DESIGNER DRUGS Presented By: Frank Clark Beth Nendza

OVERVIEW Pharmaceuticals History Body Response to Medicines Drug Reactions Human Genome Project Pharmacogenomics SNPs Cancer/other Diseases Patient Benefits

HISTORY Oldest known medical book Natives of North and South America Aztecs in Mexico Aspirin Creation of research based pharmaceutical companies

HOW DOES THE BODY RESPOND TO MEDICATIONS? 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 tissues

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 (Prozac)

Genetic Factors Genes are very similar Ten fingers, etc. Genes do have subtle differences Makes you, you! These differences cause differences in your bodies proteins 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

HUMAN GENOME PROJECT What is the HGP? Identify all the 30,000 genes in human DNA Determine the sequences of the 3 billion chemical base pairs that make up human DNA How does HGP tie into Pharmaceuticals?

PHARMACOGENOMICS 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 medication

Single-nucleotide polymorphisms (SNPs) Markers that will indicate connection between drug response and genetic makeup Definition: variation in DNA at a single base that is found in at least 1% of the population Help understand and treat human diseases Help scientists find the position on a chromosome where a particular susceptibility gene is located (Reeves)

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 (Rakestraw) 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 lost) Affects gene copy number and function

Example: patient’s cells contain two alleles for drug target 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 inhibited

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 Analysis expression levels of specific genes, good predictor of response to chemotherapy comparison of mRNA expression patterns of responsive and unresponsive expression profiling: mRNA levels measure to determine which genes are turned on at a given time

Methylation Analysis Tumors can undergo DNA hypermethylation 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 pressure 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 sensitivity sodium resistant allele: 25% were sodium sensitive 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