Patent Description:
Thromboembolism occurs when thrombus is formed within a blood vessel to the extent that the blood vessel becomes blocked. The impact of a blocked blood vessel can be serious and even life-threatening depending on the location of the blockage. For example, thrombus formation in (typically atherosclerotic) arteries can lead to peripheral arterial disease. When thrombus forms in the coronary arteries, myocardial infarction can result and thrombus in the cerebral arteries can cause ischaemic stroke. Venous thrombosis commonly occurs when thrombus forms and blocks flow in the deep veins of the leg, resulting in Deep Vein Thrombosis (DVT). Thrombus which travels through the venous system to the lungs causes Pulmonary Embolism (PE) which, in the most severe cases, can lead to sudden death. Often, but not exclusively, PE results when a part of the thrombus causing DVT breaks off and travels to the lungs.

There is evidence that incidence of thromboembolism and, in particular, venous thromboembolism is increasing. The <NUM> United States Surgeon General's Call to Action to Prevent DVT and PE estimates that <NUM>,<NUM> to <NUM>,<NUM> deaths occur annually from PE in the USA alone. The majority of deaths from acute PE result from right ventricular (RV) pressure overload and subsequent heart failure. Right ventricular dysfunction is commonly measured in terms of the right ventricular/left ventricular diameter ratio (RV/LV ratio). An RV/LV ratio which is greater than or equal to <NUM> is an independent predictive factor for mortality in PE patients, and the risk of adverse events, including death, increases as RV/LV ratio increases above <NUM> (<NPL>).

RV/LV ratios are typically measured as the apical <NUM>-chamber RV diameter divided by LV diameter, as measured from a computed tomography (CT) angiogram taken to create a <NUM> chamber view. For example, a CT is arranged to capture an apical <NUM>-chamber view and the end diastolic image is recorded. A center line is drawn through the interventricular septum and another line is drawn through the tricuspid annular line to create a cross. A sub-annular line is drawn <NUM> above the annular line. The right ventricular diameter is measured as the distance between the centre line and the endocardial border of the right ventricle, and the left ventricular diameter is measured as the distance between the center line and the endocardial border of the left ventricle. An example measurement is shown in <FIG>, which is included in two versions in the drawings. The person skilled in the art will understand that there are other methods for determining RV/LV ratio (such as maximum ventricular diameters on a apical <NUM>-chamber view) and also that RV/LV ratio is not the only method for determining and monitoring RV dysfunction. Other methodologies for determining RV dysfunction are discussed in detail in a statement from the American Heart Association, published by <NPL>.

Typically, thromboembolism is treated with anticoagulant drugs. Anticoagulant therapy is effective at preventing further clotting but it does not actively lyse thrombus. Rather, thrombolysis occurs naturally i.e. through the action of endogenous plasmin, which is generated from plasminogen by natural human tissue-type tissue plasminogen activator (t-PA) and is able to dissolve the fibrin component of the thrombus. Anticoagulant therapy is a long-term treatment option, with oral anticoagulant drugs administered over several months, or even years. However, patients with the most serious types of PE may remain at an increased risk of adverse events even during anticoagulant therapy.

Advanced therapies which involve direct thrombolysis are available.

Thrombolytic agents are able to dissolve, degrade or reduce thrombus. Generally, thrombolytic agents will be plasminogen activators, a group of serine proteases, which convert plasminogen to plasmin. Plasmin dissolves the fibrin component of thrombus. One class of thrombolytic agents are recombinant tissue plasminogen activators (r-tPA), which act on plasminogen in the same way as natural tPA. Commonly used r-tPA drugs include alteplase, reteplase and tenecteplase. Activase® (Alteplase, Genentech, Inc. ) is indicated for the treatment of acute massive pulmonary embolism with a recommended dose of <NUM> administered by IV infusion over <NUM> hours. The prescribing information for Activase carries a warning that the drug increases the risk of internal bleeding (intracranial, retroperitoneal, gastrointestinal, genitourinary, respiratory) or external bleeding, especially at arterial and venous puncture sites. Studies have shown that, in randomised clinical trials, systemic PE thrombolysis is associated with an <NUM>% risk of major bleeding and a <NUM>% risk of intracranial haemorrhage (<NPL>). For this reason, the use of large dose IV administration of tPA has declined over recent years and is currently reserved for the most seriously ill patients.

Other thrombolytic agents are available. Urokinase, which is also known as urokinase-type plasminogen activator (uPA), is a serine protease which acts in an analogous manner to r-tPA. Although urokinase dosage is measured in International Units (IU), the skilled person will understand what constitutes an equivalent dose of tPA and urokinase. For example, a typical adult dose of urokinase for systemic treatment of PE is <NUM> IU/kg ideal body weight/hr administered intravenously for up to <NUM> hours. Urokinase is typically available in doses of <NUM>,<NUM> IU.

