NEONATAL THERAPEUTIC CAFFEINE AND NEURAL DEVELOPMENT

新生儿治疗性咖啡因和神经发育

• 批准号: 3322638
• 负责人: RONNIE GUILLET
• 金额: $ 10.7万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3322638
• 关键词: adenosine; anticonvulsants; apnea; benzodiazepines; caffeine; cerebellum; cerebral cortex; chordate locomotion; convulsions; developmental neurobiology; developmental nutrition; diazepam; drug adverse effect; drug receptors; high performance liquid chromatography; hippocampus; hyperthermia; hypothalamus; laboratory rat; mother /embryo /fetus nutrition; neurochemistry; neuropharmacology; neuropsychology; newborn animals; nonhuman therapy evaluation; norepinephrine; nutrition related tag; premature infant animal; sympathetic nervous system

Apnea of prematurity is a significant problem in the under 2500gm birth-weight neonate. Current treatment involves administration of caffeine for periods of weeks, at plasma levels 5-10 times that found in the normal adult population. Although acute toxicity is minimal, there is insufficient data to ensure the absence of long- term toxicity. Exposure to exogenous chemicals at developmentally- sensitive time periods is known to result in significant, long- lasting neural and behavioral effects. This proposal aims to establish an animal model for the therapeutic use of caffeine and its possible effects on brain receptor systems and functional correlates. Precise pharmacokinetic data will be obtained initially to allow better correlation with infant drug regimens in use. Adenosine and benzodiazepine receptors will be characterized by binding parameters as a function of age and drug exposure. The functional correlates of early caffeine exposure as a consequence of drug-receptor interactions will be assessed as alterations in locomotor activity and seizure thresholds and susceptibilities. Animal's locomotor activity will be tested both in their baseline state and following challenge with exposure to a known stimulant (caffeine) or depressant (L-phenylisopropyladenosine) to assess adenosine receptor-effector integrity. The susceptibility to and threshold for hyperthermic and chemically-induced seizures, as well as the efficacy of anti-convulsant therapy (diazepam) will assess benzodiazepine receptor-effector integrity. Concomitantly developing neurochemical systems will also be examined because of their interrelationships with the adenosine and benzodiazepine receptor-effector systems. High performance liquid chromatography determination of norepinephrine levels and turnover rates will be performed. Finally, the possible interactions between early caffeine exposure and other environmental insults will be examined. The consequences for neural development of the combination of undernutrition or hypoxemia with therapeutic caffeine exposure will be assessed. These studies will provide information on neural developmental implications for human premature neonates of chronic exposure to therapeutic levels of caffeine.

早产儿呼吸暂停是2500gm以下儿童的一个严重问题。 出生体重相当的新生儿。目前的治疗包括给药 几个星期的咖啡因，血浆水平是 在正常的成年人群中发现。虽然急性毒性是 最低限度，没有足够的数据来确保长期- 长期毒性。在发育阶段暴露于外源化学物质-- 众所周知，敏感时间段会导致显著的、长期的- 持久的神经和行为影响。这项建议旨在 建立咖啡因治疗用法的动物模型 它对大脑感受器系统和功能的可能影响 相互关联。将获得准确的药代动力学数据 最初允许与婴儿药物方案更好地关联在 使用。 腺苷和苯二氮卓类受体将通过 结合参数作为年龄和药物暴露的函数。这个 作为结果的早期咖啡因暴露的功能相关性 药物-受体相互作用的变化将被评估为 运动活动、癫痫阈值和易感性。 动物的运动活动将在它们的基线上进行测试 与已知兴奋剂接触时的状态和后续挑战 (咖啡因)或镇静剂(L-苯异丙基腺苷)评估 腺苷受体-效应器的完整性。和的易感性 高热和化学诱发癫痫的阈值 因为抗惊厥治疗(地西潘)的疗效将评估 苯二氮类受体-效应器的完整性。 同时发展的神经化学系统也将是 检查是因为它们与腺苷和 苯二氮卓类受体-效应系统。高性能液体 去甲肾上腺素水平和周转率的层析测定 将执行费率。 最后，早期接触咖啡因之间可能的相互作用 以及其他环境侮辱将被审查。后果是什么？ 营养不良或神经发育不良的组合 将评估与治疗性咖啡因暴露有关的低氧血症。 这些研究将提供有关神经发育的信息。 慢性接触辐射对早产儿的影响 咖啡因的治疗水平。