, Volume 47, Issue 11, pp 845–854 | Cite as

Intraarterial reteplase and intravenous abciximab for treatment of acute ischemic stroke

A preliminary feasibility and safety study in a non-human primate model
  • Adnan I. Qureshi
  • M. Fareed K. Suri
  • Zulfiqar Ali
  • Andrew J. Ringer
  • Alan S. Boulos
  • Marian T. Nakada
  • Ronald A. Alberico
  • Lisa B. E. Martin
  • Lee R. Guterman
  • L. Nelson Hopkins
Interventional Neuroradiology


We performed a preliminary feasibility and safety study using intravenous (IV) administration of a platelet glycoprotein IIb/IIIa inhibitor (abciximab) in conjunction with intraarterial (IA) administration of a thrombolytic agent (reteplase) in a primate model of intracranial thrombosis. We introduced thrombus through superselective catheterization of the intracranial segment of the internal carotid artery in 16 primates. The animals were randomly assigned to receive IA reteplase and IV abciximab ( n =4), IA reteplase and IV placebo ( n =4), IA placebo and IV abciximab ( n =4) or IA and IV placebo ( n =4). Recanalization was assessed by serial angiography during the 6-h period after initiation of treatment. Postmortem magnetic resonance (MR) imaging was performed to determine the presence of cerebral infarction or intracranial hemorrhage. Partial or complete recanalization at 6 h after initiation of treatment (decrease of two or more points in pre-treatment angiographic occlusion grade) was observed in two animals treated with IA reteplase and IV abciximab, three animals treated with IA reteplase alone and one animal treated with IV abciximab alone. No improvement in perfusion was observed in animals that received IV and IA placebo. Cerebral infarction was demonstrated on postmortem MR imaging in three animals that received IA and IV placebo and in one animal each from the groups that received IA reteplase and IV abciximab or IV abciximab alone. One animal that received IV abciximab alone had a small intracerebral hemorrhage on MR imaging. IA reteplase with or without abciximab appeared to be the most effective regimen for achieving recanalization in our model of intracranial thrombosis. Further studies are required in experimental models to determine the optimal dose, method of administration and efficacy of these medications in acute ischemic stroke.


Antiplatelet agents Ischemic stroke Magnetic resonance imaging Primates Thrombolysis 



The study was supported by a grant from Centocor, Inc. The company assisted in the study design, interpretation of data and the writing and approval of the report.


