Ultrasound-induced tissue damage assessment

描述（由申请方提供）：拟定研究项目是一项基础科学（非临床）研究，研究潜在的显著超声（US）诱导生物学效应，即超声造影剂（UCA）在人体中的应用是否会对血管系统产生不良影响。如果这些研究表明诊断性超声对患者有重大医疗风险，并建议临床医生如何监测风险程度，则医学界将从这些研究中受益。同样，如果诊断性超声通过消除血管损伤作为临床问题而对患者不构成重大医疗风险，则医疗行业将从这些研究中受益。无论哪种情况，都有明显的医学意义。目前还没有确定这一问题所需的数据。今天，我们面临着一个重大的挑战，在人类中使用UCA，即缺乏知识，我们与UCA的相互作用是否是一个重大的医学问题，在人类。FDA也不确定UCA的安全性和/或有效性，并在批准新的UCA之前等待更多关于这些药物风险的信息，从而否认其对患者的众所周知的益处。由一个跨学科研究者小组设计的研究旨在直接解决这一“安全使用”问题，这些研究者在超声诱导的组织损伤研究方面具有丰富的经验，在美国生物物理学和相关物理学领域具有丰富的实验和理论经验。使用我们持续的主动方法，我们建议利用我们广泛的US生物效应/生物物理学专业知识，沿着我们的病理学、营养学、生物统计学建模和动物模型专业知识，以确定US与UCA的相互作用是否是人类的重大医学问题。实验（基于动物）和理论（机制开发）研究计划有四个具体目标，即，1)确定当US与UCA在体内相互作用时，正常健康新西兰白色（NZW）兔动脉损伤的US阈值; 2）确定当US与UCA在体内相互作用时，暴露后致动脉粥样硬化饮食喂养的NZW兔动脉损伤的US阈值; 3）确定当US与UCA在体内相互作用时，暴露前致动脉粥样硬化饮食喂养的NZW兔动脉损伤的US阈值;（4）体外测定UCA阈值。我们提出了7项体内研究和一组体外研究，以实现我们的实验和理论目标。

DESCRIPTION (provided by applicant): The proposed research program is a basic science (non-clinical) investigation of a potentially significant ultrasound (US)-induced biological effect, that is, whether the application of ultrasound contrast agents (UCAs) in humans adversely affects the vasculature. The medical profession benefits from these studies if it is shown that diagnostic US is a significant medical risk to the patient by advising clinicians about this risk, and by suggesting how the clinician can monitor the degree of risk. Likewise, the medical profession benefits from these studies if it is shown that diagnostic US is not a significant medical risk to the patient by eliminating vascular injury as a clinical concern. In either case, there is clear medical significance. The data necessary to decide this issue are not currently available. Today, we are faced with a significant challenge about the use of UCAs in humans, that is, the lack of knowledge as to whether the interaction of US with UCAs is a significant medical problem in humans. The FDA is also uncertain about UCAs' safety and/or effectiveness and is waiting until more is known about the risk of these agents before approving new UCAs, thus denying their well-known benefits to the patient. Studies have been designed to address directly this "safe-use" issue by an interdisciplinary group of investigators who have considerable experience with US-induced tissue damage studies, as well as considerable experimental and theoretical experience with US biophysics and related physics areas. Using our continued proactive approach, we propose to utilize our extensive US bioeffects/biophysics expertise, along with our pathological, nutritional, biostatistical modeling and animal model expertise, to determine whether the interaction of US with UCAs is a significant medical problem in humans. The experimental (animal-based) and theoretical (mechanism-development) research program has four specific aims, viz., 1) to determine the US thresholds for arterial damage in normal, healthy New Zealand white (NZW) rabbits when US interacts with UCAs in vivo; 2) to determine the US thresholds for arterial damage in post-exposure atherogenic diet-fed NZW rabbits when US interacts with UCAs in vivo; 3) to determine the US thresholds for arterial damage in pre-exposure atherogenic diet-fed NZW rabbits when US interacts with UCAs in vivo; and 4) to determine UCA thresholds in vitro. We are proposing 7 in vivo studies and a set of in vitro studies to accomplish our experimental and theoretical objectives.