Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2001-02-12
2003-02-04
Jaworski, Francis J. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S458000, C601S002000
Reexamination Certificate
active
06514203
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates in general to thrombolysis of coronary artery blood clots, and in particular to achieving rapid lysis of coronary thromboses by means of transthoracic unsound.
BACKGROUND OF THE INVENTION
It is known that coronary artery thrombosis is a leading cause of morbidity and mortality in the western world today. In this condition, a blood clot forms in a coronary artery, resulting in absent or inadequate blood flow to part of the heart muscle (myocardium). If adequate blood supply to the myocardium is not reestablished within minutes of onset of the thrombosis, the myocardiurn undergoes ischenmia (cell damage), and later infarction (cell death). Effective treatment of coronary thrombosis thus depends on achieving dissolution of the thrombus (thrombolysis) as soon as possible after the onset of symptoms, and this is most commonly achieved by intravenous adminiration of a thrombolytic agent, such as tissue plasminogen activator (tpA).
Once a coronary thrombosis has been diagnosed, early thrombolysis is initiated as soon as possible. Ideally, this is done by medical or paramedical personnel at the point at which they first encounter the patient. Thus an ambulance team may initiate early thrombolysis prior to transporting a patient to the hospital or hospital staff may initiate thrombolysis immediately upon arrival of a patient in the Emergency Room.
As the rapidity with which coronary blood flow is reestablished determines the long-term prognosis for the patient, there has been much interest in finding ways of augmenting or replacing standard early thrombolytic treatment protocols so as to achieve more rapid or more effective thrombolysis. For an early thrombolytic technique to be clinically useful, however, it is necessary that the technique be easily administered by the first medical personnel to encounter the patient (often an ambulance team or Emergency Room staff), at the point at which they first encounter the patient (often in the patient's home or in the hospital Emergency Room), over a short period of time.
It is known that application of ultrasound energy to organic tissue can result in disruption of the tissue, if the intensity of the ultrasound energy focused on the tissue is high enough Thus, ultrasonic lithotripsy has become a standard method for treating renal stones, whereby ultrasound energy focused on a renal stone causes the stone to disintegrate. Blood clots, too, have been shown to undergo thrombolysis when exposed to high intensity ultrasonic energy, and this technique has been successfully used to achieve thrombolysis both in-vitro and in-vivo.
Despite the proven efficacy of ultrasound as a method for achieving thrombolysis, clinical application of this modality in the early treatment of coronary artery thrombosis has been inhibited by the technical difficulties involved in delivering effective amounts of ultrasound energy to coronary arteries, which are both small in diameter (measuring only a few millimeters) and highly mobile (due to the constant contraction and relaxation of the myocardium in which the arteries lie). Due to the mobility and small size of coronary thrombi, it has not been possible, to date, to reliably focus transthoracic ultrasound energy on a coronary thrombosis, as the focal point changes from second to second with the beating of the heart.
Real time ultrasonic localization of blood clots has been reported by Unger et al (The Use of a Thrombus-Specific Ultrasound Contrast Agent to Detect Thrombus in Arteriovenous Fistulae Investigative Radiology; volume 35; number 1: 86-89), who showed that injection of a thrombus-specific ultrasound contrast agent facilitated the ultrasonic diagnosis of clots in AV fistulae. In Unger's report, large amounts of contrast agent adhered to static clots, thus enabling the increased echogenicity of the clots to be appreciated on ultrasound imaging. This technique, however, does not work for thromboses in the small, low flow, coronary arteries, in which only small amounts of contrast agent adhere to the thrombi. Rosenscheim et al (Ultrasound Image Guided Noninvasive Ultrasound Thrombolysis, Circulation 2000;102:238-245) have described a method for ultrasonic diagnosis of peripheral blood clots combined with immediate ultrasound thrombolysis of the detected clots. Their technique for thrombolysis, however, is slow (taking several minutes), thus precluding it's use in coronary thrombi which change location with the beating of the heart every few seconds.
It should be noted that both of the above described methods for ultrasonic diagnosis and localization of vascular thrombi employ standard ultrasonic imaging techniques, whereby the amplitudes of reflected ultrasound waves are analyzed so as to construct an image of the thrombus. In terms of standard ultrasound imaging techniques, therefore, only objects which produce reflected ultrasound signals of sufficiently high amplitude as to allow the signals to be individually detected by the receiving ultrasound crystal can be imaged.
To date, several techniques for achieving coronary ultrasound thrombolysis have been described:
1. Administration of the ultrasound by means of an intravascular ultrasound (IVUS) transducer. In this technique, a small ultrasound transducer located on the tip of a coronary artery catheter is advanced through the coronary circulation and positioned on the thrombus. Ultrasound energy is then administered directly onto the clot, allowing a sufficient intensity of ultrasound energy to be achieved in the thrombus as to cause disruption of the blood clot. As the catheter in the artery moves along with the pulsations of the myocardium, unnecessary exposure of surrounding tissue to damaging ultrasound energy is minimized. Several authors have reported. the clinical use of intravascular ultrasound to achieve coronary thrombolysis. IVUS, however, suffers from the deficiency that it entails cardiac catheterization in a catheterization laboratory. It is thus very invasive and time consuming, and cannot be performed within minutes of the onset of symptoms in a patient suffering from a coronary thrombosis.
2. Administration of ultrasound to the entire thorax (Siegel et al: Noninvasive. Transthoracic, Low-Frequency Ultrasound Augments Thrombolysis in a Canine Model of Acute Myocardial Infarcation Circulation. 2000;101:2026). In this technique as coronary angiography or IVUS are not performed, the exact spatial location of the coronary thrombosis is not known, and the entire thorax is exposed to ultrasound energy. So as to achieve a sufficient intensity of ultrasound energy in the blood clot, very high levels of ultrasound energy have to be used. This technique suffers from the deficiency that the ultrasound energy is not focused on the thrombus. Healthy tissue is thereby exposed to damaging levels of ultrasound energy. In addition, as the amount of ultrasound energy actually reaching the thrombus is small, very long treatment times (up to ninety minutes) are required to achieve thrombolysis. This technique is thus impractical and dangerous for use in humans, and not clinically useful as a method of early coronary thrombolysis.
3. Augmentation of extrathoracically applied ultrasound energy by an intravenous ultrasound contrast agent. (Wu Y et al: Binding and lysing of blood clots using X-408. Invest Radiol 1998:33: 880-885). In this technique, an ultrasound contrast agent such as MRX408 is administered intravenously, prior to the application of ultrasound energy to the entire thorax. It is known that ultrasound contrast agents may enhance the absorption of specific frequencies of ultrasound energy by the tissue to which the contrast agent is adhered. Administration of a contrast agent that specifically adheres to thrombi therefore decreases the amount of ultrasound energy that has to be administered extrathoracically so as to achieve an effective intensity of ultrasound energy in the clot. Although this technique entails lower exposure of healthy tissue to ultrasound energy than the technique
AlphaPatent Associates Lt
Sonata Technologies Ltd.
Swirsky Daniel J.
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