可溶性鸟苷酸环化酶激动剂在PAH与CTEPH中的治疗研究进展课件.ppt

1、1Hossein-Ardeschir Ghofrani University of Giessen Lung CenterKerckhoff Heart and Lung Center Bad Nauheimwww.UGLC.de23口口服服可可溶性溶性鸟苷酸鸟苷酸环化酶激动剂环化酶激动剂（soluble guanylate cyclase，sGC)。不不依赖于一氧化氮（依赖于一氧化氮（Nitric oxide，NO)。着着眼于简化的眼于简化的sGC结构结构。提高提高sGC对低水平生物活性对低水平生物活性NO的敏感性。的敏感性。在在实验动物研究中已证实其抗血血管重塑实验动物研究中已证实其抗血血

2、管重塑特性。特性。在在健康志愿者（临床试验阶段健康志愿者（临床试验阶段I）与肺动脉）与肺动脉高压患者中已证实其有效性及安全性高压患者中已证实其有效性及安全性(概念概念验证验证。Stasch JP et al.Nature 2001;410:21215;Evgenov OV et al.Circulation 2004;110:22539;Dumitrascu R et al.Circulation 2006;113:28695;Evgenov OV et al.Nat Rev Drug Discov 2006;5:75568;Schermuly et al.Eur Respir J 2008

3、Jun 11;Frey et al.J Clin Pharmacol 2008;48:92634 收缩 压力 流速 舒张 压力 流速sGC*RiociguatcGMP*native(intact)NOPDE-5-I=phosphodiesterase-5-inhibitor NO=mitroc oxide5MCTRiociguatNPMNPM+NPM+NPM+血血管肌化管肌化MCT21 daysMCT35 days*020406080100Rats2070 m percentage oftotal vessel count*p 0.05 versus control animals witho

4、ut PH;p 0.05 versus untreated animals with PH at day 35.N,non-muscularized;P,partially muscularized;M,fully muscularized.Schermuly et al.,ERJ 20086BAY 63-2521iNO*p 0.05p 0.001p 0.0001Grimminger et al.,ERJ 20097 BAY 63-2521 sGC Stimulator BAY 63-2521iNOp 100 mmHg,SBP 100 mmHg,提提高高剂量剂量 (+0.5 mg t.i.d.

5、)(+0.5 mg t.i.d.)当谷当谷值值 SBP 90100 mmHg,SBP 90100 mmHg,维持维持剂量剂量 当谷当谷值值 SBP 90 mmHg SBP 90 mmHg 但但没没有有低低血血压压症状，症状，减少减少剂量剂量(0.5 mg t.i.d.)(0.5 mg t.i.d.)当谷当谷值值 SBP 90 mmHg SBP 90 mmHg 有有低低血血压压症症状状,减少减少剂量剂量(0.5 mg t.i.d.(0.5 mg t.i.d.)2424小时后重新开始小时后重新开始2.5 mg t.i.d.2.0 mg t.i.d.1.5 mg t.i.d.1 mg t.i.d.W

6、eek 2Week 4Week 6Week 8 Week 12Day 1121314Baseline valuesPAH:316.7 127.4;CTEPH:382.9 88.1;All:354.4 111.0020406080100Baseline24681012Duration of treatment(weeks)Change in 6-minute walking distance(m)AllPAHCTEPHTitration phasen=72n=31n=4115*p 0.05;*p 0.00114121086420PAHCTEPHAllMean decrease from base

7、line in pulmonary arterial pressure(mmHg)500450400350300250200150100500PAHCTEPHAllMean decrease from baseline in pulmonary vascular resistance(dyn.s/cm5)n=20n=30n=50n=19n=29n=48*16CTEPH,chronic thromboembolic pulmonary hypertension;NYHA,New York Heart Association;PAH,pulmonary arterial hypertensionn

8、=31n=41n=721616周后周后6 6分钟步行实验的基线变化分钟步行实验的基线变化*SecondarySecondary outcome in extension,outcome in extension,*primary primary outcome in extension;outcome in extension;p.op.o.:per.:per osos-oral;TID:three times daily;-oral;TID:three times daily;NT-pro BNP:N-terminal pro brain NT-pro BNP:N-terminal pro

9、brain natriureticnatriuretic peptide;EQ-5D:quality-of-life measures;MLHF-peptide;EQ-5D:quality-of-life measures;MLHF-Q:Minnesota Living with Heart Failure Q:Minnesota Living with Heart Failure Questionnaire Questionnaire 初级结果初级结果肺肺血血阻力的基线变化，血血阻力的基线变化，WHOWHO功能分级的基线功能分级的基线变化，变化，NT-pro BNPNT-pro BNP的的基

10、线变化，基线变化，Borg Borg 评评分分量表的基线变化，量表的基线变化，EQ-5D EQ-5D 与与 MLHF-QMLHF-Q的的基线变基线变化化,临临床情况恶化的时间床情况恶化的时间安安全性全性*次次级结果级结果CHEST-1 与与-21616周后周后6 6分钟步行实验的基线变化分钟步行实验的基线变化*Secondary outcome in extension,*primary outcome in extension;p.o.:per os-oral;TID:three times daily;NT-pro BNP:N-terminal pro brain natriuretic

11、peptide;EQ-5D:quality-of-life measures;MLHF-Q:Minnesota Living with Heart Failure Questionnaire 初级结果初级结果肺肺血血阻力的基线变化，血血阻力的基线变化，WHOWHO功能分级的基线功能分级的基线变化，变化，NT-pro BNPNT-pro BNP的的基线变化，基线变化，Borg Borg 评评分分量表的基线变化，量表的基线变化，EQ-5D EQ-5D 与与 MLHF-QMLHF-Q的的基线变基线变化化,临临床情况恶化的时间床情况恶化的时间安安全性全性*次次级结果级结果FilingPhase III

12、Phase IIPH with ILD 2011eTbd.FactsStudyCHEST-1/-2 270 patients vs placebo(CHEST-1);Efficacy study and Long-term extensionChronic Thromboembolic Pulmonary HypertensionPhase INCT00694850(PH with ILD)NCT00640315(PH with COPD)20 patients(PH with interstitial lung disease-ILD)proof-of-concept;efficacy an

13、d dose-findingPH with COPD 20 patients(PH with Chronic Obstructive Pulmonary Disease-COPD)Single-dose hemodynamic studyTbd.Pulmonary Arterial Hypertension2011e 460 patients(treatment-nave or pre-treated)vs.placebo(PATENT-1);Efficacy study and Long-term extensionPATENT-1/-2 PH=pulmonary hypertensionC

14、HEST=Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial PATENT=Pulmonary Arterial Hypertension sGC-Stimulator Trial20 Riociguat可明显改善可明显改善 PAH与与CTEPH 患患者的肺者的肺循环动力学与功能循环动力学与功能 减少减少PVR/SVR比率比率 提高提高6分钟步行距离分钟步行距离 改善改善心功能（心功能（NYHA）Riociguat被使用于被使用于CTEPH与与PAH的的3个临床试个临床试验的两个阶段验的两个阶段(CHEST and PATENT)期待着更多的有益发现期待着更多的有益发现(比如：比如：ILD-PH,COPD-PH,PVH)