STUDIES OF AEROSOL PARTICLE-RELATED AND PATIENT-

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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.