Method for treating thromboembolism

Abstract

A method for treating thromboembolism comprising administering a thrombolytic agent directly to a thromboembolism in the presence of ultrasound, wherein the total dose of the thrombolytic agent administered is between 1 mg and 12 mg, and the total dose is delivered over a period of less than 15 hours. [Selected figure] Figure 2

Description

Technical Field

[0001] The present invention relates to a method for treating the effects of thromboembolism, and more particularly to a method for thrombolytic treatment of blood clots, including those associated with deep vein thrombosis (DVT), pulmonary embolism (PE) and peripheral arterial occlusion (PAO). The method of the present invention uses a reduced amount of thrombolytic agent to shorten the treatment time, enable local treatment of the thrombus, and result in improved symptoms and thrombus lysis.

Background Art

[0002] Thromboembolism occurs when a blood clot forms in a blood vessel to the extent that the vessel is blocked. The effects of vessel blockage can be severe and, depending on the location of the blockage, can even be life-threatening. For example, thrombosis in an artery (generally atherosclerotic) can cause peripheral arterial disease. When a blood clot forms in a coronary artery, a myocardial infarction occurs, and a blood clot in a cerebral artery can cause an ischemic stroke. When a blood clot forms in the deep veins of the leg and blocks blood flow, a venous clot generally occurs, resulting in deep vein thrombosis (DVT). A blood clot that migrates through the venous system to the lungs causes pulmonary embolism (PE), and in the most severe cases, can lead to sudden death. In many cases, but not limited to, a portion of the thrombus resulting from DVT breaks off and migrates to the lungs, causing PE.

[0003] It has been proven that the incidence of thromboembolism, specifically venous thromboembolism, is increasing. According to the estimates of the 2008 United States Surgeon General’s Call to Action to Prevent DVT and PE, in the United States alone, 100,000 to 180,000 deaths occur annually. The majority of deaths due to acute PE are caused by right ventricular (RV) overload and subsequent heart failure. Right ventricular dysfunction is generally measured in terms of the right ventricular / left ventricular diameter ratio (RV / LV ratio). An RV / LV ratio of 0.9 or more is an independent predictor of mortality in PE patients, and when the increase in the RV / LV ratio exceeds 1.0, the risk of adverse events including death increases (Fremont et al., CHEST 2008;133:358-362).

Brief Description of the Drawings

[0004]

Figure 1

Figure 2

[0005] The RV / LV ratio is generally measured by dividing the RV diameter of the apical four-chamber view by the LV diameter, which is measured from computed tomography (CT) angiograms taken to create a four-chamber cross-section. For example, the CT is positioned to take an apical four-chamber tomographic image, and the end-diastolic image is recorded. The center line is drawn through the ventricular septum, and another line is drawn through the tricuspid annulus line to intersect it. The sub-annular line is drawn 1 cm above the annular line. The right ventricular diameter is measured as the distance between the center 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 of the measurement is shown in FIG. 1. The figure includes two versions. Those skilled in the art will also understand that there are other methods for determining the RV / LV ratio (the maximum ventricular diameter on the apical four-chamber tomographic image), and that the RV / LV ratio is not the only way to determine and monitor RV dysfunction. Other methodologies for determining RV dysfunction have been published by Jaff et al. (“Challenging Forms of Venous Thromboembolic Disease”: Circulation. 2011; 123: 1788-1830) and are detailed in an article from the American Heart Association (the content is incorporated herein by reference). Generally, thromboembolism is treated with anticoagulants. Anticoagulant therapy is effective in preventing further clotting, but does not actively dissolve the clot. Rather, thrombolysis occurs naturally, i.e., by the action of endogenous plasmin. Endogenous plasmin is generated from plasminogen by native human tissue-type tissue plasminogen activator (t-PA) and can dissolve the fibrin component of the clot. Anticoagulant therapy is a long-term treatment option, and oral anticoagulants are administered for months or even years. However, patients with the most severe type of PE may continue to have an increased risk of adverse events even during anticoagulant therapy.

[0006] Advanced treatments involving direct thrombolysis are available.

[0007] Thrombolytic agents can dissolve, break down, or reduce blood clots. Generally, thrombolytic agents are a type of serine protease, plasminogen activator, which converts plasminogen to plasmin. Plasmin dissolves the fibrin component of blood clots. One type of thrombolytic agent is recombinant tissue plasminogen activator (r-tPA), which acts 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 100 mg administered by intravenous infusion over 2 hours. The prescribing information for Activase conveys a warning that this drug increases the risk of internal bleeding (intracranial, retroperitoneal, gastrointestinal, genitourinary, respiratory) or external bleeding, particularly at arterial and venous puncture sites. Randomized clinical trials have shown that systemic PE thrombolysis is associated with a risk of major bleeding of 11.5% and a risk of intracranial bleeding of 6.3% (Meyer, G. et al., N. Engl, J. Med. 2014;340:1402-1411). For this reason, the use of high-dose intravenous tPA has decreased in recent years and is now reserved for the most severely ill patients.

[0008] Other thrombolytic agents are available. Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease that acts in a similar way to r-tPA. Urokinase doses are measured in international units (IU), but those skilled in the art understand what constitutes equivalent doses of tPA and urokinase. For example, the typical adult dose of urokinase for systemic treatment of PE is 8800 IU / standard body weight kg / hour and is administered intravenously for up to 72 hours. Urokinase is generally available in a dose of 100,000 IU.

[0009] Ultrasound / thrombolysis combination therapy enables the treatment of local areas of thrombi. Generally, such therapy includes a drug delivery lumen (s) with a drug delivery port and an associated ultrasound source, usually in the form of one or more ultrasound transducers. The drug delivery lumen and the ultrasound source are arranged to expose the thrombus to ultrasound and facilitate the delivery of thrombolytic agents to the thrombus. The EkoSonic® Endovascular System (Ekos Corporation) is an example of such combination therapy. This device includes a drug delivery catheter and enables the delivery of high-frequency, low-power ultrasound from the catheter core, along with the simultaneous delivery of a thrombolytic agent. By combining ultrasound energy and a thrombolytic agent, thrombolysis is accelerated by increasing thrombus permeability and creating a pressure gradient that enables the transport of a greater amount of thrombolytic agent to the clot. As a result, this type of combination therapy enables more complete clot lysis in a shorter period than the above-described therapy with low doses of thrombolytic agents and reduces the risk of serious hemorrhagic complications, including intracranial hemorrhage.

