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

MICA：评估 11β-羟基类固醇脱氢酶 1 型抑制剂 (AZD4017) 对特发性颅内高压的治疗效果

• 批准号: MR/K015184/1
• 负责人: Alexandra Sinclair
• 金额: $ 52.01万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK015184%2F1
• 关键词: MICA; Assessing; therapeutic; efficacy; 11beta

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.

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还没有被证明是有效的，而且还有无法忍受的副作用。脑液分流手术可以用来挽救视力，但分流手术阻塞了超过一半的患者，因此需要多次更换。减肥等治疗方法是出了名的难。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。11β-羟基类固醇脱氢酶1(11β-HSD1)在大脑产生脑脊液(CSF)的部分产生活性类固醇。脑脊液是洗脑的液体。产生过多的脑脊液会导致IIH的脑压力增加，我们认为11beta-HSD1推动了IIH的这一过程。此外，我们已经证明，显著改善IIH的体重减轻和脑压力降低也降低了11β-HSD1的活性。因此，我们建议，通过口服AZD4017(阿斯利康开发的11β-HSD1的抑制剂)片剂来降低11β-HSD1，可能代表着IIH的一种里程碑式的治疗。通过阿斯利康和伯明翰大学的合作，我们将进行一项随机、盲目的临床研究(24名患者)，以观察AZD4017在治疗IIH中的有效性、安全性和副作用。在为期3个月的研究开始和结束时，患者将接受一系列检查，以评估脑压(通过腰椎穿刺法)、视力和头痛。我们还将定期监测尿液和血液，同时对患者进行详细的评估，以评估药物的安全性和副作用。这将是第一项研究，探讨11β-HSD1抑制剂在IIH中的作用，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可能会在其他神经系统疾病中使用，这些疾病的发病率与大脑压力升高有关。

项目成果

Headache, Opiate Use, and Prescribing Trends in Women With Idiopathic Intracranial Hypertension: A Population-Based Matched Cohort Study.

• DOI: 10.1212/wnl.0000000000201064
• 发表时间: 2022-10-31
• 期刊: Neurology
• 影响因子: 9.9
• 作者: Adderley NJ;Subramanian A;Perrins M;Nirantharakumar K;Mollan SP;Sinclair AJ
• 通讯作者: Sinclair AJ

The Health Economic Evaluation of Bariatric Surgery Versus a Community Weight Management Intervention Analysis from the Idiopathic Intracranial Hypertension Weight Trial (IIH:WT).

• DOI: 10.3390/life11050409
• 发表时间: 2021-04-30
• 期刊: Life (Basel, Switzerland)
• 作者: Aguiar M;Frew E;Mollan SP;Mitchell JL;Ottridge RS;Alimajstorovic Z;Yiangou A;Singhal R;Tahrani AA;Sinclair AJ
• 通讯作者: Sinclair AJ

Additional file 1: Table S1. of Segmentation error in spectral domain optical coherence tomography measures of the retinal nerve fibre layer thickness in idiopathic intracranial hypertension

附加文件 1：表 S1。

• DOI: 10.6084/m9.figshare.5755764
• 发表时间: 2018
• 作者: Anuriti Aojula

Dysregulation of Amino Acid, Lipid, and Acylpyruvate Metabolism in Idiopathic Intracranial Hypertension: A Non-targeted Case Control and Longitudinal Metabolomic Study.

• DOI: 10.1021/acs.jproteome.2c00449
• 发表时间: 2023-04-07
• 期刊: JOURNAL OF PROTEOME RESEARCH
• 影响因子: 4.4
• 作者: Alimajstorovic, Zerin;Mollan, Susan P.;Grech, Olivia;Mitchell, James L.;Yiangou, Andreas;Thaller, Mark;Lyons, Hannah;Sassani, Matilde;Seneviratne, Senali;Hancox, Thomas;Jankevics, Andris;Najdekr, Lukas;Dunn, Warwick;Sinclair, Alexandra J.
• 通讯作者: Sinclair, Alexandra J.

MOESM2 of Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile communicating hydrocephalus

具有直接细胞病理学验证的弥散张量成像的 MOESM2：实验性青少年交通性脑积水中核心蛋白聚糖治疗的特征

• DOI: 10.6084/m9.figshare.c.3619607_d1
• 发表时间: 2016
• 作者: Anuriti Aojula