Educational Objectives - University of Illinois at Chicago_11_ by hcj


									Research Horizons/Future Therapies

              Brad Bunney, MD

                Associate Professor
      Department of Emergency Medicine
University of Illinois College of Medicine-Chicago
                     Chicago, IL
•   Neuroprotectors & Ischemic Cascade
•   Clot Effectors
•   Near Future
•   Far Future

                       Brad Bunney, MD
•   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) 1483-1494   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
• 12 window from onset of symptoms
• Adverse effects: CNS-hallucination,

                       Brad Bunney, MD
Glutamate and the NMDA Receptor
• Aptiganel: safety trials completed
• Noncompetitive NMDA receptor
• 24 hour window from the onset of
• Adverse side effects: CNS - H/A,
  sedation; HTN
                       Brad Bunney, MD
Glutamate and the NMDA Receptor
• Glycine: neuropeptide, acts on NMDA
• GV150526 a glycine antagonist
• Safety trial completed using 12 hour
• Side effects: transient altered
  mentation and hyperbilirubinemia

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

                       Brad Bunney, MD

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

                       Brad Bunney, MD

• Clomethiazole: GABAA receptor
• 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
• 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
• Programmed cell death
• 50% of normal neurons die during growth
• Capases: enzymes that cause DNA
• 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. efficacy @ 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%

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

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

                      Brad Bunney, MD

Brad Bunney, MD
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