[0010] The safety and efficacy of ultrasound / thrombolysis combination therapy in PE patients were demonstrated in two prospective, multi-center trials involving 208 subjects. ULTIMA (Kucher, N et al., Circulation, 2014;129:479-486) was a randomized comparative trial in 59 patients and demonstrated that ultrasound / thrombolysis therapy (EkoSonic® Endovascular System) was superior to intravenous anticoagulation therapy (unfractionated heparin) without showing an increase in hemorrhagic complications. The total dose of r-tPA used in this trial was 20 mg, administered over 15 hours.

[0011] The SEATTLE II trial was a prospective, multi-center clinical trial of ultrasound / thrombolysis combination therapy involving 149 patients with acute extensive PE and submassive PE. This trial used 24 mg of r-tPA over 24 hours with the EkoSonic® Endovascular System, showed significant improvement in RV dysfunction, and had no occurrences of intracranial hemorrhage.

[0012] The ULTIMA trial and the SEATTLE II trial indicate that ultrasound / thrombolysis combination therapy is more effective at lower doses of thrombolytic agents than when thrombolytic agents are used intravenously, although relatively high doses (20 mg or more) are still being used. Whether administered systemically or locally, thrombolytic agents are generally infused slowly (1 - 2 mg / hour) over a long period (24 - 36 hours). There are two reasons for this: (i) safety - the inherent risk of bleeding due to thrombolytic drugs cannot be eliminated, so extremely slow infusion is used to reduce the risk as much as possible; (ii) r-tPA has a relatively short half-life of about 3 - 4 minutes in the systemic circulation.

[0013] Ultrasound / thrombolysis combination therapy is considerably safer than intravenous administration in terms of major bleeding and intracranial hemorrhage, but the risk of bleeding still exists. For the reasons mentioned above, treatment requires hospitalization, the treatment is slow, and generally patients are treated in the ICU and then stay in the general ward for several days. For this reason, the procedure is very time-consuming and expensive. Therefore, it is desirable to reduce the risk of bleeding as much as possible and at the same time reduce the treatment time to prevent long hospital stays. It is highly desirable to reduce the treatment time to the extent that patients can be treated in the intermediate care unit and, in some cases, avoid the ICU.

[0014] In further clinical studies of the combined ultrasonic / thrombolytic therapy, the inventors have surprisingly found that when thrombolytic agents are administered in combination with ultrasound, improvement of circulation occurs at significantly lower doses of thrombolytic agents and over a treatment time that is much shorter than that observed or predicted in previous clinical trials and current clinical diagnoses. In the PE population, RV dysfunction was significantly improved in the sickest patients by extremely low doses of thrombolytic agents administered over an extremely short period of less than 6 hours, regardless of the degree of clot lysis. In certain cases, the treatment time was as short as 2 hours and could potentially be reduced to within 1 hour. The improvement from the perspective of the RV / LV ratio in these patients was at least as good as that observed in the initial clinical trials (ULTIMA, SEATTLE II) that demonstrated the safety and efficacy of the combined ultrasonic / thrombolytic therapy, meaning that the method of the present invention provides at least as good results as the currently available treatment protocols, but with a significant reduction in the dose of thrombolytic agent and a significant reduction in the treatment time.

Summary of the Invention

[0015] The present invention provides a method for the treatment of thromboembolism, specifically for the treatment of pulmonary embolism in the blood vessels, which comprises administering a thrombolytic agent directly to the thromboembolism in the presence of ultrasound, wherein the total dose of the thrombolytic agent administered is less than 24 mg, preferably between 1 mg and 24 mg, more preferably between 1 mg and 12 mg, and the time over which the total dose is delivered is less than 15 hours, preferably between 1 hour and 15 hours, more preferably between 1 hour and 6 hours. Initial clinical trials (ULTIMA) have shown that thrombolysis can be achieved after 15 hours, but it required 20 mg of thrombolytic agent to observe a 23% improvement in RV dysfunction in the trial. Similarly, in the SEATTLE II trial, 27% improvement in RV dysfunction was shown 24 hours after administering 24 mg of thrombolytic agent. Clinical trials supporting the present invention have revealed that similar or even better levels of improvement in RV dysfunction can be achieved with much lower doses of thrombolytic agents and over much shorter treatment times.

[0016] Although not bound by theory, clinical results unexpectedly seem to indicate that when a thrombolytic agent is administered under the influence of ultrasound, a hitherto unknown mechanism occurs extremely rapidly. The pulmonary vascular response to ultrasound is to create or activate a path within the vascular structure and increase pulmonary blood flow, thereby making it possible to reduce the pressure in the right ventricle at the same time as the thrombolytic agent begins to dissolve the thrombus. Current clinical trials have for the first time demonstrated that RV dysfunction can be improved even by a small amount of thrombolysis. Despite a significant reduction in the dose administered and a shortening of the treatment time, the improvement measured by the right ventricle / left ventricle ratio is the same as or better than that shown in previous trials. This was unexpected at the time of the invention because it was thought that only an improvement level in RV dysfunction that would allow the treatment to be stopped would be seen when significant lysis occurred. Currently, what is considered is that the ultrasound / thrombolysis combination therapy utilizes additional paths such as an increase and / or dilation of capillary vasodilation in the pulmonary venous system in order to enable rapid treatment with a low dose of thrombolytic agent even if a considerable amount of thrombus remains.

[0017] In certain cases, the total dose of the thrombolytic agent administered is about 12 mg, preferably between 1 mg and 12 mg, more preferably between 2 mg and 12 mg, more preferably between 4 mg and 12 mg, more preferably between 2 mg and 6 mg, still more preferably between 4 mg and 6 mg. Thus, suitable total doses of the thrombolytic agent are 11 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg or 1 mg. These extremely low doses are advantageous because they can be administered as a bolus dose or infused in a time short enough to be considered a bolus dose.

[0018] Thus, in certain embodiments, a method of treatment is characterized in that these very low doses of thrombolytic agent are administered as a bolus in the presence of ultrasound. The ultrasound can be activated simultaneously with, or immediately prior to, administration of the thrombolytic agent to the thrombus site, or the thrombus may be exposed to ultrasound therapy for a defined period of time, such as between 1 and 10 minutes, prior to administration of the thrombolytic agent. Since the total dose of thrombolytic agent is considerably lower than that previously used, it is preferred that the thrombolytic agent be injected directly into the thrombus or in close proximity thereto to ensure maximal uptake. The ultrasound source may be external to the patient, although those skilled in the art will appreciate that such an arrangement may not be optimal as ultrasound may be absorbed by non-target tissue. Preferably, the ultrasound source is provided within the same blood vessel as the thrombus and is positioned within the thrombus region, i.e., directly within or adjacent to the thrombus. Catheters that allow injection of the thrombolytic agent and further house the ultrasound source are well known in the art. Commercially available devices such as the Ekosonic Endovascular System have received FDA approval and carry the CE mark and are thus particularly suitable for use within the scope of the methods of the present invention.

