Psychopharmacogenetics
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Transcript of Psychopharmacogenetics
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PsychoPsychopharmacopharmacogenomgenomicsics
conceptual reality or awaiting conceptual reality or awaiting dream? dream?
Dr. Swanand S PathakDr. Swanand S Pathak
MBBS MD DACM IDCR MBBS MD DACM IDCR
Dept. of PharmacologyDept. of Pharmacology
JNMC, SawangiJNMC, Sawangi
[email protected]@yahoo.co.in
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Part I Part I ( basic concepts )( basic concepts )
What is pharmacogenomics What is pharmacogenomics Difference between the pharmacogenetics and Difference between the pharmacogenetics and
pharmacogenomics.pharmacogenomics. What is psychopharmacogenomics What is psychopharmacogenomics Historical aspects of pharmacogenomics Historical aspects of pharmacogenomics What are SNPsWhat are SNPs Concept of CYP enzymes and geneticsConcept of CYP enzymes and genetics
Part II Part II ( neuropsychopharmacogenomics)( neuropsychopharmacogenomics)
Psychopharmacogenomics in relation to antideparessants , Psychopharmacogenomics in relation to antideparessants , atipsyachotics and mood stabilizersatipsyachotics and mood stabilizers. .
Psychopharmacogenomics in relation with the drug development Psychopharmacogenomics in relation with the drug development in psychiatry in psychiatry
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Part I Part I
BASIC CONCEPTSBASIC CONCEPTS
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GenomicsGenomics OM – COMPLETE OM – COMPLETE
GENEGENE
GENES GENES
GENOMEGENOME
ICS – STUDYICS – STUDY
GENOMICSGENOMICS
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PharmacoPharmacogenomics genomics
Drugs + genome = health benefit Drugs + genome = health benefit
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PharmacogeneticsPharmacogenetics : study of the : study of the effect of effect of single gene single gene on the response on the response of various drugs of various drugs
Pharmacogenomics Pharmacogenomics : study of the : study of the effect of effect of multiple genes multiple genes on the on the response of various drugs response of various drugs
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PsychoPsychopharmacogenomicspharmacogenomics ::
Study of the effects of variations in Study of the effects of variations in multiple genes on the response of multiple genes on the response of drugs used in psychiatrydrugs used in psychiatry and the and the psychiatric disorders.psychiatric disorders.
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NEED ?NEED ?
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Variability in Drug ResponseVariability in Drug Response
DiseaseDisease Drug ClassDrug Class Rate of Poor Rate of Poor responseresponse
AsthmaAsthma Beta-agonistsBeta-agonists 40-75%40-75%HypertensionHypertension VariousVarious 30%30%Solid CancersSolid Cancers VariousVarious 70%70%DepressionDepression SSRIs, tricyclicsSSRIs, tricyclics 20-40%20-40%DiabetesDiabetes Sulfonylureas, othersSulfonylureas, others 50%50%ArthritisArthritis NSAIDs, COX-2 inhibitorsNSAIDs, COX-2 inhibitors 30-60%30-60%SchizophreniaSchizophreniaVariousVarious 25-75%25-75%
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( lieberman et al N Engl J Med 2005)( lieberman et al N Engl J Med 2005)
Clinical antipsychotic trials of intervention Clinical antipsychotic trials of intervention effectiveness (CATIE) : 18 months effectiveness (CATIE) : 18 months
74% discontinued : lack of efficacy or 74% discontinued : lack of efficacy or tolerability.tolerability.
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CONVENTIONAL DRUG DEVELOPMENT APPROACH
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Scenario Scenario
All patients with same diagnosis
1
2Responders and patients not predisposed to toxicity
Non-respondersand toxic
responders
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This can be improved by
Giving the Right Drug At Right Dose
To the Right Patient At the Right Time
Patient specific selection of medication and their dosage
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““PharmacogenomicsPharmacogenomics” ”
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Pharmacogenomics holds the promise that drugs might one Pharmacogenomics holds the promise that drugs might one
day beday be tailor-madetailor-made for individuals and adapted to for individuals and adapted to each person's own genetic makeup.each person's own genetic makeup.
