Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2000-02-14
2003-07-22
Jaworski, Francis J. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C424S009520
Reexamination Certificate
active
06595925
ABSTRACT:
This invention relates to gas-containing ultrasound contrast agents, more particularly to their use in diagnostic ultrasound imaging.
It is well known that ultrasonic imaging comprises a potentially valuable diagnostic tool, for example in studies of the vascular system, particularly in cardiography, and of tissue microvasculature. A variety of contrast agents has been proposed to enhance the acoustic images so obtained, including suspensions of solid particles, emulsified liquid droplets, gas microbubbles and encapsulated gases or liquids. It is generally accepted that low density contrast agents which are easily compressible are particularly efficient in terms of the acoustic backscatter they generate, and considerable interest has therefore been shown in the preparation of gas-containing and gas-generating systems.
Initial studies involving free gas microbubbles generated in vivo by intracardiac injection of physiologically acceptable substances have demonstrated the potential efficiency of such microbubbles as contrast agents in echography; such techniques are severely limited in practice, however, by the short lifetime of the free microbubbles. Substantial interest has accordingly been shown in methods of stabilising gas bubbles for echocardiography and other ultrasonic studies, for example using emulsifiers, oils, thickeners or sugars, or by entraining or encapsulating the gas or a precursor therefor in a variety of systems, e.g. as porous gas-containing microparticles or as encapsulated gas microbubbles, and in the selection of gases which may themselves exhibit enhanced stability and duration of echogenic effect.
Prior art concerning both the use of phospholipids as components of gas-containing ultrasound contrast agents and the selection of gases said to give improved persistence in vivo is reviewed in WO-A-9729783, the contents of which are incorporated herein by reference. WO-A-9729783 itself discloses contrast agents for use in diagnostic studies comprising a suspension in an injectable aqueous carrier liquid of gas microbubbles stabilised by phospholipid-containing amphiphilic material, characterised in that the amphiphilic material consists essentially of phosphblipid predominantly comprising molecules with net charges. The phospholipid molecules are preferably negatively charged, for example as in naturally occurring (e.g. soya bean or egg yolk derived), semisynthetic (e.g. partially or fully hydrogenated) and synthetic phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids and cardiolipins.
Contrast agents in which at least 70% of the phospholipid content consists of one or more phosphatidylserines, for example saturated (e.g. hydrogenated or synthetic) natural phosphatidylserine and synthetic or semi-synthetic dialkanoylphosphatidylserines such as distearoylphosphatidylserine, dipalmitoylphosphatidylserine and diarachidoylphosphatidylserine, are said to be preferred by virtue of their stability, minimal haemodynamic side effects and ease of elimination from the body.
Gases which may be present in such contrast agents include any substances (including mixtures) substantially or completely in gaseous (including vapour) form at the normal human body temperature of 37° C. Representative gases thus include air, nitrogen, oxygen, carbon dioxide, hydrogen, nitrous oxide, inert gases, sulphur fluorides, hydrocarbons and halogenated hydrocarbons, especially fluorocarbons such as perfluorocarbons, typically containing 1-5 carbon atoms. The use of fluorinated gases such as sulphur hexafluoride, perfluoroal kanes and perfluorocycloalkanes is particularly preferred.
Ultrasound contrast agents are usually administered intravenously as a single bolus dosage, leading to a rapid and pronounced but relatively short lasting rise in backscatter intensity in respect of blood-perfused tissue and organs as the bolus mixes with surrounding blood, thereby generating a relatively narrow and high intensity backscatter signal peak in a plot against time; backscatter measurements are normally made during the existence of this peak. This may, however, give rise to problems in, for example, the imaging of deeper tissues and organs, where high backscatter from overlying tissue during the peak period may cause excessive shadowing.
It is often desirable to prolong the useful time window for imaging beyond the relatively short duration of the backscatter signal peak resulting from passage of the contrast agent bolus. In the case of non-recirculating contrast agents, i.e. agents which are incapable of surviving more than one passage through the systemic circulation, for example as a result of instability or of specific or non-specific trapping in certain tissues, this may require repeated injection or continuous infusion of the contrast agent; however, such techniques may be inconvenient in practice and may require special pharmaceutical formulations. Use of increased dosages of non-recirculating contrast agents in an attempt to prolong the imaging time window may be limited by toxicity considerations and will frequently cause excessive acoustic shadowing, thereby significantly shortening the useful time window.
Stabilised gas microbubble-containing contrast agents such as those disclosed in WO-A-9729783 are capable of surviving passage through the systemic circulation. Such agents can pass through the pulmonary capillary bed and survive the systolic pressure changes encountered in the bloodstream, and so may provide measurable backscatter levels after mixture with the whole blood pool. In such cases a plot of backscatter intensity against time will exhibit a decay phase after the peak period as a result of the presence of echogenic contrast agent in recirculating blood; this is hereinafter referred to as the “recirculating phase”. Hitherto, measurements of backscatter intensity during the recirculating phase have generally been disregarded, probably because of the low intensity levels involved. It has now surprisingly been found, however, that imaging during the recirculating phase may provide diagnostically useful results over a prolonged time period if a sufficient dosage of contrast agent is administered.
Thus the present invention is based on the finding that increasing the dose of a recirculating ultrasound contrast agent may lead to a substantial and disproportionately large increase in the useful imaging time window. Without wishing to be bound by theoretical considerations, it is thought that this unexpectedly prolonged time window may be the result of a change in the mechanism governing contrast duration. Thus, at low doses, contrast duration is determined solely by the bolus transit time, which is governed by the relationship between central blood volume and cardiac output. At high doses, on the other hand, contrast duration depends on clearance of the contrast agent from the blood, for example on the relationship between total blood volume and hepatic blood flow in the case of a contrast agent with predominantly hepatic clearance.
Thus according to one aspect of the invention there is provided a method of ultrasound imaging which comprises (i) administering an ultrasound contrast agent comprising a stabilised dispersion of gas microbubbles in an injectable carrier liquid to the vascular system of a subject in an amount which is physiologically tolerable and sufficient to generate contrast enhancement within blood in a recirculating phase following admixture of the agent with the blood pool; and (ii) generating an ultrasound image of at least a part of the vascular system of said subject during said recirculating phase.
In a further embodiment the invention provides use of stabilised gas microbubbles in the manufacture of a contrast agent for administration to the vascular system of a subject in a dosage unit which is physiologically tolerable and sufficient to generate contrast enhancement within blood in a recirculating phase following admixture of the agent with the blood pool.
The contrast agents may, for example, comprise amphiphile-stabilised, e.g
Eriksen Morten
Frigstad Sigmund
Tornes Audun
Østensen Jonny
Amersham Health AS
Jaworski Francis J.
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