NEONATAL THERAPEUTIC CAFFEINE AND NEURAL DEVELOPMENT

早产儿呼吸暂停是2500 gm以下的一个重要问题 出生体重的新生儿 目前的治疗包括给药 咖啡因的血浆水平是咖啡因的5-10倍， 在正常成年人中发现。 虽然急性毒性是 最低限度，没有足够的数据来确保没有长期- 术语毒性。 在发育阶段暴露于外源性化学物质- 众所周知，敏感的时间段会导致重大的、长期的、 持续的神经和行为影响 这项建议旨在 建立用于咖啡因治疗用途的动物模型， 其对大脑受体系统和功能的可能影响 相互关联 将获得精确的药代动力学数据 最初是为了更好地与婴儿药物方案相关联， 使用. 腺苷和苯二氮卓受体的特征在于： 结合参数作为年龄和药物暴露的函数。 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 自发活动和癫痫发作阈值和耐受性。 动物的运动活动将在其基线和 暴露于已知刺激物状态和随后激发 （咖啡因）或腺苷酸（L-苯基异丙基腺苷），以评估 腺苷受体效应器完整性。 易受感染， 高温和化学诱导癫痫发作的阈值，以及 因为抗惊厥治疗（地西泮）的疗效将评估 苯二氮卓受体效应完整性。 同时发展的神经化学系统也将是 检查，因为它们与腺苷的相互关系， 苯二氮卓受体效应系统。 高效液相 色谱法测定去甲肾上腺素水平和周转 率将执行。 最后，早期接触咖啡因与 和其他环境污染物将被检查。 后果 对于神经发育的组合营养不良或 将评估治疗性咖啡因暴露的低氧血症。 这些研究将为神经发育提供信息， 人类早产儿慢性暴露于 治疗水平的咖啡因。

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.