* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Pharmacogenomics and nutrigenomics
Survey
Document related concepts
Psychedelic therapy wikipedia , lookup
Compounding wikipedia , lookup
Orphan drug wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Drug design wikipedia , lookup
Psychopharmacology wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Drug discovery wikipedia , lookup
Pharmacognosy wikipedia , lookup
Theralizumab wikipedia , lookup
Neuropharmacology wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Prescription costs wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Transcript
Envirenmental factors + - Biological response Genetic factor Pharmacogenomics and nutrigenomics; Gene-environment interactions Orsolya Lang MD. PhD. ED 2017 To treat or not to treat? Drug +G Effect Drug + G’ Adverse effect Adverse effect: 'A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function’ (WHO 1972) Adverse drug reactions (ADR) are responsible for 5-10% of hospital admissions in the US and Europe. Traditional Medical Treatment Individual response: Variation in therapeutic response Different side effects, adverse reactions Mainly (60- 80%) caused by genetic variation Major Drugs Ineffective for Many … … and harmful to some. What is worst? Adverse drug responses are included In USA: >100,000 death/year EU: 10% of hospital admission To treat or not to treat? To Treat but Apply Personalized or Tailored treatment Fit the dose to the patient Or consider the alternative treatments Many factors influence the effective dose Genes Intrauterine environment Age Epigenetic factors Physical activity Disease Drug interaction Liver/Kidney function Intestinal flora Cyrcadian rhythm etc. … The therapy is optimal when all are considered Something new or something old? ‘right treatment for the right patient at the right time' - has been practiced for millennia. 5th century BCE Pythagoras - excitement about his mathematical pursuits overcome by a terrible depression. Hipoccrates’ treatment doled out is precise to Pythagoras, including changing his dietary habits, a temporary spate of abstinence, and a harsh purging of his bowels. Following treatment, Pythagoras is better. Only phrase to capture what is happening in our time http://www.medicinenet.com/script/main/art.asp?articlekey=15313 Sykiotis et al. 2005 Pharmacogenomics Smaller effect; multiple variant Pharmacogenomics Pharmacogenetics Large single variant effect Single gene Small number of genes The study of genetic basis for variability in drug response Complex biological pathway Whole genome Use of genetic information to guide the choice of drug and dose on an individual bases Pharmacogenetics versus pharmacogenomics • Pharmacogenomics: The study of how variations in the human genome affect the response to medications. Pharmacogenomics combines traditional pharmaceutical sciences such as biochemistry with annotated knowledge of genes, proteins, and single nucleotide polymorphisms. http://www.medicinenet.com/script/main/art.asp?articlekey=15313 Pharmacogenomics could cause changes in: Pharmacokinetics: the action of the body to the bioavailability of drugs over a period of time Pharmacodynamics: effects of the drug to the body Idiosyncrasy: not expected side effects How does genetic variation affect drug effect? Genetic polymorphisms or variants Pharmacokinetic (PK) Pharmacodynamic (PD) Receptors Absorption Distribution Excretion Metabolism ADME Immune Ion channels Enzymes Pharmacokinetics and Pharmacodynamics Effect vs concentration Concentration vs Time Effect vs Time http://www.nature.com/ijir/journal/v19/n3/fig_tab/3901522f2.html ADME Over genetic factors: Liver/Kidney function Intestinal flora … Drug Absorption Multidrug resistance protein1 (MDR1, P-gp) • Genotype Digoxin plasma level G/G2677 C/C3435 67.6% +/4.3%, G/T2677 C/T3435 80.9% +/8.9%, T/T2677 T/T3435 87.1% +/8.4%, Digoxin-cardiotonic, smal therapeutical window Exon26 mutation->lower MDR1 expression-> greater absorption> higher plasma digoxin level Pharmaceutics 2010, 2(1), 61-77 Kazuya et al. Drug Metab Pharmacokinet 23(4) 2008 Kurrata et al. Clin Pharmacol Ther. 2002 Aug;72(2):209-19. Drug Metabolism Detoxification: chemical modifications, which