Combined ultrasound/thrombolytic therapy enables loco-regional treatment of thrombus. Typically, such therapies comprise a drug delivery lumen(s) with drug delivery ports and an associated source of ultrasound, usually in the form a one or more ultrasonic transducers. The drug delivery lumen and source of ultrasound are arranged to expose thrombus to ultrasound and facilitate delivery of thrombolytic drug to the thrombus. The EkoSonic® Endovascular System (Ekos Corporation) is an example of such a combined therapy. The device comprises a drug delivery catheter that enables delivery of high frequency, low power ultrasound from the catheter core, at the same time as delivery of thrombolytic agent. The combination of ultrasound energy and thrombolytic agent accelerates thrombolysis by increasing thrombus permeability and by creating an acoustic pressure gradient to enable transport of a greater quantity of thrombolytic agent into the clot. As a result, combination therapy of this type enables more complete clot lysis in a shorter time than the therapies described above with lower doses of thrombolytic drug, which reduces the risk of major bleeding complications, including intracranial haemorrhage.

The safety and efficacy of combined ultrasound/thrombolytic therapy in PE patients was shown in two prospective, multi-center studies involving <NUM> subjects. ULTIMA (<NPL>) was a randomized-controlled study in <NUM> patients that showed ultrasound/thrombolytic therapy (EkoSonic® Endovascular System) to be superior to IV anticoagulant therapy (unfractionated heparin) without an increase in bleeding complications. The total dose of r-tPA used in the study was <NUM>, administered over <NUM> hours.

The SEATTLE II study was a prospective, multicentre trial of combined ultrasound/thrombolytic therapy involving <NUM> patients with acute massive and sub-massive PE. This study used <NUM> r-tPA with the EkoSonic® Endovascular System for <NUM> hours and showed a significant improvement in RV dysfunction with zero incidence of intracranial haemorrhage.

Although the ULTIMA and SEATTLE II studies demonstrate that combined ultrasound/thrombolytic therapy is effective with lower doses of thrombolytic agent than is used intravenously, relatively large doses (<NUM> or greater) are still used. Whether administered systemically or locally, the dose of thrombolytic agent is typically infused slowly (<NUM>-<NUM>/hr) and over a prolonged period of time (<NUM>-<NUM> hours). There are two reasons for this: (i) safety - the inherent risk of bleeding with thrombolytic drugs cannot be eliminated and so, very slow infusions are used to mitigate the risk as far as possible; (ii) r-tPA has a short half-life in systemic circulation, of approximately <NUM>-<NUM> minutes.

Whilst combined ultrasound/thrombolytic therapy is significantly safer than intravenous administration in terms of major bleeds and intracranial haemorrhage, the risk of bleeding is still present. Treatment requires hospitalisation and, for the reasons, above, treatment is slow, with patients typically treated in the ICU followed by general ward stay for several days. This makes the procedure very time-consuming and expensive. It is desirable, therefore, to mitigate the risk of bleeding as far as possible and, at the same time, to reduce treatment times to avoid lengthy hospital stays. It is highly desirable that treatment times are reduced to a point where patients could be treated in a step-down unit and potentially even avoid the ICU.

In further clinical investigations into combined ultrasound/thrombolytic therapy, the inventor has surprisingly found that, when thrombolytic drug is administered in combination with ultrasound, improvement in circulation occurs at significantly lower doses of thrombolytic drug and at much shorter treatment times than has been observed or can be predicted from previous trials and current clinical practice. In PE population, RV function was significantly improved in even the most seriously ill patients, irrespective of the degree of clot lysis, with very small doses of thrombolytic agent administered over very short periods of time, of less than <NUM> hours. In particular cases, treatment times were as short as <NUM> hours and has the potential to be reduced to <NUM> hour or less. Improvements in terms of RV/LV ratios of these patients were at least as good as those observed in the earlier clinical trials which proved the safety and efficacy of combined ultrasound/thrombolytic therapy (ULTIMA, SEATTLE II), meaning that the invention provides at least as good results as currently available treatment protocols but with vastly reduced doses of thrombolytic agent and vastly reduced treatment times.

Kucher et al. discussed a randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism in <NPL>.

<CIT> relates to a method for treating thromboembolic stroke, the method comprising the step of administering to a subject experiencing a thromboembolic stroke, therapeutically effective amounts of a thienopyridine derivative, wherein the thienopyridine derivative is ticlopidine, and a thrombolytic agent and wherein the thrombolytic agent is tPA, in an amount effective to reduce brain injury which would otherwise occur as a result of the stroke.

Engelberger and Kucher reported on the ultrasound assisted thrombolysis for acute pulmonary embolism in <NPL>.

<CIT> concerns a method for driving an ultrasound transducer coupled to an ultrasound catheter having an ultrasound transmission member extending longitudinally therethrough such that the distal end of the ultrasound transmission member oscillates at a desired operational ultrasound frequency, said method comprising the steps of a) providing a modulating signal, the modulating signal varying in amplitude and being continuous in duration; b) applying said modulating signal to an ultrasound transducer drive signal so as to modulate the ultrasound transducer drive signal; and wherein the resulting modulated ultrasound transducer drive signal is continuous in duration and devoid of high frequency components which exceed the desired operational ultrasound frequency.

