Developing and commercialising a non-invasive test of adrenal insufficiency for children on steroids.

肾上腺位于肾脏上方，是人体内分泌系统的一部分，产生至关重要的应激激素皮质醇。肾上腺功能不全(AI)是指身体无法产生足够的皮质醇水平，如果不治疗，会导致循环衰竭和肾上腺危象而死亡。由于非特异性症状，AI的诊断经常被漏诊。在英国，人工智能的原因包括爱迪生病(肾上腺炎)、脑瘤和类固醇治疗炎症性疾病(如关节炎、哮喘、癌症)引起的肾上腺抑制。在全球范围内，主要原因是结核病和艾滋病。人工智能通常是永久性的，但在服用类固醇药物的患者中，它可能是暂时的，需要重复检测。人们对与类固醇使用相关的人工智能的担忧正在上升，所有医学专科都广泛开出了有效的类固醇处方，并认识到所有类固醇都会导致人工智能。2020年8月，NHS国家患者安全局发布了一项警报，要求英国医疗机构向所有有AI风险的患者发放类固醇急救卡，包括那些服用吸入性类固醇的患者。近50万英国儿童被开出吸入类固醇(预防药物)治疗哮喘的处方，其中许多人的剂量超过了推荐剂量。短突触测试(SST)是全球最受欢迎的人工智能诊断测试。Synacten刺激肾上腺产生皮质醇。在服用Synacten之前和服用后30-60分钟进行血液测试，以测量皮质醇的上升。SST是侵入性的，需要静脉插管和采血，由于需要技术人员和医院日托入院，因此需要大量资源。这导致调查门槛提高和诊断延迟，特别是在儿童中，将患者置于肾上腺危机的风险中。实际的挑战是识别、诊断和治疗患有类固醇过量和人工智能的患者。埃尔德博士开展了一项基础性工作，开发了一种新的非侵入性人工智能检测方法，名为“纳沙辛测试”，通过鼻腔喷雾给药，并在唾液样本上测量产生的皮质醇反应。这将使儿童能够在家中或在诊所进行调查，而不需要住院和抽血。这种新药是将四糖与壳聚糖结合在一起，壳聚糖是一种鼻用药物增强剂，有助于从鼻子吸收进入血液。到目前为止，该团队已经完成了五项试点临床试验，测试了不同的剂量和配方(混合物)，并发现新药Nasachim在儿童中被可靠地吸收和良好的耐受性。这种非侵入性的Nasachim测试将允许早期诊断，防止肾上腺危机，并帮助儿科医生了解类固醇造成的疾病负担。面临的挑战是制定临床开发计划并将Nasachim商业化。在批准在临床实践中使用Nasachim测试之前，还需要进行进一步的临床研究。不同年龄和性别的健康儿童对纳沙西汀的反应需要数据，以使医生能够确定皮质醇阈值在新测试中是通过还是不通过。目前，SST的诊断阈值来自成人数据，该项目将在儿童中建立第一个正常范围。这对医生来说很重要，让他们对新的测试有信心，并将促进临床实践的采用。作为一家专注于开发人工智能疗法的领先国际内分泌学公司，Diural是帮助Dr Elder的理想选择，该公司拥有经验丰富的临床、监管和商业团队。埃尔德博士被借调到日间工作，将使她的职业生涯得到发展，提高她在药物开发方面的技能。它将把一种新产品推向市场，使英国经济受益，并为减少使用吸入性和其他类固醇的儿童的疾病负担和死亡风险做出重大贡献。

The adrenal glands sit above the kidneys and are part of the body's endocrine system and produce the vital stress hormone cortisol. Adrenal insufficiency (AI) is the inability of the body to produce adequate cortisol levels and, untreated, leads to circulatory collapse and death through adrenal crisis. Diagnosis of AI is frequently missed due to non-specific symptoms. Causes of AI in UK include Addison's disease (adrenalitis), brain tumours and adrenal suppression from steroid medication for inflammatory conditions (e.g. arthritis, asthma, cancers). Globally major causes are TB and AIDS. AI is usually permanent but in patients taking steroid medication, it may be temporary necessitating repeated testing. Concern about AI related to steroid use is rising, with widespread prescription of potent steroids in all medical specialties and recognition that all steroids can cause AI. In August 2020 the NHS National Patient Safety Agency released an alert for UK healthcare organisations to issue Steroid Emergency Cards to all patients at risk of AI, including those on inhaled steroids. Nearly half a million UK children are prescribed inhaled steroids (preventers) for asthma, many on doses exceeding recommendations. The Short Synacthen Test (SST) is the most popular diagnostic test for AI worldwide. Synacthen stimulates the adrenal glands to produce cortisol. Blood tests are taken before Synacthen is given and 30-60 minutes after in order to measure the rise in cortisol. The SST is invasive, requiring intravenous cannulation and blood sampling, and resource-intensive due to the need for skilled personnel and a hospital day-care admission. This leads to raised thresholds for investigation and delayed diagnosis, especially in children, putting patients at risk of adrenal crisis. The practical challenge is identifying, diagnosing and treating patients suffering from steroid excess and AI. Dr Elder has undertaken fundamental work developing a new non-invasive test for AI, "The Nasacthin Test", with the drug, tetracosactide (Synacthen), given via a nasal spray and the resultant cortisol response measured on saliva samples. This will enable the investigation of children at home or in clinic, without requirement for hospital attendance and blood sampling. The new drug is a combination of tetracosactide with chitosan, a nasal drug enhancer, which aids absorption from the nose into the bloodstream. To date the team have completed five pilot clinical trials testing different doses and formulations (mixtures) and found the new drug, Nasacthin, to be reliably absorbed and well tolerated in children. The non-invasive Nasacthin test will allow early diagnosis, prevent adrenal crisis and help paediatricians understand the burden of disease created by steroids. The challenge is creating a clinical development plan and commercialising Nasacthin. Before approval to use the Nasacthin test in clinical practice further clinical studies are required. Data are required on the response to Nasacthin in healthy children of different ages and sex to enable doctors to define what cortisol threshold constitutes a 'pass' or a 'fail' on the new test. Currently the diagnostic thresholds for the SST are derived from adult data and this project will establish the first normal ranges in children. This is important for doctors to have confidence in the new test and will facilitate adoption into clinical practice. Diurnal is ideally placed to help Dr Elder as a leading international endocrinology company focused on developing therapies for AI with experienced clinical, regulatory and commercial teams. Dr Elder's secondment to Diurnal will allow progression of her career, boosting her skills in drug development. It will bring a new product to market, to benefit the UK economy, and make a major contribution to the reduction in disease burden and risk of death of children using inhaled and other steroids.