Ultrasound-induced tissue damage assessment

描述(由申请人提供)：拟议的研究计划是对超声(US)诱导的潜在显著生物学效应的基础科学(非临床)研究，即在人体中应用超声造影剂(UCAS)是否对血管系统产生不利影响。如果这些研究表明诊断性US对患者来说是一个重大的医疗风险，通过向临床医生建议这种风险，并建议临床医生如何监控风险程度，医疗专业就会受益。同样，如果证明诊断性US通过消除临床上的血管损伤对患者来说不是重大的医疗风险，医疗专业也会从这些研究中受益。无论是哪种情况，都有明显的医学意义。目前还没有决定这一问题所需的数据。今天，我们面临着一个关于Ucas在人类身上使用的重大挑战，即缺乏关于US与Ucas的相互作用是否是人类的重大医学问题的知识。FDA也不确定Ucas的安全性和/或有效性，正在等待对这些药物的风险有更多了解后才批准新的Uca，从而否认了它们对患者的众所周知的好处。研究旨在由一个跨学科的研究小组直接解决这一“安全使用”问题，这些研究小组在美国诱导的组织损伤研究方面拥有丰富的经验，并在美国生物物理学和相关物理领域拥有丰富的实验和理论经验。我们继续积极主动地利用我们广泛的美国生物效应/生物物理学专业知识，以及我们的病理学、营养学、生物统计学建模和动物模型专业知识，以确定US与UCAS的相互作用是否是人类的重大医学问题。该实验(动物基础)和理论(机制发展)研究计划有四个具体目标，即1)确定US与UCAS在体内相互作用时正常健康新西兰白兔的动脉损伤阈值；2)确定暴露后致动脉粥样硬化饮食喂养的NZW兔在体内与UCAS相互作用时的US阈值；3)确定暴露前致动脉粥样硬化饮食喂养的NZW兔在US与UCAS体内相互作用时的US阈值；以及4)在体外确定UCA阈值。我们提议进行7项体内研究和一系列体外研究，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.