Oregon Anesthesiology Group, Portland, OR, USA.
Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA.
Neurocrit Care. 2022 Jun;36(3):905-915. doi: 10.1007/s12028-021-01398-8. Epub 2021 Dec 6.
Epoxyeicosatrienoates (EETs) are endogenous regulators of neuroinflammation and cerebral blood flow. Their metabolism to dihydroxyeicosatrienoates (DHETs) is catalyzed by soluble epoxide hydrolase (sEH). After subarachnoid hemorrhage (SAH), EETs' pathway amplification may be a therapeutic target for the prevention of delayed cerebral ischemia (DCI). We conducted a double-blind, placebo-controlled, phase Ib randomized trial of GSK2256294, a pharmacologic inhibitor of sEH, to evaluate the safety profile and to assess biomarkers of neurovascular inflammation in patients with aneurysmal SAH.
Patients were randomly assigned to receive 10 mg of GSK2256294 or a placebo treatment once daily for 10 days, beginning within 72 hours after aneurysm rupture. The primary study end point was safety. Secondary end points included serum and cerebrospinal fluid (CSF) EETs-to-DHETs ratio, cytokine levels, and serum endothelial injury biomarkers, measured at day 7 and day 10 after SAH. Tertiary end points included neurologic status, disposition, length of stay, incidence of DCI, and mortality; these were assessed at hospital discharge and at 90 days.
Ten patients received GSK2256294 and nine patients received a placebo. There were no adverse events related to the study drug. GSK2256294 administration resulted in a significant increase in the EET/DHET ratio at day 7 and day 10 in serum, but not in the CSF. There was a trend for decreased CSF inflammatory cytokines following GSK2256294 administration, but this did not reach statistical significance.
GSK2256294 administration was safe and well tolerated in critically ill patients with SAH, producing an increase in serum EETs and the EET-to-DHET ratio. Our findings support future studies in a larger population to evaluate the role of sEH inhibition in the prevention of DCI after SAH and other forms of brain injury and inflammatory conditions.
ClinicalTrials.gov: NCT03318783.
环氧二十碳三烯酸（EETs）是神经炎症和脑血流的内源性调节剂。它们代谢为二羟二十碳三烯酸（DHETs）是由可溶性环氧化物水解酶（sEH）催化的。蛛网膜下腔出血（SAH）后，EETs 途径的放大可能是预防迟发性脑缺血（DCI）的治疗靶点。我们进行了一项双盲、安慰剂对照、Ib 期随机试验，研究了 sEH 的药理学抑制剂 GSK2256294，以评估其安全性，并评估动脉瘤性 SAH 患者的神经血管炎症的生物标志物。
患者在动脉瘤破裂后 72 小时内，随机分为每日接受 10mg GSK2256294 或安慰剂治疗 10 天。主要研究终点为安全性。次要终点包括血清和脑脊液（CSF）EETs-DHETs 比值、细胞因子水平和 SAH 后第 7 天和第 10 天的血清内皮损伤生物标志物。次要终点包括神经状态、处置、住院时间、DCI 发生率和死亡率；这些在出院时和 90 天时进行评估。
10 名患者接受了 GSK2256294 治疗，9 名患者接受了安慰剂治疗。没有与研究药物相关的不良事件。GSK2256294 给药在第 7 天和第 10 天在血清中显著增加了 EET/DHET 比值，但在 CSF 中没有增加。GSK2256294 给药后 CSF 中的炎症细胞因子呈下降趋势，但未达到统计学意义。
在患有 SAH 的危重症患者中，GSK2256294 给药安全且耐受良好，可增加血清 EETs 和 EET/DHET 比值。我们的研究结果支持在更大的人群中进行进一步的研究，以评估 sEH 抑制在预防 SAH 后和其他形式的脑损伤和炎症状态下的 DCI 中的作用。
ClinicalTrials.gov：NCT03318783。