Environment, diet, age, lifestyle, and state of health Environment, diet, age, lifestyle, and state of health all can all can influence a person's response to medicines, but influence a person's response to medicines, but
understanding an individual's genetic makeup is thought understanding an individual's genetic makeup is thought to be the key to creating personalized drugs with greater to be the key to creating personalized drugs with greater
efficacy and safety.efficacy and safety.
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HISTORY HISTORY
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Important FactsImportant Facts Human genome = 22 chromosome pairs Human genome = 22 chromosome pairs
and 1 pair of sex chromosomesand 1 pair of sex chromosomes
Functional unit of the genome = geneFunctional unit of the genome = gene
2% of genes code for proteins, remainder 2% of genes code for proteins, remainder is structural for DNAis structural for DNA
Entire genome = 3 billion DNA pairs, with Entire genome = 3 billion DNA pairs, with ~30,000 protein coding genes~30,000 protein coding genes
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AlleleAllele
An allele is one member of a pair that An allele is one member of a pair that makes up a genemakes up a gene
2 same alleles are 2 same alleles are homozygoushomozygous (one allele (one allele on each part a pair of chromosomes)on each part a pair of chromosomes)
2 different alleles are 2 different alleles are heterozygousheterozygous
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• DNA sequence of all human beings is 99.9% identical
• Our DNAs differ by 0.1%. • Does it make a difference ?
YES !
0.1% difference translates into 3 million separate “spelling” differences in a genome of 3 billion bases
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Genetic Polymorphism?
A genetic polymorphism is any mutant or variant gene that occurs with a frequency of more than 1% in the normal population
Denoted by : *
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POLYMORPHISM TYPES
SNP INSERTIONS DELETIONS
• Missense • Missense • Missense • Nonsense • Nonsense • Nonsense • Frameshift • Frameshift •
Frameshift
Go to
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Polymorphisms
Single nucleotide polymorphisms (SNP)
……..G G T A A C T T G …...
……..G G C A A C T T G …...
• Most common • Incidence 1 per 300 - 600bp
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Normal
Missense
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Normal
Nonsense
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Normal
Frameshift
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Deleted area
After Before deletion deletion
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Duplicated area
Before duplication
After duplication
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?? MOST MOST IMPORTANTIMPORTANT
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Polymorphisms
Single nucleotide polymorphisms (SNP)
……..G G T A A C T T G …...
……..G G C A A C T T G …...
• Most common • Incidence 1 per 300 - 600bp
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CYP 450CYP 450
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Cytochrome P450 enzyme system Cytochrome P450 enzyme system terminologyterminology
Cytochrome P450 enzyme system Cytochrome P450 enzyme system terminologyterminology
““CYP”CYP” - P450 for all mammalian - P450 for all mammalian speciesspecies
““2”2” - family (17 - 14 human)- family (17 - 14 human) ““C”C” - subfamily (42 in humans)- subfamily (42 in humans) ““9”9” - enzyme/gene (55 genes)- enzyme/gene (55 genes) *2: *2: -Allele pattern-Allele pattern
CYP2C9 *2
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23 SETS OF HUMAN CHROMOSOMES
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Chromosome 10q24.2
CYP2C9 CYP2C9
P M
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Impact of CYP2C9*2 genetic polymorphism on enzymatic activity
C G T Nucleotide # 430
CYP2C9*1
Exon 3
Amino acid #144 Arg Normal enzymatic activity
Nucleotide # 430 T G T
CYP2C9*2
Exon 3
9 Amino acid #144 Cys Reduced enzymatic activity
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What do the CYPs do?What do the CYPs do?