The present invention relates to a thrombolytic agent for use in the treatment of thromboembolism, wherein the treatment comprises administering the thrombolytic agent directly to the thromboembolism in the presence of ultrasound, wherein the total dose of the thrombolytic agent is between <NUM> and <NUM> and is administered as one or more small bolus doses of between <NUM> and <NUM>, and the time over which the total dose is delivered is <NUM> hours or less. Earlier clinical studies (ULTIMA) demonstrated that thrombolysis can be achieved after <NUM> hours but that study required <NUM> of thrombolytic agent to observe a <NUM>% improvement in RV dysfunction. Similarly, the SEATTLE II study exhibited a <NUM>% improvement in RV dysfunction after administration of <NUM> of thrombolytic agent over <NUM> hours. Clinical studies underpinning the present invention have shown that similar or even better levels of improvement in RV dysfunction can be achieved with much smaller doses of thrombolytic agent and over much shorter treatment times.

The references to any methods of treatment by therapy or surgery or in vivo diagnosis methods in this description are to be interpreted as references to compounds, pharmaceutical compositions and medicaments of the present invention for use in those methods.

Without being bound by theory, it is thought that the surprising clinical results show that previously unknown mechanisms occur very quickly when thrombolytic agent is administered under the influence of ultrasound. It is possible that the pulmonary vascular response to ultrasound is one which creates or activates pathways in the vasculature, which increases pulmonary blood flow, thereby relieving pressure in the right ventricle at the same time as the thrombolytic agent starts to lyse the thrombus. The current clinical studies have shown, for the first time, that RV dysfunction is improved even with a small amount of clot lysis. Improvement, as measured by RV/LV ratio, is the same or better than has been shown
in previous studies despite significantly smaller doses and reduced treatment times. This is unexpected because, at the date of invention, it was thought that the levels of improvement in RV dysfunction that allow for treatment to be stopped were only seen when significant lysis had occurred. It is now thought that combined ultrasound/thrombolytic therapy utilises additional pathways, such as increased and/or extended vasodilation of capillary vessels in the pulmonary venous system, to allow for rapid treatment with low doses of thrombolytic, even if significant thrombus remains.

In particular cases, the total dose of thrombolytic agent to be administered is approximately <NUM> and, preferably between <NUM> and <NUM>, more preferably between <NUM> and <NUM>, more preferably between <NUM> and <NUM>, more preferably between <NUM> and <NUM> and more preferably still between <NUM> and <NUM>. Suitable total doses of thrombolytic therefore are <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>. These very small doses are advantageous because they can be administered as a bolus dose or infused over such a short time period as to be considered a bolus dose.

The very small doses of thrombolytic agent are to be administered as a bolus dose in the presence of ultrasound. The ultrasound may be activated at the same time or just prior to administration of the thrombolytic agent to the site of the thrombus or alternatively the thrombus may be subjected to ultrasound therapy for a period of time, such s between <NUM> and <NUM> minutes, prior to administration of the thrombolytic agent. As the total dose of thrombolytic agent is significantly lower than has been used previously, it is preferred that it is injected directly into the thrombus or very close to the thrombus to ensure maximum uptake. The source of ultrasound can be external to the patient but it will be understood by the person skilled in the art that such an arrangement, whereby ultrasound will be absorbed by non-target tissue, may not be optimal. Preferably the source of ultrasound is provided within the same blood vessel as the thrombus and placed within the region of the thrombus i.e. directly in or adjacent the thrombus. Catheters which allow for the infusion of thrombolytic agent and which also house a source of ultrasound are well known in the art. Commercially available devices, such as the Ekosonic Endovascular System, are FDA-cleared and CE-marked and, thus, are particularly suitable for use within the invention.

Alternatively, the thrombolytic agent may be infused at rates which still result in much shorter treatment times than have been reported before. Suitably, thrombolytic agent is to be administered at rate of between <NUM>/hr and <NUM>/hr, such as between <NUM> and <NUM>/hr and preferably between <NUM> and <NUM>/hr and even more preferably between <NUM> and <NUM>/hr. In a particular embodiment, the thrombolytic agent is infused at a rate of <NUM>/hour.

In another particular embodiment, the thrombolytic agent is infused at rate of <NUM>/hour or less. This rate may be particularly useful for the lowest doses of thrombolytic agent, such as <NUM>, <NUM>, <NUM> or <NUM> allowing for treatment times of <NUM>, <NUM>, <NUM> or <NUM> hours.

Infusion rates of <NUM>/hour can be useful in severe acute PE patients, for example, who may require bilateral PE treatment. In these cases, bilateral treatment can be achieved with two ultrasound/drug delivery catheters being used in the same patients to deliver two doses at the same time. The infusion rates are well tolerated and will result in total treatment times which are less than <NUM> hours, for example: bilateral treatment with <NUM> thrombolytic agent, infused at <NUM>/hour results in a total dose of <NUM> and a treatment time of <NUM> minutes; bilateral treatment with <NUM> thrombolytic agent, infused at <NUM>/hour results in a total dose of <NUM> and a treatment time of <NUM> hours; bilateral treatment with <NUM> thrombolytic agent, infused at <NUM>/hour results in a total dose of <NUM> and a treatment time of <NUM> hours; and bilateral treatment with <NUM> thrombolytic agent, infused at <NUM>/hour results in a total dose of <NUM> and a treatment time of <NUM> hours. Dosage rates can be varied provided the total dosage rate and total treatment time remain the same. For example, a <NUM> dose of thrombolytic agent may be administered at a rate of <NUM>/hour for one hour, and the remaining <NUM> administered at <NUM>/hour, resulting in a total treatment time of three hours. It is anticipated that smaller doses, such as <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, are therapeutically useful and could be used, for example, in the treatment of more minor thromboembolism.

