Research Horizons/Future Therapies

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Research Horizons/Future Therapies

• Brad Bunney, MD
• Associate Professor
• Department of Emergency Medicine
• University of Illinois at Chicago
• College of Medicine
• Chicago, 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 at Ineurophannacology 39 (2000)
  1483-1494

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Glutamate and the NMDA Receptor

• Glutamate is released with ischemia
• Acts on NDMA 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 NDMA 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 trails completed
• Noncompetitive NMDA receptor antagonist
• 12-hour window from the 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, aglycine antagonist
• Safety trial completed using 12-hour window
• Side effects transient altered mentation and
  hyperbilirubinenemia

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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

• Scavenges convert free radicals into O2 and H2O
• Ebselen given within 48 hours
• Significant efficacy at 1 month but not 3 months
• Subgroup analysis significant to 3 months, if
  give 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-hour 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

• Breakdown fibrinogen into inactive parts and
  prevent thrombus formation
• Ancrod pit viper venom
• Achieved significant efficacy _at_ 90 days (Barthel
  Index gt 95)
• Sympotmatic ICH higher
• Asymptomatic ICH significantly higher

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Intra-arterial Thrombolysis

• Requires emergent cerebral angiogram
• PROACT II Prourokinase, 6-hour window
• MCA infarcts only
• Significant 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, MD bbunney_at_uic.edu 312
413 7484