AEROSOL FUROSEMIDE FOR DYSPNEA RELIEF: LABORATORY AND CLINICAL STUDIES

用于缓解呼吸困难的呋塞米气雾剂：实验室和临床研究

• 批准号: 8705293
• 负责人: ROBERT B BANZETT
• 金额: $ 44.15万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705293
• 关键词: Adverse effects; Aerosols; Age; Air; American; Area; Back; Breathing; Characteristics; Chronic lung disease; Clinic; Clinical; Clinical Protocols; Clinical Research; Clinical Sciences; Clinical Trials; Clinical effectiveness; Confusion; Conscious; Constipation; Deposition; Development; Disadvantaged; Disease; Dose; Drug Delivery Systems; Dyspnea; Effectiveness; Evaluation; Failure; Feedback; Funding; Furosemide; Future; Generations; Grant; Heart Diseases; Human; Hunger; Illusions; Impairment; Individual; Inpatients; Laboratories; Laboratory Finding; Laboratory Study; Lead; Lung; Lung diseases; Malignant Neoplasms; Measurement; Measures; Mental Depression; Metered Dose Inhaler Device; Methods; Modeling; Morphine; Nausea; Opiates; Outcome; Palliative Care; Particle Size; Patients; Pattern; Pharmaceutical Preparations; Physiological; Placebo Control; Procedures; Protocols documentation; Provider; Pulmonary Stretch Receptors; Quality of Care; Regimen; Research; Respiration; Science; Scientist; Sensory; Shortness of Breath; Site; Source; Specificity; Stimulus; Symptoms; Testing; Therapeutic Effect; Time; Translating; Translational Research; Translations; Treatment Effectiveness; Treatment Efficacy; Treatment Failure; United States National Institutes of Health; Variant; Ventilator; Work; aerosolized; analog; clinical practice; cost; design; effectiveness clinical trial; effectiveness research; end of life; experience; improved; member; minimal risk; novel; palliation; randomized placebo controlled trial; receptor; residence; response; symptom management; translational approach; treatment effect

DESCRIPTION (provided by applicant): Dyspnea is a major problem in many classes of patients including ICU patients, patients with chronic lung and heart disease, and patients nearing the end of life from most causes. The armamentarium for treatment of intractable dyspnea is very limited. The only drugs proven effective in reducing dyspnea when treatment of the underlying disease has not brought relief are systemic opiates. Opiates carry many disadvantages including depression of respiration, confusion, nausea and constipation. Inhaled furosemide aerosol has shown promise in relieving dyspnea with none of these side effects. Both controlled laboratory studies and small clinical studies have produced encouraging but very variable results. Evidence suggests that furosemide works locally in the lung by sensitizing slowly adapting pulmonary stretch receptors, giving the sensory 'illusion' of larger breaths; we have previously shown that stimulation of pulmonary stretch receptors with larger ventilator- delivered breaths relieves dyspnea; the bigger the breath, the greater the relief. Two placebo-controlled laboratory human studies of aerosol furosemide (one from our lab) have shown that the response in individual subjects ranges from profound relief of air hunger to no response. Importantly, no subjects experienced worsening of air hunger, showing that the positive effect observed in many subjects is not merely measurement variability. This variation of response among subjects has resulted in experimental results that are encouraging if inconclusive. Given this variation of response in laboratory conditions, it is not surprising that overall outcomes of the few small clinical trials have varied greatly; the majority of trials have been encouraging but none has been conclusive. We hypothesize that treatment failures have been due to two factors: 1) inconsistent aerosol drug delivery and 2) failure to adjust drug dose according to individual phenotypic sensitivity to the drug. Before undertaking a large clinical trial of this promising therapy, it is necessary to discover how to make the treatment more uniformly effective. Our aim is to show that this can be achieved by: a) controlling aerosol inhalation characteristics such as aerosol particle size, inspiratory volume and flow rate, and residence time (i.e., inspiratory pause); a large body of aerosol science research demonstrates that these factors have profound effects on drug deposition. b) determining the effect of higher dose on treatment efficacy. We will perform definitive laboratory studies to determine aerosol administration protocols and dose regimens that give consistent dyspnea relief. Having optimized aerosol delivery and dose, we will perform studies aimed at translating laboratory findings into clinical practice. These studies in hospitalized patients requiring palliation for dyspnea will lead to larger scale clinical effectiveness trials. We believe this integration of laboratory and clinical studies within one grant will optimize translation of results from laboratory to patient.

描述(申请人提供)：呼吸困难是许多类别的患者的主要问题，包括ICU患者，慢性肺病和心脏病患者，以及由于各种原因而濒临死亡的患者。用于治疗顽固性呼吸困难的医疗器械非常有限。在基础疾病的治疗没有缓解的情况下，被证明有效地减少呼吸困难的唯一药物是全身阿片类药物。鸦片类药物有许多缺点，包括呼吸抑制、神志不清、恶心和便秘。吸入速尿气雾剂在缓解呼吸困难方面表现出了希望，没有这些副作用。对照实验室研究和小型临床研究都产生了令人鼓舞但非常不稳定的结果。有证据表明，速尿在肺部局部起作用，是通过敏化慢慢适应的肺伸展感受器，给人一种呼吸较大的感官“错觉”；我们之前已经证明，用呼吸机提供的较大呼吸来刺激肺伸展感受器可以缓解呼吸困难；呼吸越大，缓解越大。两项对气雾剂速尿进行的安慰剂对照的实验室人体研究(其中一项来自我们的实验室)表明，个别受试者的反应范围从空气饥饿的显著缓解到没有反应。重要的是，没有受试者经历空气饥饿的恶化，这表明在许多受试者中观察到的积极影响不仅仅是测量变异性。受试者之间的这种反应差异导致了实验结果，尽管不是决定性的，但也是令人鼓舞的。考虑到实验室条件下反应的这种差异，少数几个小型临床试验的总体结果差异很大也就不足为奇了；大多数试验令人鼓舞，但没有一个是决定性的。我们假设治疗失败是由于两个因素：1)不一致的气雾剂给药和2)未能根据个体对药物的表型敏感性调整药物剂量。在对这种有希望的疗法进行大规模临床试验之前，有必要发现如何使治疗更加统一有效。我们的目的是表明，这可以通过以下方式实现：a)控制气雾剂的吸入特性，如气雾剂颗粒大小、吸气量和流速以及停留时间(即吸气暂停)；大量的气雾剂科学研究表明，这些因素对药物沉积有深远的影响。B)确定较高剂量对治疗效果的影响。我们将进行明确的实验室研究，以确定气雾剂给药方案和给药方案，以缓解持续的呼吸困难。在优化了气雾剂的释放和剂量后，我们将进行旨在将实验室发现转化为临床实践的研究。这些针对需要缓解呼吸困难的住院患者的研究将导致更大规模的临床疗效试验。我们相信，这种将实验室和临床研究整合在一笔赠款中的做法将优化实验室与患者之间的成果转化。