At the end of the treatment (i.e. administration of the total dose of thrombolytic) patients may be given or may resume standard of care anticoagulant therapy to prevent growth of any remaining thrombus and/or that new thrombus does not form.

Thrombolytic agents, which are suitable for use with the present invention are well known and approved for use in several territories. In a particular embodiment the thrombolytic agent is recombinant tissue plasminogen activator (r-tPA).

Ultrasound sources are also well known in the art. A suitable example of an ultrasound element for generation of ultrasound energy includes, but is not limited to, a piezoelectric ceramic oscillators. A single ultrasound source may be sufficient but preferably a plurality of ultrasound sources are utilised to give spatial and directional control over the ultrasound.

A plurality of ultrasound elements can be advantageously wired individually, in parallel or in series to provide maximum flexibility and control over the ultrasound.

The inventor has found that internal ultrasound provided at a frequency of between <NUM> - <NUM> is sufficient to obtain the advantages of the invention. The maximum pulse power of the ultrasound is preferably 50W and is preferred that then ultrasound is provided in pulses of randomly variable waveforms, as this appears to provide useful source of ultrasound, without undue heating of surrounding tissue. As mentioned above, devices, such as the Ekosonic Endovascular System, are commercially available and can be used in the invention without further modification.

The present invention provides the thrombolytic agent for use according to claim <NUM>.

Preferably, the total dose of thrombolytic agent to be administered is between <NUM> and <NUM>. More preferably, the total dose of thrombolytic agent to be administered is between <NUM> and <NUM>. More preferably, the total dose of thrombolytic agent to be administered is between <NUM> and <NUM>. More preferably, the total dose of thrombolytic agent to be administered is <NUM>. More preferably, the thrombolytic agent is infused at a rate of <NUM>/hour. More preferably, the thrombolytic agent is infused at rate of <NUM>/hour. More preferably, the thrombolytic agent is recombinant tissue plasminogen activator (r-tPA) or urokinase. More preferably, ultrasound is provided at a frequency of between <NUM> - <NUM>. More preferably, the maximum pulse power of the ultrasound is 50W.

Herein disclosed for reference, but not claimed, is a method for the treatment of thromboembolism comprising:.

In this aspect, the method ensures treatment times are shortened to a maximum of <NUM> hours. The method may be used with single or bilateral catheter placement depending on the type and location of the thromboembolism. For example, for treatment of bilateral PE cases, two catheters may be placed at the same time, with each catheter delivering up to <NUM> of thrombolytic drug at a rate of up to <NUM>/hour so that the total dose is <NUM> but the total treatment time is <NUM> hours.

The method may otherwise be performed with a single catheter which delivers the total dose of drug and the ultrasound. The maximum total dose of thrombolytic agent administered through the catheter is <NUM> and the total dose of thrombolytic agent is administered at a maximum rate of <NUM>/hour, such that treatment times limited to a maximum of <NUM> hours. Although much smaller doses are effective, there will be a practical lower dose that can be handled routinely within a pharmacy or hospital and so, although it is unlikely that doses of less than <NUM> of thrombolytic agent would be used in a clinical setting, it is possible that smaller doses, such as <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, could be used for minor thromboembolism.

Preferably, the total dose of thrombolytic agent administered through the catheter is between <NUM> and <NUM> and the total dose of thrombolytic agent is administered at a rate of <NUM>/hour. More preferably, the total dose of thrombolytic agent administered through the catheter is between <NUM> and <NUM> and the total dose of thrombolytic agent is administered at a rate of <NUM>/hour. Preferably, the total dose of thrombolytic agent administered through the catheter is between <NUM> and <NUM> and the total dose of thrombolytic agent is administered at a rate of <NUM>/hour. Preferably, the thrombolytic agent is recombinant tissue plasminogen activator (r-tPA) or urokinase. Preferably, ultrasound is provided at a frequency of between <NUM> - <NUM>. Preferably, the maximum pulse power of the ultrasound is 50W. Preferably, the catheter is the comprises an inner core into which the ultrasound radiating members may be removal inserted and which is independent of the fluid delivery lumen, through which the thrombolytic agent is administered at <NUM>/hour to give a total treatment time which is less than <NUM> hours. Preferably, the total treatment time is <NUM> hours. Preferably, the total treatment time is <NUM> hours. Preferably, the thrombolytic agent is administered through <NUM> catheters simultaneously.

