Background:PDE1 (phosphodiesterase type 1) hydrolyzes cyclic adenosine and guanosine monophosphate. ITI-214 is a highly selective PDE1 inhibitor that induces arterial vasodilation and positive inotropy in larger mammals. Here, we assessed pharmacokinetics, hemodynamics, and tolerability of single-dose ITI-214 in humans with stable heart failure with reduced ejection fraction.Methods:Patients with heart failure with reduced ejection fraction were randomized 3:1 to 10, 30, or 90 mg ITI-214 single oral dose or placebo (n=9/group). Vital signs and electrocardiography were monitored predose to 5 hours postdose and transthoracic echoDoppler cardiography predose and 2-hours postdose.Results:Patient age averaged 54 years; 42% female, and 60% Black. Mean systolic blood pressure decreased 3 to 8 mm Hg (P<0.001) and heart rate increased 5 to 9 bpm (P≤0.001 for 10, 30 mg doses, RM-ANCOVA). After 4 hours, neither blood pressure or heart rate significantly differed among cohorts (supine or standing). ITI-214 increased mean left ventricular power index, a relatively load-insensitive inotropic index, by 0.143 Watts/mL²·10⁴ (P=0.03, a +41% rise; 5–71 CI) and cardiac output by 0.83 L/min (P=0.002, +31%, 13–49 CI) both at the 30 mg dose. Systemic vascular resistance declined with 30 mg (–564 dynes·s/cm–⁵, P<0.001) and 90 mg (–370, P=0.016). Diastolic changes were minimal, and no parameters were significantly altered with placebo. ITI-214 was well-tolerated. Five patients had mild-moderate hypotension or orthostatic hypotension recorded adverse events. There were no significant changes in arrhythmia outcome and no serious adverse events.Conclusions:Single-dose ITI-214 is well-tolerated and confers inodilator effects in humans with heart failure with reduced ejection fraction. Further investigations of its therapeutic utility are warranted.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03387215.

中文翻译：

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ITI-214抑制磷酸二酯酶1对人类收缩性心力衰竭的急性血流动力学影响和耐受性

背景：PDE1（1 型磷酸二酯酶）水解环状腺苷和鸟苷一磷酸。ITI-214 是一种高度选择性的 PDE1 抑制剂，可在较大的哺乳动物中诱导动脉血管舒张和正性肌力作用。在这里，我们评估了单剂量 ITI-214 在射血分数降低的稳定心力衰竭患者中的​​药代动力学、血流动力学和耐受性。方法：射血分数降低的心力衰竭患者按 3:1 随机分配至 10、30 或 90 mg ITI-214 单次口服剂量或安慰剂（n=9/组）。在给药前至给药后 5 小时监测生命体征和心电图，在给药前和给药后 2 小时进行经胸超声多普勒心电图监测。结果：患者平均年龄 54 岁；42% 女性，60% 黑人。平均收缩压降低 3 至 8 mm Hg ( P<0.001) 和心率增加 5 至 9 bpm ( P ≤0.001 10, 30 mg 剂量, RM-ANCOVA)。4 小时后，两组（仰卧位或站立位）的血压或心率均无显着差异。ITI-214 使平均左心室功率指数（一种对负荷相对不敏感的正性肌力指数）增加 0.143 Watts/mL ² ·10 ⁴（P =0.03，增加 +41%；5–71 CI）和心输出量增加 0.83 L/ min ( P =0.002, +31%, 13–49 CI) 均为 30 mg 剂量。全身血管阻力随 30 mg (–564 dynes·s/cm– ⁵ , P <0.001) 和 90 mg (–370, P=0.016）。舒张压变化很小，安慰剂没有显着改变参数。ITI-214 耐受性良好。五名患者有轻度中度低血压或直立性低血压记录的不良事件。心律失常结果没有显着变化，也没有严重的不良事件。结论：单剂量 ITI-214 对射血分数降低的心力衰竭患者具有良好的耐受性和扩张作用。有必要对其治疗效用进行进一步调查。注册：URL：https://www.clinicaltrials.gov；唯一标识符：NCT03387215。