Gomberg-Maitland Mardi, Schilz Robert, Mediratta Anuj, Addetia Karima, Coslet Sandra, Thomeas Vasiliki, Gillies Hunter, Oudiz Ronald J
Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois, USA ; Committee on Clinical Pharmacology and Pharmacogenomics, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, School of Medicine, Case Western University, Cleveland, Ohio, USA.
Pulm Circ. 2015 Dec;5(4):691-700. doi: 10.1086/683813.
Pulmonary arterial hypertension (PAH) causes right ventricular ischemia, dysfunction, and failure. PAH patients may benefit from antianginal agents based on a shared pathophysiology with left ventricular ischemia. A single-center, randomized, placebo-controlled trial (1∶1) to assess the acute vasoreactivity and safety of ranolazine in PAH was conducted. Plasma samples for pharmacokinetic (PK) studies were drawn during hemodynamic measurements at 0, 60, 90, 120, 240, and 360 minutes from a Swan-Ganz catheter. All patients received 500-mg doses, uptitrated to 1,000 mg at week 4, monthly evaluations, and a complete objective assessment after 12 weeks, followed by an open-label extension. Thirteen patients were randomized and 12 enrolled (6 ranolazine, 6 placebo). All patients completed the acute phase; 10 completed the 12-week study. There were no acute changes in invasive hemodynamics. At 12 weeks ranolazine was well tolerated. Only 1 of the 5 patients on ranolazine had a serum concentration considered to be in the therapeutic range. Two serious adverse events required early withdrawal (both in the ranolazine group); gastrointestinal complaints were the most common adverse event. Efficacy measures did not demonstrate any differences between treatment groups. During the open-label trial, 2 additional patients reached a therapeutic concentration. Ranolazine in PAH appears safe, without acute hemodynamic effects after a 500-mg dose. Ranolazine administrated to PAH patients receiving background PAH therapies did not consistently reach therapeutic levels. Future studies should first perform PK analysis in PAH patients receiving PAH therapies and explore the safety and tolerability of the higher doses perhaps necessary to achieve therapeutic levels in PAH patients. (
Clinicaltrials.gov identifier NCT01757808.).
肺动脉高压（PAH）可导致右心室缺血、功能障碍和衰竭。基于与左心室缺血相同的病理生理学机制，PAH患者可能从抗心绞痛药物中获益。开展了一项单中心、随机、安慰剂对照试验（1∶1），以评估雷诺嗪在PAH中的急性血管反应性和安全性。在血流动力学测量期间，于0、60、90、120、240和360分钟从 Swan-Ganz 导管采集用于药代动力学（PK）研究的血浆样本。所有患者均接受500毫克剂量，第4周时剂量增加至1000毫克，每月进行评估，并在12周后进行全面客观评估，随后进行开放标签扩展研究。13例患者被随机分组，12例入组（6例接受雷诺嗪，6例接受安慰剂）。所有患者均完成急性期；10例完成了12周研究。有创血流动力学无急性变化。12周时，雷诺嗪耐受性良好。接受雷诺嗪治疗的5例患者中只有1例血清浓度被认为处于治疗范围内。2例严重不良事件需要提前退出试验（均在雷诺嗪组）；胃肠道不适是最常见的不良事件。疗效指标未显示治疗组之间存在任何差异。在开放标签试验期间，又有2例患者达到治疗浓度。PAH患者使用雷诺嗪似乎安全，500毫克剂量后无急性血流动力学影响。接受PAH背景治疗的PAH患者使用雷诺嗪后未能持续达到治疗水平。未来研究应首先对接受PAH治疗的PAH患者进行PK分析，并探索可能需要的更高剂量在PAH患者中达到治疗水平的安全性和耐受性。（试验注册号：Clinicaltrials.gov标识符NCT01757808。）
