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: 8333936
• 负责人: ROBERT B BANZETT
• 金额: $ 48.39万
• 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/8333936
• 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（由申请人提供）：呼吸困难是许多类别患者的主要问题，包括ICU患者、慢性肺和心脏病患者以及因大多数原因接近生命终点的患者。难治性呼吸困难的治疗手段非常有限。当基础疾病的治疗没有带来缓解时，唯一被证明有效减轻呼吸困难的药物是全身性阿片类药物。阿片类药物有许多缺点，包括呼吸抑制、意识模糊、恶心和便秘。吸入呋塞米气雾剂已显示出缓解呼吸困难的承诺，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差异很大的结果。有证据表明，呋塞米通过使缓慢适应的肺牵张受体敏感化而在肺中局部起作用，从而产生较大呼吸的感觉"错觉";我们先前已经表明，用较大呼吸机输送的呼吸刺激肺牵张受体可缓解呼吸困难;呼吸越大，缓解越大。两个安慰剂对照的实验室人体研究气雾剂呋塞米（一个来自我们的实验室）表明，在个别受试者的反应范围从深刻缓解空气饥饿没有反应。重要的是，没有受试者经历空气饥饿恶化，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令人鼓舞的实验结果，即使不是决定性的。鉴于实验室条件下反应的这种变化，少数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，但没有一项是结论性的。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。在对这种有前途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均匀有效。我们的目的是表明这可以通过以下方式实现：a）控制气雾剂吸入特性，例如气雾剂粒度、吸气体积和流速以及停留时间（即，吸气暂停）;大量的气溶胶科学研究表明这些因素对药物沉积具有深远的影响。B）确定较高剂量对治疗功效的影响。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，使呼吸困难持续缓解。在优化气雾剂输送和剂量后，我们将进行旨在将实验室发现转化为临床实践的研究。这些在需要缓解呼吸困难的住院患者中进行的研究将导致更大规模的临床有效性试验。我们相信，这种实验室和临床研究的整合将优化结果从实验室到患者的转化。