Intravenous Iloprost: A New Therapeutic Option for Patients with Post-Transplant Distal Limb Syndrome (PTDLS)

The purpose of this study was to investigate the application of intravenous iloprost as a novel therapy for the treatment of post-transplant distal limb syndrome (PTDLS). PTDLS is a benign but disabling complication in the first year after renal transplantation. It is characterized by bilateral, often incapacitating pain in the feet and or knees on motion and a significant rise in alkaline phosphatase levels on laboratory evaluation. On MRI, bone marrow edema of the affected bone regions can be demonstrated. PTDLS differs from steroid induced osteonecrosis of the hip in terms of localization, an average cumulative steroid dosage within expected limits, and a benign outcome, as PTDLS does not progress to overt cell necrosis. From August 2003 to April 2005 we treated 10 patients with MRI-proven diagnosis of PTDLS following a standardized regimen of intravenous iloprost over 5 days. Iloprost led to prompt pain relief measured on a visual analogous scale (VAS) ranging from 1 to 10 (5.6 +/- 1.5 before vs. 2.1 +/- 1.3 after treatment, p = 0.0004). PTDLS represents a benign but disabling complication following renal transplantation. Intravenous iloprost might be a promising therapeutic concept leading to a quick relief of symptoms without relevant side effects.     

前列环素类药物治疗肺动脉高压的进展

研究显示前列环素减少和肺动脉高压的发生有关,前列环素类药物依前列醇、曲前列环素、贝前列环素、伊洛前列腺素均能降低肺动脉压力、肺血管阻力,增加心输出量、6min步行距离,同时无明显不良反应,从而改善肺动脉高压患者的症状和预后。     

Prostacyclin analogs stimulate receptor-mediated cAMP synthesis and ATP release from rabbit and human erythrocytes

Objectives: The purpose of this study was to establish that the prostacyclin (PGI₂) receptor (IP receptor) is present on rabbit and human erythrocytes and that its activation stimulates cyclic adenosine monophosphate (cAMP) synthesis and adenosine triphosphate (ATP) release. Methods: The effect of incubation of erythrocytes with the active PGI₂ analogs, iloprost or UT‐15C, on cAMP levels and ATP release was determined in the absence and presence of the IP receptor antagonist, CAY10441. Western analysis was used to determine the presence of the IP receptor on isolated membranes. To establish that effects of PGI₂ analogs were not due to prostaglandin E₂(PGE₂) receptor activation, the effect of PGE₂ on cAMP levels and ATP release was determined. Results: Rabbit and human erythrocytes possess IP receptors. Iloprost and UT‐15C stimulated increases in cAMP and ATP release that were prevented by the IP receptor antagonist, CAY10441. PGE₂ did not stimulate cAMP accumulation or ATP release and did not inhibit iloprost‐induced increases in cAMP. Conclusions: This study establishes that the IP receptor is present on rabbit and human erythrocytes and that its activation results in increases in cAMP and ATP release. These results suggest a novel mechanism by which PGI₂ and its active analogs, when administered pharmacologically, could produce vasodilation.     

Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension.

AIMS: To describe the long-term clinical efficacy of inhaled iloprost as first-line vasodilator mono-therapy in patients with idiopathic pulmonary arterial hypertension (IPAH). METHODS AND RESULTS: Seventy-six IPAH patients were prospectively identified and treated with inhaled iloprost. Clinical, haemodynamic, and exercise parameters were obtained at baseline, after 3 and 12 months of therapy and yearly thereafter. Four endpoints were prospectively defined as follows: (i) death, (ii) transplantation, (iii) switch to intravenous (i.v.) therapy, or (iv) addition of or switch to other active oral therapy. During follow-up (535+/-61 days), 11 patients died, six were transplanted, 25 were switched to i.v. prostanoids, 16 received additional or other oral therapy, and 12 patients discontinued iloprost inhalation for other reasons. Event-free survival at 3, 12, 24, 36, 48, and 60 months was 81, 53, 29, 20, 17 and 13%, respectively. Among haemodynamic and exercise parameters, mixed venous oxygen saturation (P<0.001), right atrial pressure (P<0.001), and peak oxygen uptake (P=0.002) were associated with event-free survival. CONCLUSION: In this study, only a minority of patients could be stabilized with inhaled iloprost mono-therapy during a follow-up period of up to 5 years. In the presence of multiple treatment options, chronic iloprost inhalation as mono-therapy appears to have a limited role.     