[0019] Alternatively, the thrombolytic agent can be infused at a rate that still results in a treatment time that is much shorter than previously reported. Optionally, the thrombolytic agent is administered at a rate between 1 mg / hour and 6 mg / hour, such as between 1 mg / hour and 4 mg / hour, preferably between 1 mg / hour and 3 mg / hour, more preferably between 1 mg / hour and 2 mg / hour. In certain embodiments, the thrombolytic agent is infused at a rate of 2 mg / hour. A dosing / infusion rate of 2 mg / hour is low to moderate dosing, i.e., 2 mg, 4 mg, 6 mg, or 8 mg of thrombolytic agent, which is short enough to consider outpatient or one-day treatment, i.e., a treatment time of 1 hour, 2 hours, or 3 hours, and is particularly useful.

[0020] In another specific embodiment, the thrombolytic agent is infused at a rate of 1 mg / hour or less. This rate can be particularly useful in the case of a minimum dose of thrombolytic agent such as 1 mg, 2 mg, 3 mg, or 4 mg, which allows for a treatment time of 1 hour, 2 hours, 3 hours, or 4 hours.

[0021] An infusion rate of 2 mg / hour can be useful, for example, in severely ill acute PE patients who may require bilateral PE treatment. In these cases, bilateral treatment can be achieved by delivering two doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 mg via each catheter) simultaneously using two ultrasound / drug delivery catheters in the same patient to administer a maximum total dose of 24 mg. The infusion rate is well tolerated and results in a total treatment time of less than 6 hours. For example, bilateral treatment with 1 mg of thrombolytic agent, when infused at 2 mg / hour, results in a total dose of 2 mg and a treatment time of 30 minutes; bilateral treatment with 4 mg of thrombolytic agent, when infused at 2 mg / hour, results in a total dose of 8 mg and a treatment time of 2 hours; bilateral treatment with 6 mg of thrombolytic agent, when infused at 2 mg / hour, results in a total dose of 12 mg and a treatment time of 2 hours; bilateral treatment with 12 mg of thrombolytic agent, when infused at 2 mg / hour, results in a total dose of 24 mg and a treatment time of 6 hours.

[0022] Accordingly, in certain embodiments, the present invention provides a method for treating pulmonary embolism, comprising directly administering a thrombolytic agent to pulmonary embolism in the presence of ultrasound, wherein the total dose of the thrombolytic agent administered is between 1 mg and 24 mg and is administered at a rate between 1 mg / hour and 2 mg / hour.

[0023] Of course, it will be understood by those skilled in the art that the actual infusion rate need not be exactly 1 mg / hour or 2 mg / hour, and the infusion rate can vary provided that the total infusion rate and treatment time remain the same. For example, a 4 mg dose of thrombolytic agent can be administered at a rate of 2 mg / hour for 1 hour, and the remaining 2 mg can be administered at 1 mg / hour, resulting in a total treatment time of 3 hours.

[0024] Doses less than 1 mg are not expected to be substantially useful (in terms of the processing required to achieve such low doses), although small amounts, such as amounts of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9 mg, are expected to be therapeutically useful and can be used, for example, in the treatment of smaller thromboembolic disorders.

[0025] At the end of treatment (i.e., administration of the total dose of thrombolytic agent), the patient may be given, or may resume, standard treatment anticoagulation therapy to prevent growth of any remaining thrombus and / or to prevent new thrombus from forming.

[0026] Thrombolytic agents suitable for use by the present method are well known and are approved for use in several areas. In certain embodiments, the thrombolytic agent is recombinant tissue plasminogen activator (r-tPA).

[0027] Ultrasonic sources are also well known in the art. Suitable examples of ultrasonic elements for generating ultrasonic energy include, but are not limited to, piezoelectric ceramic oscillators. A single ultrasonic source may preferably be sufficient by utilizing a plurality of ultrasonic sources to effect spatial and directional control of the ultrasound. It is advantageous that a plurality of ultrasonic elements can be individually wired in parallel or in series to provide maximum flexibility and controllability of the ultrasound.

[0028] The inventors have found that internal ultrasound provided at a frequency between 2 and 3 MHz is sufficient to obtain the advantages of the present invention. The maximum pulse power of the ultrasound is preferably 50 W, and since this then appears to provide a useful ultrasonic source without subjecting the surrounding tissue to heating, the ultrasound is preferably provided in pulses of a randomly variable waveform. As described above, devices such as the Ekosonic Endovascular System are commercially available and can be used in the method of the present invention without further modification.

[0029] According to a first aspect, there is provided a method for the treatment of thromboembolism comprising administering a thrombolytic agent directly to the thromboembolism in the presence of ultrasound, wherein the total dose of thrombolytic agent administered is between 1 mg and 12 mg, and the time period over which the total dose is delivered is less than 15 hours.

[0030] Preferably, the total dose of thrombolytic agent administered is between 1 mg and 10 mg. More preferably, the total dose of thrombolytic agent administered is between 2 mg and 6 mg. More preferably, the total dose of thrombolytic agent administered is between 2 mg and 4 mg. More preferably, the total dose of thrombolytic agent administered is 2 mg. More preferably, the thrombolytic agent is delivered as a bolus dose. More preferably, the thrombolytic agent is infused at a rate of 2 mg / hour. More preferably, the thrombolytic agent is infused at a rate of 1 mg / hour. More preferably, the thrombolytic agent is recombinant tissue plasminogen activator (r-tPA) or urokinase. More preferably, the ultrasound is provided at a frequency between 2 and 3 MHz. More preferably, the maximum pulse power of the ultrasound is 50 W.

[0031] In a second aspect, the present invention provides a method for the treatment of thromboembolic disease, comprising: providing a catheter including a fluid delivery lumen having at least one outlet and a plurality of ultrasound radiating members arranged in the region of the fluid outlet and connected to a power source located outside the catheter and arranged to drive the ultrasound radiating members; placing the catheter into or adjacent to the thrombus; activating a plurality of ultrasound radiating members; and Inserting a thrombolytic agent into the fluid delivery lumen so that the thrombolytic agent flows from the fluid delivery lumen and the outlet. Including, The total dose of thrombolytic agent administered through the catheter is 12 mg or less, such as between 1 mg and 12 mg, and is administered at a rate where the total dose of thrombolytic agent is 2 mg / hour or less, such as a rate between 1 mg / hour and 2 mg / hour.

