CYP2D6-Related Therapeutic Response in Alzheimer's Disease
Transcript of CYP2D6-Related Therapeutic Response in Alzheimer's Disease
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Alzheimer’s Disease
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Alzheimer’s Disease
Aging Genomics Epigenetics
Cerebrovascular disorders Metabolic disorders Environmental factors
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Medicina
Genómica
Ambiente
Nutrición
Etiología
Tratamiento
Diagnóstico
Genómica
Transcriptómica
Proteómica
Metabolómica
Nutrigenética
Nutrigenómica
Farmacogenética
Farmacogenómica
Quimiogenómica
Toxicogenómica
Terapia Génica
Clonación
Programa EuroEspes de Medicina Genómica
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Genotipo
Perfil Genómico
Fenotipo
SNC
Respuesta
Farmacogenómica
Etnia
Historia Familiar
Genotipo de Enfermedad
Genotipo Farmacogenético
Genotipo Farmacogenómico
Genotipo Nutrigenético
Genotipo Nutrigenómico
Fenotipo de Enfermedad
Edad y Sexo
Edad de Comienzo
Estadio y Severidad
Patología Concomitante
Correlación Genotipo-Fenotipo
Condiciones Nutricionales
Genómica Funcional
Transcriptómica
Proteómica
Metabolómica
Intervención Terapéutica
Genotipo-Metabolismo Farmacológico
Farmacocinética
Farmacodinámica
Modificación Fenotípica
Bioquímica
Neuroquímica
Neuropsicología
Humor
Conducta
Memoria y Aprendizaje
Funcionamiento
Neuroimagen
Función cerebral
Función cerebrovascular
Perfil de Expresión Génica
Transcriptómica
Proteómica
Metabolómica
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Alzheimer’s Disease
Pathogenesis
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Alzheimer’s Disease Macroscopic Neuropathology
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Alzheimer’s Disease Microscopic Neuropathology
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APP Mutations Alzheimer’s disease
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Presenilin-1 (PSEN1) and 2 (PSEN2) Mutations
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MAPT Mutations
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Alzheimer’s Disease Microscopic Neuropathology
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D D
C
N
APP
PEN-2
APH-1 APH-2
Nicastrin γ-Secretase
β-Secretase
α-Secretase
Notch
C
N
GACE
TACE
C83 C99
p3 Aβ
Membrane
Cytosol
γ-Secretase
Inhibitors
β-Secretase
Inhibitors
α-Secretase
Analogs
Agonists
Internalization
Neuronal Damage
Externalization
Fibrillogenesis
Amyloid
Deposition
Senile Plaques
Amyloid Angiopathy
Brain Damage
Cerebrovascular Damage
APP
21q21
PS1
14q24.3
PS2
1q31-q32
BACE
11q23.3
TACE
2p25
GACE
???
Nicastrin
Chr.1
PARK1
4p21
NOTCH
19p13.2-p13.1
PEN-2
Chr.19
APH-1
Chr.1/5
APOE
19q13.2
ACE
17q23
TAU
17q21.1
CASP3
4q35
UB
17p12-p11.1
IDE
10q23-q25
A2M
12p13.3-p12.3
PSMC1
19p13.3
PSMC2
7q22.1-q22.3
HSPD1
2q33.1
LRP1
12q13.1-q13.3
PRNP
20pter-p12
CTSB
8p22
Genomic Integration
Protein Synthesis Protein Misfolding
Ubiquitin
26S Proteasome
Conformational
Change
Aggregation
Protofibrils
Oligomers
Aggregates Chaperones
Aβ Vaccination
Immunization
Aβ Aggregation Inhibitors
β-Breakers
CHO Regulators Neuroprotective Agents
Antioxidants
Anti-inflammatory Drugs
Gene Therapy
RNAi
Vasoactive Agents
Brain Amyloidogenesis and Potential Therapeutic Interventions
R. Cacabelos, Pharmacogenomics 2004; 5(8):1049-1105
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Alzheimer’s Disease
Immunotherapy
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Vacuna EuroEspes EB-101
Ratón APP/PS1
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Vacuna EuroEspes EB-101
Pre-Symptomatic
Onset Mild
Severe
0 5 10 15 20
Preventive Vaccination 2-11 months
Therapeutic Vaccination 10-18 months
