brain ischemic
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Oleh : dr. Jacobus Soleh, SpS
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Urgent Condition Within the First 3 6 hEarly admissionIntensive stroke unit ( ISU ) Neuroimaging service ( CT / MRI ) Laboratory : glucose, electrolytes, blood gases, Neurosurgeon Neurologist trained in resucitation Cardiologistrheological & coagulation
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MAIN DIRECTION of BASIC THERAPY> Correction of Respiratory & Cardio Vascular Disturbances> Water & Electrolyte imbalanced>Prevention & Treatment Intracranial Hypertension & Brain Edema > Autonomic Disorders >Complication of Ischemic Stroke
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Within 3 h :Within 6 h :12 36 h after onset :2 3rd day :The energy failure is maximally pronounced- Glutamate exitotoxicity- Calcium homeostasis disorders- Lactic acidosisDecreasing by the end of the 3rd dayActivity of oxidant stress & Local inflammation reach a peakPeak activity of apoptosis
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SCHEME of SEQUENTIAL ISCHEMIC CASCADE EVENTSCBF decreaseIon pump failure & glutamate exitotoxicityIntracellular accumulation of calciumActivation of intracellular enzymeIncreased NO synthesis & development of oxidative stressExpression of early response genesReactions of activated glia( local inflammation, microcirculation disturbances, BBB damage )Apoptosis
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METABOLIC RESPONSES of BRAINCBF70 80 %First Critical Level< 50 55 ml / 100 grInhibition of Protein Synthesis CBF50 % ( 35 ml / 100 gr )2nd Critical LevelActivate Anaerobic Glycolysis LactateLactate Acidosis & Cytotoxic Edema
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CBF30 % ( 20ml / 100 gr )3rd Critical LevelDepletion ATP SynthesisEnergetic DefisitDysfunction Active Ion Transport ChannelCell Membrans InstabilityExcessive Efflux of Excitatory Neurotransmiter a.aCBF20 % ( 10 15ml / 100 gr )Lose Ion GradientAmoxic Depolaritation of MembransIrreversible Cell Damage
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Bila CBF < 10ml / 100 grIrreversible Damage Within 6 8 min( ISCHEMIC CORE )
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TWO BASIC DIRECTIONS THERAPY1ST Stage :Improvement of Brain Tissue Perfusion( Therapeutic ReperfusionThrombolysis / Anticoagulan )2nd 8th :Neuroprotective / cytoprotective therapy Primary Neuroprotection : first minute ( 12 h ) Secondary Neuroprotection : 3 6 h
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MAIN DIRECTION of the PRIMARY NEUROPROTECTION
Sheet1
DirectionBasic Drug GroupsRepresentativesPresent State of Study
Potential-dependentDihydropiridinesNimodipineEfficacy is not proven
Calcium channel
AntagonistsDarodipineEfficacy is not proven. X
( PY 108-068 )
IsradipineSevere adverse effects. X
FlunarizineEfficacy is not proven. X
CerebrokrastEfficacy is not proven. X
Glutamate recertorsNMDA receptor
Antagonistsantagonists
non-competitiveDizopcipineSevere adverse effects. X
MK-801
DextrorphanSevere adverse effects. X
DextromethorphanSevere adverse effects. X
CerestatSevere adverse effects. X
( CNS-1102,
aptiganel
hydrochloride )
RemacemideStudies are in progress
hydrochloride
Magnesium sulfateStudies are in progress
CompetitiveSelfotelSevere adverse effects. X
( CGS-19755 )
DirectionBasic Drug GroupsRepresentativesPresent State of Study
Selective :
- polyaminesEliprodilEfficacy is not proven. X
site blockers( SL-82.0715 )
- glycine siteGavestinelEfficacy is not proven. X
blockers( GV-150526A )
LicostinelEfficacy is not proven.
( ACEA-1021 )
AMPA receptorsNBOXSevere adverse effects. X
antagonists
ZK 200775Severe adverse effects. X
Inhibitors ofBW-619C89Severe adverse effects. X
synthesis and
presynaptic release
of glutamate
PropentofyllineSevere adverse effects. X
PhenytoinEfficacy is not proven.
Fos-PhenytoinEfficacy is not proven.
LubeluzoleEfficacy is not proven. X
GABA agonistsChlomethiazoleStudies are in progress
GlycineGlycineStudies are in progress
Notes : X - trials are stopped
Sheet2
Sheet3
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MAIN DIRECTION of the PRIMARY NEUROPROTECTION
Sheet1
DirectionBasic Drug GroupsRepresentativesPresent State of Study
Potential-dependentDihydropiridinesNimodipineEfficacy is not proven
Calcium channel
AntagonistsDarodipineEfficacy is not proven. X
( PY 108-068 )
IsradipineSevere adverse effects. X
FlunarizineEfficacy is not proven. X
CerebrokrastEfficacy is not proven. X
Glutamate recertorsNMDA receptor
Antagonistsantagonists
non-competitiveDizopcipineSevere adverse effects. X
MK-801
DextrorphanSevere adverse effects. X
DextromethorphanSevere adverse effects. X
CerestatSevere adverse effects. X
( CNS-1102,
aptiganel
hydrochloride )
RemacemideStudies are in progress
hydrochloride
Magnesium sulfateStudies are in progress
CompetitiveSelfotelSevere adverse effects. X
( CGS-19755 )
DirectionBasic Drug GroupsRepresentativesPresent State of Study
Selective :
- polyaminesEliprodilEfficacy is not proven. X
site blockers( SL-82.0715 )
- glycine siteGavestinelEfficacy is not proven. X
blockers( GV-150526A )
LicostinelEfficacy is not proven.
