A NOVEL THERAPEUTIC MODALITY FOR CONGENITAL ADRENAL HYPERPLASIA

先天性肾上腺增生症的新治疗方式

• 批准号: 7950638
• 负责人: MOREY W HAYMOND
• 金额: $ 1.21万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950638
• 关键词: Acne; Adolescent; Adrenal Glands; Adult; Adverse effects; Androgen Suppression; Bolus Infusion; Child; Chronic; Circadian Rhythms; Clinical; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Congenital adrenal hyperplasia; Corticotropin; Dose; Elements; Excretory function; Face; Funding; Glucocorticoids; Grant; Growth; Height; Hormonal; Hormones; Hour; Hydrocortisone; Hydroxyprogesterone; Infertility; Infusion Pumps; Infusion procedures; Institution; Insulin; Ketosteroids; Life; Maintenance Therapy; Measurement; Measures; Methods; Modality; Oral; Oral Administration; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Physiological; Plasma; Precocious Puberty; Production; Progesterone; Protocols documentation; Qualifying; Quality of life; Recommendation; Reporting; Research; Research Personnel; Resources; Route; Serum; Side; Sodium Chloride; Source; Steroids; Tablets; Testing; Testosterone; Time; Treatment Protocols; United States National Institutes of Health; bone age; clinical practice; improved; male; novel therapeutics; premature adrenarche; prevent; response; standard care; subcutaneous; urinary; wasting; Acne; Adolescent; Adrenal Glands; Adult; Adverse effects; Androgen Suppression; Bolus Infusion; Child; Chronic; Circadian Rhythms; Clinical; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Congenital adrenal hyperplasia; Corticotropin; Dose; Elements; Excretory function; Face; Funding; Glucocorticoids; Grant; Growth; Height; Hormonal; Hormones; Hour; Hydrocortisone; Hydroxyprogesterone; Infertility; Infusion Pumps; Infusion procedures; Institution; Insulin; Ketosteroids; Life; Maintenance Therapy; Measurement; Measures; Methods; Modality; Oral; Oral Administration; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Physiological; Plasma; Precocious Puberty; Production; Progesterone; Protocols documentation; Qualifying; Quality of life; Recommendation; Reporting; Research; Research Personnel; Resources; Route; Serum; Side; Sodium Chloride; Source; Steroids; Tablets; Testing; Testosterone; Time; Treatment Protocols; United States National Institutes of Health; bone age; clinical practice; improved; male; novel therapeutics; premature adrenarche; prevent; response; standard care; subcutaneous; urinary; wasting

