MENTORED PATIENT ORIENTED RESEARCH CAREER DEVELOPMENT AW

（改编自申请人摘要）：有越来越多的兴趣 在CF肺病的早期干预中， 防止不可逆的肺损伤 雾化抗生素是一种 有吸引力的潜在疗法，理论上提供高气道 浓度，同时最大限度地减少全身毒性的风险。 第一步 在使吸入抗生素适应最年轻年龄段的过程中， 最佳剂量。 拟议研究的目标是制定 吸入抗生素的剂量，产生较低的气道浓度 足以杀死细菌（有效），同时尽量减少全身吸收 （安全）。 申请人提出一系列合乎逻辑的调查， 在这个剂量下。 第一，有效的抗生素浓度 CF痰中的细菌杀灭，已知其抑制抗生素 生物活性，将被确定。 接下来，申请人将确定是否 该目标抗生素浓度在下呼吸道中达到 小儿气溶胶给药后的肠道分泌物。 最后 将测定吸入抗生素的药代动力学，作为 由于全身吸收引起的毒性。 通过这些目标，建议 研究将试图开发一个合理的综合系统模型 吸入性抗生素给药在非常年幼的儿童。 初始开发 将利用雾化妥布霉素进行拟议模型的研究，其中 已被证明是安全和有效的治疗CF患者超过 六岁，最近被FDA许可使用。 的 然后，将进一步开发和完善方法， 多粘菌素E1是一种很有前途的替代吸入剂， 临床前开发。 这两个阶段的发展目标是产量 适用于研究各种吸入剂的模型系统。 拟议研究的结果和经验可能有助于 严格进行未来的临床试验，吸入剂在婴儿， 有和没有CF

(Adapted from the applicant's abstract): There is a growing interest in early intervention in CF pulmonary disease, with the goal of delaying or preventing irreversible lung damage. Aerosolized antibiotics are an attractive potential therapy, theoretically providing high airway concentrations while minimizing the risk of systemic toxicity. The first step in adapting an inhaled antibiotic to the youngest age range is determination of an optimal dose. The objective of the proposed research is to formulate doses of inhaled antibiotics that produced lower airway concentrations adequate to kill bacteria (effective) while minimizing systemic absorption (safe). The applicant proposes a logical series of investigations to arrive at this dose. First, the antibiotic concentration necessary for effective bacterial killing in CF sputum, which is known to inhibit antibiotic bioactivity, will be determined. Next, the applicant will ascertain whether this target antibiotic concentration is achieved in the lower respiratory tract secretions of young children after aerosol dosing. Lastly, the pharmacokinetics of the inhaled antibiotic will be determined, as a measure of toxicity due to systemic absorption. Through these aims, the proposed research will attempt to develop an integrated systems model for the rational dosing of inhaled antibiotics in very young children. The initial development of proposed model will be conducted utilizing aerosolized tobramycin, which has been shown to be safe and effective in the treatment of CF patients over six years of age and was recently licensed for use by the FDA. The methodologies will then be further developed and refined by applying them to the study of polymyxin E1, a promising alternative inhaled agent currently in pre-clinical development. The goal of this two-phase development is to yield model systems applicable to the study of a broad variety of inhaled agents. The results and experience gained by the proposed studies may aid in the rigorous conduct of future clinical trials of inhaled agents in infants both with and without CF.