increase the speed of excretion of a drug Phase I enzymes e.g. Cytochrome P450 - chemical modifications, which change the polarity of the molecule Phase II enzymes e.g. N-acetyl-Transferase, Glucuronyltransferase, Glutatione-transferase Conjugation: - binding a very polar molecule to the drug Phase I: Cytochrome P450 enzymes (CYP) Flavin monooxygenases (FMO) Monoamine oxidases(MAO) Esterases, including carboxylesterases (CEs), cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)) and paraoxonase (PON) Aldehyde oxidase (AO) Aldehyde dehydrogenase (ALDH1A1) Aldo-keto reductases (AKR) Phase II: UDP-glucuronyltransferases (UGT) Sulphotransferases (SULT) N-Acetyltransferases (NAT) Glutathione S-transferases (GST) Evans and Relling (1999). Science, 286, 487-491 Phase I metabolism (oxidation by CYP450s) Over 1000 CYP450 enzymes identified (50 active enzymes in human). Expressed mainly in liver. • Multiple alleles with different frequencies in different ethnic groups • P450 enzymes oxidize drugs or other xenobiotics in order to: 1. increase polarity, and enhance excretion (decrease resorption in distal nephron) 2. convert to substrate for phase2 metabolism • RH + O2 + NADPH + H+ • CYP450 ROH +H2O +NADP+ CYPs are involved 92% of drug metabolism Cytochrome P450 polymorphism CYP 1A2 individual: fast, medium, and slow turnover of caffeine CYP 2B6 missing in 3-4 % of the caucasian population CYP 2C9 deficit in 1-3 % of the caucasian population CYP 2C19 individuals with inactive enzyme (3-6 % of the caucasian and 1520 % of the asian population) CYP 2D6 poor metabolizers in 5-8 % of the european, 10 % of the caucasian, and <1% of the japanese population. Over expression (gene duplication) among parts of the african and oriental population. CYP 3A4 only few mutations UM. Zanger, M Schwab Pharmacology & Therapeutics 2013 Drug Metabolism A. Poor metabolizer B. Intermedier metabolizer C. Extenzive metabolizer D. Ultrarapid metabolizer ___ Normal Plazma szint …… Polimorfic Plasma level (c) /time (t) Plasma concentration depending on genetic variants in the population Plasma concentration Genetic Polymorphism Based on Drug Metabolizing Ability Cytochrome P450 polymorphism • 62 year old patient with bilateral pneumonia, fiver, cough • Creatinine: 2,0 mg/dl • Part of therapy: Clarithromycin, Codein Cytochrome P450 polymorphism After four days patient is in coma, symptoms show morphine toxification He is receiving Naloxon (antimorphine) – he feels better Metabolite (ug/L) in the urine Patient (ug/L) Normally after codein therapy (ug/L) Codein 114 <75 Morphine 80 <10 Morphine-6 glucuronide 136 <13 Morphine-3 glucuronide 580 <70 Cytochrome P450 polymorphism Codein 10% CYP2D6 Morphine 90% CYP3A4 Norcodeine Codeine-6-glukuronide Analgesic effect Inactive metabolites Cytochrome P450 polymorphism Genotypization: 4 copies of CYP2D6 gene Codeine 10% CYP2D6 CYP2D6 CYP2D6 CYP2D6 90% CYP3A4 Clarithromycine Morphine toxification Norcodeine Codeine-6-glucuronid Drug metabolism-phase II enzymes Tuberculosis treatment -> e.g. Izoniasid Inactivated by NAT1 and 2 (N-acetyl-transferase) NAT2 variants Acetylator phenotype NAT2*5A/N AT2*5B Slow NAT2*5A/N AT2*6A Slow Hepatotoxicity, hepatitis NAT2*5B/N AT2*5B Slow Hepatotoxicity, hepatitis NAT2*5B/N AT2*6A Slow Hepatotoxicity, hepatitis NAT2*6A/N AT2*6A Slow Hepatotoxicity, hepatitis NAT2*4/NA T2*5B Intermedier - NAT2*4/NA T2*6A Intermedier - NAT2*4/NA T2*4 Fast Drug resistance Side effect Frequency of fast acetylators in the population Hepatotoxicity, hepatitis Population Canadian eskimos Frekvency % 95-100 Polinesian 93 Japanese 90 German 43 Czechs 40 Egyptian 18 Hungarian 43 Drug Elimination Mrp2 is the main determinants for rapid elimination of methotrexate and its toxic metabolite 7hydroxymethotrexate in vivo A mutation in mrp2 could be associated with impaired methotrexate elimination Liver toxicity, hepatocarcinoma Mol Cancer Ther 2009;8(12):3350–9] Methotrexate: autoimmun diseases, cancer Drug receptor targets and their effect β2-Adrenoceptors Asthma bronchiale and β2 agonists • 16% of population is homozygote for β2 Adrenozeptor in Position 16 (Arg/Arg) • Asthmatic patients with Arg/Arg-allele do not tolerate β2-Agonists • it can be even worse, and