Laboratory research has shown that various ultrasound frequencies can enhance clot lysis in the presence of tissue plasminogen activator (TPA). Dr Alexandrov has obtained pilot non-randomized data indicating recanalization and recovery rates higher than can be expected from the NINDS TPA Stroke Study when TPA infusion was monitored by 2 MHz transcranial Doppler JCD) in patients with acute ischemic stroke. The goal of this proposal is to develop a practical operator- independent ultrasound device and to demonstrate its effectiveness and safety in enhancing thrombolytic therapy for ischemic stroke. Enhancing performance of TPA with inexpensive external ultrasound can result in earlier recanalization, accelerated patient recovery and improved outcome. Major objectives of this proposal are: 1. to develop an operator- independent ultrasound device for diagnosis and monitoring of intracranial occlusions 2. to compare rates of recanalization and recovery between patients treated with standard TPA dose versus patients treated with TPA and also continuously monitored by the operator-independent ultrasound device in phase II-III randomized trials. Dr Alexandrov will learn biometry and clinical trial design methods under supervision of Dr James Grotta, UT-Houston, TX and develop the device under the supervision of Dr Merrill Spencer, Institute for Applied Physiology in Medicine, Seattle, WA. Also under Dr Grotta's supervision, Dr Alexandrov will then design and execute a randomized phase II trial. The primary specific aims for this pilot phase II study are: 1. To determine complete recanalization and early clinical recovery rates in patients treated with intravenous TPA and continuously monitored with an external ultrasound compared to those treated with standard TPA dose alone. 2. To determine if continuous monitoring of TPA infusion with external ultrasound is safe and will not result in higher rates of symptomatic intracerebral hemorrhage compared to controls. Data generated during this phase II trial will form the basis for a design of a properly powered multicenter phase III trial. Time table includes: Courses in biometry, statistical methods and research design (1st year, 2nd year) Device development, adjustments and pilot patient studies (1st year, 2nd year) Phase II randomized trial and preliminary data analysis (2nd year, 3rd year) Manuscript preparation, data presentation and follow-up grant writing (4th year)

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23NS002229-03
Application #
6629242
Study Section
NST-2 Subcommittee (NST)
Program Officer
Marler, John R
Project Start
2001-02-01
Project End
2005-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
3
Fiscal Year
2003
Total Cost
$155,083
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Neurology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Barreto, Andrew D; Alexandrov, Andrei V; Shen, Loren et al. (2013) CLOTBUST-Hands Free: pilot safety study of a novel operator-independent ultrasound device in patients with acute ischemic stroke. Stroke 44:3376-81
Barreto, Andrew D; Alexandrov, Andrei V; Lyden, Pat et al. (2012) The argatroban and tissue-type plasminogen activator stroke study: final results of a pilot safety study. Stroke 43:770-5
Saqqur, Maher; Sharma, Vijay K; Tsivgoulis, Georgios et al. (2010) Real-time hemodynamic assessment of downstream effects of intracranial stenoses in patients with orthostatic hypoperfusion syndrome. Cerebrovasc Dis 30:355-61
Molina, Carlos A; Barreto, Andrew D; Tsivgoulis, Georgios et al. (2009) Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial. Ann Neurol 66:28-38
Alexandrov, Andrei V; Mikulik, Robert; Ribo, Marc et al. (2008) A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke. Stroke 39:1464-9
Tsivgoulis, Georgios; Culp, William C; Alexandrov, Andrei V (2008) Ultrasound enhanced thrombolysis in acute arterial ischemia. Ultrasonics 48:303-11
Saqqur, M; Tsivgoulis, G; Molina, C A et al. (2008) Symptomatic intracerebral hemorrhage and recanalization after IV rt-PA: a multicenter study. Neurology 71:1304-12
Tsivgoulis, Georgios; Alexandrov, Andrei V (2007) Ultrasound-enhanced thrombolysis in acute ischemic stroke: potential, failures, and safety. Neurotherapeutics 4:420-7
Mikulik, Robert; Ribo, Marc; Hill, Michael D et al. (2007) Accuracy of serial National Institutes of Health Stroke Scale scores to identify artery status in acute ischemic stroke. Circulation 115:2660-5
Choi, John Y; Pary, Jennifer K; Alexandrov, Andrei V et al. (2006) Does clinical-CT 'mismatch' predict early response to treatment with recombinant tissue plasminogen activator? Cerebrovasc Dis 22:384-8

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