Chronic Sildenafil for Severe Diaphragmatic Hernia

慢性西地那非治疗严重膈疝

• 批准号: 6898993
• 负责人: ROBERTA L KELLER
• 金额: $ 12.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6898993
• 关键词: clinical research; clinical trials; congenital disorders; developmental neurobiology; diaphragm; drug administration rate /duration; drug screening /evaluation; hernia; human subject; human therapy evaluation; infant human (0-1 year); longitudinal human study; lung development; newborn human (0-6 weeks); patient oriented research; phosphodiesterase inhibitors; preschool child (1-5); pulmonary hypertension; respiratory circulation; respiratory disorder chemotherapy; vasodilators

DESCRIPTION (provided by applicant): Congenital diaphragmatic hernia (CDH) occurs 1 in 3000 live births. Infants born with severe CDH have poor lung function and persistent pulmonary hypertension of the newborn, secondary to pulmonary hypoplasia. These infants require aggressive, prolonged neonatal support. Postnatal lung growth is critical for long-term survival in severe CDH. However, measures required to support these infants may cause direct lung injury, impairing further growth. Normal alveolar development is dependent on normal microvascular growth. Therefore, in severe CDH, vascular injury may also impact postnatal lung growth and development. Experimental models of pulmonary hypertension (PH) demonstrate attenuation of abnormal pulmonary vascular remodeling with early manipulation of the nitric oxide (NO)-cyclic guanosine monophosphate pathway through administration of inhaled NO or phosphodiesterase-5 inhibitors. The local and systemic factors that result in abnormal postnatal lung and vascular growth, development, and remodeling in the CDH population are unknown. However, chronic PH and chronic lung disease are significant problems in this population, resulting in late mortality, extended neonatal hospital stays and prolonged supplemental oxygen therapy, which is associated with poor neurodevelopmental outcome in children with CDH. The aims of this study are 1) to evaluate pulmonary vascular function and reactivity in severe CDH in the subacute stage of illness; 2) to evaluate the effect of chronic sildenafil on pulmonary vascular function and reactivity in a randomized clinical trial; and 3) to compare 1 & 2 year health and neurodevelopmental outcomes in severe CDH after chronic sildenafil therapy in infancy. This project has the further aim of extending and developing the research expertise of the Principal Investigator, so that she may be positioned for an independent research career. This broad objective will be accomplished through completion of the scientific protocol, didactic training, and careful mentoring by successful senior faculty members at her institution.

描述（由申请人提供）： 先天性腹股沟疝（CDH）发生率为1/3000活产。出生时患有重度CDH的婴儿肺功能较差，继发于肺发育不良的新生儿持续性肺动脉高压。这些婴儿需要积极的，长期的新生儿支持。出生后肺的生长对于重度CDH的长期生存至关重要。然而，支持这些婴儿所需的措施可能会导致直接的肺损伤，阻碍进一步的生长。正常的肺泡发育依赖于正常的微血管生长。因此，在严重的CDH中，血管损伤也可能影响出生后肺的生长和发育。肺动脉高压（PH）的实验模型表明，通过吸入NO或磷酸二酯酶-5抑制剂，早期操纵一氧化氮（NO）-环磷酸鸟苷途径，可减轻异常肺血管重塑。导致先天性肺发育不良患者出生后肺和血管生长、发育和重塑异常的局部和全身因素尚不清楚。然而，慢性PH和慢性肺部疾病是这一人群中的重要问题，导致晚期死亡率，新生儿住院时间延长和补充供氧治疗延长，这与CDH儿童的神经发育结局不良有关。本研究的目的是：1）评价重度CDH亚急性期的肺血管功能和反应性; 2）在随机临床试验中评价慢性西地那非对肺血管功能和反应性的影响; 3）比较婴儿期重度CDH慢性西地那非治疗后1年和2年的健康和神经发育结局。该项目的进一步目标是扩展和发展主要研究员的研究专长，使她能够独立从事研究工作。这一广泛的目标将通过完成科学协议，教学培训，并在她的机构成功的高级教师的认真指导。