the side effects could be present also after one week! The morning peak flow increased in salmeterol-treated patients with the glycine/glycine genotype, but declined in the arginine/arginine patients compared with placebo, suggesting that the arginine/arginine patients taking a LABA (long-acting beta agonists) would experience an adverse effect in their morning peak flow. Asthma Guidelines and Effective Utilization of Long-Acting Beta-Agonists Role of serotonin transporter polymorfism in therapy Serotonine transporter polymorphism 2 alleles: „s” and „l” Mutation in promoter region S alleles: transcription Higher chances for mood disorders SSRIs (selective serotonin reuptake inhibitors) acts slower . Gressier F et al..Psychiatr Genet. 2009 Aug;19(4):195-200 Warfarin: Significant Problems for Rats! Warfarin: Significant Problems for Humans! • Ranks #1 in total mentions of deaths for drugs causing adverse events (from death certificates) • Ranks among the top drugs associated hospital emergency room visits for bleeding • Overall frequency of major bleeding range from 2% to 16% (versus 0.1% for most drugs) • Minor bleeding event rates in randomized control trials of new anticoagulants has been as high as 29% per year. Pharmacokinetic and Pharmacodynamic changes Warfarin pharmacogenetics Warfarin pharmacogenetics Warfarin anticoagulant blocks VKORC1(Vitamin K epoxid reductase complex subunit1) Warfarin is metabolized in the liver by CYP2C9 How Does the Warfarin Levels Depend on the Two Enzymes – CYP2C9 & VKORC1? PK PD How we can determine the optimal dose of warfarin? How the therapeutic effect can be measured? Why Maintaining Warfarin Therapeutic Range is Critical Optimal dose provide an INR (International Normalised Ratio )2.0-3.0 European Atrial Fibrillation Trial Study Group, N Engl J Med 1995;333:5-10. Several common CYP2D6 alleles are comprised of combinations of 3 or more polymorphisms gene is deleted (3–5% allelic frequency worldwide) gene duplications with from 2– 12 tandem copies, (allele frequencies range from about 1 to about 30%, depending on the population) More than 80 polymorphisms within the coding and promoter regions are known: SNPs, In/Dels, repeats, and gene conversion events 41 Nature Reviews Drug Discovery 3, 749-761 (September 2004) Affects of different genetic variations of CYP2D6 Poor metabolizers: Drugs are metabolized very slowly, so they may accumulate to toxic concentrations Prevalence of poor metabolizers Europian poor metabolizers 20-30 million Ultrarapid metabolizer : (1% to 2%) Unusually high rate of drug metabolism. Drugs may not reach therapeutic concentrations, (drugs may be ineffective at standard dosages). Amplification Europian ultra rapid metabolizers 15-20 million 42 http://www.avma.org/onlnews/javma/oct08/081015q.asp Estimated Warfarin Dose (mg/day) Based on Genotypes Frequency of VKORC1 Alleles in Various Populations Sconce et al. Blood 2005, Yuan et al. Human Mol Genetics 2005, Schelleman et al. Clin Pharmacol Ther 2007, Montes et al Br J Haemat 2006 Warfarin pharmacogenetics INFINITI™ 2C9 & VKORC1 Multiplex Assay for Warfarin Ha az INR 2,0-nél kisebb, nem elégséges a trombózissal szembeni védő hatás, míg az INR 3,0 fölött fokozott a vérzésveszély http://www.warfarindosing.org/Source/Home.aspx INR international normalized ratio; protrombin idő PTtest/PTnormal Idiosyncrasy: not expected side effect Drug intake causes side effects which can not be explained with the pharmacodinamic effects of the drug or with the dose Genetic variations in genes coding for proteins, which are not in the drug target or pharmacokinetic pathways, but could cause side effects Affected organs are usually liver (liver toxicity) or skin (pseudoallergy) e.g. Chloramphenycol (antibiotics); aplastic anemia ( in case of oral administration affecting 1 in 24,000–40,000) FDA – List of the Drugs with pharmacogenomic Biomarkers 238 rows in the table (not as many molecules e.g warfarin 3 rows) The winner area is oncology, Anesthesiology, infectious dieases with dental relevance as well CYP gene family is the most frequent https://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm Indication of Cevimeline ? Cevimeline EVOXAC™ Capsules (cevimeline hydrochloride) Cevimeline is indicated for the treatment of symptoms of dry mouth in patients with Sjögren’s Syndrome. PD: It is a cholinergic agonist which binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts. PK: … Metabolism: Isozymes CYP2D6 and CYP3A3/4 are responsible for the metabolism of cevimeline. After 24 hours 86.7% of the dose was recovered (16.0% Unchanged, 44.5% as cis and trans-sulfoxide, 22.3% of the dose as glucuronic acid conjugate and 4% of the dose as Noxide of cevimeline). Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate and eliminated. Cevimeline did not inhibit cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. How does PG change the medicine? Pharmacogenomics in drug development I. Current existing therapies only hit about 400 different drug targets There are at least 10 times more drug targets The identification of NEW DRUG TARGETS can significantly be accelerated by the new high throughput genomic methods Genomic methods can be hypothesis-free 51 Pharmacogenomics in drug development II. Adverse effects Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal. The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%. Fatal adverse drug reactions account for approximately 3% of all deaths in the general population. (Wester et al. 2008) Adverse drug reaction (ADR) are responsible for 5-10% of hospital admissions in the US and Europe, Lead to the withdrawal of 4% of new medicines. (Ingelman-Sundberg 2005) 52 Br J Clin Pharmacol. 2008 April; 65(4): 573–579. Effects of about 20% of the drugs on the market are influenced by polymorphisms in genes coding for enzymes responsible for the degradation of the drugs. 53 54 Drug development – Preclinical phase Pharmacogenomics Pharmacogenomics useful in target indentification Allen D. Roses Nature Reviews Genetics 5, 645-656 (September 2004) Drug development - Clinical trial How are doses are determined? Clinical development Clinical trial Non- responder Potential responder Hyper responder Allen D. Roses Nature Reviews Genetics 5, 645-656 (September 2004) 59 24th of December 2004 …what many thought would not happen has already happened To detect CYP 2D6 and 2C19 variability How does it work? PCR Detection 1.DNA Isolation 2.PCR amplification of the genes. 3.Fragmentation and labeling of the PCR productc 4.Hybridization and staining on the AmpliChip DNA microarray. 5.Scanning the chip. 6.Data analysis. Advantage of pharmacogenomics To predict a patient’s response to drug To develope customized prescriptions To minimize or eliminate adverse evenets To improve efficacy and patient compliance To improve rational drug development Pharmacogenetic test need only be conducted once during the life time To improve the accuracy of determining appropiate dosage of drugs To screen and monitor certain diseases To develop more powerful, safer vaccines To allow improvements in drug discovery and development Nutrigenomics Nutrigenomics, nutrigenetics „Let food be thy medicine and let thy medicine be food.” Hippocrates Genes Nutrigenomics Nutrigenetics Investigates complex gene-nutrient interaction on genome level Investigates interaction with genetic background Nutrients Both healthy and unhealthy subjects belongs to target population 66 The Pharmacogenomics Journal (2003) 3, 191–193 Importance of nutrigenomics 1. Malnutrition could cause health problems or disease 2. Symptomps of many genetic diseases could be minimized by proper diet 3. Food and food additives have direct effect on gene expression 4. The effect of food depends on the genetic background 5. Healthy nutrition is part of prevention in many diseases 6. Part of the approach of nutrigenomics involves finding markers of the early phase of diet related diseases; this is the phase at which intervention with nutrition can return the patient to health. Transcription factors involved in nutrient –gene interactions 68 Soya-derived phytoestrogens • • • • • Genistein, daidzein, coumesterol and equol binds to ER-and ER- Modulates cell proliferation, growth, differentiation Antioxidant, antiangiogenic molecule Reduce risk for hormone-related cancers such as breast cancer, uterine cancer and prostate cancer Reduce the symptoms of menopause by mimicking estrogen 69 Example of polimorphism-dependent action of phytoestrogenes ERß Promoter SNP (-13950 T/C) ERα (Ex1-192G>C ) In subjects with this polimorfism, the chances of prostate cancer are increasing with phytoestrogen administration Nutr Cancer 2006, 56 (1):31-39 . Chae et al. PLoS One. 2009 Aug 5;4(8):e6523 TT-no correlation with phytoestrogenes TC, CC: the chances of prostate cancer are decreasing with phytoestrogen administration 70 Prostate. 