dúvidas denucci@dglnet.br arquivo farmacogenômica (eurofarma) site gdenucci

Dúvidas denucci@dglnet.com.br

Arquivo FarmacogenômicaFarmacogenômica

(Eurofarma)(Eurofarma)

Sitewww.gdenucci.com

Dúvidas denucci@dglnet.com.br

Arquivo FarmacogenômicaFarmacogenômica

(Eurofarma)(Eurofarma)

Sitewww.gdenucci.com

PharmacogenomicsPharmacogenomics

Drug Receptor AffinityDrug Receptor AffinityDrug Receptor AffinityDrug Receptor Affinity Drug Targeting Gene ProductsDrug Targeting Gene ProductsDrug Targeting Gene ProductsDrug Targeting Gene Products

Drug ExcretionDrug ExcretionDrug ExcretionDrug ExcretionDrug DistributionDrug DistributionDrug DistributionDrug Distribution

Drug AbsorptionDrug AbsorptionDrug AbsorptionDrug Absorption

Curr Probl Cardiol, May 2003

Apolipoprotein 4

Days Since Randomization(a) Treatment with Placebo

Pro

por

tion

Ali

veNot Not -Carriers-Carriers

N=312N=312

-Carriers-CarriersN=166N=166

Curr Probl Cardiol, May 2003

1.00

0.95

0.90

0.85

0.800 500 1000 1500 2000 2500

Alelos da apo

• apo 2

• apo 3

• apo 4

Simvastatin treatment reduces mortality

• 13% in non apo 4

• 50% in apo 4

Days Since Randomization(b) Treatment with Simvastatin

Pro

por

tion

Ali

veNot -Carriers

N=3014-Carriers

N=187

Curr Probl Cardiol, May 2003

1.00

0.95

0.90

0.85

0.800 500 1000 1500 2000 2500

ACE genotype

Months Follow Up(a)

Tra

nsp

lan

t-fr

ee S

urv

ival

ACE II (N=69)ACE ID (N=154)ACE DD (N=105)

p = 0.04p = 0.04

Curr Probl Cardiol, May 2003

1.00

0.80

0.60

0.40

0.20

0.000 6 12 18 24 30

ACE DD

Months Follow Up(b)

Tra

nsp

lan

t-fr

ee S

urv

ival

Beta Blocker (N=154)No Beta Blocker (N=105)

p = 0.007p = 0.007

Curr Probl Cardiol, May 2003

1.00

0.80

0.60

0.40

0.20

0.000 6 12 18 24 30

Trial DrugEvent Rates (%)

Benefit /100Lack of

Benefit/100Placebo Treated

Hope

APTC

FTT

4S

EPIC

CURE

Ramipril

Aspirin

Thrombolytics

Simvastatin

Abciximab

Clopidogrel

17.8

14

11.5

28

12.8

11.5

14

10

9.6

19

8.3

9.3

3.8

4

1.9

9

4.5

2.2

96.2

96

98.1

91

95.5

97.8

Established Pharmacotherapies With Strong Clinical Efficacy and Percentage of Patients Benefiting and Not

Benefiting With Treatment

Gene Polymorphism

Medications Effect Related to Polymorphism

CYP2C9

CYP2D6

Thiopurine methyl-transferase

CYP3A4

Warfarin, phenytoin

β-blockers, codeine, debrisoquin, flecainide, propafenone, sparteine

Mercaptopurine, thioguanine, azathioprine

Mibefradil

Anticoagulant effect, bleeding risk

β–blocker effect, inadequate pain relief

Safety, efficacy

Safety, efficacy

Selected Examples of Clinically Relevant Polymorphisms Influencing Medication Efficacy and Safety

Gene Polymorphism

Medications Effect Related to Polymorphism

Angiotensin converting enzyme

HERG Potassium channel

KvLQT1

hKCNE2

β2–adrenargic receptor

Enalapril, lisinopril, captopril

Quindine, cisapride

Terfenadine, disopyramide,

mefloquine

Clarithromycin

Albuterol

Renal protection effects, blood pressure, cardiac indices

Long QT syndrome, torsade de pointes

Long QT syndrome

Arrhythmias

Airway responsiveness

Selected Examples of Clinically Relevant Polymorphisms Influencing Medication Efficacy and Safety