MUCOCILIARY CLEARANCE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。题目：健康受试者的粘膜纤毛清除率：左旋布特罗和外消旋沙丁胺醇的比较目的：量化和比较10名健康受试者在吸入安慰剂（无药物）、左旋布特罗气雾剂或外消旋沙丁胺醇气雾剂一周后的三次研究访问中的粘膜纤毛清除率（MCC）和咳嗽清除率（CC）。假设：在健康受试者中，吸入一周左旋布特罗气雾剂比吸入一周安慰剂或外消旋沙丁胺醇气雾剂在增强粘膜纤毛清除（MCC）和咳嗽清除（CC）方面明显更有效。背景：在健康的肺中，在呼吸过程中吸入的细菌、病毒、抗原和毒素沉积在气管支气管气道粘液中，并在几小时内通过粘膜纤毛清除（MCC）从肺中清除。当MCC不堪重负或受损时，一些粘液可通过机械或咳嗽清除（CC）清除。MCC损伤通常会导致气道粘液积聚，这反过来又与急性感染、慢性细菌定植和慢性炎症有关。吸入含有放射性同位素99mtechnetium (99mTc)-硫-胶体的气溶胶后，用伽马照相机对肺部进行连续成像，从而量化MCC。随着时间的推移，同位素从肺中移动的量化提供了MCC的测量。吸入或皮下注射-肾上腺素能刺激化合物硫酸特布他林已被证明可增加健康受试者的MCC。本研究将检验健康受试者吸入左旋布特罗气雾剂一周后MCC是否会显著增强，左旋布特罗是外消旋沙丁胺醇的强效r -异构体。沙丁胺醇的r -和s -异构体的外消旋混合物已被证明可以刺激不同患者群体的粘膜纤毛清除。然而，据我们所知，还没有人研究过左旋布特罗在改善健康受试者MCC方面的作用。外消旋沙丁胺醇的s -异构体缺乏明显的β - 2-肾上腺素能亲和力，与左旋沙丁胺醇作用相反。我们假设左旋布特罗在增强健康受试者MCC和CC方面比外消旋布特罗更有效，因为s -异构体对其有效性的反对将不存在。研究设计：这将是一个随机、双盲、安慰剂对照的临床试验。研究程序总结：所有受试者将参加一次同意访问和三次研究访问。所有访问将在约翰霍普金斯医院Blalock 3号312手术室的儿科临床研究部门（PCRU）进行。同意来访：受试者将首先与主要研究者一起审阅同意书。如果他们同意参加这些程序，他们将签署同意书。然后，他们将接受病史和身体检查，测量生命体征（脉搏、呼吸频率、血压、脉搏血氧仪、身高和体重）和肺功能测试。该研究的女性候选人也将接受怀孕测试。合格的男性和女性受试者将背对伽马照相机坐着，吸入133氙气。这将提供他们肺部的通风图像，该图像将用于在研究访问1-3的后续气溶胶图像中识别肺部边界。然后，受试者将被给予研究药物（即安慰剂、左旋布特罗或外消旋沙丁胺醇）、压缩机和雾化器带回家。药物或安慰剂的盲法库存将由Sepracor提供。受试者将被指示在家吸入药物或安慰剂7天。给药顺序将随机化。第7天，他们将返回实验室进行研究访问1。研究访问1：男性和未怀孕的女性受试者将接受体格检查，包括病史或间歇史，测量生命体征（脉搏、呼吸频率、血压、脉搏血氧仪、身高和体重）和肺功能测试。然后，他们将吸入含有放射性同位素99mTc （99mTc）硫胶体的气溶胶。然后，受试者将背对伽马相机坐着，而伽马相机每四分钟记录一次他们肺部的连续图像，持续76分钟。MCC将通过分析获得的每张肺图像获得的数据来计算。CC将在MCC评估结束时测量。然后，志愿者将获得第二批盲药，并被告知7天内不要服用该药。在此之后，他们将被指示开始吸入第二种药物七天，并返回实验室进行研究访问2。研究访问2：在研究访问2时，受试者将接受体格检查，包括病史或间歇史，测量生命体征（脉搏、呼吸频率、血压、脉搏血氧仪、身高和体重）和肺功能测试。然后，他们将吸入含有放射性同位素99mtc -硫胶体的气溶胶，背对着伽马相机坐着，而伽马相机每四分钟记录一次他们肺部的连续图像，持续76分钟。MCC将通过分析获得的每张肺图像获得的数据来计算。CC将在MCC评估结束时测量。然后，志愿者将获得第三批盲药，并被告知七天内不要服用该药。在此之后，他们将被指示开始吸入第三种药物7天，并返回实验室进行研究访问3。研究访问3：在研究访问3时，受试者将接受体格检查，包括病史或间歇史，测量生命体征（脉搏、呼吸频率、血压、脉搏血氧仪、身高和体重）和肺功能测试。然后，他们将吸入含有放射性同位素99mtc -硫胶体的气溶胶，背对着伽马相机坐着，而伽马相机每四分钟记录一次他们肺部的连续图像，持续76分钟。MCC将通过分析获得的每张肺图像获得的数据来计算。CC将在MCC评估结束时测量。

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.