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. Title: Mucociliary Clearance in Healthy Subjects: Comparison of Levalbuterol and Racemic Albuterol Objectives: To quantify and compare mucociliary clearance (MCC) and cough clearance (CC) in 10 healthy subjects on three Study Visits after one week each of inhalation of placebo (no drug), levalbuterol aerosol or racemic albuterol aerosol. Hypothesis: One week of inhalation of levalbuterol aerosol will be significantly more potent than one week of inhalation of placebo or racemic albuterol aerosol in enhancing mucociliary clearance (MCC) and cough clearance (CC) in healthy subjects. Background: In healthy lungs, bacteria, viruses, antigens and toxins, that are inhaled during respiration, deposit in the tracheobronchial airway mucus and are removed from the lung in a matter of hours by mucociliary clearance (MCC). When MCC is overwhelmed or impaired some mucus can be removed by mechanical or cough clearance (CC). Impairment of MCC typically leads to the accumulation of mucus in the airways, and this in turn is associated with acute infections, chronic bacterial colonization and chronic inflammation. MCC is quantified by sequential imaging of the lungs with a gamma camera following the inhalation of an aerosol containing the radioisotope 99mtechnetium (99mTc)-sulfur-colloid. Quantification of the movement of isotope out of the lungs over time provides a measure of MCC. Inhalation or subcutaneous administration of the beta-adrenoceptor stimulating compound terbutaline sulfate has been shown to increase MCC in healthy subjects. This research study will examine whether MCC can be significantly enhanced in healthy subjects by one week of inhalation of levalbuterol aerosol, the potent R-isomer of racemic albuterol. Racemic mixtures of the R-and S-isomers of albuterol have been shown to stimulate mucociliary clearance in various patient populations. However, to our knowledge, no one has ever examined the effect of levalbuterol in terms of improving MCC in healthy subjects. The S-isomer of racemic albuterol lacks significant beta2-adrenergic affinity and acts in opposition to levalbuterol. We hypothesize that levalbuterol will be more potent than racemic albuterol in enhancing MCC and CC in healthy subjects because the opposition of the S-isomer to its effectiveness will not be present. Study Design: This will be a randomized, double-blind, placebo-controlled clinical trial. Summary of Study Procedures: All subjects will participate in a Consenting Visit and three Study Visits. All visits will take place in the Pediatric Clinical Research Unit (PCRU), Procedure Room 312, on Blalock 3 of the Johns Hopkins Hospital. Consenting Visit: Subjects will first review the consent form with the principal investigator. If they agree to participate in the procedures, they will sign the consent form. Then, they will undergo a medical history and physical exam with measurement of vital signs (pulse, respiratory rate, blood pressure, pulse oximetry, height and weight) and pulmonary function testing. Female candidates for the study will also undergo a pregnancy test. Qualified male and female subjects will then inhale 133xenon gas while sitting with their back to a gamma camera. This will provide a ventilation image of their lungs, which will be used to identify the lung borders on subsequent aerosol images on Study Visits 1-3. Subjects will then be given study drug (i.e. placebo, levalbuterol or racemic albuterol), compressors and nebulizers to take home. Blinded stocks of drug or placebo will be supplied by Sepracor. Subjects will be instructed to inhale drug or placebo at home for 7 days. The order of drug administration will be randomized. On the 7th day, they will return to the laboratory for Study Visit 1. Study Visit 1: Males and non-pregnant females subjects will undergo a physical exam with medical or interval history, measurement of vital signs (pulse, respiratory rate, blood pressure, pulse oximetry, height and weight) and pulmonary function testing. Then, they will inhale an aerosol containing the radioisotope 99mtechnetium (99mTc)-sulfur colloid. Subjects will then sit with their back to the gamma camera while it records sequential images of their lungs every four minutes for 76 minutes. MCC will be calculated from data obtained by analyzing each of the acquired lung images. CC will be measured at the end of the MCC assessment. Volunteers will then be supplied with a second stock of blinded drug and instructed not to take the drug for seven days. After that time, they will be instructed to begin inhalation of the second drug for seven days and to return to the laboratory for Study Visit 2. Study Visit 2: On Study Visit 2, subjects will undergo a physical exam with medical or interval history, measurement of vital signs (pulse, respiratory rate, blood pressure, pulse oximetry, height and weight) and pulmonary function testing. Then, they will inhale the aerosol containing the radioisotope 99mTc-sulfur colloid and will sit with their back to the gamma camera while it records sequential images of their lungs every four minutes for 76 minutes. MCC will be calculated from data obtained by analyzing each of the acquired lung images. CC will be measured at the end of the MCC assessment. Volunteers will then be supplied with a third stock of blinded drug and instructed not to take the drug for seven days. After that time, they will be instructed to begin inhalation of the third drug for seven days and to return to the laboratory for Study Visit 3. Study Visit 3: On Study Visit 3, subjects will undergo a physical exam with medical or interval history, measurement of vital signs (pulse, respiratory rate, blood pressure, pulse oximetry, height and weight) and pulmonary function testing. Then, they will inhale the aerosol containing the radioisotope 99mTc-sulfur colloid and will sit with their back to the gamma camera while it records sequential images of their lungs every four minutes for 76 minutes. MCC will be calculated from data obtained by analyzing each of the acquired lung images. CC will be measured at the end of the MCC assessment.
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