Further herein disclosed for reference, but not claimed, is a pharmaceutical composition comprising <NUM>-<NUM> recombinant tissue plasminogen activator (r-tPA) and a pharmaceutically acceptable excipient, for use in the treatment of thromboembolism. Preferably, the composition is administered intravenously, in the presence of ultrasound and administration is completed in between <NUM> and <NUM> hours. More preferably, the composition is administered directly to the thromboembolism via a catheter which comprises a fluid delivery lumen having at least one outlet and a plurality of ultrasound radiating members, said ultrasound radiating members arranged in the region of the fluid outlet and being connected to an electrical power source which is located externally to the catheter and arranged to drive the ultrasound radiating members to produce ultrasound as the composition is administered.

As set out in claim <NUM>, the present invention relates to a thrombolytic agent for use in the treatment of thromboembolism, wherein the treatment comprises administering the thrombolytic agent directly to the thromboembolism in the presence of ultrasound,
wherein the total dose of the thrombolytic agent is between <NUM> and <NUM> and is administered as one or more small bolus doses of between <NUM> and <NUM>, and the time over which the total dose is delivered is <NUM> hours or less.

Preferably, the total dose of thrombolytic agent to be administered is between <NUM> and <NUM>. More preferably, the total dose of thrombolytic agent to be administered is between <NUM> and <NUM>. More preferably, the total dose of thrombolytic agent to be administered is between <NUM> and <NUM>. Most preferably, the total dose of thrombolytic agent to be administered is <NUM>. Preferably, the thrombolytic agent is infused at a rate of <NUM>/hour. More preferably, the thrombolytic agent is infused at rate of <NUM>/hour. Preferably, the thrombolytic agent is recombinant tissue plasminogen activator (r-tPA) or urokinase. Preferably, ultrasound is provided at a frequency of between <NUM> - <NUM>. Preferably, the maximum pulse power of the ultrasound is 50W.

As has been described above the thrombolytic agent is any agent which stimulates the conversion of plasminogen to plasmin and, preferably, recombinant tissue plasminogen activator (r-tPA) or urokinase-type plasminogen activator.

Piezoelectric ceramic oscillators, as described above are suitable sources of ultrasound. These ultrasound elements can be shaped as a cylinder, a hollow cylinder and a disk which are concentric with the catheter. The ultrasound elements can also be an array of smaller ultrasound elements or a thin plate positioned within the body of the catheter. Similarly, a single ultrasound element can be composed of several smaller ultrasound elements.

Ultrasound may be provided in accordance with the protocols described in <CIT>.

As expounded herein, ultrasonic energy is often used to enhance the delivery and/or effect of a therapeutic compound. For example, in the context of treating vascular occlusions, ultrasonic energy has been shown to increase enzyme mediated thrombolysis by enhancing the delivery of thrombolytic agents into a thrombus, where such agents lyse the thrombus by degrading the fibrin that forms the thrombus. The thrombolytic activity of the agent is enhanced in the presence of ultrasonic energy in the thrombus. However, it should be appreciated that the invention should not be limited to the mechanism by which the ultrasound enhances treatment unless otherwise stated. In other applications, ultrasonic energy has also been shown to enhance transfection of gene-based drugs into cells, and augment transfer of chemotherapeutic drugs into tumor cells. Ultrasonic energy delivered from within a patient's body has been found to be capable of producing non-thermal effects that increase biological tissue permeability to therapeutic compounds by up to or greater than an order of magnitude.

As used herein, the terms "ultrasonic energy", "ultrasound" and "ultrasonic" are broad terms, having their ordinary meanings, and further refer to, without limitation, mechanical energy transferred through longitudinal pressure or compression waves. Ultrasonic energy can be emitted as continuous or pulsed waves, depending on the requirements of a particular application. Additionally, ultrasonic energy can be emitted in waveforms having various shapes, such as sinusoidal waves, triangle waves, square waves, or other wave forms. Ultrasonic energy includes sound waves. In certain embodiments, the ultrasonic energy has a frequency between about <NUM> and about <NUM>. For example, in one embodiment, the waves have a frequency between about <NUM> and about <NUM>. in another embodiment, the waves have a frequency between about <NUM> and about <NUM>. In yet another embodiment, the waves have a frequency of about <NUM>. The average acoustic power is between about <NUM> watts and <NUM> watts. In one embodiment, the average acoustic power is about <NUM> watts.

As used herein, the term "ultrasound radiating member" refers to any apparatus capable of producing ultrasonic energy. For example, in one embodiment, an ultrasound radiating member comprises an ultrasonic transducer, which converts electrical energy into ultrasonic energy. A suitable example of an ultrasonic transducer for generating ultrasonic energy from electrical energy includes, but is not limited to, piezoelectric ceramic oscillators. Piezoelectric ceramics typically comprise a crystalline material, such as quartz, that change shape when an electrical current is applied to the material. This change in shape, made oscillatory by an osculating driving signal, creates ultrasonic sound waves. In other embodiments, ultrasonic energy can be generated by an ultrasonic transducer that is remote from the ultrasound radiating member, and the ultrasonic energy can be transmitted, via, for example, a wire that is coupled to the ultrasound radiating member.

