MICA: Assessing the therapeutic efficacy of 11beta-hydroxysteroid dehydrogenase type 1 inhibitor (AZD4017) in idiopathic intracranial hypertension

特发性颅内高压（IIH）是一种脑压升高的情况，是年轻超重女性失明的常见原因。这种情况的根本原因尚未完全确定，治疗IIH的最佳方法尚不清楚。像乙酰唑胺这样的药物没有被证明是有效的，而且还有难以忍受的副作用。脑液分流手术可用于挽救视力，但分流器在一半以上的患者中堵塞，因此需要更换，通常是多次更换。减肥之类的治疗是出了名的困难。我们最近的研究强调了一种在脑组织中局部产生类固醇的酶的潜在作用。1型β -羟基类固醇脱氢酶（11β - hsd1）在大脑中产生脑脊液（CSF）的部分产生活性类固醇，脑脊液是浸泡在大脑中的液体。脑脊液分泌过多可导致IIH患者脑压升高，我们认为11β - hsd1在IIH中推动了这一过程。此外，我们已经证明，体重减轻和脑压降低可以显著改善IIH，也可以降低11β - hsd1的活性。因此，我们认为口服AZD4017片（阿斯利康开发的11β - hsd1抑制剂）降低11β - hsd1可能是IIH的里程碑式治疗。通过阿斯利康和伯明翰大学的合作，我们将进行一项随机、盲法临床研究（24例患者），以观察AZD4017治疗IIH的有效性、安全性和副作用。在为期3个月的研究开始和结束时，患者将接受一系列调查，以评估脑压（通过腰椎穿刺）、视力和头痛。我们还将定期监测尿液和血液，并对患者进行详细评估，以评估药物安全性和副作用。这将是第一个研究11β - hsd1抑制剂在IIH中的作用的研究，并有可能为这种可能导致失明的疾病提供一种新的治疗方法。此外，如果有效，AZD4017可能用于其他神经系统疾病，其中发病率与脑压升高有关。

Idiopathic intracranial hypertension (IIH), a condition of raised brain pressure, is a common cause of blindness in young overweight women. The underlying cause of the condition has not been fully established and the best way to treat IIH is not known. Drugs such as acetazolamide, have not been shown to be effective and additionally have intolerable side effects. Brain fluid shunting surgery can be used to save vision, but shunts block in over half of patients and therefore need replacing, often multiple times. Treatments such as weight loss are notoriously difficult. Our recent research has highlighted the potential role of an enzyme that generates steroid locally in brain tissues. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) generates active steroid within the parts of the brain that produce cerebrospinal fluid (CSF) - the fluid that bathes the brain. Production of too much CSF can lead to increased brain pressure in IIH and we believe that 11beta-HSD1 drives this process in IIH. Additionally, we have demonstrated that weight loss and brain pressure reduction which significantly improve IIH also reduced 11beta-HSD1 activity. We therefore suggest that reducing 11beta-HSD1, with an oral tablet of AZD4017 (an inhibitor of 11beta-HSD1 developed by AstraZeneca) may represent a landmark treatment for IIH.Through a partnership between AstraZeneca and University of Birmingham we will conduct a randomised, blinded, clinical study (24 patients) to look at the effectiveness, safety and side effects of AZD4017 in the treatment of IIH. Patients will undergo a series of investigations to assess brain pressure (through a lumbar puncture), vision and headaches at the start and end of the 3 month study. We will also be conducting regular monitoring of urine and blood alongside detailed patient assessments to evaluate drug safety and side effects.This will be the first study to investigate the role of 11beta-HSD1 inhibitors in IIH and has the potential to offer a novel treatment in this condition which can cause blindness. Additionally, if effective, AZD4017 may have uses in other neurological conditions where the morbidity is related to elevated brain pressure.