STUDIES OF AEROSOL PARTICLE-RELATED AND PATIENT-

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。将来，为了预防或治疗疾病的目的，在肺功能正常的人的肺内给药局部活性和系统活性药物可能是有利的。虽然已知有许多因素影响气溶胶沉积，但目前尚不清楚这些因素是否可以被操纵来靶向将药物输送到肺功能正常的人的不同肺部区域。该研究项目有三个长期目标：(1)寻找可行的方法来改变口服吸入液体气雾剂在肺功能正常的人肺中的沉积情况；(2)确定沉积情况的变化是否会增加口服吸入的大分子的全身吸收的程度和速度；以及(3)确定灌流情况的变化是否会增加口服吸入的大分子的全身吸收的程度和速度。这些目标将在三个不同的议定书下在几年内实现。在方案1中，健康的、不吸烟的受试者(男性和未怀孕的女性)，18岁，肺功能正常(FEV1和FVC；=预测值的80%)将吸入液体气雾剂，液体气雾剂将由喷射雾化器产生，由0.9%的盐水溶液与放射性同位素99mTc和化合物二乙三胺五乙酸(DTPA)混合而成。在六次研究访问中，我们将在小颗粒(MMAD=1-2um)和大颗粒(MMAD=4-5um)之间改变气溶胶颗粒尺寸，并将不同的给药方式，使其发生在快速(100MAD/分钟)或较慢(25 L/分钟)吸入时，从20%肺活量(VC)、50%VC或70%VC开始，同时受试者直立或仰卧。吸入气雾剂后，受试者将用伽马相机进行肺部成像，以记录气雾剂在肺部的沉积位置。每次雾化给药后获得的肺部伽马相机图像将根据中央与外周(I：O)比率和心尖与基础(A：B)比率进行分析。二次测量将是肺沉积分数，以每次吸入期间雾化器可供吸入的气雾量的百分比表示(发射剂量)。将计算每次研究访问的A：B比、I：O比和沉积分数的平均标准偏差。A：B和I：O比率将在所有检查中进行比较，以确定在肺功能正常的受试者中，什么气雾剂颗粒大小和呼吸动作对这种液体气雾剂的沉积情况影响最大。作为第1A号议定书的一部分，多达五名哮喘患者将接受一套类似的研究访问。在议定书2期间，同样健康的受试者将参加六次研究访问中的两次，这些访问最有希望在两个不同的场合改变沉积模式，以测试重复性。在方案3期间，2型糖尿病患者将参加5-6次访问，以确定由于颗粒大小和/或呼吸动作的变化而导致的沉积或灌注情况的变化是否会增加口服吸入的大分子胰岛素的全身吸收的程度和速度。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the future, it may be advantageous to target the delivery of locally active and systemically-active drugs in the lungs of individuals with normal pulmonary functions for purposes of disease prevention or treatment. Although a number of factors are known to affect aerosol deposition, it is not clear whether these factors can be manipulated to target delivery of drugs to different lung regions in individuals with normal pulmonary functions. This research project has three long-term goals: (1) to find practical ways of changing the deposition profile of orally inhaled liquid aerosols in the lungs of individuals with normal pulmonary functions; (2) to determine if alterations in the deposition profile enhance the extent and rate of systemic absorption of an orally inhaled macromolecule; and (3) to determine if alterations in the perfusion profile enhance the extent and rate of systemic absorption of an orally inhaled macromolecule. These goals will be achieved over several years under three different protocols. During Protocol 1, healthy, non-smoking subjects (males and non-pregnant females), >18 years old, with normal pulmonary functions (FEV1 and FVC>= 80% of predicted values)will inhale liquid aerosol particles that will be generated by a jet nebulizer from a 0.9% saline solution admixed with the radioisotope 99mtechnetium and the chemical compound diethylene triamine pentaacetic acid (DTPA). On six study visits, we will vary aerosol particle size between small particles (MMAD = 1-2um) and larger particles (MMAD = 4-5um) and will vary the delivery so that it occurs during rapid (100 L/min) or slower (25 L/min) inspirations, starting from 20% vital capacity (VC), 50% VC or 70% VC, while the subject is sitting upright or supine. Following aerosol inhalation, subjects will undergo lung imaging with a gamma camera to record where aerosol deposits in the lungs. Gamma camera images of the lung, obtained after each aerosol administration procedure, will be analyzed in terms of central versus peripheral (I:O) ratios and apical versus basal (A:B) ratios. A secondary measure will be lung deposition fraction, expressed as a percentage of the amount of aerosol that will be available for inhalation from the nebulizer during each inspiration (emitted dose). Mean¿¿standard deviation will be calculated for A:B ratio, I:O ratio and deposition fraction on each of the study visits. A:B and I:O ratios will be compared on all visits to determine what aerosol particle size and breathing maneuver has the greatest effect on the deposition profile of this liquid aerosol in subjects with normal lung functions. Up to five patients with asthma will undergo a similar set of study visits as part of Protocol 1A. During Protocol 2, similarly healthy subjects will participate in two of the six study visits that show the most promise for changing deposition pattern on two different occasions to test for reproducibility. During Protocol 3, patients with Type 2 diabetes will participate in 5-6 visits to determine if alterations in deposition or perfusion profiles that result from changes in particle size and/or breathing maneuvers enhance the extent and rate of systemic absorption of the orally inhaled macromolecule:insulin.