Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial
Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial
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DOI：
10.1038/jcbfm.2014.23
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发表时间：
2014-05-01
影响因子：
6.3
通讯作者：
Hutchinson, Peter J.
中科院分区：
文献类型：
--
作者：
Helmy, Adel;Guilfoyle, Mathew R.;Hutchinson, Peter J.
创伤性脑损伤（TBI）是40岁以下人群死亡和残疾的最常见原因。白细胞介素-1受体拮抗剂（里拉）是一种内源性竞争性白细胞介素-1受体（IL-1 R）拮抗剂。IL-1 R的拮抗作用在几种神经元损伤的啮齿动物模型（即，创伤、中风和兴奋性中毒）。我们描述了一个单中心，II期，开放标签，随机对照研究重组人IL-1 ra（rhIL-1 ra，阿那白滞素）在严重的TBI，剂量为100毫克皮下注射，每天一次，5天，在20例患者随机1：1。我们提供了这种病理学的安全性数据（主要结局），利用脑微透析直接测定ILI ra和41种细胞因子和趋化因子的脑细胞外浓度，并使用主成分分析（PCA）探索所得的脑细胞因子谱。白细胞介素1受体拮抗剂安全，可渗透入血浆和脑细胞外液。PCA显示IL 1 ra给药后细胞因子谱分离。来自该分析的候选细胞因子，巨噬细胞衍生的趋化因子，在rhIL 1 ra治疗组中显著降低。我们的研究结果为rhIL 1 ra作为治疗候选药物提供了有希望的数据，首次显示了安全性，脑渗透性和对TBI神经炎症反应的修饰，这是一种公认的神经保护剂。
Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (Lira) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in severe TBI, at a dose of 100 mg subcutaneously once a day for 5 days in 20 patients randomized 1:1. We provide safety data (primary outcome) in this pathology, utilize cerebral microdialysis to directly determine brain extracellular concentrations of ILI ra and 41 cytokines and chemokines, and use principal component analysis (PCA) to explore the resultant cerebral cytokine profile. Interleukin-1 receptor antagonist was safe, penetrated into plasma and the brain extracellular fluid. The PCA showed a separation in cytokine profiles after IL1ra administration. A candidate cytokine from this analysis, macrophage-derived chemoattractant, was significantly lower in the rhIL1ra-treated group. Our results provide promising data for rhIL1ra as a therapeutic candidate by showing safety, brain penetration and a modification of the neuroinflammatory response to TBI by a putative neuroprotective agent in humans for the first time.