Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
2000-04-20
2004-11-02
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C424S009500, C600S458000
Reexamination Certificate
active
06811766
ABSTRACT:
This invention relates to ultrasound imaging, more particularly to use of ultrasound imaging in visualising tissue perfusion, i.e. blood flow per unit of tissue mass, in particular cardiac perfusion.
It is well known that contrast agents comprising dispersions of gas microbubbles are particularly efficient backscatterers of ultrasound by virtue of the low density and ease of compressibility of the microbubbles. Such microbubble dispersions, if appropriately stabilised, may permit highly effective ultrasound visualisation of, for example, the vascular system and tissue microvasculature, often at advantageously low doses.
Measurements of tissue perfusion are of importance in, for example, tumour detection, tumour tissue typically having different vascularity from healthy tissue, and studies of the myocardium, e.g. to evaluate the blood supply thereto. Whilst contrast agent detection using current ultrasound imaging techniques may provide information as to whether particular organs or regions thereof are perfused or not, it does not readily permit quantification of levels of perfusion. Such information, which is useful in assessing whether a patient is at risk owing to low perfusion and so may benefit from preventative methods and/or treatment, must currently be obtained using radioisotopic imaging techniques such as scintigraphy, positron emission tomography or single photon emission computed tomography. These techniques all involve injection of radioactive substances, with potential safety risks for both the patient and medical staff, and use of expensive imaging equipment; this inevitably prohibits their widespread use.
It is known from radionucleide cardiac imaging that patients may be subjected to physical or pharmacological stress in order to enhance the distinction, and thus the difference in imaging intensities, between normally perfused myocardium and any myocardial regions supplied by stenotic arteries. Such stress induces vasodilatation and increased blood flow in healthy myocardial tissue, whereas blood flow in underperfused tissue supplied by a stenotic artery is substantially unchanged since the capacity for arteriolar vasodilatation is already exhausted by inherent autoregulation seeking to increase the restricted blood flow.
The application of stress as physical exercise or pharmacologically by administration of adrenergic agonists may cause discomfort such as chest pains in patient groups potentially suffering from heart disease, and it is therefore preferable to enhance the perfusion of healthy tissue by administration of a vasodilating drug.
The present invention is based on the finding that ultrasound contrast agents capable of accumulation in tissue microvasculature may be used in perfusion imaging, especially of the myocardium, when coadministered with a pharmacologically effective amount of a vasodilating drug. Because such contrast agents will accumulate in tissue in concentrations related to the regional rate of tissue perfusion, ultrasound imaging modalities such as conventional or harmonic B-mode imaging where the display is derived from return signal intensities will provide images which may be interpreted as perfusion maps in which the displayed signal intensity is a function of local perfusion. This is in contrast to images obtained using free-flowing contrast agents, where the regional concentration of contrast agent and corresponding return signal intensity depend on the actual blood content rather than the rate of perfusion of local tissue.
A disadvantage of existing radionucleide cardiac imaging techniques is that the uptake of radionucleide tracers such as thallium 201 and technetium sestamibi is limited by low contact time between tracer and tissue and so may require maintenance of vasodilatation for the whole period of blood pool distribution for the tracer (e.g. 4-6 minutes for thallium scintigraphy) to ensure optimum effect. Accumulative ultrasound contrast agents used in accordance with the present invention, on the other hand, do not suffer such diffusion or transport limitations and, especially where accumulation occurs through a process of physical entrapment, may undergo highly efficient retention in tissue microvasculature. The period of vasodilatation needed to achieve cardiac or other perfusion imaging in accordance with the invention may therefore be short, for example less than one minute; this will reduce the duration of any possible discomfort caused to patients by administration of vasodilator drugs.
In accordance with one embodiment of the invention there is provided a combined preparation for use as a contrast agent in ultrasound perfusion imaging, especially cardiac perfusion imaging, said preparation comprising:
i) an ultrasound contrast agent capable of accumulation in tissue microvasculature, e.g. of the myocardium; and
ii) a pharmacologically effective amount of a vasodilator drug.
According to a further embodiment of the invention there is provided a method of generating enhanced perfusion images, especially cardiac perfusion images, of a human or non-human animal subject which comprises the steps of:
i) injecting an ultrasound contrast agent capable of accumulation in tissue microvasculature, e.g. of the myocardium, into the vascular system of said subject;
ii) coadministering a pharmacologically effect amount of a vasodilator drug; and
iii) generating an ultrasound image representing perfusion of a target organ or tissue, especially the myocardium.
Representative vasodilator drugs useful in accordance with the invention include endogenous/metabolic vasodilators such as lactic acid, adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, adenosine, nitric oxide and agents causing hypercapnia, hypoxia/hypoxemia or hyperemia; phosphodiesterase inhibitors such as dipyridamole and sildenafil; sympathetic activity inhibitors such as clonidine and methyldopa; smooth muscle relaxants such as papaverine, hydralazine, dihydralazine and nitroprusside; beta receptor agonists such as dopamine, dobutamine, arbutamine, albuterol, salmeterol and isoproterenol; alpha receptor antagonists such as doxazosin, terazosin and prazosin; organic nitrates, such as glyceryl trinitrate, isosorbide dinitrate and isosorbide mononitrate; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril; angiotensin II antagonists (or AT1 receptor antagonists) such as valsartane, losartan and candesartan; calcium channel blockers such as amlodipine, nicardipine, nimodipine, felodipine, isradipine, diltiazem, verapamil and nifedipine; prostaglandins such as alprostadil; and endothelium-dependent vasodilators.
In view of the fact that the required vasodilatation may need only to be short lasting, adenosine is a particularly useful vasodilating drug, being both an endogenous substance and having a very short-lasting action as evidenced by a blood pool half-life of only a few seconds. Vasodilatation will accordingly be most intense in the heart, since the drug will tend to reach more distal tissues in less than pharmacologically active concentrations, and may result in coronary blood flow in healthy myocardial tissue increasing by more than 400%. It will be appreciated that because of this short half-life, repeated injection or infusion of adenosine may be necessary during cardiac imaging in accordance with the invention; by way of example, an initial administration of 150 &mgr;g/kg of adenosine may be made substantially simultaneously with administration of the contrast agent, followed 10 seconds later by slow injection of a further 150 &mgr;g/kg of adenosine, e.g. over a period of 20 seconds.
One category of accumulative contrast agents useful in accordance with the invention comprise gas-containing contrast agent preparations which promote controllable and temporary growth of the gas phase in vivo following administration owing to the presence of a diffusible component capable of inward diffusion into the dispersed gas phase to promote temporary growth thereof, ther
Eriksen Morten
Frigstad Sigmund
Rongved Pål
Østensen Jonny
Amersham Health AS
Cai Li
Hartley Michael G.
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