Sonothromblysis in Combination with Thrombolytic Drugs in a Rabbit Model Using MRI-Guidance

Christakis Damianou, Nicos Mylonas, Kleanthis Ioannides

Cyprus University of Technology, Cyprus.
Frederick University Cyprus, Limassol, Cyprus.
Polikliniki Ygia, Limassol, Cyprus.

DOI: 10.4236/eng.2013.510B071                

Abstract

The potential of MRI-guided focused ultrasound (MRgFUS) combined with the thrombolytic drug recombinant tissue plasminogen activator (rt-PA), to dissolve clots in the carotid of a New Zealand rabbitin vivois evaluated. A spherically-focused transducers of 5 cmdiameter; focusing at10 cmand operating at 1 MHz was used. A pulsed ultrasound protocol was used that maintains a tissue temperature increase of less than 1℃ in the clot (called safe temperature). MRgFUS has the potentials to dissolve clots that are injected in the carotid of rabbits in vivo. It was found that the time needed for opening the carotid artery using ultrasound and rt-PA was decreased compared to just using rt-PA. The proposed protocol was monitored using Magnetic Resonance Angiography (MRA) every 1 min.

Keywords

Ultrasound; MRI; Stroke; Thrombolysis

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	R. Trubestein, H. R. Bernard, F. Etzel, A. Sobbe, A. Cremer and U. Stumpff, “Thrombolysis by Ultrasound,” Clinical Science & Molecular Medicine, Vol. 51, 1976, pp. 697-698.
[2]	K. Tachibana and S. Tachibana, “Ultrasonic Vibration for Boosting Fibrinolytic Effects of Urokinase in Vivo,” Thrombosis and Haemostasis, Vol. 46, 1981, p. 211.
[3]	M. Kimura, S. Iijima, K. Kobayashi and H. Furuhata, “Evaluation of the Thrombolytic Effect of Tissue-Type Plasminogen Activator with Ultrasound Irradiation: In Vitro Experiment Involving Assay of the Fibrin Degradation Products from the Clot,” Biological & Pharmaceutical Bulletin, Vol. 17, No. 1, 1994, pp. 126-130. http://dx.doi.org/10.1248/bpb.17.126
[4]	K. Spengos, S. Behrens, M. Daffertshofer, C. E. Dempfle and M. Hennerici, “Acceleration of Thrombolysis with Ultrasound through the Cranium in a Flow Model,” Ultrasound in Medicine & Biology, Vol. 26, 2000, pp. 889- 895. http://dx.doi.org/10.1016/S0301-5629(00)00211-8
[5]	C. W. Francis, A. Blinc, S. Lee and C. Cox, “Ultrasound Accelerates Transport of Recombinant Tissue Plasminogen Activator into Clots,” Ultrasound in Medicine & Biology, Vol. 21, 1995, pp. 419-424. http://dx.doi.org/10.1016/0301-5629(94)00119-X
[6]	A. Blinc, C. W. Francis, J. L. Trudnowski and E. L. Carstensen, “Characterization of Ultrasound-Potentiated Fibrinolysis in Vitro,” Blood, Vol. 81, 1993, pp. 2636-2643.
[7]	J. F. Polak, “Ultrasound Energy and the Dissolution of Thrombus,” The New England Journal of Medicine, Vol. 351, 2004, pp. 2154-2155. http://dx.doi.org/10.1056/NEJMp048249
[8]	Y. Birnbaum, H. Luo, T. Nagai, M. C. Fishbein, T. M. Peterson, S. Li, D. Kricsfeld, T. R. Porter and R. J. Siegel, “Noninvasive in Vivo Clot Dissolution without a Thrombolytic Drug: Recanalization of Thrombosed Iliofemoral Arteries by Transcutaneous Ultrasound Combined with Intravenous Infusion of Microbubbles,” Circulation, Vol. 97, 1998, pp. 130-134. http://dx.doi.org/10.1161/01.CIR.97.2.130
[9]	W. C. Culp, E. Erdem, P. K. Roberson and M. M. Husain “Microbubble Potentiated Ultrasound as a Method of Stroke Therapy in a Pig Model: Preliminary Findings,” Journal of Vascular and Interventional Radiology, Vol. 14, No. 11, 2003, pp. 1433-1436. http://dx.doi.org/10.1097/01.RVI.0000096767.47047.FA
[10]	C. K. Holland and R. E. Apfel, “Thresholds for Transient Cavitation Produced by Pulsed Ultrasound in a Controlled Nuclei Environment,” Journal of the Acoustical Society of America, Vol. 88, No. 5, 1990, pp. 2059-2069. http://dx.doi.org/10.1121/1.400102