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Vacuna EuroEspes EB-101
Analytical Process Antibody titers EB-101 Prophylactic Effects EB-101 Therapeutic Effects AD Neuropathological Markers Immune Response Behavioral changes
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Vacunación Preventiva Placas de β-amiloide
Vacuna
Liposomas
PBS
Vacuna EuroEspes EB-101
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Placas de β-amiloide
PBS
Vacuna
Liposomas
Vacuna EuroEspes EB-101
Vacunación Terapéutica
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DRUGS Metabolism Disease
PH
AR
MA
CO
GE
NO
MIC
S
PH
AR
MA
CO
GE
NE
TIC
S
Cacabelos (2005)
Genetic Polymorphisms
Pharmacokinetics
Absortion
Distribution
Metabolism
Excretion
Pharmacodynamics
Receptors
Ion channels
Enzymes
Proteins
Pathogenic mechanisms
Transcriptomics
Proteomics
Metabolomics
Safety Efficacy
30-90%
variability
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Pathogenic Genes
Drug Metabolism
Drug Transporters
Pleiotropic Genes
Drug Action
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Disease PGx Outcome
Phenotype-A Phenotype-B
Genotype Surrogate markers
Biomarkers
Treatment
Pathogenic genes
Pleiotropic genes
Mechanism of Action
Drug Metabolism
Drug Transporters
Transcriptomics
Proteomics
Metabolomics Disease/Phenotype Modification
Genomics
Substrates Inducers
Inhibitors
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Influence of APOE genotypes on Alzheimer’s disease-related phenotypes
APOE
Beta-Amyloid
Deposition
Lymphocyte
Apoptosis
CSF Tau
NFT
Cytokine - Histamine
Levels
ApoE Levels
Arterial
Atherosclerosis
Brain Function
EEG/FNI
Brain Function
Cognition
Senile Plaques Amyloid Angiopathy
CHO/ApoE
Receptors
Cholesterol
HDL/LDL/VLDL/TG
Plasma & CSF
BAP
Brain Perfusion
CV Hemodynamics Brain Atrophy
Liver Function
GOT/GPT/GGT
Cardiovascular
Function
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APOE Genotype DistributionAPOE Distribution in Hypertension, Diabetes and Dementia
Cacabelos et al., EuroEspes Biomedical Research Center, 2000
Control
Hypertension
Diabetes
Dementia
0% 20% 40% 60% 80% 100%
APOE-2/2
APOE-2/3
APOE-2/4
APOE-3/3
APOE-3/4
APOE-4/4
Cacabelos, Psychogeriatrics (2000)
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Control GDS-3 GDS-4 GDS-5 GDS-6 GDS-7
APOE-2/2 APOE-2/3 APOE-2/4 APOE-3/3 APOE-3/4 APOE-4/4
R. Cacabelos (2005)
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Basal Stimulation Recovery
APOE-2/3
APOE-2/4
APOE-3/3
APOE-3/4
APOE-4/4
Op
tica
l Bra
in T
op
ogr
aph
y
AP
OE
Ge
no
typ
e-R
ela
ted
C
ort
ical
DO
T H
em
ogl
ob
in C
on
sum
pti
on
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R. Cacabelos, Expert Rev Mol Diag (2009)
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CYP2D6-Related Therapeutic Response in Alzheimer's Disease
Cognitive Performance in Extensive (EM), Intermediate (IM), Poor (PM) and Ultra-rapid Metabolizers (UM)
EM-0 EM-1 EM-3 EM-6 EM-9EM-12 IM-0 IM-1 IM-3 IM-6 IM-9 IM-12 PM-0 PM-1 PM-3 PM-6 PM-9 PM-12UM-0 UM-1 UM-3 UM-6 UM-9UM-12
0
5
10
15
20
25
30
35
X
SD
X 21,58 21,57 21,53 21,54 22,66 23,78 21,4 21,67 22,2 22,1 22,5 22,71 20,74 20,65 20,24 19,04 18,57 18,07 22,65 23,02 22,49 21,73 21,34 21,28
SD 9,02 7,46 6,99 5,17 8,09 5,81 6,28 5,58 6,2 6,48 6,39 5,07 6,72 6,52 6,11 5,39 5,52 5,86 6,76 5,67 4,62 5,68 4,99 7,75
ExtensiveMetabolizers
IntermediateMetabolizers
PoorMetabolizers
Ultra-rapidMetabolizers
MMSE Score
Cacabelos et al (2007)
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Food Drug
Nutrigenomics Pharmacogenomics
Outcome
Efficacy Safety
Personalized Nutrition
Personalized Therapeutics
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