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  Presented By:
   Frank Clark
  Beth Nendza
   Pharmaceuticals           Pharmacogenomics
       History                   SNPs
       Body Response to          Cancer/other
        Medicines                  Diseases
       Drug Reactions            Patient Benefits
       Human Genome
       Pharmacogenomics
   Oldest known medical book
   Natives of North and South America
   Aztecs in Mexico
   Aspirin
       Creation of research based pharmaceutical
   What are drugs used for?
       Fight infections
       Reverse a disease process
       Relieve symptoms
       Restore normal functions
       Aid in diagnosis
       Inhibit normal body processes
       Maintain health
   How is it administered?
       Orally
       Intravenously
       Intramuscular
       Subcutaneous
       Rectal
   How do medicines work in the body?
       Administration of medications
       Absorption into blood stream
       Distribution throughout the body
            Effected by:
                 Blood supply
                 Organ/Compartment size
                 Permeability of tissue membranes
                 Binding of drug to various components of blood and
            DRUG REACTIONS
   Journal of American Medical Association
   Pharmaceutical companies can’t predict
    drug reactions
       All medications come with warning labels
   Why do some people experience drug
    reactions while others don’t?
       Dose-related effect
       Food/Drink in stomach
       Biological Variability
       Age
            Fat content increases
            Liver metabolism
            Kidney excretion
            Blood protein decreases
            Increasing sensitivity
   Circadian Rhythm
       Body temperature varies 2-4C
       Pulse and blood pressure
            Not many drugs effected
   Obesity
       Drugs that work with a build up of time
   Genetic Factors
       Genes are very similar
            Ten fingers, etc.
       Genes do have subtle differences
            Makes you, you!
            These differences cause differences in your bodies
                  Medications interact with the body’s proteins
                     Therefore, people will react differently to medications

                     This is why people suffer from nausea and even death

                       from medicine toxicity
   What is the HGP?
       Identify all the 30,000 genes in human
       Determine the sequences of the 3 billion
        chemical base pairs that make up human
   How does HGP tie into
   Imagine 50 years down the road
       Gene test for what medication is suitable
        for you
       Pharmacists being able to look at your
        genome and help figure out what OTC
        drugs are best for you
   What is pharmacogenomics?
       Pharmacogenomics is the study of how an
        individual’s genetic inheritance affects the body’s
        response to drugs.
       Pharmacogenomics= Pharmaceuticals + Genomics
            Holds the promise of individual made drugs
            Keeping in mind that other factors effect drug reaction
                  Pharmacogenomics is believed to be the key to creating
                   medications that will reduce the harmful side effects of
      polymorphisms (SNPs)
   Markers that will indicate
    connection between drug
    response and genetic
   Definition: variation in DNA
    at a single base that is found
    in at least 1% of the
   Help understand and treat
    human diseases
   Help scientists find the
    position on a chromosome
    where a particular
    susceptibility gene is located
   SNP Consortium:
      non-profit organization,

      in the process of publishing a high-density

       SNP map of the human genome.
      Goal: map 300,000 SNPs
   Orchid Bio Sciences (Princeton, N.J.)
       Collaboration with SNP Consortium (two projects)
       Confirms many of the SNPs in the public database
       Confirmation of SNP: pull together an ethnically diverse
        panel of DNA, assay for presence or absence of that SNP
   Allele frequency determination
       Allele: alternative form of a gene
       What is the frequency of occurrence of that SNP within the
        members of ethnically diverse populations?
       Formula: # of times SNP appears within each of the
        populations/total = allele frequency
   Sequenom (San Diego)
       Mass spectrometric methods to study SNPs
        (self validating instrument)
       Scientists focusing on the changes in the
        frequency of SNPs as the population ages
    Cancer and Other Diseases
   Cancer and Pharmacogenomics
       Pharmacogenomics more crucial to treatment of
        cancer as opposed to other diseases
   Current Cancer Therapies
       suffer form low efficacy rates
       high rates of toxicity
       adverse effects
       significant consequences of incorrect therapy
   Variagenics Inc.
       company that wants to use pharmacogenomic
        pathway approach to develop cancer therapeutics
   Markers
       SNPs and haplotyping
       Haplotyping: identifies the groups of
        polymorphism that occur together in each gene.
   Additional genetic markers
       efficacy of cancer treatment depends on genetic
        properties of the tumor
   Loss of heterozygosity
       Measure of chromosomal loss
       Early phases of tumor formation (DNA are
       Affects gene copy number and function
   Example:
       patient’s cells contain
        two alleles for drug
       1 highly expressed and 1
        with low expression
       LOH leaves low
        expression allele
       Drug target will be
        present at small amounts
        in the tumor
       Less target protein to be
   Study (Cairncross et al., J. Natl.
    Cancer Institute, 1998)
       100% (24/24) of oligodendrogliomas
        carrying specific markers for LOH
        responded well to chemotherapy
       25% (3/12) lacking the marker responded
   mRNA Expression
       expression levels of
        specific genes, good
        predictor of response to
       comparison of mRNA
        expression patterns of
        responsive and
       expression profiling:
        mRNA levels measure
        to determine which
        genes are turned on at
        a given time
   Methylation
       Tumors can
        undergo DNA
       Occurs at CpG
        island in the
        promoter regions of
        specific genes
       Poor expression of
        genes in the region
       Methylation Analysis (cont.)
        Methylation could affect how tumor
         respond to drug treatment, if genes are
         related to drug action
        Comparison of normal vs. methylation
         patterns in tumor tissue and non
         responsive and responsive patients
        Goal: investigate the significance of
         methylation patterns to drug response
   Heart Disease
       High salt diet may result in high blood
       Coronary artery disease and stroke
       reduce salt intake
       Problem: everyone cannot reduce their
        salt intake by eating a low sodium diet
       Solution: find genes that link high blood
        pressure to high sodium
   University of Minnesota study
    (American Journal of Hypertension)
       Correlating variation in angiotensin-converting
        enzyme (ACE) gene with sodium sensitivity
       24/35 patients with high blood pressure were
        sodium sensitive
       three alleles of ACE correlated with sodium
       sodium resistant allele: 25% were sodium
       71% with sodium sensitive allele and 83% with
        both alleles were sodium sensitive
   Other Applications
       Pain Management
       Environmental Medicine
       Depression
                Patient Benefits
1. More Powerful Medicines

2. Better, Safer Drugs

3. Accurate Methods of Determining Appropriate Drug Dosages

4. Advanced Screening for Disease

5. Better Vaccines

6. Improvements in Drug Discovery and Approval Process

7. Decrease in Cost of Health Care

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