Translating experimental stroke therapy to patients: determination of optimal dosing and biological efficacy of IL-1ra

中风是全球第三大杀手，也是英国成年人残疾的最常见原因。未来十年，中风造成的死亡人数将增加近一倍。尽管如此，治疗方法很少。许多潜在的新治疗方法的研究都失败了，其中一些是因为没有完全了解治疗是如何起作用的，以及如何最好地给予它。当大脑的血液供应中断时，就会发生中风。这会导致大脑发炎。我们一直在研究一种可能的治疗中风的新方法，称为IL-1ra。IL-1ra是一种自然产生的化学物质的复制品，可以阻止炎症，已经被用于类风湿性关节炎等疾病。它将在中风后不久服用，并通过保护脑细胞免受损害而起作用。我们已经给了一小部分中风患者使用IL-1ra，以检查其安全性。我们正计划进入下一阶段的治疗开发(第三阶段研究)，看看它的效果如何。在此之前，我们希望确保以最好的方式给予正确的剂量。我们已经完成了一项关于IL-1ra如何从血液进入大脑的研究。这项研究是在蛛网膜下腔出血(SAH)患者中进行的，他们从大脑周围通过管道引流液体(脑脊液，CSF)来缓解压力。我们收集了脑脊液样本来测量IL-1ra，发现可能需要长达四个小时才能达到保护水平。中风后，我们需要尽快让足够的IL-1ra进入大脑，以保护它免受损害。在拟议的研究中，我们希望：1.给予不同剂量的IL-1ra，以找到使足够的IL-1ra快速进入脑脊液的剂量。2.使用研究1中发现的剂量，测量IL-1ra对SAH患者脑部炎症的影响。这将通过测量脑脊液样本和脑内炎症标记物(使用一种称为微透析的技术)来完成。对中风患者给予IL-1ra，以检查其是否具有与SAH患者相同的效果。这将确保我们设计出尽可能最安全和最有效的临床试验。

Stroke is the third biggest killer world wide and the most common cause of adult disability in the UK. Deaths caused by stroke will nearly double in the next decade. Despite this, there are few treatments.Many studies of potential new treatments have failed, some because it was not fully understood how the treatment worked and how best to give it.A stroke occurs when the blood supply to the brain is disrupted. This causes inflammation in the brain. We have been working on a possible new treatment for stroke, called IL-1ra. IL-1ra is a copy of a naturally occurring chemical that blocks inflammation and is already used in diseases like rheumatoid arthritis. It would be given soon after a stroke and would work by protecting brain cells from damage. We have given IL-1ra to a small number of stroke patients to check that is safe. We are planning to move on to the next stage of developing the treatment (Phase III study) to see how effective it is. Before we do this we want to be sure we are giving the right dose, in the best way.We have completed a study which looked at how the IL-1ra gets into brain from the blood stream. This study was done in patients with subarachnoid haemorrhage (SAH) who had a tube draining fluid (cerebrospinal fluid, CSF) from around the brain to relieve pressure. We collected samples of the CSF to measure IL-1ra and found that it can take up to four hours to reach protective levels. After a stroke we need to get enough IL-1ra into the brain as quickly as possible to protect it from damage. In the proposed studies we want to:1. Give different amounts of IL-1ra to find the dose that gets enough IL-1ra into the CSF quickly. 2. Measure the effect of IL-1ra on inflammation in the brain of patients with SAH, using the dose found in study 1. This will be done by measuring markers of inflammation in samples of CSF and from within the brain (using a technique called microdialysis).3. Give IL-1ra to patients with stroke to check whether it is having the same effect as in patients with SAH. This will ensure that we design the safest and most effective clinical trial that we can.