[0032] In this embodiment, by this method, the treatment time is surely shortened to a maximum of 6 hours. This method can be used with single or bilateral catheter placement depending on the type and location of the thromboembolism. For example, for the treatment of bilateral PE cases, although the total dose is 24 mg, two catheters can be placed simultaneously so that the total treatment time is 6 hours, and each catheter delivers up to 12 mg of the thrombolytic agent at a rate of up to 2 mg / hour.

[0033] Otherwise, this method may be performed with a single catheter that delivers the total dose of the drug and ultrasound. The maximum total dose of the thrombolytic agent administered via the catheter is 12 mg, and the total dose of the thrombolytic agent is administered at a maximum rate of 2 mg / hour so that the treatment time is limited to a maximum of 6 hours. Much smaller doses are effective, but there are substantial low doses that can be routinely handled in pharmacies or hospitals, so doses of less than 1 mg of the thrombolytic agent are unlikely to be used in the clinical setting, but small amounts such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9 mg can be used in small thromboembolisms.

[0034] Preferably, the total dose of the thrombolytic agent administered via the catheter is between 1 mg and 6 mg, and the total dose of the thrombolytic agent is administered at a rate of 1 mg / hour. More preferably, the total dose of the thrombolytic agent administered via the catheter is between 2 mg and 4 mg, and the total dose of the thrombolytic agent is administered at a rate of 1 mg / hour. Preferably, the total dose of the thrombolytic agent administered via the catheter is between 2 mg and 4 mg, and the total dose of the thrombolytic agent is administered at a rate of 2 mg / hour. Preferably, the thrombolytic agent is recombinant tissue plasminogen activator (r-tPA) or urokinase. Preferably, the ultrasound is provided at a frequency between 2 and 3 MHz. Preferably, the maximum pulse power of the ultrasound is 50 W. Preferably, the catheter includes an inner core into which an ultrasonic radiation member can be removably inserted, the core is independent of the fluid delivery lumen, and the thrombolytic agent is administered at 2 mg / hour through the core for a total treatment in less than 6 hours. Preferably, the total treatment time is 4 hours. Preferably, the total treatment time is 2 hours. Preferably, the thrombolytic agent is administered simultaneously via two catheters.

[0035] According to a further aspect, there is provided a pharmaceutical composition for use in the treatment of thromboembolism, comprising 1 to 12 mg of recombinant tissue plasminogen activator (r-tPA) and a pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition is administered intravenously in the presence of ultrasound, and the administration is completed between 1 hour and 6 hours. More preferably, the pharmaceutical composition is administered directly to the thromboembolism via a catheter comprising a fluid delivery lumen having at least one outlet and a plurality of ultrasonic radiation members, and the ultrasonic radiation members are arranged in the region of the fluid outlet and located outside the catheter and are connected to a power source arranged to drive the ultrasonic radiation members so as to generate ultrasound when the pharmaceutical composition is administered.

[0036] According to a further aspect, there is provided a thrombolytic agent for use in the treatment of thromboembolism, the treatment of thromboembolism including administering the thrombolytic agent directly to the thromboembolism in the presence of ultrasound. The total dosage of the thrombolytic agent administered is between 1 mg and 12 mg, and the time over which the total dosage is delivered is less than 15 hours.

[0037] Preferably, the total dosage of the thrombolytic agent administered is between 1 mg and 10 mg. More preferably, the total dosage of the thrombolytic agent administered is between 2 mg and 6 mg. More preferably, the total dosage of the thrombolytic agent administered is between 2 mg and 4 mg. Most preferably, the total dosage of the thrombolytic agent administered is 2 mg. Preferably, the thrombolytic agent is delivered as a bolus administration. Preferably, the thrombolytic agent is infused at a rate of 2 mg / hour. More preferably, the thrombolytic agent is infused at a rate of 1 mg / hour. Preferably, the thrombolytic agent is recombinant tissue plasminogen activator (r-tPA) or urokinase. Preferably, the ultrasound is provided at a frequency between 2 and 3 MHz. Preferably, the maximum pulse power of the ultrasound is 50 W.

[0038] According to a further aspect, there is provided the use of a thrombolytic agent in the preparation of a medicament for use in the treatment of thromboembolism, the treatment including administering the thrombolytic agent directly to the thromboembolism in the presence of ultrasound, the total dosage of the thrombolytic agent administered being between 1 mg and 12 mg, and the time over which the total dosage is delivered being less than 15 hours.

[0039] Preferably, the total dosage of the thrombolytic agent administered is between 1 mg and 10 mg.

[0040] More preferably, the total dosage of the thrombolytic agent administered is between 2 mg and 6 mg. More preferably, the total dosage of the thrombolytic agent administered is between 2 mg and 4 mg. More preferably, the total dosage of the thrombolytic agent administered is 2 mg. More preferably, the thrombolytic agent is delivered as a bolus dose. Preferably, the thrombolytic agent is infused at a rate of 2 mg / hour. Preferably, the thrombolytic agent is infused at a rate of 1 mg / hour. Preferably, the thrombolytic agent is recombinant tissue plasminogen activator (r-tPA) or urokinase. Preferably, the ultrasonic wave is provided at a frequency between 2 and 3 MHz. Preferably, the maximum pulse power of the ultrasonic wave is 50 W.

[0041] In certain examples, the method most likely to be used in routine clinical practice allows for a total dosage of thrombolytic agent of 6 mg or less administered via a catheter, and the total dosage of the thrombolytic agent is administered at a rate of 1 mg / hour. In another example, the total dosage of the thrombolytic agent administered via a catheter is 4 mg or less, and the total dosage of the thrombolytic agent is administered at a rate of 1 mg / hour. In a further example, the total dosage of the thrombolytic agent administered via a catheter is 4 mg or less, and the total dosage of the thrombolytic agent is administered at a rate of 2 mg / hour.

[0042] As described above, the thrombolytic agent is any agent that promotes the conversion of plasminogen to plasmin, and recombinant tissue plasminogen activator (r-tPA) or urokinase-type plasminogen activator is preferred.

[0043] As described above, the piezoelectric ceramic vibrator is a suitable ultrasonic wave source. These ultrasonic wave elements can be formed as a cylinder, a hollow cylinder, and a disk that are concentric with the catheter. Also, the ultrasonic wave element can be an array of even smaller ultrasonic wave elements, or a thin plate disposed within the catheter body. Similarly, a single ultrasonic wave element can also be composed of several smaller ultrasonic wave elements.

[0044] Ultrasound can be provided according to the protocol described in International Publication No. WO 2008 / 086372, the entire content of which is incorporated herein by reference.

