Research HorizonsFuture Therapies Brad Bunney, MD Associate Professor Department of Emergency Medici

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

• Neuroprotectors Ischemic Cascade
• Clot Effectors
• Near Future
• Far Future

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Neuroprotectors

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

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

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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

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Glutamate and the NMDA Receptor

• Remacemide Safety trials completed
• Noncompetitive NMDA receptor antagonist
• 12 window from onset of symptoms
• Adverse effects CNS-hallucination, agitation

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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

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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

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Glutamate and the NMDA Receptor

• Licostinel glycine site competitive antagonist
• 48 hour window from symptom onset
• Side effects CNS and GI

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GABA

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

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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

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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

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Free Radical Scavengers

• Citicoline membrane stabilizer, prevents free
  radical formation
• Improved outcome in 6 weeks
• No significant side effects
• Decreases infarct size

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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

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Problems with current studies

• Lack of efficacy
• Side effects
• Inadequate dosing
• Delay in initiation of treatment
• Inadequate drug penetration

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Clot Effectors

• IIb/IIIa Inhibitors
• Fibrinogen Inhibition
• Intra-arterial Thrombolysis

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Coagulation Cascade
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Fibrinolytic Pathway
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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

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Fibrinogen Inhibitors

• Break down fibrinogen into inactive parts and
  prevent thrombus formation
• Ancrod pit viper venom
• Achieved sign. efficacy _at_ 90 days (Barthel Index
  gt 95)
• Symptomatic ICH higher
• Asymptomatic ICH sign. higher

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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
  lt)
• Symptomatic ICH 10 drug vs. 2 control

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Near Future Clot Effectors

• Intra-arterial thrombolysis already being used
• IIb/IIIa inhibitors hold promise
• New clotting inhibitors are being tested

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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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Questions?? Brad Bunney, MDbbunney_at_uic.edu3
12 413 7484