In a preferred embodiment, the ultrasound radiating members <NUM> comprise rectangular lead zirconate titanate ("PZT") ultrasound transducers that have dimensions of about <NUM> inches by about <NUM> inches by about <NUM> inches. In other embodiments, other configuration may be used. For example, discshaped ultrasound radiating members <NUM> can be used in other embodiments. In a preferred embodiment, the common wire <NUM> comprises copper, and is about <NUM> inches thick, although other electrically conductive materials and other dimensions can be used in other embodiments. Lead wires <NUM> are preferably <NUM> gauge electrical conductors, while positive contact wires <NUM> are preferably <NUM> gauge electrical conductors. However, one of ordinary skill in the art will recognize that other wire gauges can be used in other embodiments.

As described above, suitable frequencies for the ultrasound radiating member <NUM> include, but are not limited to, from about <NUM> to about <NUM>. In one embodiment, the frequency is between about <NUM> and <NUM>, and in another embodiment <NUM> and <NUM>. In yet another embodiment, the ultrasound radiating members <NUM> are operated with a frequency of about <NUM>.

The ultrasound radiating members are preferably operated in a pulsed mode. For example, in one embodiment, the time average electrical power supplied to the ultrasound radiating members is between about <NUM> watts and <NUM> watts and can be between about <NUM> watts and <NUM> watts. In certain embodiments, the time average electrical power over treatment time is approximately <NUM> watts or <NUM> watts. The duty cycle is between about <NUM>% and <NUM>% and can be between about <NUM>% and <NUM>%. In certain embodiments, the duty ratio is approximately <NUM>%, <NUM>% or a variation between <NUM>% to <NUM>%. The pulse averaged electrical power can be between about <NUM> watts and <NUM> watts and can be between approximately <NUM> watts and <NUM> watts. In certain embodiments, the pulse averaged electrical power is approximately <NUM> watts, <NUM> watts,<NUM> watts, or a variation of <NUM> to <NUM> watts. As will be described above, the amplitude, pulse width, pulse repetition frequency, average acoustic pressure or any combination of these parameters can be constant or varied during each pulse or over a set of portions. In a non-linear application of acoustic parameters the above ranges can change significantly. Accordingly, the overall time average electrical power over treatment time may stay the same but not real-time average power.

In one embodiment, the pulse repetition rate is preferably between about <NUM> and <NUM> and more can be between about <NUM> and <NUM>. In certain preferred embodiments, the pulse repetition rate is approximately <NUM>, or a variation of <NUM> to <NUM>. The pulse duration or width is can be between about <NUM> millisecond and <NUM> milliseconds and can be between about <NUM> millisecond and <NUM> milliseconds. In certain embodiments, the pulse duration is approximately <NUM> milliseconds, <NUM> or a variation of <NUM> to <NUM> milliseconds. In addition, the average acoustic pressure can be between about <NUM> to 2MPa or in another embodiment between about <NUM> or <NUM> to <NUM>.

In one particular embodiment, the transducers are operated at an average power of approximately <NUM> watts, a duty cycle of approximately <NUM>%, a pulse repetition rate of <NUM>, a pulse average electrical power of approximately <NUM> watts and a pulse duration of approximately <NUM> milliseconds.

The ultrasound radiating member used with the electrical parameters described herein preferably has an acoustic efficiency than <NUM>% and can be greater than <NUM>%. The ultrasound radiating member can be formed a variety of shapes, such as, cylindrical (solid or hollow), flat, bar, triangular, and the like. The length of the ultrasound radiating member is preferably between about <NUM> and about <NUM>. The thickness or diameter of the ultrasound radiating members is preferably between about <NUM> and about <NUM>.

As will be described below, the ultrasound catheter includes one or more one or more ultrasound radiating members positioned therein. Such ultrasound radiating members can comprise a transducer (e.g., a PZT transducer), which is configured to convert electrically energy into ultrasonic energy. In such embodiments, the PZT transducer is excited by specific electrical parameters (herein "power parameters" or "acoustic parameters" that cause it to vibrate in a way that generates ultrasonic energy). As will be explained below, Applicants have discovered that non-linearly varying (e.g.,. randomly or pseudo randomly) one or more of the power parameters the effectiveness of the ultrasound catheter (e.g., the effectiveness of enhancing the removal of a thrombus) can be significantly enhanced. By non-linearly varying one or more of the power parameters the ultrasound radiating members create nonlinear acoustic pressure, which as described above can increase the effectiveness of the acoustic pressure in enhancing a therapeutic compound. In one application, the effect of nonlineariy varying acoustic pressure has been found by Applicant to enhance enzyme medicated thrombolysis by almost <NUM> times as compared to the application of substantially constant acoustic pressure. Examples of nonlinear variances include, but are not limited to, multi variable variations, variations as a function of a complex equation, sinusoidal variations, exponential variations, random variations, pseudo random variations and/or arbitrary variations. While nonlinear variance is preferred, in other arrangements it is anticipate that one or more of the parameters discussed can be varied in a linear manner either alone or combination with the nonlinear variance.