[11]	P. A. Schumann, J. P. Christiansen, R. M. Quigley, T. P. McCreery, R. H. Sweitzer and E. C. Unger, “Targeted-Microbubble Binding Selectively to GPIIb IIIa Receptors of Platelet Thrombi,” Investigative Radiology, Vol. 37, No. 11, 2002, pp. 587-593. http://dx.doi.org/10.1097/00004424-200211000-00001
[12]	V. Frenkel, J. Oberoi, M. Stone, M. Park, C. Deng, B. Wood, Z. Neeman, M. Horne III and K. Li, “Pulsed High-Intensity Focused Ultrasound Enhances Thrombolysis in an in Vitro Model,” Radiology, Vol. 239, No. 1, 2006, pp. 86-93. http://dx.doi.org/10.1148/radiol.2391042181
[13]	G. Shawa, J. Meunier, S. Huang, C. Lindsell, D. McPherson, C. Holland, “Ultrasound-Enhanced Thrombolysis with tPA-Loaded Echogenic Liposomes,” Thrombosis Research, Vol. 124, No. 3, 2009, pp. 306-310. http://dx.doi.org/10.1016/j.thromres.2009.01.008
[14]	T. Hölscher, D. Fisher, R. Raman, K. Ernstrom, E. Zadicario, W. Bradley and A. Voie, “Noninvasive Transcranial Clot Lysis Using High Intensity Focused Ultrasound,” Journal of Neurology & Neurophysiology, Vol. 1, 2011, pp. 1-6.
[15]	S. Laing, M. Moody, B. Smulevitz, H. Kim, P. Kee, S. Huang, C. Holland and D. McPherson, “Ultrasound-Enhanced Thrombolytic Effect of Tissue Plasminogen Activator–Loaded Echogenic Liposomes in an in Vivo Rabbit Aorta Thrombus Model—Brief Report,” Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 31, No. 6, 2011, pp. 1357-1359. http://dx.doi.org/10.1161/ATVBAHA.111.225938
[16]	A. V. Alexandrov, A. W. Wojner and J. C. Grotta, “Clotbust Investigators Clotbust: Design of a Randomized Trial of Ultrasound-Enhanced Thrombolysis for Acute Ischemic Stroke,” Journal of Neuroimaging, Vol. 14, 2004, pp. 108-12
[17]	The IMS Study Investigators, “Combined Intravenous and Intraarterial Recanalization for Acute Ischemic Stroke: The Interventional Management of Stroke Study,” Stroke, Vol. 35, 2004, pp. 904-912. http://dx.doi.org/10.1161/01.STR.0000121641.77121.98
[18]	M. Daffertshofer, A. Gass and P. Ringleb, “Transcranial Low Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia: Increased Risk of Hemorrhage with Combined Ultrasound and Tissue Plasminogen Activator,” Stroke, Vol. 36, 2005, pp. 1441-1446. http://dx.doi.org/10.1161/01.STR.0000170707.86793.1a
[19]	A. Barreto, V. Sharma, A. Lao, P. Schellinger, P. Amarenco, P. Sierzenski, A. Alexandrov and C. Molina, “Safety and Dose-Escalation Study Design of Transcranial Ultrasound in Clinical SONolysis for Acute Ischemic Stroke: the Tucson Trial,” International Journal of Stroke, Vol. 4, 2009, pp. 42-48. http://dx.doi.org/10.1111/j.1747-4949.2009.00252.x
[20]	A. V. Alexandrov, C. A. Molina and J. C. Grotta “Ultrasound Enhanced Systemic Thrombolysis for Acute Ischemic Stroke,” The New England Journal of Medicine, Vol. 351, 2004, pp. 2170-2178. http://dx.doi.org/10.1056/NEJMoa041175
[21]	C. K. Holland, S. S Vaidya, S. Datta, C. C. Coussios and G. J. Shaw, “Ultrasound Enhanced Tissue Plasminogen Activator Thrombolysis in an in Vitro Porcine Clot Model,” Thrombosis Research, Vol. 121, 2008, pp. 663-673. http://dx.doi.org/10.1016/j.thromres.2007.07.006
[22]	T. Saguchi, H. Onoue, M. Urashima, T. Ishibashi, T. Abe and H. Furuhata, “Effective and Safe Conditions of Low-Frequency Transcranial Ultrasonic Thrombolysis for Acute Ischaemic Stroke: Neurologic and Histologic Evaluation in a Rat Middle Cerebral Artery Stroke Model,” Stroke, Vol. 39, 2008, pp. 1007-1011. http://dx.doi.org/10.1161/STROKEAHA.107.496117
[23]	E. Jürgen, R. K. Inke, K. Bj?rn, H. G?tz and S. Günter, “Sonothrombolysis with Transcranial Color-Coded Sonography and Recombinant Tissue-Type Plasminogen Activator in Acute Middle Cerebral Artery Main Stem Occlusion: Results from a Randomized Study,” Stroke, Vol. 39, 2008, pp. 1470-1475. http://dx.doi.org/10.1161/STROKEAHA.107.503870