Drug metabolism throughout Drug metabolism throughout the bodythe body
Activate drugsActivate drugs Detoxify substances and Detoxify substances and
activate non-toxic substances activate non-toxic substances into toxic substancesinto toxic substances
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Proportion of Drugs Metabolized by CYP Enzymes
Proportion of Drugs Metabolized by CYP Enzymes
CYP3A4/536%
CYP2C8/916%
CYP1A1/211%
CYP2E14%
CYP2A63%
CYP2B63%
CYP2C198%
CYP2D619%
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Neuro Neuro psychopharmacogenompsychopharmacogenom
ics ics
Part IIPart II
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Consequences of polymorphisms
Drug metabolism Drug transport
Disease Receptor Polymorphisms susceptibility sensitivity
ADR
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Disease susceptibility Disease susceptibility
Alzheimer’s disease : Apo E Alzheimer’s disease : Apo E
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Drug metabolism Drug metabolism
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CYP2D6 Vs Starting dose of nortriptyline
Normal CYP2D6 : 150 mg/day Mutant CYP2D6 : 10-20 mg/day
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CYP2C9 Vs Phenytoin maintenance dose
Genotype Mean dose (mg/d)
CYP2C9 *1/*1 314 mg/d
CYP2C9 *1/*2 193 mg/d
CYP2C9 *2/*3 150 mg/d
(Source: Pharmacogenetics, 2001, 11, 287-291)
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Why diazepam metabolism is slower in Asians compared to Caucasians?
Because Asians have high frequency of mutant alleles CYP2C19
Genotype Allele Diazepam t1/2
caucasiansFM
CYP2C19 *1/*1 20 hours
AsiansPM
CYP2C19 *2/*2 84 hours
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Transport Transport
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Function of P-gp
The human MDR1 encodes a membrane P-glycoprotein that mediates ATP-dependent efflux.
P-gp resides in the plasma membrane and functions as an efflux transporter of a wide variety of natural compounds and dugs
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Receptor sensitivity Receptor sensitivity
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Receptor Sensitivity/Effect
Subjects with Gly 389 have reduced β1 receptor gene
sensitivity to beta-blockers
Arg389Gly
Ser49Gly Subjects with Gly 49 have increased sensitivity to beta-blockers
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Podlowski, et al. J Mol Med 2000;78:90.
Beta-1 Adrenergic ReceptorBeta-1 Adrenergic Receptor
Codon 49 SerGly
Codon 389ArgGly
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Adverse drug reaction Adverse drug reaction
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CYP2C9 polymorphism and phenytoin toxicity
Ataxia, nystagmus, drowsiness, gingival hyperplasia
Genotype : CYP2C9*3/*3
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This girl may develop side effects to
Warfarin Glibenclamide
Acenocoumarol Tolbutamide
Losartan Ibuprofen
Irbesartan Flurbiprofen
Glipizde Diclofenac
All metabolized by CYP2C9 enzyme
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CYP2D6 Polymorphisms and CYP2D6 Polymorphisms and Psychiatric Drug ResponsePsychiatric Drug Response
Increased rate of adverse effects in poor Increased rate of adverse effects in poor metabolizers due to increased plasma metabolizers due to increased plasma concentrations of drug:concentrations of drug:
Fluoxetine Fluoxetine (Prozac(Prozac) death in child attributed to ) death in child attributed to CYP2D6 poor metabolizer genotypeCYP2D6 poor metabolizer genotype
Side effects of antipsychotic drugs occur more Side effects of antipsychotic drugs occur more frequently in CYP2D6 poor metabolizersfrequently in CYP2D6 poor metabolizers
CYP2D6 poor metabolizers with severe mental CYP2D6 poor metabolizers with severe mental illness had more adverse drug reactions, illness had more adverse drug reactions, increased cost of care, and longer hospital staysincreased cost of care, and longer hospital stays
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Pharmacogenomics Information in Pharmacogenomics Information in the Published Literaturethe Published Literature
Zineh I et al. Ann Pharmacother. 2006; 40: 639-44
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Antidepressants Antidepressants
Antipsychotics Antipsychotics
Mood stabilizers Mood stabilizers
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AntidepressantsAntidepressants 119 pharmacogenomic studies reported 119 pharmacogenomic studies reported
CYP 2D6 , CYP 2C19CYP 2D6 , CYP 2C19
PM : more side effects PM : more side effects
UM : more therapeutic effect UM : more therapeutic effect Association with 5 HTR2A , GRIK2 genes.Association with 5 HTR2A , GRIK2 genes.
