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Objectives

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  1. Research Horizons/Future Therapies Brad Bunney, MDAssociate ProfessorDepartment of Emergency MedicineUniversity of Illinois College of Medicine-ChicagoChicago, IL

  2. Objectives • Neuroprotectors & Ischemic Cascade • Clot Effectors • Near Future • Far Future

  3. Neuroprotectors • Glutamate and the NMDA receptor • GABA vs. Glutamate • Free Radical Scavengers • Apoptosis

  4. Ischemic Cascade A.P, Green et at INeurophannacology 39 (2000) 1483-1494

  5. Glutamate and the NMDA Receptor • Glutamate is released with ischemia • Acts on NMDA receptors • Calcium influx occurs • Free radical are formed in the cytoplasm • Mitochondria shut down • DNA degenerates • Membrane breakdown occurs

  6. Glutamate and the NMDA Receptor • Inhibiting the ischemic cascade • Stop glutamate release • Block the NMDA Receptor • Many compounds tested • Good animal model results • Lack of efficacy or adverse effects in humans

  7. Glutamate and the NMDA Receptor • Remacemide: Safety trials completed • Noncompetitive NMDA receptor antagonist • 12 window from onset of symptoms • Adverse effects: CNS-hallucination, agitation

  8. Glutamate and the NMDA Receptor • Aptiganel: safety trials completed • Noncompetitive NMDA receptor antagonist • 24 hour window from the onset of symptoms • Adverse side effects: CNS - H/A, sedation; HTN

  9. Glutamate and the NMDA Receptor • Glycine: neuropeptide, acts on NMDA • GV150526 a glycine antagonist • Safety trial completed using 12 hour window • Side effects: transient altered mentation and hyperbilirubinemia

  10. Glutamate and the NMDA Receptor • Licostinel: glycine site competitive antagonist • 48 hour window from symptom onset • Side effects: CNS and GI

  11. GABA • Inhibitory neurotransmitter • Agonists inhibits glutamate response • GABAA receptor the primary site

  12. GABA • Clomethiazole: GABAA receptor modulator • 12 hour window from onset of symptoms • CLASS trial • Adverse effects: sedation • Efficacy: not established, but subgroup efficacy being studied

  13. Free Radical Scavengers • Scavengers convert free radicals into O2 and H2O • Ebselen: given within 48 hours • Sign. efficacy at 1 month but not 3 months • Subgroup analysis sign. to 3 months if given within 24 hours

  14. Free Radical Scavengers • Citicoline: membrane stabilizer, prevents free radical formation • Improved outcome in 6 weeks • No significant side effects • Decreases infarct size

  15. Apoptosis • Programmed cell death • 50% of normal neurons die during growth • Capases: enzymes that cause DNA degradation • Capase-3: activated by ischemia • Z-VAD(OMe)-CH2F and DEVD(OMe)-CH2F: inhibit capase-3 • Obstacles: BBB and pharmacokinetics

  16. Problems with current studies • Lack of efficacy • Side effects • Inadequate dosing • Delay in initiation of treatment • Inadequate drug penetration

  17. Clot Effectors • IIb/IIIa Inhibitors • Fibrinogen Inhibition • Intra-arterial Thrombolysis

  18. Coagulation Cascade

  19. Fibrinolytic Pathway

  20. IIb/IIIa Inhibitors • Used in ACS, only recently in stroke • Abciximab: safety study with 24 window • No cases of major intracranial hemorrhage • Incidental hemorrhages were 7% in Abciximab and 5% in control • Trend toward efficacy

  21. Fibrinogen Inhibitors • Break down fibrinogen into inactive parts and prevent thrombus formation • Ancrod: pit viper venom • Achieved sign. efficacy @ 90 days (Barthel Index > 95) • Symptomatic ICH higher • Asymptomatic ICH sign. higher

  22. Intra-arterial Thrombolysis • Requires emergent cerebral angiogram • PROACT II: Prourokinase, 6 hour window • MCA infarcts only • Sign. Efficacy at 90 days (modified Rankin 2 or <) • Symptomatic ICH: 10% drug vs. 2% control

  23. Near Future = Clot Effectors • Intra-arterial thrombolysis already being used • IIb/IIIa inhibitors hold promise • New clotting inhibitors are being tested

  24. Far Future = Neuroprotectants • Problems will be solved • More selective antagonists will be developed • Novel ways of providing protection will be discovered

  25. Questions?? Brad Bunney, MDbbunney@uic.edu312 413 7484