A NOVEL THERAPEUTIC MODALITY FOR CONGENITAL ADRENAL HYPERPLASIA
先天性肾上腺增生症的新治疗方式
基本信息
- 批准号:8166690
- 负责人:
- 金额:$ 0.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-12-01 至 2010-11-30
- 项目状态:已结题
- 来源:
- 关键词:AcneAdolescentAdrenal GlandsAdultAdverse effectsAndrogen SuppressionBolus InfusionChildChronicCircadian RhythmsClinicalComputer Retrieval of Information on Scientific Projects DatabaseCongenital adrenal hyperplasiaCorticotropinDoseElementsExcretory functionFaceFundingGlucocorticoidsGrantGrowthHeightHormonalHormonesHourHydrocortisoneHydroxyprogesteroneInfertilityInfusion PumpsInfusion proceduresInstitutionInsulinKetosteroidsLifeMaintenance TherapyMeasurementMeasuresMethodsModalityOralOral AdministrationPathway interactionsPatientsPatternPharmaceutical PreparationsPhysiologicalPlasmaPrecocious PubertyProductionProgesteroneProtocols documentationQualifyingQuality of lifeRecommendationRegimenReportingResearchResearch PersonnelResourcesRouteSerumSideSodium ChlorideSourceSteroidsTabletsTestingTestosteroneTimeTreatment ProtocolsUnited States National Institutes of Healthbone ageclinical practiceimprovedmalenovel therapeuticspremature adrenarchepreventresponsestandard caresubcutaneousurinarywasting
项目摘要
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.
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.
1) 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.
2) 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.
这个子项目是许多研究子项目中的一个
由NIH/NCRR资助的中心赠款提供的资源。子项目和
研究者(PI)可能从另一个NIH来源获得了主要资金,
因此可以在其他CRISP条目中表示。所列机构为
研究中心,而研究中心不一定是研究者所在的机构。
简介:先天性肾上腺皮质增生症(CAH)患儿的标准口服糖皮质激素和盐皮质激素治疗是非生理性的。 使用我们的标准护理,患者每天都面临过度治疗和治疗不足的问题。 过度使用类固醇会阻碍生长,并可能导致库欣戈尔德特征。 治疗不足会导致持续性高雄激素血症,加速生长、骨龄提前和生长中心早期融合,导致最终成人身高显著受损。 高雄激素血症还可引起肾上腺素过早分泌、性早熟、不孕、痤疮和多毛症。 目前治疗的所有这些副作用降低了这些患者的生活质量。 因此,CAH仍然是次优管理和寻求改善治疗是明确合理的。
背景资料:理想的治疗方法应是以最小的替代剂量有效地抑制异常的糖皮质激素副作用途径。 LWPES/ESPE共识声明建议给予10-15 mg/m2/天氢化可的松作为维持治疗。 最近的研究报告称,健康青春期前男性的每日皮质醇总产量为6.1+/-0.4 mg/m2/天,青春期男性为5.3+/-0.5 mg/m2/天(2)。 然而,在临床实践中,雄激素产生的抑制通常需要15-25 mg/m2/天的氢化可的松,这与健康儿童中测量的皮质醇产生率(约7 mg/m2/天)相比是过量的(3,4)。
除了正确的剂量,成功的皮质醇治疗的其他关键因素是,剂量的时间和使用的给药途径。 Wallace等人证实,正常儿童的ACTH和皮质醇分泌具有正常的昼夜节律,24小时皮质醇曲线也显示连续的基础皮质醇分泌(6)。 口服给药(每天服用两到三次皮质醇片剂)代表间歇性皮质醇输送,不能模拟健康肾上腺的连续皮质醇生产。 此外,白天服用药物的时间与促肾上腺皮质激素和皮质醇自然爆发的时间有很大不同。 缺乏生理手段管理皮质醇具有巨大的临床后果,包括总体激素控制不良和绝大多数患者生活质量下降。
目的:开发一种更符合生理的方法,使用可编程胰岛素输注泵治疗儿童和青少年CAH。 评价口服氢化可的松治疗儿童的血清皮质醇、17-羟孕酮和血浆ACTH浓度,并研究这些变量对皮下基础和推注皮质醇的反应。
我们要检验的假设是:
当与患有耗盐性先天性肾上腺增生(CAH)的儿童的标准常用口服氢化可的松方案相比时,以7 mg/m2/24小时的剂量皮下输注氢化可的松模拟皮质醇分泌的生理模式持续7天将抑制早期上午ACTH激增并导致正常上午8点血清17-羟孕酮浓度。
本方案的目的是帮助开发一种更符合生理学的方法,使用可编程胰岛素输注泵管理CAH儿童和青少年。 该方案的长期目标是提供更好的激素控制,预防慢性和解决目前次优治疗方法的不可逆后果,并改善盐耗性CAH儿童的生活质量。
1)在CAH儿童中,我们将测量皮质醇、17-羟孕酮的血清激素浓度、4-雄烯二酮、睾酮和ACTH的变化率以及17-羟皮质类固醇和17-酮类固醇的24小时尿排泄
- 当他们在他们通常的口服治疗方案,
- 在连续皮下皮质醇输注期间,并将在连续皮下皮质醇输注治疗后一周重复这些测量。
2)我们将比较两种不同治疗方案的结果,并确定连续皮下皮质醇输注是否抑制上午8点ACTH峰并导致正常血清17-羟孕酮浓度。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MOREY W HAYMOND其他文献
MOREY W HAYMOND的其他文献
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7605861 - 财政年份:2007
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