2006 Oct1;66(14):1512-20 PLoS One. 2009 Aug 5;4(8):e6523. Metabolic-diseases and nutrigenetics Disease Symptoms Genetic polymorphism Diet Lactase persistance Diarochea, vomitus MCM6 Lactose-free diet Phenylketonuria Mental problems Phenilalaninehidroxilase (PAH) Phenilalanine-free diet Galactosemia Letargia, yellow skin, sepsis Galactose metabolism (GALE, GALK1 and GALT) Galactose-free diet Alkaptonuria Arthritis, Dark spots on the sclera Homogentisinaciddioxigenase (HGD) Vitamin C rich diet Coeliakia Ulcus, abdominal pain HLA genes Gluten-free diet Bassen-Kornzweg Syndrome Off-balance, muscle weakness, problems with vision Mikrosomal triglicerid transfer protein (MTP) Vitamin (A, D, E) and non-saturated fatty acids from diet 71 Lactase persistence At birth lactase enzyme activity is high and with age it is reduced. The genetically programmed hypolactasia is physiological and too much lactose in adulthood could cause symptoms of lactose intolerance . Lactase persistence is the continued activity of the enzyme lactase in adulthood. Lactase activity with age birth suckling childhood adulthood 72 Global-spread of lactase persistence • In Europeans the percentage of lactose persistence is high • It could be explained with the fact that lactose persistence is typical to those nations where milk is used frequently in diet Milk: 1/ Source of nutrients 2/ source of water (for e.g. in the desert ->Tuaregs) 3/ Source of Ca +2 (In Scandinavia ->Vitamin D ) 4/ Milk is rich in riboflavine (flavin deficiency gives protection against Malaria-> in Malaria affected regions the % of lactose persistence is very low (South-East Asia) LCT*P (lactase persistence) 73 Lactase persistence The level of lactase enzyme is regulated by MCM6 gene which is upstream from LCT promoter C/T(-13910) substitution (autosomal dominant) shows correlation with lactose persistence MCM6-minichromosome maintenance complex component 6 n. b. Lactose intolerance is not the same as lactose persistence. It is an autosomal recessive enzimophaty. These patients can not process lactose at all. Enattah et al. (2002) Nature Genet. 30, 233-237 Phenylketonuria (PKU) Inherited (AR) disorder, that increases the level of phenylalanine in the blood Penylketonuria Symptoms: Mental retardation, schizoid personality Hipertonic muscles, hyperactive reflexes Problems in melanin synthesis Phenylketonuria (PKU) PKU is not curable. However, if PKU is diagnosed early enough, an affected newborn can grow up with normal brain development by managing and controlling phenylalanine ("Phe") levels through diet, or a combination of diet and medication. PKU-test: 3-4 days after birth Guthrie test - B. Subtilis growing capacity is higher in the presence of blood full of PHE Vitamin D receptor (VDR) – osteoporosis-coffein RFLP of VDR (TT, Tt, tt) • Association: osteoporosis (tt: spinal bone weight ) • Depends from diet – Ca2+ (decreases the risk) – Coffein (increases the risk) >300mg coffein/day <300mg coffein/day Rapuri et al. Am J Clin Nutr, 2001 78 ~ 2 cup of coffee Interactions of genes and environmental factors G Ph G’ Ph G’+ E + E Ph’ Favism (Ph’) • Vicia fava (Bean) = E • Induces haemolysis (G6PD defficiency= G’) • G6PD NADPH (H2O2 reduction) • X recessive inheritance Favism • More frequent in territories smitted with malaria • Inducer drugs are (E): - anti-malaria drugs (1950), - sulfonamides - chloramphenicol - aspirin • Allels (376A (202G (563C G) normal enzyme A) activity enzyme T) activity Fatal Smoking-genome interactions 82 Genomic background of smoking • Heritability: 60%. • D2 dopamine receptor gene (DRD2,11q23), A1 allele is associated with stressinduced cigarette craving. 83 Arg16 of the adrenergic β2 receptor gene (ADRB2), had a significantly increased the risk of asthma in smokers 84