Research Horizons/Future Therapies Brad Bunney, MD Associate Professor Department of Emergency Medicine University of Illinois College of Medicine-Chicago Chicago, IL

Brad Bunney, MD Objectives Neuroprotectors & Ischemic Cascade Clot Effectors Near Future Far Future

Brad Bunney, MD Neuroprotectors Glutamate and the NMDA receptor GABA vs. Glutamate Free Radical Scavengers Apoptosis

Brad Bunney, MD Ischemic Cascade A.P, Green et at INeurophannacology 39 (2000)

Brad Bunney, MD 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

Brad Bunney, MD 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

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

Brad Bunney, MD 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

Brad Bunney, MD Glutamate and the NMDA Receptor Glycine: neuropeptide, acts on NMDA GV a glycine antagonist Safety trial completed using 12 hour window Side effects: transient altered mentation and hyperbilirubinemia

Brad Bunney, MD Glutamate and the NMDA Receptor Licostinel: glycine site competitive antagonist 48 hour window from symptom onset Side effects: CNS and GI

Brad Bunney, MD GABA Inhibitory neurotransmitter Agonists inhibits glutamate response GABAA receptor the primary site

Brad Bunney, MD 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

Brad Bunney, MD 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

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

Brad Bunney, MD 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

Brad Bunney, MD Problems with current studies Lack of efficacy Side effects Inadequate dosing Delay in initiation of treatment Inadequate drug penetration

Brad Bunney, MD Clot Effectors IIb/IIIa Inhibitors Fibrinogen Inhibition Intra-arterial Thrombolysis

Brad Bunney, MD Coagulation Cascade

Brad Bunney, MD Fibrinolytic Pathway

Brad Bunney, MD 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

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

Brad Bunney, MD 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

Brad Bunney, MD Near Future = Clot Effectors Intra-arterial thrombolysis already being used IIb/IIIa inhibitors hold promise New clotting inhibitors are being tested

Brad Bunney, MD Far Future = Neuroprotectants Problems will be solved More selective antagonists will be developed Novel ways of providing protection will be discovered

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