MENTORED PATIENT ORIENTED RESEARCH CAREER DEVELOPMENT AW

(改编自申请者的摘要)：人们的兴趣越来越大 在对慢性肺疾病的早期干预中，目标是延迟或 预防不可逆转的肺损伤。雾化抗生素是一种 诱人的潜在疗法，理论上提供高位呼吸道 浓度，同时将全身毒性风险降至最低。第一步 使吸入型抗生素适应最年轻的年龄范围是决心 最佳剂量。拟议研究的目标是制定 吸入抗生素剂量会产生较低的呼吸道浓度 足以杀灭细菌(有效)，同时最大限度地减少全身吸收 (安全)。申请人提出了一系列符合逻辑的调查结果 在这个剂量下。首先，有效所需的抗生素浓度 已知可抑制抗生素的CF痰中的细菌杀灭 生物活性，将被确定。下一步，申请人将确定是否 这一目标抗生素浓度是在下呼吸道实现的 气雾剂给药后幼儿的呼吸道分泌物。最后， 吸入抗生素的药代动力学将被测定，作为一种措施 全身吸收所致的毒性。通过这些目标，建议的 研究将尝试为Rational开发一个集成的系统模型 年幼儿童吸入抗生素的剂量。最初的发展 建议的模型将使用雾化妥布霉素进行，其中 已被证明是安全和有效的治疗CF患者超过 六岁，最近获得了FDA的使用许可。这个 然后将通过应用它们来进一步开发和改进方法 新型吸入剂多粘菌素E_1的研究 临床前发展。这两个阶段的发展目标是让 适用于多种吸入剂研究的模型系统。 拟议研究的结果和经验可能有助于 严格进行婴幼儿吸入剂的未来临床试验 带和不带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.