Intravenous Targeted Microbubbles Carrying Urokinase versus Urokinase Alone in Acute Peripheral Arterial Thrombosis in a Porcine Model

Nederhoed, J.H.; Ebben, Harm P.; Slikkerveer, Jeroen; Hoksbergen, Arjan W.J.; Kamp, Otto; Tangelder, Geert Jan; Wisselink, Willem; Musters, René J.P.; Yeung, Kak K.

doi:10.1016/j.avsg.2017.05.011

Cited by 17 publications

(12 citation statements)

References 20 publications

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“…Another promising line of research would be non-invasive thrombolysis with thrombolytic entrapped microbubbles for targeted thrombolytic delivery. 15 Theoretically, this so called ultrasound facilitated thrombolysis could increase thrombus dissolution by fibrin targeted microbubble adhesion combined with high intensity ultrasound leading to a local release of the preloaded thrombolytic agent. 16 While some studies provide proof of concept, additional preclinical studies are necessary to further illuminate the clinical potential of accelerated drug delivery.…”

Section: Discussionmentioning

confidence: 99%

Microbubbles and Ultrasound Accelerated Thrombolysis for Peripheral Arterial Occlusions: The Outcomes of a Single Arm Phase II Trial

Doelare

Pierre

Nederhoed

et al. 2021

European Journal of Vascular and Endovascular Surgery

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WHAT THIS PAPER ADDSSince the introduction of thrombolysis in the 1990s, significant changes have been made in thrombolytic agents and administration techniques. Numerous methods, such as ultrasound assisted thrombolysis, have been investigated to improve the results of the technique. The efficacy and associated complication rates have, nevertheless, remained unchanged. The aim of this study was to investigate an experimental ultrasound technique combined with microbubbles as a potential accelerator of conventional intra-arterial thrombolysis.Objective: Acute peripheral arterial occlusions can be treated by catheter directed thrombolysis (CDT). However, CDT is time consuming and accompanied by the risk of bleeding complications. The addition of contrast enhanced ultrasound and microbubbles could improve thrombus susceptibility to thrombolytic agents and potentially shorten treatment time with a lowered risk of bleeding complications. This article reports the outcomes of the safety and feasibility of this novel technique. Methods: In this single arm phase II trial, 20 patients with acute lower limb ischaemia received CDT combined with an intravenous infusion of microbubbles and locally applied ultrasound during the first hour of standard intra-arterial thrombolytic therapy. The primary endpoint was safety, i.e., occurrence of serious adverse events (haemorrhagic complications and/or amputation) and death within one year. Secondary endpoints included angiographic and clinical success, thrombolysis duration, additional interventions, conversion, and quality of life.Results: The study included 20 patients (16 men; median age 68.0 years; range, 50.0 e 83.0; and 40% native artery and 60% bypass graft). In all patients, the use of microbubble contrast enhanced sonothrombolysis could be applied successfully. There were no serious adverse events related to the experimental treatment. Duplex examination showed flow distal from the occlusion after 23.1 hours (range 3.1 e 46.5) with a median thrombolysis time of 47.5 hours (range 6.0 e 81.0). The short term ABI and pain scores significantly improved; however, no changes were observed before or after thrombolysis in the microcirculation. Overall mortality and amputation rates were both 2% within one year. The one year patency rate was 55%. Conclusion: Treatment of patients with acute peripheral arterial occlusions with contrast enhanced sonothrombolysis is feasible and safe to perform in patients. Further research is necessary to investigate the superiority of this new treatment over standard treatment.

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Section: Discussionmentioning

confidence: 99%

Microbubbles and Ultrasound Accelerated Thrombolysis for Peripheral Arterial Occlusions: The Outcomes of a Single Arm Phase II Trial

Doelare

Pierre

Nederhoed

et al. 2021

European Journal of Vascular and Endovascular Surgery

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“…Only two studies reported on thrombus weight as an outcome of the therapy, Ebben et al in 2015 andNederhoed et al in 2017. In the first study, standard intra-arterial CDT was compared with intra-arterial CDT enhanced with intravenous MBs and locally applied US. CEST resulted in a significantly lower thrombus weight at the end of therapy in this study (1.1g vs. 1.6 g, p = 0.01).…”

Section: Thrombus Weightmentioning

confidence: 99%

“…Another development in CEST is the ability to load the microbubble with a lytic agent, such as tissue plasminogen activator (tPA) or urokinase. In addition, arginineÀglycineÀaspartic acidÀserine peptide (RGDS) can be added to the surface of the microbubble as a targeting ligand for thrombus (Nederhoed et al 2017). Both developments might increase the efficacy of CEST even further, as the MBs will adhere to the surface of the thrombus and the lytic agent can be released locally.…”