In one embodiment, one way of implementing a randomization protocol is to generate and execute a plurality of ultrasonic cycle profiles, where each ultrasonic cycle profile can have randomly generated power parameter values. As previously mentioned, power parameters include, but are not limited to, peak power, pulse width, pulse repetition frequency and pulse repetition interval. Generally, for each power parameter, a random number generator, for example, can be used to select a value within a bounded range determined by the operator. Examples of suitable ranges are described above. For example, one ultrasonic cycle profile can have a randomly selected peak power value, while the other power parameters are non-randomly selected. Another ultrasonic cycle profile may have a plurality of randomly selected power parameters values, such as peak power and pulse width. This process can be used to generate the desired number of ultrasonic cycle profiles.

Each ultrasonic cycle profile can be run for a profile execution time. For example, if the profile execution time is approximately <NUM> seconds, each ultrasonic cycle profile will be run for approximately <NUM> seconds before the next ultrasonic cycle profile is run. In some embodiments, the profile execution time is less than about <NUM> seconds. For example, in some embodiments the profile execution time is between about one second and about <NUM> seconds. In some embodiments, the profile execution time is less than about one second. In some embodiments, the profile execution time is increased so that accurate measurements can be taken of the executed power parameters. In some embodiments, the profile execution time itself can be selected randomly from a predetermined range.

In some embodiments, it is desirable to deliver a particular time averaged power. Because the power parameters may be randomized, it may take the execution of a plurality of ultrasonic cycle profiles before the time averaged power approaches an asymptotic value, in some embodiments, the execution of about <NUM> to <NUM> ultrasonic cycle profiles is required for the time averaged power to become asymptotic. In other embodiments, less than about <NUM> ultrasonic cycle profiles are required, while in yet other embodiments, more than about <NUM> ultrasonic cycle profiles are required. In some embodiments, ultrasonic cycle profiles are executed until the time average power approaches an asymptotic value. For example, if the profile execution time is <NUM> seconds and the overall execution time is <NUM> minutes, <NUM> ultrasonic cycle profiles will be executed, which in some embodiments is sufficient for the time average power to approach an asymptotic value.

In addition, although many embodiments have been described in the context of an intravascular catheter it should be appreciated that the non-linear application of one or more power parameters can also be applied to non-intravascular catheters or devices and/or non catheter applications. For example, the non-linear varying of one or more power parameters may also find utility in applications in which the ultrasound is applied through an external (with respect to the body or with respect to the vascular system). In particular, the discussion above can be applied to external ultrasound application in which the ultrasound source is external to the patient and/or treatment site. It is also anticipated that the techniques described herein can be applied to non-vascular applications.

Preferably, ultrasound is provided at a frequency of between <NUM> - <NUM>.

Suitable catheter systems are available commercially which may be used in the present invention. Catheters described in <CIT>
are particularly suitable for administration of thrombolytic agent at a rate which is between <NUM> and <NUM>/hour to give treatment time which is between <NUM> and <NUM> hours. As described above the thromboembolism may be Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE) or Peripheral Arterial Occlusions (PAO). The composition is useful for treatment of thromboembolism using the techniques described herein.

In a preferred embodiment, the pharmaceutical composition is to be administered directly to the thromboembolism via a catheter which comprises a fluid delivery lumen having at least one outlet and a plurality of ultrasound radiating members, said ultrasound radiating members arranged in the region of the fluid outlet and being connected to an electrical power source which is located externally to the catheter and arranged to drive the ultrasound radiating members to produce ultrasound as the composition is administered. Suitable catheters and ultrasound protocols are described in <CIT> and <CIT>, respectively.

The invention will now be described by way of example, which is intended to describe particular embodiments of the invention. The embodiments are illustrative and not intended to limit the scope of protection of the claims.

The optimum dose of thrombolytic agent and duration of the ultrasound procedure in combined ultrasound/thrombolytic therapy (described in this example as the APT Procedure) was determined for acute submassive PE. The Acoustic Pulse Thrombolysis (APT) Procedure utilised the EkoSonic® Endovascular System (Ekos Corporation) to deliver high frequency (<NUM>- <NUM>), low power ultrasound in combination with low doses of recombinant tissue plasminogen activator (r-tPA).

Eligible subjects had acute (symptoms < <NUM> days) proximal PE located in at least one main or proximal lobar pulmonary artery and a right ventricular (RV)-to-left ventricular (LV) end-diastolic diameter ratio ≥ <NUM> on chest computed tomographic angiography (CTA). Eligible subjects were required to receive treatment within <NUM> of the diagnostic CTA. The primary efficacy endpoint was reduction of the RV/LV ratio by > <NUM> on CTA at <NUM> after starting treatment. The primary safety endpoint was major bleeding events within <NUM> after initiating the procedure. Secondary endpoints included the Modified Miller Score (MMS; embolic burden on CTA).

The Ekosonic Endovascular Device was used in accordance with the published Instructions for Use. The system generates ultrasound waves in the treatment zone of the catheter through the piezoelectric conversion of radiofrequency energy. The ultrasound emanates radially from the treatment zone to improve the dispersion of infused physician-specified fluids, including thrombolytics.

