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Microbubble administration during prolonged 2 mhz tcd improves recanalization and long-term functional outcome in acute stroke patients treated with iv thrombolysis for isolated mca m1 occlusion

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... However, two trials, MUST and CLOTBUST [84,85], have been interrupted after significant levels of intracerebral hemorrhages were recorded, without prognostic improvement at 3 months. Other clinical trials have been conducted, but the significant loss (60%) of subjects at 3 months [85] and/or absence of study randomization [86,87] were notable concerns. A more recent clinical trial, NOR-SASS [88], has been prematurely ended for lack of funding. ...
Article
Introduction: Recent developments in ultrasound imaging and ultrasound contrast agents (UCAs) improved diagnostic confidence in echography and set into motion their combined use as a tool for drug delivery and therapeutic monitoring. Non-invasive, precise and targeted delivery of drug molecules to pathological tissues by employing different mechanisms of drug release is becoming feasible. Areas covered: We sought to describe: the nature and features of UCAs; outline current contrast-specific imaging modes; before describing a variety of strategies for using ultrasound and microbubbles as a drug delivery system. Our expert opinion focusses on results and prospects of using ultrasound and microbubbles as a dual modality for drug delivery and therapeutic monitoring. Expert opinion: Today, ultrasound and microbubbles present a realistic prospect as drug delivery tools that have been demonstrated in a variety of animal models and clinical indications. Besides delivering drugs, ultrasound and microbubbles have demonstrated added value through therapeutic monitoring and assessment. Successful evaluation of the sonoporation mechanism(s), ultrasound parameters, drug type and dose will need to be addressed before translating this technology for clinic use. Ultimately, the development of a strategy for monitoring targeted delivery and its implementation in clinical practice would advance therapeutic treatment to a new qualitative level.
... The CLOT-BUST trial demonstrated the positive biological effect of low intensity 2 MHz pulsed wave transcranial Doppler on enhancement of tPA-induced early recanalization. It paved the road for subsequent studies that included combination of ultrasound with gaseous microspheres [23][24][25][26][27][28][29] (Table 1). Detailed analysis of microspheres data is beyond the scope of this update since at the moment the clinical developments in the field of sonothrombolysis are focused on the ultrasound device, i.e. drug-device combination. ...
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Intravenous tissue plasminogen activator (tPA) remains the only approved, fastest and widely feasible treatment of acute ischemic stroke. Systemic tPA induces recanalization of an occluded vessel, the process thought to lead to neurological recovery. Augmentation of this fibrinolytic activity can be safely achieved with diagnostic ultrasound frequencies and intensities. Ultrasound delivers mechanical pressure waves to thrombi exposing more thrombus surface to circulating drug. International multi-center CLOTBUST trial showed that patients with acute stroke treated with sonothrombolysis (tPA+2 MHz TCD) had more dramatic clinical recovery coupled with arterial recanalization (25% vs 8%) at no increase in the risk of symptomatic intracerebral hemorrhage (sICH). Based on this trial and subsequent phase I–II studies of a novel operator-independent device for delivery of the CLOBUST levels of ultrasound energy, a phase III efficacy trial of sonothrombolysis (named CLOTBUSTER) is being launched in Europe and North America.
Article
Introduction: Ultrasound enhancement of thrombolysis (sonothrombolysis) is further potentiated by administration of acoustically active microbubbles, which may be developed into powerful adjuvant therapies for thrombolytic treatment of occlusive conditions such as ischaemic stroke. Areas covered: The role of microbubbles in sonothrombolysis is evaluated based on published in vitro and in vivo evidence and a critical review of clinical trials to date. Microbubble, ultrasound and drug parameters compiled from a broad search of the existing literature are tabulated. Mechanisms of microbubble-enhanced sonothrombolysis are discussed, with particular focus on acoustic cavitation and thermal effects. A number of challenges to widespread clinical adoption are identified. Key factors for future optimisation of treatment and microbubble design are proposed. Expert opinion: Microbubble enhancement of thrombolysis is supported by a broad range of in vitro and in vivo evidence that demonstrates improved lysis compared to conventional drug treatment or ultrasound without microbubbles. Clinically, this is shown by accelerated recanalisation of occluded arteries; however, further research is needed to ensure patient safety. Before such techniques can enter widespread clinical practice, an improved understanding of the role of microbubbles in sonothrombolysis is required, in addition to demonstration of significant improvement over existing treatments and the development of reliable real-time monitoring protocols.
Article
OBJECTIVES To assess the evidence on the safety and efficacy of sonothrombolysis in acute stroke. SEARCH METHODS Electronic databases and grey literature were searched under different MeSH terms from 1970 to present. SELECTION CRITERIARandomized control trials (RCTs) and case control studies (CCSs) on sonolysis and sonothrombolysis alone or with microsphere in acute stroke patients (>18 old). Outcome measures included complete recanalization (CR) at 1-2 and 24 hours, 3 months modified Rankin Scale (mRS), and symptomatic intracerebral hemorrhage (sICH). Data was extracted to Review Manager software. RESULTSFifty-seven studies were retrieved and analyzed. Ten studies (7 RCTs and 3 CCSs) were included in our meta-analysis, which revealed that sonolysis and sonothrombolysis are safe (OR of sICH: 1.14; 95% confidence interval (CI): 0.56- 2.34;P=0.71) and effective (OR of CR at 1-2 hours: 2.95;95% CI: 1.81-4.81;P<0.00001) and have more than two-fold higher likelihood of favourable long-term outcome (3-month mRS 0-2; OR: 2.20; CI:1.52-3.19;P<0.0001). Further subgroup analysis based on the presence of microsphere revealed that it is safe (OR of sICH: 1.18; CI:0.433.24;P=0.75) and effective (OR of CR: 2.61; CI: 1.36-4.99;P=0.004). Subgroup analysis based on sonolysis revealed to be safe and effective. CONCLUSIONS This novel treatment appears safe and effective. The evidence of microsphere as an enhancement of sonothrombolysis is evolving.
Article
Full-text available
Intravenous administration of recombinant tissue plasminogen activator remains the fastest and widely feasible strategy to initiate treatment in acute ischemic stroke. Because it works by inducing recanalization of an occluded vessel, augmentation of this process is desirable and diagnostic transcranial Doppler ultrasound can accomplish this safely. Ultrasound delivers mechanical pressure waves to the clot, thus exposing more thrombus surface to circulating drug. Moreover, intravenous gaseous microspheres with ultrasound have been shown to be a potential alternative to fibrinolytic agents to recanalize discrete thrombotic arterial occlusions. For the first time in clinical medicine, the international multicenter CLOTBUST trial showed that ultrasound enhances the thrombolytic activity. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with arterial recanalization (38% vs. 13%). Th e rates of symptomatic intracerebral hemorrhage (sICH) were similar in the active and placebo group (4.8% vs. 4.8%). A microsphere dose-escalation study called TUCSON showed sustained complete recanalization rates of 67% in patients receiving TCD monitoring with a 1.4-mL perfl utren-lipid microsphere dose compared with controls receiving rt-PA alone with no increase in hemorrhage rate. Smaller clinical trials using transcranial color coded sonography reported recanalization rates ranging from 27% to 86% and sICH rates of 0–18%. In this article, we review the current applications of ultrasound and microspheres in stroke management including augmentation of systemic thrombolysis.
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