Section: Introductionmentioning

confidence: 99%

“…CEST holds considerable promise for therapeutic use in acute peripheral arterial thrombosis. Several studies have been conducted on recanalization using microbubbles (MBs) and US; however, their therapeutic use in peripheral arterial thrombosis has been reported in only a few studies (Ebben et al 2015;Nederhoed et al 2017). As very little research has been done on CEST in the setting of peripheral arterial thrombosis, we investigated the effectiveness and safety of CEST in any setting of arterial thrombosis, excluding articles on microvascular arterial thrombosis.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Use of Microbubbles and Ultrasound in Acute Peripheral Arterial Thrombosis: A Systematic Review

Nederhoed

Tjaberinga

Otten

et al. 2021

Ultrasound in Medicine & Biology

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Catheter-directed thrombolysis (CDT) for acute peripheral arterial occlusion is time consuming and carries a risk of major hemorrhage. Contrast-enhanced sonothrombolysis (CEST) might enhance outcomes compared with standard CDT. In the study described here, we systematically reviewed all in vivo studies on contrastenhanced sonothrombolysis in a setting of arterial thrombosis. A systematic search of the PubMed, Embase, Cochrane Library and Web of Science databases was conducted. Two reviewers independently performed the study selection, quality assessment and data extraction. Primary outcomes were recanalization rate and thrombus weight. Secondary outcome was any possible adverse event. The 35 studies included in this review were conducted in four different (pre)clinical settings: ischemic stroke, myocardial infarction, (peripheral) arterial thrombosis and arteriovenous graft occlusion. Because of the high heterogeneity among the studies, it was not possible to conduct a meta-analysis. In almost all studies, recanalization rates were higher in the group that underwent a form of CEST. One study was terminated early because of a higher incidence of intracranial hemorrhage. Studies on CEST suggest that adding microbubbles and ultrasound to standard intra-arterial CDT is safe and might improve outcomes in acute peripheral arterial thrombosis. Further research is needed before CEST can be implemented in daily practice.

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“…In this regard, microbubble oscillation and fragmentation under high mechanical index US imaging mechanically dissolve the thrombus and increase the penetration of thrombolytics into the thrombus, thus potentiating fibrinolysis and accelerating thrombolysis. 41 This method proved to be successful in animal models and in a phase II single-arm clinical trial involving patients with acute peripheral arterial occlusions eligible for thrombolytic treatment. 42 Furthermore, preclinical trials have demonstrated that CEUS was suitable to restore epicardial and microvascular flow after ST-segment elevation myocardial infarction (STEMI) in pigs 43 and a phase II clinical trial is ongoing, evaluating the effect of sonothrombolysis after STEMI (NCT03092089).…”

Section: Therapeutic Ceus In Cardiovascular Applicationsmentioning

confidence: 99%

Ultrasound Microbubbles for Diagnosis and Treatment of Cardiovascular Diseases

Rix

Curaj

Liehn

et al. 2019

Semin Thromb Hemost

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Ultrasound (US) imaging of heart and major arteries and veins is among the most frequently used diagnostic techniques applied in humans. Conventional cardiovascular US sessions include anatomical B-mode and functional M-, pulsed-wave- and Doppler mode, which have their limitations in both precise cardiac chambers' delineation and small vessel imaging. The introduction of contrast-enhanced US, employing microbubble suspensions as contrast agent, has enabled a better delineation of heart chambers, the visualization of myocardial microvasculature, and the atherosclerotic plaque neovascularization. Moreover, specific disease-related molecular tracers have been developed by modifying the microbubbles with targeting ligands directed to biological markers exposed to the luminal side of the blood vessels. Microbubble functionalization has enabled in vivo molecular US imaging of various stages of atherosclerosis, from plaque initiation to plaque vulnerability, and neointima formation following revascularization procedures. Furthermore, oscillating microbubbles have been used to mechanically dissolve thrombus material and may act as carriers of drugs and nucleic acids that are released locally by US pulses. This review article summarizes recent advances in functional and molecular US images and discusses therapeutic applications of microbubbles. The addressed topics include an overview on microbubble formats, microbubble detection methods, molecular targets of cardiovascular diseases, and the use of microbubbles for thrombolysis and drug delivery.

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Intravenous Targeted Microbubbles Carrying Urokinase versus Urokinase Alone in Acute Peripheral Arterial Thrombosis in a Porcine Model

Cited by 17 publications

References 20 publications

Microbubbles and Ultrasound Accelerated Thrombolysis for Peripheral Arterial Occlusions: The Outcomes of a Single Arm Phase II Trial

Microbubbles and Ultrasound Accelerated Thrombolysis for Peripheral Arterial Occlusions: The Outcomes of a Single Arm Phase II Trial

Therapeutic Use of Microbubbles and Ultrasound in Acute Peripheral Arterial Thrombosis: A Systematic Review

Ultrasound Microbubbles for Diagnosis and Treatment of Cardiovascular Diseases

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