[0045] As described herein, ultrasonic energy is often used to improve the delivery and / or effect of therapeutic compounds. For example, in connection with the treatment of vascular occlusion, ultrasonic energy has been shown to increase enzyme-mediated thrombolysis by improving the delivery of thrombolytic agents to thrombi. Such agents dissolve thrombi by degrading fibrin that forms the thrombus. The thrombolytic activity of this agent is enhanced in thrombi under ultrasonic energy. However, it will be understood that the present invention should not be limited to the mechanism by which ultrasound improves treatment, unless otherwise specified. In other applications, ultrasonic energy has further been shown to improve the transfection of gene-based drugs into cells and increase the transfer of chemotherapeutic agents to tumor cells in tumor cells. It has been found that ultrasonic energy delivered from within a patient's body can produce a non-thermal effect that increases the tissue permeability to therapeutic compounds by up to or more than an order of magnitude.

[0046] As used herein, the terms "ultrasonic energy", "ultrasound", and "ultrasonic" are broad terms that have their ordinary meanings and further refer to mechanical energy that travels through axial pressure or compression waves, but are not limited thereto. Depending on the conditions of a particular application, ultrasonic energy can be emitted as a continuous wave or as a pulsed wave. Further, ultrasonic energy can be emitted in waveforms having various shapes such as, for example, sine waves, triangular waves, rectangular waves, or other waveforms. Ultrasonic energy includes sound waves. In certain embodiments, ultrasonic energy has a frequency between about 20 kHz and about 20 MHz. For example, in one embodiment, the sound wave has a frequency between about 500 kHz and about 20 MHz. In another embodiment, the sound wave has a frequency between about 1 MHz and about 3 MHz. In yet another embodiment, the sound wave has a frequency of about 2 MHz. The average acoustic power is between about 0.01 watt and 300 watts. In one embodiment, the average acoustic power is about 15 watts.

[0047] As used herein, the term "ultrasonic emitting member" refers to any device capable of generating ultrasonic energy. For example, in one embodiment, the ultrasonic emitting member includes an ultrasonic probe that converts electrical energy into ultrasonic energy. Suitable examples of ultrasonic probes for generating ultrasonic energy from electrical energy include, but are not limited to, piezoelectric ceramic vibrators. Piezoelectric ceramics typically include crystalline substances such as quartz, and when an electric current is applied to the substance, its shape changes. This change in shape, made vibratory by a contact drive signal, generates ultrasound. In other embodiments, ultrasonic energy can be generated by an ultrasonic probe that is remote from the ultrasonic emitting member, and the ultrasonic energy can be sent, for example, via wires connected to the ultrasonic emitting member.

[0048] In a preferred embodiment, the ultrasonic radiating member 40 includes a rectangular lead zirconate titanate (「PZT」) ultrasonic probe having dimensions of approximately 0.017 inches × approximately 0.010 inches × approximately 0.080 inches. In other embodiments, other configurations may be used. For example, a disk-shaped ultrasonic radiating member 40 can be used in other embodiments. In a preferred embodiment, the common wire 108 includes copper and has a thickness of approximately 0.005 inches, but in other embodiments, other conductive materials and other dimensions can be used. The lead wire 110 is preferably a 36-gauge conductor, while the positive electrode contact wire 112 is preferably a 42-gauge conductor. However, those skilled in the art will recognize that other wire gauges can be used in other embodiments.

[0049] As described above, suitable frequencies for the ultrasonic radiating member 40 include, but are not limited to, from about 20 kHz to about 20 MHz. In one embodiment, the frequency is between about 500 kHz and 20 MHz, and in another embodiment, the frequency is between 1 MHz and 3 MHz. In yet another embodiment, the ultrasonic radiating member 40 operates at a frequency of about 2 MHz.

[0050] The ultrasonic emitting member preferably operates in a pulse mode. For example, in one embodiment, the time-averaged power supplied to the ultrasonic emitting member is between about 0.001 watt and 5 watts, and can also be between about 0.05 watt and 3 watts. In certain embodiments, the time-averaged power over the treatment time is about 0.45 watt, or 1.2 watts. The duty ratio is between about 0.01% and 90%, and can also be between about 0.1% and 50%. In certain embodiments, the duty ratio is about 7.5%, 15%, or varies between 1% and 30%. The pulse average power can be between about 0.01 watt and 20 watts, and can be between about 0.1 watt and 20 watts. In certain embodiments, the pulse average power is about 4 watts, 8 watts, 16 watts, or varies between 1 watt and 8 watts. As described above, the amplitude, pulse width, pulse repetition frequency, average sound pressure, or any combination of these parameters can also be constant or vary between each pulse or over a series of segments. In non-linear applications of the acoustic parameters, the above ranges can vary significantly. Therefore, the overall time-averaged power over the treatment time can be kept in the same state, but it is not the real-time average power.

[0051] In one embodiment, the pulse repetition rate is preferably between about 1 Hz and 2 kHz, and more preferably can be between about 1 Hz and 50 Hz. In certain preferred embodiments, the pulse repetition rate is about 30 Hz, or varies between 10 Hz and 40 Hz. The pulse duration or pulse width can be between about 0.5 milliseconds and 50 milliseconds, and can be between about 0.1 milliseconds and 25 milliseconds. In certain embodiments, the pulse duration is about 2.5 milliseconds, 5 milliseconds, or varies between 1 and 8 milliseconds. Additionally, the average sound pressure can be between about 0.1 and 2 MPa, or in another embodiment can be 0.5 MPa or between 0.74 and 1.7 MPa.

[0052] In a particular embodiment, the probe is operated at an average power of about 0.6 watts, a duty cycle of about 7.5%, a pulse repetition rate of 30 Hz, a pulse average power of about 8 watts, and a pulse duration of about 2.5 milliseconds.

[0053] The ultrasonic radiation member used with the electrical parameters described herein preferably has an acoustic efficiency greater than 50% and up to more than 75%. The ultrasonic radiation member can be formed in various shapes, such as cylindrical (solid or hollow), flat plate, rod, triangular, etc. The length of the ultrasonic radiation member is preferably between about 0.1 cm and about 0.5 cm. The thickness or diameter of the ultrasonic radiation member is preferably between about 0.02 cm and about 0.2 cm.