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Mood stabilizers Mood stabilizers
102 pharmacogenomic studies 102 pharmacogenomic studies reported reported
Association with GRIA2, ODZ4 genes Association with GRIA2, ODZ4 genes decrease efficacy decrease efficacy
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AntipsychoticsAntipsychotics
84 pharmacogenomic studies reported 84 pharmacogenomic studies reported
EPF1 ,NOVA 1 : antipsychotic induced EPF1 ,NOVA 1 : antipsychotic induced parkinsonism parkinsonism
ZNF202 : extrapyramidal side effects ZNF202 : extrapyramidal side effects
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PsychopharmacogenomicPsychopharmacogenomics s
and and
Drug DevelopmentDrug Development
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• An investigative drug showed NO statistically significant effect when given to 400 Alzheimer’s patients,
• A clinically significant response was elicited when patients were stratified according to ApoE subtype
(Richard et al., 1997).
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Tacrine
No statistical significant response
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Genotyped
Tacrine ApoE1
ApoE2
No statistical significant response ApoE3
ApoE4
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ApoE2 ApoE1
Stratify the patients according to genotypes
ApoE4 ApoE3
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ApoE1
Tacrine No statistical
significant response ApoE2
ApoE3
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Tacrine Statistical significant response
ApoE4
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Pre-clinical Gene ExpressionPre-clinical Gene Expression
Toxicogenomics Toxicogenomics
Predict toxicity of candidate compoundsPredict toxicity of candidate compounds Identify mechanisms of toxicityIdentify mechanisms of toxicity
Identify potential biomarkers for Identify potential biomarkers for toxicity or efficacy for future clinical toxicity or efficacy for future clinical studiesstudies
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Phase I studies
Exclude or include specific patients
Normalize genotype frequencies
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Phase II/III studiesPhase II/III studies
Identify genetically-defined groups Identify genetically-defined groups with more pronounced or rapidly with more pronounced or rapidly progressing diseaseprogressing disease
Exclude/include at-risk individualsExclude/include at-risk individuals Stratify studies based on Stratify studies based on
genotypesgenotypes Clinical responseClinical response Risk of adverse eventsRisk of adverse events
Where appropriate, develop drugs Where appropriate, develop drugs for specific groupsfor specific groups
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FDA and PharmacogenomicsFDA and Pharmacogenomics FDA published: “Draft Guidance for FDA published: “Draft Guidance for
Industry: Pharmacogenomic Data Industry: Pharmacogenomic Data Submission” in 2003. (currently under Submission” in 2003. (currently under revision)revision)
Set criteria for Voluntary Genomic Data Set criteria for Voluntary Genomic Data Submission (VGDS)Submission (VGDS)
(http://www.fda.gov/cder/guidance/5900dft.pdf)
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What are the anticipated What are the anticipated benefits of benefits of
Pharmacogenomics?Pharmacogenomics?
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Individualized MedicinesIndividualized Medicines
Pharmaceutical companies will be able to Pharmaceutical companies will be able to create drugs based on the proteins, enzymes, create drugs based on the proteins, enzymes, and RNA and RNA molecules associated with genes molecules associated with genes and diseases.and diseases.
This will facilitate drug discovery and allow This will facilitate drug discovery and allow drug makers to produce a drug makers to produce a therapy more therapy more targeted to specific diseases. targeted to specific diseases. This accuracy This accuracy not only will maximize therapeutic effects but not only will maximize therapeutic effects but also decrease damage to nearby healthy also decrease damage to nearby healthy cells. cells.
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Cost Effectiveness ?
• Phase III trial - CNS product -4500 patients- Cost per patients
$ 8000 - $ 12,000
• Eliminate 10% (Approx 450 subjects) of trial population (Non-
responders) Using
Pharmacogenomic
Save $ 3,60,000 - $5,40,000.
(Murphy , Pharmacogenetics, 2000; 10:1-7)
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Some ethical IssuesSome ethical Issues
Could the development of medicines for Could the development of medicines for specific groups of the population exclude specific groups of the population exclude others? others?
Will the development of unprofitable, but Will the development of unprofitable, but desirable, medicines be neglected?desirable, medicines be neglected?
Who will have access to genetic information Who will have access to genetic information and databases?and databases?
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Research IssuesResearch Issues
• Narrower target population could exclude those
who might also benefit from therapies
• Evaluating therapies in smaller, targeted trials
might miss critical, albeit rare, adverse drug events
Translating
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Social IssuesSocial Issues Will I develop this Will I develop this
disease ten years disease ten years from now?from now?
