Histological Observations and the Process of Ultrasound Contrast Agent Enhancement of Tissue Plasminogen Activator Thrombolysis With Ultrasound Exposure

Kondô, Isao; Mizushige, Katsufumi; Ueda, Takashi; Masugata, Hisashi; Ohmori, Koji; Matsuo, Hirohíde

doi:10.1253/jcj.63.478

Cited by 36 publications

(17 citation statements)

References 28 publications

(34 reference statements)

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“…They also found that stable cavitation increased rt-PA penetration into the sample porcine clot. Others have found similar results for human clots (Francis et al 1995;Kondo et al 1999). In the absence of ultrasound, exogenous tPA diffuses into the clot down the concentration gradient (Blinc et al 1993;Shaw et al 2007) and converts plasminogen to plasmin.…”

Section: Discussionsupporting

confidence: 66%

Tissue Plasminogen Activator Concentration Dependence of 120 kHz Ultrasound-Enhanced Thrombolysis

Shaw

Meunier

Lindsell

et al. 2008

Ultrasound in Medicine & Biology

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It has been known for some time that the application of ultrasound can enhance the efficacy of thrombolytic medications such as recombinant tissue plasminogen activator (rt-PA). Potential clinical applications of this ultrasound-enhanced thrombolysis (UET) include the treatment of myocardial infarction, acute ischemic stroke, deep venous thrombosis and other thrombotic disorders. It may be possible to reduce the dose of rt-PA while maintaining lytic efficacy; however there is little data on the rt-PA concentration dependence of UET. In this work, the rt-PA concentration dependence of clot lysis resulting from 120 kHz UET exposure was measured in an in vitro human clot model. Clots were exposed to rt-PA for 30 min, with (UET treated) or without 120 kHz ultrasound (rt-PA treated) at 37 degrees C, and the clot width measured as a function of time. The rt-PA concentration ranged from 0-10 microg/mL. The initial lytic rate for the UET-treated group was greater than that of the rt-PA group at almost all rt-PA concentrations, and exhibited a maximum over concentration values of 1-3 microg/mL.

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Section: Discussionsupporting

confidence: 66%

Tissue Plasminogen Activator Concentration Dependence of 120 kHz Ultrasound-Enhanced Thrombolysis

Shaw

Meunier

Lindsell

et al. 2008

Ultrasound in Medicine & Biology

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“…Experimental evidence suggests that ultrasound substantially increases the thrombolytic effect of TPA, particularly if used in low MHz-kHz frequency range. Ultrasound exposure causes various changes, such as reversible disaggregation of non-cross-linked fibrin fibers, microcavity formation in the shallow layers of thrombus, an increase in the enzymatic transport of TPA improving its uptake, and penetration of TPA into clots as well as residual flow enhancement with microstreaming and vessel dilation [28][29][30].…”

Section: Therapeutic Tcdmentioning

confidence: 99%

Role of transcranial Doppler ultrasonography in evaluation of patients with cerebrovascular disease

Sharma

Tsivgoulis²,

Lao³

et al. 2007

Curr Neurol Neurosci Rep

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Transcranial Doppler ultrasonography (TCD) is the only noninvasive examination method that enables the reliable evaluation of blood flow from the basal intracerebral vessels, adding physiologic information to the anatomic images. TCD is relatively inexpensive, can be performed at bedside, and allows monitoring in acute emergency settings and for prolonged periods with a high temporal resolution, making it ideal for studying dynamic cerebrovascular responses. In acute stroke, TCD is capable of providing rapid information about the hemodynamic status of the cerebral circulation and monitoring recanalization in real-time, with a potential for enhancing tissue plasminogen activator-induced thrombolysis. Extended applications such as emboli monitoring, right-to-left shunt detection, and vasomotor reactivity make TCD an important and valuable tool for evaluating stroke mechanisms, planning and monitoring treatment, and determining prognosis.

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“…2,3 Ultrasound can induce various changes such as reversible disaggregation of cross-linked fibrin fibers, 4 microcavity formation in the shallow layer of thrombus, 5 and increasing uptake and penetration of tPA into clots. 6 Insonation through the skull is associated with a remarkable loss of energy at frequencies used for diagnostic purposes (2 to 4 MHz).…”

mentioning

confidence: 99%

Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia

Daffertshofer

Gass

Ringleb

et al. 2005

Stroke

382

204

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Background— Clinical studies using ultrasound at diagnostic frequencies in transcranial Doppler devices provided encouraging results in enhancing thrombolysis with tissue plasminogen activator (tPA) in acute stroke. Low-frequency ultrasound does not require complex positioning procedures, penetrates through the skull better, and has been demonstrated to accelerate thrombolysis with tPA in animal experiments in wide cerebrovascular territories without hemorrhagic side effects. We therefore conducted the first multicenter clinical trial to investigate safety of tPA plus low-frequency ultrasound (300 kHz). Methods— Acute stroke patients within a 6-hour time window were included (National Institutes of Health Stroke Scale scores >4). Magnetic resonance imaging (MRI) was used to document vascular occlusion and to rule out cerebral hemorrhage. Patients were allocated to combination therapy alternately; the first patient received tPA only, the second patient received tPA plus ultrasound, etc. Follow-up included serial MRI directly thereafter and 24 hours later to confirm recanalization and tissue imaging. Clinical recovery was measured after treatment and 3 months later. Results— 26 patients (70.4±9.7 years) entered the trial (12 tPA, 14 tPA plus ultrasound). The study was prematurely stopped because 5 of 12 patients from the tPA only group but 13 of 14 patients treated with the tPA plus ultrasound showed signs of bleeding in MRI ( P <0.01). Within 3 days of treatment, 5 symptomatic hemorrhages occurred within the tPA plus ultrasound group. At 3 months, neither morbidity nor treatment-related mortality or recanalization rates differed between both groups. Conclusions— This study demonstrated bioeffects from low-frequency ultrasound that caused an increased rate of cerebral hemorrhages in patients concomitantly treated with intravenous tPA.

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Histological Observations and the Process of Ultrasound Contrast Agent Enhancement of Tissue Plasminogen Activator Thrombolysis With Ultrasound Exposure

Cited by 36 publications

References 28 publications

Tissue Plasminogen Activator Concentration Dependence of 120 kHz Ultrasound-Enhanced Thrombolysis

Tissue Plasminogen Activator Concentration Dependence of 120 kHz Ultrasound-Enhanced Thrombolysis

Role of transcranial Doppler ultrasonography in evaluation of patients with cerebrovascular disease

Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia

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