( ACEA-1021 )
AMPA receptorsNBOXSevere adverse effects. X
antagonists
ZK 200775Severe adverse effects. X
Inhibitors ofBW-619C89Severe adverse effects. X
synthesis and
presynaptic release
of glutamate
PropentofyllineSevere adverse effects. X
PhenytoinEfficacy is not proven.
Fos-PhenytoinEfficacy is not proven.
LubeluzoleEfficacy is not proven. X
GABA agonistsChlomethiazoleStudies are in progress
GlycineGlycineStudies are in progress
Notes : X - trials are stopped
Sheet2
Sheet3
-
MAIN DIRECTION in SECONDARY NEUROPROTECTION
Sheet1
DirectionBasic Drug GroupsRepresentativesPresent State of Study
Potential-dependentDihydropiridinesNimodipineEfficacy is not proven
Calcium channel
AntagonistsDarodipineEfficacy is not proven. X
( PY 108-068 )
IsradipineSevere adverse effects. X
FlunarizineEfficacy is not proven. X
CerebrokrastEfficacy is not proven. X
Glutamate recertorsNMDA receptor
Antagonistsantagonists
non-competitiveDizopcipineSevere adverse effects. X
MK-801
DextrorphanSevere adverse effects. X
DextromethorphanSevere adverse effects. X
CerestatSevere adverse effects. X
( CNS-1102,
aptiganel
hydrochloride )
RemacemideStudies are in progress
hydrochloride
Magnesium sulfateStudies are in progress
CompetitiveSelfotelSevere adverse effects. X
( CGS-19755 )
DirectionBasic Drug GroupsRepresentativesPresent State of Study
Selective :
- polyaminesEliprodilEfficacy is not proven. X
site blockers( SL-82.0715 )
- glycine siteGavestinelEfficacy is not proven. X
blockers( GV-150526A )
LicostinelEfficacy is not proven.
( ACEA-1021 )
AMPA receptorsNBOXSevere adverse effects. X
antagonists
ZK 200775Severe adverse effects. X
Inhibitors ofBW-619C89Severe adverse effects. X
synthesis and
presynaptic release
of glutamate
PropentofyllineSevere adverse effects. X
PhenytoinEfficacy is not proven.
Fos-PhenytoinEfficacy is not proven.
LubeluzoleEfficacy is not proven. X
GABA agonistsChlomethiazoleStudies are in progress
GlycineGlycineStudies are in progress
Notes : X - trials are stopped
Sheet2
DirectionBasic Drug GroupsRepresentativesPresent State of Study
AntioxidantsFree radicalTirilazad mesylateEfficacy is not proven. X
scavengers( U-74006F )
Phenyl-t-butyl nitronePreclinical studies
( PBN )
NO-synthase7-NitroindazolePreclinical studies
blockers1-(2-Fluoromethyl-phenyl)-
imidazolePreclinical studies
AminoguanidinesPreclinical studies
Selen-organicEbselenStudies are in progress
compound of
complex
antioxidant action
InhibitorsAntibodies toEnlimomabSevere adverse effects. X
of localintercellular
inflammationadhesionHuman antibodies toPreclinical studies,
moleculesleukocyte integrins,start of clinical
( anti-ICAM )CD11 CD18studies
Pro-inflammatoryEndogenous antagonists of
cytokineTNF and IL-1 receptorsPreclinical studies
inhibitorsZinc protoporphyrin ( ZnPP )Preclinical studies
Endogenous anti-TGF-Preclinical studies
inflammatory
cytokinesIL-10Preclinical studies
DirectionBasic Drug GroupsRepresentativesPresent State of Study
StatinsStatins3-Hydroxy-3-methylglutarylPreclinical studies,
coenzyme A ( HMG-CoA )start of clinical
reductase inhibitorsstudies
EstrogensEstrogensEstrogensPreclinical studies,
start of clinical
studies
Trophic factorsNeurotrophicBasic fibroblastic growthStudies are in progress
factorsfactor ( bFGF )
Brain-derived neurotrophicPreclinical studies
factor ( BDXF )
Insulin-dependent growthPreclinical studies
factor ( IGF )
Osteogenic protein-1Preclinical studies
( OP-1 )
NeuromodulatorsNeuropeptidesSemax ( ACTH 4-10 )Studies are in progress
CerebrolysinStudies are in progress
NAP ( NAPVSIPQ )Preclinical studies, start of
clinical studies
RegulatorsGangliosidesGMIStudies are in progress
of receptor
structures
Notes : X - trials are stopped
Sheet3
-
MAIN DIRECTION in SECONDARY NEUROPROTECTION
Sheet1
DirectionBasic Drug GroupsRepresentativesPresent State of Study
Potential-dependentDihydropiridinesNimodipineEfficacy is not proven
Calcium channel
AntagonistsDarodipineEfficacy is not proven. X
( PY 108-068 )
IsradipineSevere adverse effects. X
FlunarizineEfficacy is not proven. X
CerebrokrastEfficacy is not proven. X
Glutamate recertorsNMDA receptor
Antagonistsantagonists
non-competitiveDizopcipineSevere adverse effects. X
MK-801
DextrorphanSevere adverse effects. X
DextromethorphanSevere adverse effects. X
CerestatSevere adverse effects. X
( CNS-1102,
aptiganel
hydrochloride )
RemacemideStudies are in progress
hydrochloride
Magnesium sulfateStudies are in progress
CompetitiveSelfotelSevere adverse effects. X
( CGS-19755 )
DirectionBasic Drug GroupsRepresentativesPresent State of Study
Selective :
- polyaminesEliprodilEfficacy is not proven. X
site blockers( SL-82.0715 )
- glycine siteGavestinelEfficacy is not proven. X
blockers( GV-150526A )
LicostinelEfficacy is not proven.