[0054] As described below, the ultrasonic catheter includes one or more ultrasonic radiation members disposed therein. Such an ultrasonic radiation member can include a probe (e.g., a PZT probe) configured to convert electrical energy into ultrasonic energy. In such an embodiment, the PZT probe is excited by specific electrical parameters (referred to herein as "power parameters" or "acoustic parameters" that cause it to vibrate in a manner that generates ultrasonic energy). As will be explained below, the applicant has found that by non-linearly varying (e.g., randomly or pseudo-randomly) one or more power parameters, the effectiveness of the ultrasonic catheter (e.g., the effectiveness of enhancing thrombus removal) can be significantly increased. By non-linearly varying one or more power parameters, the ultrasonic radiation member generates a non-linear sound pressure. This can increase the effectiveness of the sound pressure in enhancing therapeutic compounds, as described above. In one application, the applicant has found that the effect of the non-linearity in varying the sound pressure enhances enzymatic thrombolysis by nearly 1.9 times compared to an application with a substantially constant sound pressure. Examples of non-linear dispersion include, but are not limited to, multivariate variation, variation as a function of a complex equation, sinusoidal variation, exponential variation, random variation, pseudo-random variation, and / or arbitrary variation. Non-linear dispersion is preferred, although in other arrangements, one or more of the parameters considered can be expected to vary linearly, either alone or in combination with non-linear dispersion.

[0055] In one embodiment, a method of executing a randomization protocol is to generate and execute a plurality of ultrasonic cycle profiles, and each ultrasonic cycle profile may have randomly generated power parameter values. As described above, examples of 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 can be used to select a value within a limit range determined, for example, by an operator. Examples of suitable ranges have been described above. For example, one ultrasonic cycle profile can have a randomly selected peak power value, while other power parameters are selected non-randomly. Another ultrasonic cycle profile can have a plurality of randomly selected power parameter values such as peak power and pulse width. Using this process, a desired number of ultrasonic cycle profiles can be generated.

[0056] Each ultrasonic cycle profile can be executed during a profile execution time. For example, if the profile execution time is about 5 seconds, each ultrasonic cycle profile is executed for about 5 seconds before the next ultrasonic cycle profile is executed. In some embodiments, the profile execution time is less than about 5 seconds. For example, in some embodiments, the profile execution time is between about 1 second and about 30 seconds. In some embodiments, the profile execution time is less than about 1 second. In some embodiments, the profile execution time is increased so that accurate measurements can be made on the execution power parameters. In some embodiments, the profile execution time itself can be randomly selected from a predetermined range.

[0057] In some embodiments, it is desirable to deliver a specific time-averaged power. Since the power parameters can be randomized, multiple ultrasonic cycle profiles can be executed before the time-averaged power approaches the asymptotic value. In some embodiments, the execution of about 40 to 50 ultrasonic cycle profiles is required for the time-averaged power to asymptote. In other embodiments, less than about 40 ultrasonic cycle profiles are required, while in still other embodiments, more than about 50 ultrasonic cycle profiles are required. In some embodiments, the ultrasonic cycle profiles are executed until the time-averaged power approaches the asymptotic value. For example, if the profile execution time is 5 seconds and the total execution time is 30 minutes, 360 ultrasonic cycle profiles are executed. This is sufficient in some embodiments for the time-averaged power to approach the asymptotic value.

[0058] In addition, although many embodiments have been described in connection with intravascular catheters, it should be understood that the non-linear use of one or more power parameters can also be applied to non-intravascular catheters or devices, and / or non-catheter applications. For example, non-linear variations of one or more power parameters can also find utility in applications where ultrasound is applied externally (to the body or to the vasculature). In particular, the above considerations can be applied to external ultrasound applications where the ultrasound source is external to the patient and / or the treatment site. The methods and techniques described herein can be applied to extravascular applications. In addition, in some embodiments, the therapeutic effect of ultrasound can be utilized alone without a therapeutic compound.

[0059] Preferably, the ultrasound is provided at a frequency between 2 and 3 MHz.

[0060] Suitable catheter systems that can be used in the present method are commercially available. The catheter described in U.S. Patent No. 7,220,239 (the entire content of which is incorporated herein by reference) is particularly suitable for the administration of thrombolytic agents at a rate between 1 mg / hour and 2 mg / hour so that the treatment time is between 1 hour and 6 hours. In certain embodiments, the total dose of the thrombolytic agent is selected such that the total treatment time is 4 hours. In another embodiment, the total dose of the thrombolytic agent is selected such that the total treatment time is 2 hours.

[0061] In another aspect, the present invention provides a pharmaceutical composition for use in the treatment of thromboembolism, comprising 1 to 12 mg of recombinant tissue plasminogen activator (r-tPA) and a pharmaceutically acceptable excipient. As described above, thromboembolism can be deep vein thrombosis (DVT), pulmonary embolism (PE) or peripheral arterial occlusion (PAO). The pharmaceutical composition is useful for the treatment of thromboembolism using the methods described herein. The compositions of the present invention are particularly suitable for intravenous administration in the presence of ultrasound, and the administration is completed in less than 6 hours.

[0062] In a preferred embodiment, the pharmaceutical composition is administered directly to the thromboembolism via a catheter comprising a fluid delivery lumen having at least one outlet and a plurality of ultrasonic emission members, and the ultrasonic emission members are arranged in the region of the fluid outlet and located outside the catheter and are connected to a power source arranged to drive the ultrasonic emission members so as to generate ultrasound when the pharmaceutical composition is administered. Suitable catheters and ultrasonic protocols are described in U.S. Patent No. 7,220,239 and International Publication No. 2008 / 086372, respectively.

[0063] Here, the present invention will be described by way of example for the purpose of describing specific embodiments of the present invention. The embodiments are illustrative and are not intended to limit the scope of protection of the claims.

Modes for Carrying Out the Invention

[0064] Example: Optimal Duration and Dose of r-tPA by Ultrasound for Moderate-Risk (Submassive) Pulmonary Embolism For acute submassive PE, the appropriate dose of thrombolytic agent and the duration of ultrasound treatment (described as APT treatment in this example) in the combined ultrasound / thrombolysis therapy were determined. The acoustic pulse thrombolysis (APT) treatment delivered high-frequency (2 - 3 MHz), low-power ultrasound in combination with a low dose of recombinant tissue plasminogen activator (r-tPA) using the EkoSonic® Endovascular System (Ekos Corporation).

[0065] Materials and Methods: Eligible subjects had acute (symptoms less than 14 days) proximal PE located in at least one main pulmonary artery or proximal lobar pulmonary artery, and had a right ventricle (RV) to left ventricle (LV) end-diastolic diameter ratio of ≥0.9 on chest computed tomography angiography (CTA). Eligible subjects had to receive treatment within 48 hours from the diagnostic CTA. The primary efficacy assessment item at 48 hours after treatment initiation was to reduce the RV / LV ratio on CTA by >0.2. The primary safety assessment item was a major bleeding event within 72 hours after treatment initiation. Secondary assessment items included the modified mirror score (MMS; embolism burden on CTA).