Pharmacokinetics and pharmacodynamics of the prostacyclin analogue iloprost in man

Summary Plasma levels of the prostacyclin analogue, iloprost, were measured by antibody/GC/MS in healthy male volunteers given 1 and 3 ng/kg per min i.v. for 45 min, and 1 µg/kg p.o. Following i.v. infusion, the steady-state plasma levels of iloprost were strictly dose-dependent (46±8 pg/ml and 135±24 pg/ml). The disposition was biphasic with half-lives of 3–4 min and 0.5 h. After oral administration, absorption of the drug was extremely rapid, the maximum plasma level of 251±32 pg/ml being achieved after 10±6 min. The bioavailability was 16±4%. Platelet aggregation induced by 2 µM ADP was reduced by 53% and 68% at the end of the two different infusions, and by 68% 15 min after p.o. administration. The ex-vivo inhibition of platelet aggregation by iloprost was not affected by preceding drug treatment. The cAMP content of platelets was increased by a factor of 2.5 at the end of the infusions and to a lesser extent 15 min after oral dosing. A slight increase in heart rate occurred during the infusion and within 30 min after oral administration; blood pressure was virtually unaffected. Except for transient side-effects (facial flush and headache) no adverse reactions were observed.     

伊洛前列素对缺氧性肺动脉高压自由基代谢的影响

目的研究雾化吸入伊洛前列素对缺氧性肺动脉高压（HPH）患者自由基代谢的影响。方法在海拔3700 m、4300 m、5200 m和5380 m高原,对56例HPH患者采用雾化吸入伊洛前列素5μg 1次,吸药前、吸入后即刻采血检测超氧化物歧化酶（SOD）、丙二醛（MDA）、乳酸（BLA）、一氧化氮（NO）及其合酶（NOS）的含量。结果吸入后较吸入前,在海拔3700 m,SOD（90.50±7.13）U/ml vs（73.00±10.51）U/ml、NO（73.64±13.42）μmol/L vs（49.60±11.31）μmol/L、NOS（90.50±7.13）U/ml vs（73.00±10.51）U/ml增高,MDA（4.23±0.71）nmol/ml vs（5.61±1.13）nmol/ml、BLA（1.27±0.25）mmol/L vs（1.79±0.62）mmol/L降低,有非常显著差异（P〈0.01）;在海拔4300 m,SOD（86.78±5.12）U/ml vs（69.39±4.59）U/ml、NO（73.51±6.37）μmol/L vs（48.79±3.76）μmol/L、NOS（44.60±2.64）U/ml vs（40.23±2.31）U/ml增高,MDA（4.24±0.80）nmol/ml vs（6.44±1.51）nmol/ml、BLA（1.46±0.28）mmol/L vs（1.89±0.28）mmol/L降低,有显著差异（P〈0.05或P〈0.01）;在海拔5000 m以上,SOD（86.46±9.05）U/ml vs（66.00±9.95）U/ml、NO（65.50±8.32）μmol/L vs（47.62±11.38）μmol/L、NOS（37.06±2.22）U/ml vs（33.18±2.99）U/ml增高,MDA（6.42±1.59）nmol/ml vs（8.24±2.09）nmol/ml和BLA（2.46±1.24）mmol/L vs（5.18±1.48）mmol/L降低,有非常显著差异（P〈0.01）。结论伊洛前列素可改善HPH患者肺氧合效应,增强机体抗氧化酶活性和乳酸清除能力。     

Medical therapeutics for pulmonary arterial hypertension: from basic science and clinical trial design to evidence-based medicine