The EKOS Device consists of two main components:.

The IDDC is <NUM> French with a <NUM> or <NUM> working length. It includes two luer ports for coolant fluid and thrombolytic delivery and an electrical connector for the thermocouples that monitor the catheter system temperature. Radiopaque markers are located approximately <NUM> proximal and <NUM> distal to the treatment zone. The IDDC central lumen is compatible with a <NUM>" guidewire, accepts the MSD and delivers coolant during operation. Each EkoSonic Device requires its own infusion tubing and infusion pump with coolant of normal saline to run at <NUM>/hr/device. The MSD locks to the luer connector on the central lumen of the IDDC aligning the ultrasound-generating segment to the treatment zone of the IDDC. The device uses multiple ultrasound transducers to emit ultrasound energy radially from the long axis of the catheter system.

The EkoSonic® Control System provides electrical power to the piezoelectric elements in the treatment zone of the Device and monitors operating parameters during operation. The Control System also provides the user interface through the front panel display and keypad.

The r-tPA used in this study was commercially available drug marketed in the participating geographies under various brand names for fibrinolysis of pulmonary embolism by systemic peripheral infusion. The r-tPA was prepared from standard pharmacy supplies and prepared following the manufacturer's instructions. r-tPA was be delivered through the EkoSonic® Endovascular System (ultrasonic infusion catheter) to the site of the clot rather than by systemic infusion. The drug was administered using standard infusion pumps to administer the total dose of drug at a rate of either <NUM>/hour or <NUM>/hour. Doses of r-tPA administered were <NUM>, <NUM>, and <NUM> through a single catheter. In some bilateral cases, total dose of r-tPA was <NUM>, <NUM> or <NUM>, with a maximum treatment time of <NUM> hours.

All patients met the following criteria to be eligible for participation in this clinical trial:.

Venous access was obtained via venipuncture of the common femoral vein (CFV) and/or internal jugular vein (IJV), under ultrasound guidance. The pulmonary artery was then catheterized, according to the treating physician's preferred techniques, for example, via the transfemoral approach is using a <NUM>- or <NUM>-Fr pigtail catheter in conjunction with a hydrophilic Glidewire® (Terumo, Sommerset, NJ) and torque control device or standard Tefloncoated wire using tip-deflecting techniques. A sheath was then placed into the artery or was completed prior to catheterisation. Selective contrast injection into the main left or right PA was then undertaken to identify the largest thrombosed arterial branch(es).

A simplified model of the pulmonary arteries is shown in <FIG> (which is included in two versions in the drawings) to illustrate the example placement or catheters for single and bilateral treatment (depending on the location of the thrombus). Note, that the segmental branches of the upper lobe, middle lobe, and lingula are not shown in this simplified model.

The EkoSonic Device was then prepped per protocol from the manufacturer's Instructions for Use and the infusion catheter was inserted over the respective guidewire and buried within the previously identified thrombosed artery.

Once the infusion catheters were properly positioned and connected to IV pumps, catheter directed thrombolysis was initiated using alteplase (rt-PA; Genentech, South San Francisco,CA). Once rtPA infusion is initiated through the catheter(s), the cathter control unit was activated for ultrasound energy transmission. Treatment continued at the protocol prescribed infusion rate and dose i.e. dose per catheter was between <NUM> and <NUM> and infusion rates were <NUM> or <NUM>/hr. Following completion of catheter-directed thrombolysis, the patient was given a follow-up CTA to measure changes,.

Ninety-one subjects (mean age <NUM>, BMI <NUM>, female <NUM>%, Caucasian <NUM>%) at <NUM> centers were enrolled and randomized to one of four Cohorts (Table <NUM>). All received therapeutic anticoagulation in addition to the specific USCDT treatment regimen. Significant improvement was observed in RV/LV ratio at <NUM> post-procedure in all Cohorts. Similarly, significant improvements occurred in the MMS, with increasing reduction from Cohort <NUM> to <NUM>.

The overall major bleeding rate was <NUM>/<NUM> (<NUM>%). No major bleeding events were reported in Cohorts <NUM> and <NUM>. The major bleeding event in Cohort <NUM> was anemia secondary to facial trauma after syncope. The major bleeding events in Cohort <NUM> were bleeding from a splenic pseudoaneurysm treated with coil embolization, and ICH in a <NUM> year-old male patient with a prior history of thrombocytopenia and labile hypertension. Another major bleeding event of ICH was reported following systemic administration of tPA <NUM>; the subject recovered completely.

Two patient populations for analysis: Efficacy (N=<NUM>) and Safety (N=<NUM>). Difference are the number of evaluable patients (Pre and post treatment CTs) - see Tables <NUM> and <NUM>.

Claim 1:
A thrombolytic agent for use in the treatment of thromboembolism, wherein the treatment comprises administering the thrombolytic agent directly to the thromboembolism in the presence of ultrasound, wherein the total dose of the thrombolytic agent is between <NUM> and <NUM> and is administered as one or more small bolus doses of between <NUM> and <NUM>, and the time over which the total dose is delivered is <NUM> hours or less.