  1. 1.
    Antman EM, Giugliano RP, Gibson CM, et al (1999) Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 trial. The TIMI 14 Investigators. Circulation 99:2720–2732PubMedGoogle Scholar
  2. 2.
    Qureshi AI, Luft AR, Sharma M, Guterman LR, Hopkins LN (2000) Prevention and treatment of thromboembolic and ischemic complications associated with endovascular procedures: Part I—Pathophysiological and pharmacological features. Neurosurgery 46:1344–1359CrossRefPubMedGoogle Scholar
  3. 3.
    Bihour C, Durrieu-Jais C, Besse P, Nurden P, Nurden AT (1995) Flow cytometry reveals activated GP IIb-IIIa complexes on platelets from patients undergoing thrombolytic therapy after acute myocardial infarction. Blood Coagul Fibrinolysis 6:395–410PubMedGoogle Scholar
  4. 4.
    Fitzgerald DJ, Catella F, Roy L, FitzGerald GA (1988) Marked platelet activation in vivo after intravenous streptokinase in patients with acute myocardial infarction. Circulation 77:142–150PubMedGoogle Scholar
  5. 5.
    Coller BS (1997) GPIIb/IIIa antagonists: pathophysiologic and therapeutic insights from studies of c7E3 Fab. Thromb Haemost 78:730–735PubMedGoogle Scholar
  6. 6.
    Lee VM, Burdett NG, Carpenter A, et al (1996) Evolution of photochemically induced focal cerebral ischemia in the rat. Magnetic resonance imaging and histology. Stroke 27:2110–2118PubMedGoogle Scholar
  7. 7.
    Moseley ME, Kucharczyk J, Mintorovitch J, et al (1990) Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats. AJNR 11:423–942PubMedGoogle Scholar
  8. 8.
    Connolly TM, Condra C, Feng DM, et al (1994) Species variability in platelet and other cellular responsiveness to thrombin receptor-derived peptides. Thromb Haemost 72:627–633PubMedGoogle Scholar
  9. 9.
    Weiner EJ, Stucchi AF, Foxall TL, Shwaery GT, Yoganathan S, Nicolosi RJ (1994) The effects of doxazosin on platelet aggregation, platelet adhesion and blood coagulation in cynomolgus monkeys. Atherosclerosis 107:35–44CrossRefPubMedGoogle Scholar
  10. 10.
    Deitch JS, Williams JK, Adams MR, et al (1998) Effects of beta3-integrin blockade (c7E3) on the response to angioplasty and intra-arterial stenting in atherosclerotic nonhuman primates. Arterioscler Thromb Vasc Biol 18:1730–1737PubMedGoogle Scholar
  11. 11.
    Meden P, Overgaard K, Sereghy T, Boysen G (1993) Enhancing the efficacy of thrombolysis by AMPA receptor blockade with NBQX in a rat embolic stroke model. J Neurol Sci 119:209–216CrossRefPubMedGoogle Scholar
  12. 12.
    Shuaib A, Yang Y, Li Q, Siddiqui MM, Kalra J (1998) Intraarterial urokinase produces significant attenuation of infarction volume in an embolic focal ischemia model. Exp Neurol 154:330–335CrossRefPubMedGoogle Scholar
  13. 13.
    Ringer AJ, Guterman LR, Hopkins L N (2001) Site-specific thromboembolism: A novel animal model for stroke. 50th Annual Meeting of the Congress of Neurological Surgeons, San Antonio, TexasGoogle Scholar
  14. 14.
    The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581–1587CrossRefPubMedGoogle Scholar
  15. 15.
    Neuhaus KL, von Essen R, Vogt A, et al (1994) Dose finding with a novel recombinant plasminogen activator (BM 06.022) in patients with acute myocardial infarction: results of the German Recombinant Plasminogen Activator Study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausarzte (ALKK). J Am Coll Cardiol 24:55–60PubMedGoogle Scholar
  16. 16.
    Tebbe U, von Essen R, Smolarz A, et al (1993) Open, noncontrolled dose-finding study with a novel recombinant plasminogen activator (BM 06.022) given as a double bolus in patients with acute myocardial infarction. Am J Cardiol 72:518–524CrossRefPubMedGoogle Scholar
  17. 17.
    The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators (1997) A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 337:1118–1123CrossRefPubMedGoogle Scholar
  18. 18.
    Qureshi AI, Ali Z, Suri MF, et al (2001) Intra-arterial third-generation recombinant tissue plasminogen activator (reteplase) for acute ischemic stroke. Neurosurgery 49:41–48CrossRefPubMedGoogle Scholar
  19. 19.
    Qureshi AI, Suri MF, Shatla AA, et al (2000) Intraarterial recombinant tissue plasminogen activator for ischemic stroke: an accelerating dosing regimen. Neurosurgery 47:473–476PubMedGoogle Scholar
  20. 20.
    Boehringer Mannheim GmbH. Retavase-reteplase recombinant (1997) Product monographGoogle Scholar