Pulmonary arterial hypertension is a severe disease with poor prognosis, caused by obliteration of the pulmonary vasculature as a result of pulmonary-vascular remodeling, active vasoconstriction and in situ thrombosis. Left untreated, pulmonary arterial hypertension results in right-ventricular failure and death. There has been dramatic progress in the treatment of pulmonary arterial hypertension during recent years. A remarkable number of randomized-controlled trials with agents known to target specific abnormalities present in pulmonary arterial hypertension have been completed. Most commonly, therapeutic efficacy was judged by the ability of the drug under study to improve exercise capacity and to decrease the rate of severe complications. Completed clinical trials have mainly evaluated patients with relatively advanced disease. Despite these advances, responses to therapy in pulmonary arterial hypertension are not uniformly favorable and frequently incomplete. In addition, the methods of delivery and the adverse effect profile of the currently available pulmonary arterial hypertension-specific drugs create further management difficulties. Based on newly identified pathobiologic abnormalities in the pulmonary vasculature, future studies are likely to focus on the discovery of new therapeutic targets. Clinical trial design will continue to evolve in an attempt to enable inclusion of patients with less advanced disease and evaluation of treatment combinations or comparisons of the currently approved drugs.     

吸入伊洛前列素在肺动脉高压急性肺血管反应试验中的应用

目的 观察先天性心脏病合并肺动脉高压患者吸入伊洛前列素前后血流动力学变化.方法 34 例先天性心脏病患者,其中房间隔缺损10 例、室间隔缺损19 例、动脉导管未闭2 例、室间隔缺损合并动脉导管未闭2 例、室间隔缺损合并房间隔缺损1 例,均在接受右心导管检查后进行吸入氧气和吸入伊洛前列素试验,记录吸氧前后、吸药前后的血流动力学指标变化.结果 平均肺动脉压吸氧前、吸氧后和吸药后分别为(74.53±12.48)mmHg(1mmHg=0.133kPa),(64.35±14.44)mmHg,(57.41±12.94)mmHg,吸氧及吸药后平均肺动脉压均明显降低,且吸药后更显著(P<0.01) ;全肺阻力吸氧前、吸氧后和吸药后分别为(1 291.85±417.19)dyn/(s·cm5),(958.03±355.83)dyn/(s·cm5),(762.59±296.86)dyn/(s·cm5),吸氧后及吸药后全肺阻力明显降低,且吸药后更显著(P<0.01) ;心脏指数吸氧前、吸氧后和吸药后分别为(2.43±0.44)L/(min·m2),(3.07±0.58)L/(min·m2),(3.34±0.58)L/(min·m2),吸氧及吸药后心脏指数明显增加,且吸药后更显著(P<0.01).同时患者心率及血压均无明显变化.吸氧及吸药试验的阳性率分别是为64.71% 和76.47%,两者比较有统计学差异(P<0.05).结论 与吸氧试验相比,吸入伊洛前列素进行急性肺血管试验可以更好地判断肺血管的反应性.     

吸入伊洛前列素对初入高海拔地区青年自由基代谢的影响

目的观察雾化吸入伊洛前列素溶液对初入高海拔地区青年自由基代谢的影响,为促进高原习服提供新的措施,以预防和治疗急性高原病。方法将32名受试者随机分为伊洛前列素组（n=16）和对照组（n=16）,自海拔1 400 m历时5d进入5 200 m。从进入海拔5 200 m当天开始,伊洛前列素组每天4次雾化吸入伊洛前列素溶液,连续5 d。对照组用同样的方法吸入少量生理盐水。于吸入伊洛前列素溶液生理盐水第5天检测血中超氧化物歧化酶（SOD）、丙二醛（MDA）、乳酸（BLA）、一氧化氮（NO）及一氧化氮合酶（NOS）的含量。结果伊洛前列素组较对照组,SOD、MDA、BLA、NO及NOS差异有统计学意义（P〈0.01）。结论在高海拔地区雾化吸入伊洛前列素溶液能增强移居者抗氧化酶活性和乳酸清除能力,可以促进高原习服、预防和治疗急性高原病。