( ACEA-1021 )
AMPA receptorsNBOXSevere adverse effects. X
antagonists
ZK 200775Severe adverse effects. X
Inhibitors ofBW-619C89Severe adverse effects. X
synthesis and
presynaptic release
of glutamate
PropentofyllineSevere adverse effects. X
PhenytoinEfficacy is not proven.
Fos-PhenytoinEfficacy is not proven.
LubeluzoleEfficacy is not proven. X
GABA agonistsChlomethiazoleStudies are in progress
GlycineGlycineStudies are in progress
Notes : X - trials are stopped
Sheet2
DirectionBasic Drug GroupsRepresentativesPresent State of Study
AntioxidantsFree radicalTirilazad mesylateEfficacy is not proven. X
scavengers( U-74006F )
Phenyl-t-butyl nitronePreclinical studies
( PBN )
NO-synthase7-NitroindazolePreclinical studies
blockers1-(2-Fluoromethyl-phenyl)-
imidazolePreclinical studies
AminoguanidinesPreclinical studies
Selen-organicEbselenStudies are in progress
compound of
complex
antioxidant action
InhibitorsAntibodies toEnlimomabSevere adverse effects. X
of localintercellular
inflammationadhesionHuman antibodies toPreclinical studies,
moleculesleukocyte integrins,start of clinical
( anti-ICAM )CD11 CD18studies
Pro-inflammatoryEndogenous antagonists of
cytokineTNF and IL-1 receptorsPreclinical studies
inhibitorsZinc protoporphyrin ( ZnPP )Preclinical studies
Endogenous anti-TGF-Preclinical studies
inflammatory
cytokinesIL-10Preclinical studies
DirectionBasic Drug GroupsRepresentativesPresent State of Study
StatinsStatins3-Hydroxy-3-methylglutarylPreclinical studies,
coenzyme A ( HMG-CoA )start of clinical
reductase inhibitorsstudies
EstrogensEstrogensEstrogensPreclinical studies,
start of clinical
studies
Trophic factorsNeurotrophicBasic fibroblastic growthStudies are in progress
factorsfactor ( bFGF )
Brain-derived neurotrophicPreclinical studies
factor ( BDXF )
Insulin-dependent growthPreclinical studies
factor ( IGF )
Osteogenic protein-1Preclinical studies
( OP-1 )
NeuromodulatorsNeuropeptidesSemax ( ACTH 4-10 )Studies are in progress
CerebrolysinStudies are in progress
NAP ( NAPVSIPQ )Preclinical studies, start of
clinical studies
RegulatorsGangliosidesGMIStudies are in progress
of receptor
structures
Notes : X - trials are stopped
Sheet3
-
SECONDARY PREVENTION Blood Pressure, Glucose, Lipid Control Anti Platelets ( Aspirin, Cilostazol / pletaal, Clopidogrel, ticlopidine, dipiridomol )
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REPARATIVE THERAPY It is difficult to define the borders between Neuroprotection & Reparative Therapy Piracetam Citicoline
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Fungsi Otak Tergantung Pada Supply Glucose( menjaga metabolisme energy )Bila Glucose Use the free fraction of glycogenCardiac arrest, severe cardiac rhytm disorder Severe Systemic HypertensionGlobal Brain IschemicKalau mengenai 1 arteriTotal Brain Ischemic or TIAContoh :
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Morphologic Changes :Stenosis & Occlunous, Vessel AnomaliesVessel Shape & ConfigurationGlobal & Cerebral HemodynamicsCBFC V InsuffPhysical & Chemical ChangesCoagulability, Aggregation, Viscosity & Other Rheological,Protein Fraction, Electrolytes.Individual & Age DependentCerebral Ischemia Brain Infaction ( Irreversible )
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