[0066] The Ekosonic Endovascular Device was used according to the published instructions for use. This system generates ultrasound in the treatment zone of the catheter by piezoelectric conversion of high-frequency energy. To improve the variability of the injected physician-specified liquid (e.g., thrombolytic agent), the ultrasound radiates radially from the treatment zone.

[0067] The EKOS device consists of the following two main components: 1. A single-use sterile device consisting of: a. Intelligent Drug Delivery Catheter (IDDC) b. Microsonic Device (MSD) 2. EkoSonic® Control System (reusable)

[0068] The IDDC is French scale 5.4 and has a working length of 106 cm or 135 cm. The IDDC includes two luer ports for coolant and thrombolytic delivery and an electrical connector for a thermocouple to monitor the temperature of the catheter system. The radiopaque markers are located approximately 1 cm proximal and 1 cm distal to the treatment zone. The IDDC central lumen is compatible with a 0.035” guidewire, accepts the MSD, and delivers coolant during the procedure. Each EkoSonic Device requires its own infusion tubing to flow at 35 mL / hour / device and an infusion pump with normal saline coolant. The MSD locks onto a luer connector on the central lumen of the IDDC and aligns the ultrasonic transducer segment to the treatment zone of the IDDC. The device uses multiple ultrasonic transducers to emit ultrasonic energy radially from the long axis of the catheter system.

[0069] The EkoSonic® control system powers the piezoelectric elements within the treatment zone of the device and monitors the operating parameters during the procedure. The control system further provides a user interface via a front panel display and keypad.

[0070] The r-tPA used in this study was a commercially available drug sold under various brand names for fibrinolysis of pulmonary embolism by systemic peripheral infusion in the participating regions. The r-tPA was prepared from standard pharmacy supplies and prepared according to the manufacturer's instructions. The r-tPA was delivered to the site of the clot rather than by systemic infusion via the EkoSonic® Endovascular System (ultrasonic infusion catheter). The drug was administered using a standard infusion pump to deliver a total drug dose at a rate of either 1 mg / hour or 2 mg / hour. The doses of r-tPA administered were 4, 6, and 12 mg by a single catheter. In some bilateral cases, the total dose of r-tPA was 8, 12, or 24 mg, and the maximum treatment time was 6 hours.

[0071] Protocol All patients met the following criteria to be eligible for participation in this clinical trial: 1.Male or female, 18 years of age or older and less than 75 years of age 2.CTA findings of proximal PE (filling defect in at least one main or lobar pulmonary artery) 3.Duration of PE symptoms less than 14 days 4.Submassive PE: RV / LV diameter ratio from CTA ≧ 0.9 and hemodynamically stable 5.Treatment was initiated within 48 hours of diagnosis of PE by CTA 6.Informed consent was obtained from the subject or legal representative

[0072] Venous access was obtained by ultrasound-guided venipuncture of the common femoral vein (CFV) and / or internal jugular vein (IJV). The pulmonary artery was then catheterized by a transfemoral arterial approach using a combination of the treating physician's choice of techniques, such as a hydrophilic Glidewire® (Terumo, Sommerset, NJ) and torque control device, and a 5 or 6 French pigtail catheter, or by a standard Teflon-coated wire using an apex deflection technique. The sheath was then inserted into the artery or completed prior to catheter placement. Selective contrast agent injection was then performed in the main left or right pulmonary artery to identify the arterial branch in which the largest thrombus had formed.

[0073] A simplified model of the pulmonary artery is shown in Figure 2 (which includes two versions of the figure) to illustrate examples of catheter placement or catheters for single and bilateral treatments (depending on the location of the thrombus). Note that the zonal branches of the upper, middle, and lingular lobes are not shown in this simplified model.

[0074] The EkoSonic Device was then prepared according to the protocol from the manufacturer's instructions for use, the infusion catheter was inserted over each guidewire, and placed into the thrombus-forming artery identified thus far.

[0075] When the infusion catheter was properly placed and connected to the venous pump, transcatheter thrombolysis was initiated using alteplase (rt-PA; Genentech, South San Francisco, CA). Once rtPA infusion was initiated via the catheter, the catheter control unit was activated to deliver ultrasonic energy. Treatment was continued according to a protocol that defined the infusion rate and dosage. Specifically, the dosage per catheter was between 4 mg and 12 mg, and the infusion rate was 1 or 2 mg / hour. After transcatheter thrombolysis was completed, the patient underwent follow-up CTA to measure the changes.

[0076] Results: Ninety-one subjects (mean age 57.5, BMI 35.9, 48% female, 59% Caucasian race) were enrolled at 17 comprehensive facilities and randomized to one of four cohorts (Table 1). All subjects were administered therapeutic anticoagulants in addition to a specific USCDT treatment regimen. In all cohorts, a significant improvement in the RV / LV ratio was observed at 48 hours after the procedure. Similarly, a significant improvement occurred in the MMS, with an increasing decrease in cohorts 1 - 4.

[0077]

Table 1

[0078] The overall major bleeding rate was 3 / 91 (3%). Major bleeding events were not reported in cohorts 1 and 3. The major bleeding event in cohort 2 was secondary anemia from facial trauma after loss of consciousness. The major bleeding events in cohort 4 were bleeding from a splenic pseudoaneurysm treated with coil embolization and ICH in a 75-year-old male patient with a history of thrombocytopenia and labile hypertension. Another major bleeding event of ICH was reported after systemic administration of 50 mg of tPA, and the subject fully recovered.

[0079] Two patient populations for analysis: efficacy (N = 81) and safety (N = 91). The difference is the number of evaluable patients (pre-treatment CT and post-treatment CT) - see Tables 2 and 3.

