyclase 刺激劑、前列腺環素類似物(prostacyclinanalogues)，以及prostacyclin 受體促進劑（11）。
　　一氧化氮路徑(nitric oxide (NO) pathway)是導致肺動脈高壓的病理機轉之一，儘管一氧化氮是強效的血管擴張劑，吸入一氧化氮需要複雜的輸送系統。而一氧化氮的肺血管擴張作用是透過cyclic guanosine monophosphate (cGMP)，而cGMP會被phosphodiesterases降解 (13)。第五型磷酸二酯酶(phosphodiesterase type 5, PDE-5) 是肺部主要的phosphodiesterase isoform，代謝cGMP進而造成肺部血管收縮，造成肺動脈高壓 (13)。Sildenafil是一種PDE-5抑制劑，是治療肺動脈高壓的第一線藥物。它是一種強效、口服、和選擇性抑制劑，已廣泛應用於成人肺動脈高壓的單一療法或合併療法 (13)。根據Galie等人的multicenter, randomized, double-blind, placebo-controlled trial研究發現肺動脈高壓患者在接受12週sildenafil治療後，會降低患者的肺動脈高壓，增加六分鐘行走距離(6 min walk distance) (13)。另外，根據Wang等人的統合分析（Meta-analysis）研究顯示，持續超過12週的Sildenafil治療可以顯著減少肺動脈高壓產生的臨床惡化，改善六分鐘行走距離、改善肺動脈高壓患者的WHO功能分級、改善血流動力學和健康相關生活品質(14)。

　　肺動脈高壓是心臟衰竭常見的嚴重併發症。許多研究一致認為，心臟衰竭患者出現肺動脈高壓是預後不良的徵兆(15)。選擇性的PDE-5阻斷劑sildenafil可改善心臟衰竭相關之肺動脈高壓患者的運動能力和生活品質(16) 對於左心室心臟衰竭無論是否合併肺動脈高壓患者，sildenafil不僅可以降低肺血管阻力(pulmonary vascular resistance)，也可能改善左心室收縮和舒張功能(17-22)。根據Lewis等人研究顯示，心臟衰竭合併肺動脈高壓患者在接受12週sildenafil治療後，會改善患者的尖峰攝氧量(peak oxygen consumption)，六分鐘行走距離，或生活品質。甚至會增加患者的運動心輸出量(cardiac output with exercise)，降低肺血管阻力 (20)。在一項雙盲單中心研究中，Guazzi 等人將44名心臟衰竭合併肺動脈高壓患者隨機分配接受sildenafil（劑量50毫克，每日三次，n=22）或對照組（n=22）。治療12個月後研究發現，對照組的血流動力學(haemodynamics)無變化。接受sildenafil治療患者的平均肺動脈壓(mean pulmonary artery pressure)從39毫米汞柱降至21毫米汞柱，右心房壓(right atrial pressure)從23毫米汞柱降至9毫米汞柱，肺動脈楔壓(PAWP) 從22毫米汞柱降至18毫米汞柱，肺血管阻力(pulmonary vascular resistance)從3.9 Wood units降至1.0 Wood units (23)。

　　肺動脈高壓是慢性阻塞性肺病(COPD)的一種常見嚴重的併發症，慢性阻塞性肺病併發肺動脈高壓具有高的併發症和死亡率。慢性阻塞性肺病患者併發肺動脈高壓的發生率為30% 至70%，且慢性阻塞性肺病的嚴重程度與肺動脈壓力具有相關性(24)。此外，肺動脈高壓是慢性阻塞性肺病的預後因素，也是慢性阻塞性肺病患者肺移植的標準(25, 26)。慢性阻塞性肺病併發肺動脈高壓患者的endothelial nitric oxide synthase (eNOS)表現降低，eNOS表現降低會導致內源性NO (endogenous NO)生成減少。而降低NO會增加生長因子表現，促進肺血管細胞(pulmonary vascular cell)增殖，進而導致肺動脈內膜(pulmonary artery intima)增厚、肺動脈中層肥大(middle hypertrophy)及肺血管收縮(27)。Sildenafil為選擇性PDE-5抑制劑，能透過增強NO訊息傳遞路徑(NO signal pathway)鬆弛肺動脈平滑肌，增強右心室心肌收縮力(28)。根據Hao等人的統合分析顯示，Sildenafil治療可以改善慢性阻塞性肺病併發肺動脈高壓患者的六分鐘行走距離和肺動脈收縮壓(Pulmonary artery systolic pressure) (29)。根據Chen等人的統合分析(Metaanalysis)顯示，Sildenafil可以改善慢性阻塞性肺病併發嚴重肺動脈高壓患者的運動能力並降低肺動脈壓 (30)。根據Vitulo等人的隨機對照多中心臨床試驗顯示，Sildenafil治療可以改善慢性阻塞性肺病相關的嚴重肺動脈高壓患者的生活品質，BODE (指數體重指數、呼氣氣流受阻程度、呼吸困難、運動能力），降低肺血管阻力(31)。

結論
　　肺動脈高壓是個致命卻不易診斷的疾病。過去幾年，肺動脈高壓的治療取得了迅速發展。Sildenafil在治療肺動脈高壓方面發揮越來越大的作用。一些研究顯示Sildenafil治療可改善肺動脈高壓患者的六分鐘行走距離，生活品質和降低肺血管阻力。這些研究結果應透過大規模、精心設計的隨機對照試驗加以驗證。

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