Ring Arne, Morris Tom, Wozniak Marcin, Sullo Nikol, Dott William, Verheyden Veerle, Kumar Tracy, Brunskill Nigel, Vaja Rakesh, Murphy Gavin J
University of the Free State, Bloemfontein, South Africa.
medac GmbH, Wedel, Germany.
Br J Clin Pharmacol. 2017 Apr;83(4):709-720. doi: 10.1111/bcp.13162. Epub 2016 Dec 1.
Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio , Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre-clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients.
We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil.
Thirty-six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC 537 ng h ml , C 189.4 ng ml and t 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post-surgery nitric oxide bioavailability.
Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery.
急性肾损伤（AKI）是心脏手术常见且严重的并发症。目前尚无有效的预防或治疗方法。磷酸二酯酶5抑制剂西地那非柠檬酸盐（Revatio，辉瑞公司）在临床前研究中可预防心脏手术后的AKI，但有症状的心血管疾病患者禁用。本研究的目的是评估静脉注射西地那非在心脏手术患者中的安全性和药代动力学。
我们进行了一项开放标签、剂量递增研究，每个剂量水平纳入6名患者。六个剂量分别为2.5毫克、5毫克或10毫克静脉推注，单独使用或随后再静脉输注2.5毫克西地那非2小时。
36名患者进入试验，其中33名完成试验。平均年龄为69.9岁。1名患者在手术期间死亡，另外2名在给药前退出试验（均为5毫克 + 2.5毫克剂量水平）。西地那非的药代动力学特征与先前发表的研究相似。对于10毫克静脉推注后再2小时内输注2.5毫克的剂量，结果为AUC 537纳克·小时/毫升、Cmax 189.4纳克/毫升和t1/2 10.5小时。该药物耐受性良好，未出现与药物给药相关的严重不良事件。较高剂量的西地那非可使术后一氧化氮生物利用度稳定。
体外循环期间西地那非的药代动力学与其他患者群体相当。该药物在治疗血浆水平下耐受性良好。这些结果支持进一步评估西地那非预防心脏手术中AKI的作用。