[0080]

Table 2

[0081]

Table 3

[0082]

Table 4

Claims

Claim 1 A thrombolytic agent for use in the treatment of pulmonary embolism, wherein the treatment comprises providing a catheter comprising a fluid delivery lumen having at least one outlet and a plurality of ultrasonic emitting members, wherein the ultrasonic emitting members are arranged in the region of the outlet, are located outside the catheter, and are connected to a power source arranged to drive the ultrasonic emitting members; placing the catheter into or adjacent to a thrombus; activating the plurality of ultrasonic emitting members to generate ultrasonic waves; and inserting a thrombolytic agent into the fluid delivery lumen such that the thrombolytic agent is directly administered to the thrombus by flowing through the fluid delivery lumen and the outlet, for example by being injected directly into the thrombus, wherein the total dose of the thrombolytic agent directly administered to the thrombus, for example by being injected directly into the thrombus through the catheter, is between 1 mg and 12 mg, the total dose of the thrombolytic agent is administered at a rate between 1 mg / hour and 2 mg / hour, the treatment time for delivering the total dose is 6 hours or less, and the thrombolytic agent is recombinant tissue plasminogen activator (r-tPA). Claim 2 The thrombolytic agent according to claim 1, wherein the total dose of the thrombolytic agent administered through the catheter is between 1 mg and 6 mg, and the total dose of the thrombolytic agent is administered at a rate of 1 mg / hour. Claim 3 The thrombolytic agent according to claim 1, wherein the total dose of the thrombolytic agent administered through the catheter is between 2 mg and 4 mg, and the total dose of the thrombolytic agent is administered at a rate of 1 mg / hour. Claim 4 The thrombolytic agent according to claim 1, wherein the total dose of the thrombolytic agent administered through the catheter is between 2 mg and 4 mg, and the total dose of the thrombolytic agent is administered at a rate of 2 mg / hour. Claim 5 The thrombolytic agent according to any one of claims 1 to 4, wherein the ultrasonic waves are provided at a frequency between 2 and 3 MHz. Claim 6 The thrombolytic agent according to any one of claims 1 to 5, wherein the maximum pulse power of the ultrasonic waves is 50 W. Claim 7 The catheter includes an inner core, an ultrasonic emitting member can be removably inserted into the core, the core is independent of the fluid delivery lumen, and the thrombolytic agent is administered at 2 mg / hour via the core so that the total treatment time is less than 6 hours. The thrombolytic agent according to any one of claims 1 to 6.

8. The thrombolytic agent according to claim 7, wherein the total treatment time is 4 hours.

9. The thrombolytic agent according to claim 7, wherein the total treatment time is 2 hours.

10. The thrombolytic agent according to any one of claims 1 to 9, wherein the thrombolytic agent is administered simultaneously via two catheters.

11. Comprising 1 to 12 mg of recombinant tissue plasminogen activator (r-tPA) and a pharmaceutically acceptable excipient, A pharmaceutical composition for use in the treatment of thromboembolism, which is administered directly to a thrombus, for example, by injection directly into the thrombus via a catheter in the presence of ultrasound, and the administration is completed between 1 hour and 6 hours.

12. The catheter includes a fluid delivery lumen having at least one outlet and a plurality of ultrasonic emitting members, and the ultrasonic emitting members are arranged in the region of the outlet and are located outside the catheter and are connected to a power source arranged to drive the ultrasonic emitting members so as to generate ultrasound when the pharmaceutical composition is administered. The pharmaceutical composition according to claim 11.

13. Including administering a thrombolytic agent directly to a thromboembolism, for example, by injection directly into the thrombus in the presence of ultrasound, the total dose of the thrombolytic agent administered being between 1 mg and 12 mg, and the time for delivering the total dose being between 1 hour and 6 hours. A thrombolytic agent which is recombinant tissue plasminogen activator (r-tPA) for use in the treatment of thromboembolism.

14. The thrombolytic agent for use in the treatment of thromboembolism according to claim 13, wherein the total dose of the thrombolytic agent administered is between 1 mg and 10 mg.

15. The thrombolytic agent for use in the treatment of thromboembolism according to claim 13, wherein the total dose of the thrombolytic agent administered is between 2 mg and 6 mg.

16. The thrombolytic agent for use in the treatment of thromboembolism according to claim 13, wherein the total dose of the thrombolytic agent administered is between 2 mg and 4 mg.

17. The thrombolytic agent for use in the treatment of thromboembolism according to claim 13, wherein the total dose of the administered thrombolytic agent is 2 mg.

18. The thrombolytic agent for use in the treatment of thromboembolism according to any one of claims 13 to 17, wherein the thrombolytic agent is delivered as a bolus administration.

19. The thrombolytic agent for use in the treatment of thromboembolism according to any one of claims 13 to 17, wherein the thrombolytic agent is infused at a rate of 2 mg / hour.

20. The thrombolytic agent for use in the treatment of thromboembolism according to any one of claims 13 to 17, wherein the thrombolytic agent is infused at a rate of 1 mg / hour.

21. The thrombolytic agent for use in the treatment of thromboembolism according to any one of claims 13 to 20, wherein the ultrasonic wave is provided at a frequency between 2 and 3 MHz.

22. The thrombolytic agent for use in the treatment of thromboembolism according to claim 21, wherein the maximum pulse power of the ultrasonic wave is 50 W.

23. Use of a thrombolytic agent in the preparation of a drug for use in the treatment of thromboembolism, wherein the treatment comprises administering the thrombolytic agent directly to the thromboembolism, for example, by injecting the thrombolytic agent directly into the thrombus in the presence of ultrasonic waves, the total dose of the administered thrombolytic agent being between 1 mg and 12 mg, the time over which the total dose is delivered being between 1 hour and 6 hours, and the thrombolytic agent being recombinant tissue plasminogen activator (r-tPA).

24. Use of a thrombolytic agent in the preparation of a drug for use in the treatment of thromboembolism according to claim 23, wherein the total dose of the administered thrombolytic agent is between 1 mg and 10 mg.

25. Use of a thrombolytic agent in the preparation of a drug for use in the treatment of thromboembolism according to claim 23, wherein the total dose of the administered thrombolytic agent is between 2 mg and 6 mg.

26. Use of a thrombolytic agent in the preparation of a drug for use in the treatment of thromboembolism according to claim 23, wherein the total dose of the administered thrombolytic agent is between 2 mg and 4 mg.

27. Use of a thrombolytic agent in the preparation of a drug for use in the treatment of thromboembolism according to claim 23, wherein the total dose of the administered thrombolytic agent is 2 mg.

28. Use of a thrombolytic agent in the preparation of a drug for use in the treatment of thromboembolism according to any of claims 23 to 27, wherein the thrombolytic agent is delivered as a bolus administration.

29. Use of a thrombolytic agent in the preparation of a drug for use in the treatment of thromboembolism according to any of claims 23 to 27, wherein the thrombolytic agent is infused at a rate of 2 mg / hour.

30. Use of a thrombolytic agent in the preparation of a drug for use in the treatment of thromboembolism according to any of claims 23 to 27, wherein the thrombolytic agent is infused at a rate of 1 mg / hour.

31. Use of a thrombolytic agent in the preparation of a drug for use in the treatment of thromboembolism according to any of claims 1 to 30, wherein the ultrasonic wave is provided at a frequency between 2 and 3 MHz.

32. Use of a thrombolytic agent in the preparation of a drug for use in the treatment of thromboembolism according to claim 31, wherein the maximum pulse power of the ultrasonic wave is 50 W.

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