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction: The standard oral glucocorticosteroid and mineralocorticosteroid therapy of children with congenital adrenal hyperplasia (CAH&) is non-physiological. Using our standard care, patients face both over-treatment and under-treatment throughout each day and across time. Over-treatment with steroids stunts growth and may cause Cushingold features. Under-treatment results in persistent hyperandrogenemia, which accelerates growth, bone age advancement and early fusion of growth centers leading to significantly impaired final adult height. Hyperandrogenemia also causes premature adrenarche, precocious puberty, infertility, acne, and hirutism. All these side effects of the current treatment reduce the qualify of life of these patients. Therefore CAH remained sub-optimally managed and a search for improvement of therapy is clearly justified. Background: The ideal therapy shuld provide the smallest replacement dose of glucocorticoid to effectively suppress the abnormal steroid side pathways. The LWPES/ESPE concensus statement recommendation is to give 10-15 mg/m2/day hydrocortisone, as maintenance therapy. Recent studies have reported total daily cortisol production in healthy pre pubertal males of 6.1+/-0.4 mg/m2/day and in pubertal males 5.3+/-0.5 mg/m2/day (2). However, in the clinical practice suppression of the androgen production frequently requires 15-25 mg/m2/day of hydrocortisone, which is excessive compared to the cortisol production rates measured in healthy children (-7 mg/m2/day) (3,4). Besides the right dose, the other key elements of successful cortisol therapy are, the timing of the dose and the route of administration used. Wallace et al. confirmed normal circadian rhythm of ACTH and cortisol secretion in normal children and the 24-hour cortisol profile displayed continuous basal cortisol secretion, as well (6). The oral administration (taking cortisol tablets two or three times a day) represents intermittent cortisol delivery and cannot mimic the continuous cortisol production of a healthy adrenal gland. In addition, the time when the medication is taken during the day is very much different from the times when the natural bursts of ACTH and cortisol production occur. The lack of a physiologic means of administering cortisol has tremendous clinical consequences including poor overall hormone control and reduced quality of life in the vast majority of patients. Objective: To develop a more physiologic approach to the management of children and adolescents with CAH using a programmable insulin infusion pump. To evluate the serum cortisol, 17-hydroxyprogesterone and plasma ACTH concentrations in children treated with oral hydrocortisone and to investigate these variables in response to subcutaneous basal and bolus cortisol infusions. Our hypothesis to be tested is: subcutaneous infusion of hydrocortisone mimicking physiologic pattern of cortisol secretion at a dose of 7 mg/m2/24 hour for 7 days will suppress the early a.m. ACTH surge and result in mormal 8 a.m. serum 17-hydroxyprogesterone concentration in children with salt wasting Congenital Adrenal Hyperplasia &(CAH) when compared to their standard usual oral hydrocortisone regimen. SPECIFIC AIMS The purpose of this protocol is to help developing a more physiological approach to the management of children and adolescents with CAH using a programmable insulin infusion pump. The long-term objective of the protocol is to provide better hormonal control, to prevent the chronic and solve irreversible consequences of the current sub-optimaltreatment method and to improve the qualify of life of children with salt wasting CAH. In children with CAH we will measure the serum hormone concentrations of cortisol, 17-hydroxy-progesterone, rate of change-4-androstendione, testosterone and ACTH and the 24-hour urinary excretion of 17-hydroxycorticosteroids and 17-ketosteroids -while they are on their usual oral treatment regimen and-during continuous subcutaneous cortisol infusion and will repeat these measurements one week after continuous subcutaneous cortisol infusion treatment. We will compare the results of the two different treatment regimens and determine whether the continuous subcutaneous cortisol infusion suppresses the 8 a.m. ACTH surge and results in normal serum 17-hydroxyprogesterone concentration.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 简介：先天性肾上腺增生（CAH＆）的标准口服糖皮质激素和矿体皮质类固醇治疗是非生理学的。 使用我们的标准护理，患者每天和整个时间都面临过度治疗和治疗。 与类固醇的过度治疗可特技生长，并可能导致库欣德特征。 不足的治疗导致持续性高雄激素血症，这加速了生长，骨龄增长和生长中心的早期融合，从而导致最终成人的最终高度严重损害。 高狂力血症还会引起过早的肾上腺素，早熟的青春期，不育症，痤疮和休毒症。 当前治疗的所有这些副作用降低了这些患者的生命资格。 因此，CAH仍然是次优的管理，寻找改善治疗的方法是合理的。 背景：理想的疗法支架提供了最小的糖皮质激素替代剂量，可有效抑制异常的类固醇侧途径。 LWPES/ESPE共识声明建议是给出10-15 mg/m2/天氢化可的松作为维护疗法。 最近的研究报道了健康的青春期前男性每日皮质醇总产生6.1 +/- 0.4 mg/m2/day和青春期男性5.3 +/- 0.5 mg/m2/day（2）。 然而，在临床实践抑制雄激素的情况下，经常需要15-25 mg/m2/天的氢化可的松，这与健康儿童（-7 mg/m2/day）中的皮质醇生产率相比过高（3,4）。 除正确的剂量外，成功的皮质醇治疗的其他关键要素是剂量的时间和所使用的给药途径。 华莱士等。正常儿童的ACTH和皮质醇分泌的正常昼夜节律和24小时皮质醇谱也显示出连续的基底皮质醇分泌（6）。 口服给药（每天服用两次或三次皮质醇片剂）代表间歇性皮质醇的递送，无法模仿健康肾上腺的连续皮质醇产生。 此外，白天服用药物的时间与ACTH和皮质醇产生的自然爆发的时代大不相同。 缺乏给予皮质醇的生理手段会带来巨大的临床后果，包括较差的总体激素控制和绝大多数患者的生活质量降低。 目的：使用可编程胰岛素输注泵来开发一种更生理的方法，以使用CAH管理儿童和青少年。 为了避免口服氢化可的松治疗的儿童中的血清皮质醇，17-羟孕酮和血浆ACTH浓度，并研究这些变量以响应皮下皮质溶质和推注的皮质醇输注。 我们要检验的假设是： 在7天内以7 mg/m2/24小时的剂量以7 mg/m2/24小时的剂量模仿皮质醇分泌的生理模式的皮下输注，将抑制上午早期的ACTH激增，并在上午8点导致血清17-羟基糖浓度的血清降水液含量为17-羟基肾上腺肾上腺肾上腺肾上腺肾上腺肿瘤和标准性肾上腺含量（C）。方案。 具体目标 该方案的目的是帮助使用可编程胰岛素输注泵来为使用CAH的儿童和青少年的管理一种更生理的方法。 该方案的长期目标是提供更好的荷尔蒙控制，以防止当前的亚疗法方法的慢性和难以可逆的后果，并提高浪费盐的儿童生活的资格。 在患有CAH的儿童中，我们将测量皮质醇的血清激素浓度，17-羟基抗激酮，变化4-及植物的变化速率，睾丸激素和ACTH以及24小时的尿液排泄17-羟基皮质类固醇和17-酮固醇​​的尿液和外骨的经常性或外径，并进行了繁殖，并进行了繁殖，并进行了繁殖。连续皮质皮质溶液输注治疗后一周进行这些测量。 我们将比较两种不同的治疗方案的结果，并确定连续皮质的皮质醇输注是否抑制了上午8点ACTH激增，并导致正常的血清17-羟基耐蛋白酶浓度。