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Oleh : dr. Jacobus Soleh, SpS
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
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
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
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
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
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
Bila CBF < 10ml / 100 grIrreversible Damage Within 6 8 min( ISCHEMIC CORE )
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
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 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 )
REPARATIVE THERAPY It is difficult to define the borders between Neuroprotection & Reparative Therapy Piracetam Citicoline
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 :
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 )