• • Can I indulge in Can I indulge in unhealthy habits unhealthy habits (e.g., smoking, junk(e.g., smoking, junk
food, not food, not exercising, etc.) if I exercising, etc.) if I don’t have a don’t have a particular disease particular disease susceptibility?susceptibility?
Health Horoscope
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Patient requires Treatment
Examination by the Physician
Genomic testing Traditional investigations
EXPERT SYSTEM
Decision making by Physician, assisted by an Expert System (interactive interpretation)
Prescribes individualized drug treatment
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Tools for prediction Tools for prediction
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Roche AmpliChip: FDA-ApprovedRoche AmpliChip: FDA-ApprovedCYP2D6 , CYP 2C19CYP2D6 , CYP 2C19
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The Next Diagnostic Chips?The Next Diagnostic Chips?
Additional diagnostics are neededAdditional diagnostics are needed::
GeneralGeneral: CYP2C9; CYP3A5; CYP2B6; : CYP2C9; CYP3A5; CYP2B6; MDR-1; UDP Glucuronosyltransferases MDR-1; UDP Glucuronosyltransferases (UGTs); (UGTs); N-acetyltransferases (NATs)N-acetyltransferases (NATs)
OncologyOncology: : thiopurine thiopurine methyltransferase (methyltransferase (TMPT); TMPT);
Thymidilate synthase; Thymidilate synthase; dihydropyrimidine dehydrogenase dihydropyrimidine dehydrogenase (for 5-FU dosing)(for 5-FU dosing)
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S M A R T C A R D
Praveen khairkar97236407611
GENOME(Confidential)
Personalized Medicine: “when?”
Opinion: This sort of card would initially (~2025?) include mostly information related to drug metabolizing enzymes
Around ~2050 it might include an entire individual genome (or at least, few millions SNPs..)
In your wallet by 2025?
Or maybe by 2050?
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Science or Science Fiction ?Science or Science Fiction ?
Unrealistic projections for 2025:Unrealistic projections for 2025:
MostMost medicines will be prescribed medicines will be prescribed according to patient genotypingaccording to patient genotyping
Genomics would allow Genomics would allow full insightfull insight into the biological basis of complex into the biological basis of complex human diseaseshuman diseases
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PGx: Science and Science FictionPGx: Science and Science Fiction
Realistic projections for 2025Realistic projections for 2025Genotyping would allow far smaller Genotyping would allow far smaller rates of adverse reactions for most rates of adverse reactions for most drugsdrugs
In several medical disciplines, In several medical disciplines, genomics would allow far better genomics would allow far better medical treatment medical treatment
(oncology; psychiatry; neurology) (oncology; psychiatry; neurology)
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“Here is my sequence”
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TiPS 24:122-126 (2003)
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Part IPart I
What is pharmacogenomics What is pharmacogenomics Difference between the pharmacogenetics and Difference between the pharmacogenetics and
pharmacogenomics.pharmacogenomics. What is psychopharmacogenomics What is psychopharmacogenomics Historical aspects of pharmacogenomics Historical aspects of pharmacogenomics What are SNPsWhat are SNPs Concept of CYP enzymes and geneticsConcept of CYP enzymes and genetics
Part IIPart II
Psychopharmacogenomics in relation to antideparessants , Psychopharmacogenomics in relation to antideparessants , atipsyachotics and mood stabilizersatipsyachotics and mood stabilizers. .
Psycchopharmacogenomics in relation with the drug Psycchopharmacogenomics in relation with the drug development in psychiatry development in psychiatry
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Conceptual reality or awaiting dream ?Conceptual reality or awaiting dream ?
Definitely a Definitely a conceptualconceptual reality reality
For grass root patients and For grass root patients and practitioners … there is still a long practitioners … there is still a long long way to go …to fulfill the dream long way to go …to fulfill the dream … …
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AcknowledgementsAcknowledgements
Dr. Praveen Khairkar Dr. Praveen Khairkar Dr. Sushil VermaDr. Sushil Verma Dr. Aniket Shukla Dr. Aniket Shukla Dr. Adithan Dr. Adithan Google and Wikipedia Google and Wikipedia
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