Skip to main content

Advertisement

SpringerLink
Log in

Intraarterial reteplase and intravenous abciximab for treatment of acute ischemic stroke

A preliminary feasibility and safety study in a non-human primate model

  • Interventional Neuroradiology
  • Published:
Neuroradiology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  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 99:2720–2732

    PubMed  Google Scholar 

  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 46:1344–1359

    Article  PubMed  Google Scholar 

  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 6:395–410

    PubMed  Google Scholar 

  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 77:142–150

    PubMed  Google Scholar 

  5. Coller BS (1997) GPIIb/IIIa antagonists: pathophysiologic and therapeutic insights from studies of c7E3 Fab. Thromb Haemost 78:730–735

    PubMed  Google Scholar 

  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 27:2110–2118

    PubMed  Google Scholar 

  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 11:423–942

    PubMed  Google Scholar 

  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 72:627–633

    PubMed  Google Scholar 

  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 107:35–44

    Article  PubMed  Google Scholar 

  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 18:1730–1737

    PubMed  Google Scholar 

  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 119:209–216

    Article  PubMed  Google Scholar 

  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 154:330–335

    Article  PubMed  Google Scholar 

  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, Texas

  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 333:1581–1587

    Article  PubMed  Google Scholar 

  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 24:55–60

    PubMed  Google Scholar 

  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 72:518–524

    Article  PubMed  Google Scholar 

  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 337:1118–1123

    Article  PubMed  Google Scholar 

  18. Qureshi AI, Ali Z, Suri MF, et al (2001) Intra-arterial third-generation recombinant tissue plasminogen activator (reteplase) for acute ischemic stroke. Neurosurgery 49:41–48

    Article  PubMed  Google Scholar 

  19. Qureshi AI, Suri MF, Shatla AA, et al (2000) Intraarterial recombinant tissue plasminogen activator for ischemic stroke: an accelerating dosing regimen. Neurosurgery 47:473–476

    PubMed  Google Scholar 

  20. Boehringer Mannheim GmbH. Retavase-reteplase recombinant (1997) Product monograph

  21. Martin U, Kaufmann B, Neugebauer G (1999) Current clinical use of reteplase for thrombolysis. A pharmacokinetic-pharmacodynamic perspective. Clin Pharmacokinet 36:265–276

    PubMed  Google Scholar 

  22. Noble S, McTavish D (1996) Reteplase. A review of its pharmacological properties and clinical efficacy in the management of acute myocardial infarction. Drugs 52:589–605

    PubMed  Google Scholar 

  23. Wooster MB, Luzier AB: Reteplase (1999): a new thrombolytic for the treatment of acute myocardial infarction. Ann Pharmacother 33:318–324

    Article  PubMed  Google Scholar 

  24. The Abciximab in Ischemic Stroke Investigators (2000) Abciximab in acute ischemic stroke: a randomized, double-blind, placebo- controlled, dose-escalation study. Stroke 31:601–609

    PubMed  Google Scholar 

  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 101:239–243

    PubMed  Google Scholar 

  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 33:998–1004

    Article  PubMed  Google Scholar 

  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 96:1809–1818

    PubMed  Google Scholar 

  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):537–542

    PubMed  Google Scholar 

  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 17:528–535

    PubMed  Google Scholar 

  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 282:2003–2011

    Article  PubMed  Google Scholar 

  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-489

  32. Merlini PA, Bauer KA, Oltrona L, et al (1994) Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 90:61–68

    PubMed  Google Scholar 

  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 26:1665–1671

    Article  PubMed  Google Scholar 

  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 118:219–225

    PubMed  Google Scholar 

  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 124:1635–1645

    Article  PubMed  Google Scholar 

  36. Anderson HV, Willerson JT (1993) Thrombolysis in acute myocardial infarction. N Engl J Med 329:703–709

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Toshiba Stroke Research Center Department of Neurosurgery, State University of New York, Buffalo, New York, USA

    M. Fareed K. Suri, Zulfiqar Ali, Andrew J. Ringer, Alan S. Boulos, Lee R. Guterman & L. Nelson Hopkins

  2. Department of Radiology, Neuroradiology and Head and Neck Imaging, State University of New York, Buffalo, New York, USA

    Ronald A. Alberico

  3. Department of Comparative Medicine and Laboratory Animals Facilities, Roswell Park Cancer Institute, State University of New York, Buffalo, NY, USA

    Lisa B. E. Martin

  4. Centocor Inc., Malvern, PA, USA

    Marian T. Nakada

  5. Zeenat Qureshi Stroke Research Center, The University of Medicine and Dentistry of New Jersey, DOC 8100, 90 Bergen Street, Newark, NJ, 07103, USA

    Adnan I. Qureshi

Authors
  1. Adnan I. Qureshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Fareed K. Suri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zulfiqar Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew J. Ringer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alan S. Boulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marian T. Nakada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ronald A. Alberico
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lisa B. E. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lee R. Guterman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L. Nelson Hopkins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adnan I. Qureshi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qureshi, A.I., Suri, M.F.K., Ali, Z. et al. Intraarterial reteplase and intravenous abciximab for treatment of acute ischemic stroke. Neuroradiology 47, 845–854 (2005). https://doi.org/10.1007/s00234-003-1097-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00234-003-1097-7

Keywords

Search

Navigation