Microbubble Administration Accelerates Clot Lysis During Continuous 2-MHz Ultrasound Monitoring in Stroke Patients Treated With Intravenous Tissue Plasminogen Activator

Molina, Carlos A.; Ribó, Marc; Rubiera, Marta; Montaner, Joan; Santamarina, Esteban; Delgado‐Mederos, Raquel; Arenillas, Juan F.; Huertas, Rafael; Purroy, Francisco; Delgado, Pilar; Álvarez-Sabín, José

doi:10.1161/01.str.0000199064.94588.39

Cited by 428 publications

(327 citation statements)

References 29 publications

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“…Next to diagnostic applications, randomized clinical studies suggest therapeutic efficacy of ultrasound on recanalization of acute cerebral artery occlusion in terms of an acceleration of fibrinolysis with recombinant tissue-type plasminogen activator (rt-PA) (Alexandrov et al, 2004;Eggers et al, 2008). Echo contrast agents may further improve treatment efficacy (Molina et al, 2006;Perren et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Combined Contrast-Enhanced Ultrasound and rt-PA Treatment is Safe and Improves Impaired Microcirculation after Reperfusion of Middle Cerebral Artery Occlusion

Nedelmann

Ritschel

Doenges

et al. 2010

J Cereb Blood Flow Metab

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In monitoring of recanalization and in sonothrombolysis, contrast-enhanced ultrasound (CEUS) is applied in extended time protocols. As extended use may increase the probability of unwanted effects, careful safety evaluation is required. We investigated the safety profile and beneficial effects of CEUS in a reperfusion model. Wistar rats were subjected to filament occlusion of the right middle cerebral artery (MCA). Reperfusion was established after 90 minutes, followed by recombinant tissue-type plasminogen activator (rt-PA) treatment and randomization to additional CEUS (contrast agent: SonoVue; 60 minutes). Blinded outcome evaluation consisted of magnetic resonance imaging (MRI), neurologic assessment, and histology and, in separate experiments, quantitative 3D nano-computed tomography (CT) angiography (900 nm 3 voxel size). Nano-CT revealed severely compromised microcirculation in untreated animals after MCA reperfusion. The rt-PA partially improved hemispheric perfusion. Impairment was completely reversed in animals receiving rt-PA and CEUS. This combination was more effective than treatment with either CEUS without rt-PA or rt-PA and ultrasound or ultrasound alone. In MRI experiments, CEUS and rt-PA treatment resulted in a significantly reduced ischemic lesion volume and edema formation. No unwanted effects were detected on MRI, histology, and intracranial temperature assessment. This study shows that CEUS and rt-PA is safe in the situation of reperfusion and displays beneficial effects on the level of the microvasculature.

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Section: Introductionmentioning

confidence: 99%

Combined Contrast-Enhanced Ultrasound and rt-PA Treatment is Safe and Improves Impaired Microcirculation after Reperfusion of Middle Cerebral Artery Occlusion

Nedelmann

Ritschel

Doenges

et al. 2010

J Cereb Blood Flow Metab

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“…Ultrasound enhances thrombolysis, particularly when applied in conjunction with intravenous administration of thrombolytic agents [45][46][47].Microbubble oscillation has also been shown to enhance the breakup of a clot, with maximal efficacy achieved with the combined effect of insonation, thrombolytic agents and microbubbles [46,47].Challenges for clinical translation include the development of systems for reliable control of the applied ultrasound dose and the great challenges of achieving the required timely intervention (3-6h after the thrombus formation) in the critical applications of stroke and myocardial infarction.…”

Section: Applicationsmentioning

confidence: 99%

Driving delivery vehicles with ultrasound

Ferrara

2008

Advanced Drug Delivery Reviews

231

162

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Therapeutic applications of ultrasound have been considered for over 40 years, with the mild hyperthermia and associated increases in perfusion produced by ultrasound harnessed in many of the earliest treatments. More recently, new mechanisms for ultrasound-based or ultrasound-enhanced therapies have been described, and there is now great momentum and enthusiasm for the clinical translation of these techniques. This dedicated issue of Advanced Drug Delivery Reviews, entitled "Ultrasound for Drug and Gene Delivery," addresses the mechanisms by which ultrasound can enhance local drug and gene delivery and the applications that have been demonstrated at this time. In this commentary, the identified mechanisms, delivery vehicles, applications and current bottlenecks for translation of these techniques are summarized. KeywordsUltrasound; Therapy; Drug delivery; Gene delivery; Sonoporation; Cavitation As an imaging modality, ultrasound is widely employed and valued for its real time applications, low cost, simplicity, and safety. Waves of alternating increased and decreased pressure propagate from the transducer, typically resulting in a maximum intensity in a focal region chosen by the operator. The dimensions of the focal region can vary from tens of microns for high frequency ultrasound to centimeters for an unfocused therapeutic beam. Most clinical instruments are engineered to effectively image from the body surface to 24 or more centimeters in depth. The ability to locally control and maximize energy deposition deep within the body facilitates a broad range of clinical opportunities for ultrasound imaging and therapy. Developing over four decades, clinical and commercial application of ultrasonic therapies spans hyperthermia, drug delivery, lipoplasty, and thrombolysis [1,2]. A complete and precise summary of the potential applications for ultrasonic enhancement of drug and gene delivery remains challenging as the mechanisms are multiple and not fully characterized. From an engineering viewpoint, the methods by which ultrasound facilitates drug and gene delivery can be summarized as direct changes in the biological or physiological properties of tissues facilitating transport, direct changes in the drug or vehicle increasing bioavailability or enhancing efficacy, and indirect effects by which ultrasound acts on the vehicle to produce changes in the surrounding tissue. While there are common mechanisms between these methods, the engineering challenges associated with the optimization of ultrasound systems and drug and vehicle design are unique for each method. Promising examples of each of these methods can be identified at this time and are addressed below.☆ This commentary is part of the Advanced Drug Delivery Reviews theme issue on "Ultrasound in Drug and Gene Delivery".

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“…These authors observed an increase in the rate of sustained complete recanalization within 2 h after the administration of rt-PA in those patients receiving the combined therapy. Building on this strategy for therapeutic success, Molina et al administered galactose-based microbubbles (Levovist™) in combination with 2.0-MHz transcranial Doppler ultrasound during rt-PA therapy and observed a further increase in the rate of complete recanalization [25]. However, another study carried out in patients using 300-kHz transcranial ultrasound with a spatial peak temporal average intensity of 0.7 W/cm 2 in combination with rt-PA demonstrated an increased rate of cerebral hemorrhage and the study was prematurely stopped [26].…”

Section: Introductionmentioning

confidence: 99%

Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model

Holland

Vaidya

Datta

et al. 2008

Thrombosis Research

100

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Microbubble Administration Accelerates Clot Lysis During Continuous 2-MHz Ultrasound Monitoring in Stroke Patients Treated With Intravenous Tissue Plasminogen Activator

Abstract: Administration of MBs induces further acceleration of US-enhanced thrombolysis in acute stroke, leading to a more complete recanalization and to a trend toward better short- and long-term outcome.

Cited by 428 publications

References 29 publications

Combined Contrast-Enhanced Ultrasound and rt-PA Treatment is Safe and Improves Impaired Microcirculation after Reperfusion of Middle Cerebral Artery Occlusion

Combined Contrast-Enhanced Ultrasound and rt-PA Treatment is Safe and Improves Impaired Microcirculation after Reperfusion of Middle Cerebral Artery Occlusion

Driving delivery vehicles with ultrasound

Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model

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