  21. 21.
    Martin U, Kaufmann B, Neugebauer G (1999) Current clinical use of reteplase for thrombolysis. A pharmacokinetic-pharmacodynamic perspective. Clin Pharmacokinet 36:265–276PubMedGoogle Scholar
  22. 22.
    Noble S, McTavish D (1996) Reteplase. A review of its pharmacological properties and clinical efficacy in the management of acute myocardial infarction. Drugs 52:589–605PubMedGoogle Scholar
  23. 23.
    Wooster MB, Luzier AB: Reteplase (1999): a new thrombolytic for the treatment of acute myocardial infarction. Ann Pharmacother 33:318–324CrossRefPubMedGoogle Scholar
  24. 24.
    The Abciximab in Ischemic Stroke Investigators (2000) Abciximab in acute ischemic stroke: a randomized, double-blind, placebo- controlled, dose-escalation study. Stroke 31:601–609PubMedGoogle Scholar
  25. 25.
    de Lemos JA, Antman EM, Gibson CM, et al (2000) Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction. Observations from the TIMI 14 trial. Circulation 101:239–243PubMedGoogle Scholar
  26. 26.
    Koch KC, vom DJ, Kleinhans E, (1999) Influence of a platelet GPIIb/IIIa receptor antagonist on myocardial hypoperfusion during rotational atherectomy as assessed by myocardial Tc-99m sestamibi scintigraphy. J Am Coll Cardiol 33:998–1004CrossRefPubMedGoogle Scholar
  27. 27.
    Gawaz M, Neumann FJ, Dickfeld T, et al (1997) Vitronectin receptor (alpha(v)beta3) mediates platelet adhesion to the luminal aspect of endothelial cells: implications for reperfusion in acute myocardial infarction. Circulation 96:1809–1818PubMedGoogle Scholar
  28. 28.
    Murphy JF, Bordet JC, Wyler B, et al (1994) The vitronectin receptor (alpha v beta 3) is implicated, in cooperation with P-selectin and platelet-activating factor, in the adhesion of monocytes to activated endothelial cells. Biochem J 304 (Pt 2):537–542PubMedGoogle Scholar
  29. 29.
    Simon DI, Xu H, Ortlepp S, Rogers C, Rao NK (1997) 7E3 monoclonal antibody directed against the platelet glycoprotein IIb/IIIa cross-reacts with the leukocyte integrin Mac-1 and blocks adhesion to fibrinogen and ICAM-1. Arterioscler Thromb Vasc Biol 17:528–535PubMedGoogle Scholar
  30. 30.
    Furlan A, Higashida R, Wechsler L (1999) Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 282:2003–2011CrossRefPubMedGoogle Scholar
  31. 31.
    Harrington RA, Ohman EM, Sigmon KN, et al (1995) Intensity of inhibition of the platelet glycoprotein IIb/IIIa receptor differs among disease states. Circulation 92 [Suppl I]:I-488–I-489Google Scholar
  32. 32.
    Merlini PA, Bauer KA, Oltrona L, et al (1994) Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 90:61–68PubMedGoogle Scholar
  33. 33.
    Kleiman NS, Raizner AE, Jordan R, et al (1995) Differential inhibition of platelet aggregation induced by adenosine diphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GPIIb/IIIa receptors. J Am Coll Cardiol 26:1665–1671CrossRefPubMedGoogle Scholar
  34. 34.
    Boyko OB, Alston SR, Fuller GN, Hulette CM, Johnson GA, Burger PC (1994) Utility of postmortem magnetic resonance imaging in clinical neuropathology. Arch Pathol Lab Med 118:219–225PubMedGoogle Scholar
  35. 35.
    De Groot CJ, Bergers E, Kamphorst W, et al (2001) Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p) reactive lesions. Brain 124:1635–1645CrossRefPubMedGoogle Scholar
  36. 36.
    Anderson HV, Willerson JT (1993) Thrombolysis in acute myocardial infarction. N Engl J Med 329:703–709CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Adnan I. Qureshi
    • 5
  • M. Fareed K. Suri
    • 1
  • Zulfiqar Ali
    • 1
  • Andrew J. Ringer
    • 1
  • Alan S. Boulos
    • 1
  • Marian T. Nakada
    • 4
  • Ronald A. Alberico
    • 2
  • Lisa B. E. Martin
    • 3
  • Lee R. Guterman
    • 1
  • L. Nelson Hopkins
    • 1
  1. 1.Toshiba Stroke Research Center Department of NeurosurgeryState University of New YorkBuffaloUSA
  2. 2.Department of Radiology, Neuroradiology and Head and Neck ImagingState University of New YorkBuffaloUSA
  3. 3.Department of Comparative Medicine and Laboratory Animals Facilities, Roswell Park Cancer InstituteState University of New YorkBuffaloUSA
  4. 4.Centocor Inc.MalvernUSA
  5. 5.Zeenat Qureshi Stroke Research CenterThe University of Medicine and Dentistry of New JerseyNewarkUSA

Personalised recommendations