Guest guest Posted January 24, 2011 Report Share Posted January 24, 2011 Respected members, Pharmacogenetics involves the study of single gene mutations and their effect on drug response. The term pharmacogenomics is much broader and it involves surveying the entire genome to assess several determinants of drug responses. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 24, 2011 Report Share Posted January 24, 2011 Genotype is the genetic constitution of an organism (specific set of alleles are inherited at a locus) Phenotype is the observable biochemical or physiological characteristics of the expression of the gene. There is association between the presence of a certain mutations (genotype) and the resulting physical trait, personality, abnormality or pattern of abnormalities (phenotype). Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 25, 2011 Report Share Posted January 25, 2011 Respected members, Some basic concepts are, - Three billion base pairs in human genome - These bases in the DNA form the genotype of an individual. - Genotype is responsible for the expression of phenotype. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 25, 2011 Report Share Posted January 25, 2011 If mutation of gene occur i.e. permanent, heritable change in the genetic sequence subsequently phenotype may also change, but it is not compulsory that every mutation will be expressed phenotypically. Mutations could be due to: - Single base substitution - Insertions or deletions - Chromosomal mutations Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 26, 2011 Report Share Posted January 26, 2011 Respected members, Variations in the DNA sequence that is present at an allele and is with frequency of & #8805;1% in a human population. It can be SNPs(Single nucleotide polymorphism) or INDELS (Insertion, deletion) SNP occur when a single nucleotide (A,T,C,or G) in the genome sequence is altered, e.g., AAGGCTAA to ATGGCTAA There is approximately one SNP per 1000-2000 base pairs. SNPs exist every 100 to 300 bases along the 3-billion-base human genome. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 26, 2011 Report Share Posted January 26, 2011 SNPs Comprise 90% of all human genetic variation. They are found in both coding (i.e., gene) and noncoding regions of the genome. Most of the SNPs are situated in the intron(noncoding) part of the DNA. So usually they have no effect on cell function, but some could predispose people to disease or influence their response to a drug. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 26, 2011 Report Share Posted January 26, 2011 Variations in the DNA sequence that is present at an allele and is with frequency of & #8805;1% in a human population Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 26, 2011 Report Share Posted January 26, 2011 Respected members, There are 2 main mechanisms for altered drug response. 1. Pharmacokinetic 2. Pharmacodynamic Pharmacokinetic variation is at level the transport and metabolism. a.Transport--in the past 17 years have pharmacologists became fully aware of the impact of transmembrane drug transporters on the uptake of drugs from the gut into the human body and from the circulation into the target tissues and into the metabolizing and eliminating organs. This carriermediated transmembrane transport becomes particularly important in molecules with larger molecular diameters Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 26, 2011 Report Share Posted January 26, 2011 Respected members, Some substrates for P-gp are & #61591; Anticancer drugs-Actinomycin D, Vincristine. & #61591; Cardiac drugs- Digoxin, Quinidine. & #61591; HIV Protease inhibitors- Ritonavir, Indinavir. & #61591; Immunosuppresants- Cyclosporine, Tacrolimus & #61591; Antibiotics- Erytromycin, Levofloxacin Lipid Lowering agents- Lovastatin, Atorvastatin Regards, Dr. Amruta Dawari JR1 Dept. of Pharmacology, GMCH, Nagpur. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 Respected members, Some of the best studied metabolizing enzymes in relation to altered drug responce are - & #151;Cytochrome P450 & #151;-N-acetyl transferase isoenzyme & #151;-UDP glucuronoyl transferase & #151;-Methyl transferase Regards, Dr. Amruta dawari JR1,Dept of Pharmacology GMCH,Nagpur Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 Respected members, CYP 450 are most important & major metabolizing enzymes. There is large Intra and Interspecies variability. There are - 12 families of CYP 450 in mammels - 30 families of CYP 450 in humans The code is same for genes which codes for protein CYP 1 – CYP 4 are mostly used for metabolism of various drugs Same drug may be metabolised by two Iso-enzymes e.g. & #61607; Imipramine Hydroxylation occurs by CYP 2D6 & #61607; Imipramine Demethylation occurs by CYP 1A2, CYP 2C19 Dr. Amruta Dawari JR1 Dept. of Pharmacology, GMCH, Nagpur Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 Respected members, CYP 3A4 metabolize 50% of all drugs & CYP 2D6 metabolize 20% of all drugs. Unlike other P450 (e.g. CYP 2D6) there is no evidence of deletion/null allele for CYP 3A4. Variance in coding region of CYP 3A4 occur at allele frequency of less than 5% & appear as heterozygous with wild type allele. These coding varicosity may contribute to, but are not likely to be major cause of interindividual difference of CYP3A4 dependent clearance. There is need to further explore CYP 3A4 polymorphism and it's functional impact. Dr. Amruta Dawari JR1 Dept. of Pharmacology, GMCH, Nagpur Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 Respected members, Some of the mutant alleles of CYP 2D6*1 are: *1XN,*2XN which show increased enzymatic activity. *3,*4,*5,*6 which show absence of enzyme. *9,*10,*17 show decreased enzyme activity. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 Substrate for CYP 2D6 are, clonidine, codeine, promethazine, propranolol, clozappine, fluoxetine, haloperidol, amitryptiline. Mutant alleles of CYP 2C19*1 are *2, *3, *4, *5, *6, *7, *8 which show absence of enzye & substrates for this enzyme are proguanil, imipramine, ritonavir, nelfinavir, cyclophosphamide Mutant alleles of CYP 2C9*1 are *2, *3, *4, *5, *6 which sow reduced activity of enzyme & substrate for this enzyme are warfarin, losartan, phenytoin, tolbutamide. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 NAT2 (n-acetyl transferase 2)show considerable heterogeneity worldwide Eg. Slow acetylator phenotype frequency is 50% in American whites and Blacks 60-70% in North Europeans 5-10% in Southeast Asians Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 1.TPMT: 6-Mercaptopurine, 6-thioguanine, azathioprine 2.Dihydropyrimidine dehydrogenase (DPD) 5-Fluorouracil, capecitabine 3.Uridin diphospho-glucuronic acid transferase type (1A1)UGT1A1: Bilirubin, irinotecan 4.Vitamin K epoxide reductase (VKORC1): Warfarin, acenocoumarol, phenprocoumon 5. NAT (NAT 2) :INH, Hydralazine,Sulfonamides,Procainamide Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 Respected members, Here are some examoles of pharmacodynamic variations of drug response. There are genetic polymorphisms in the gene coding for the beta1 adrenergic receptor (ADRB1) and in that coding for the beta2 receptor (ADRB2). In ADRB1, a Ser49Gly variant may be associated with enhanced agonist-induced downregulation, whereas a Gly389Arg variant was found to bring about a fourfold higher agonist stimulated signal transduction to the Gs protein compared with the Gly allele. Dr. Amruta Dawari JR1 Dept. of Pharmacology, GMCH, Nagpur Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 Respected members, Severe (and in some cases fatal) allergic reactions to the HIV nucleoside analogue drug abacavir have been explained by the HLA-B*5701 allele, and a HLA-B*5701, HLA-DR7, and HLA-DQ3 haplotype even had positive and negative predictive values of 100 and 97%, respectively , strongly advocating routine testing before abacavir prescription. Such a testing may not only be medically needed, but it may also be cost-effective. Amruta Dawari JR1 Dept. of Pharmacology, GMCH, Nagpur Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 Respected members, Identification of pharmacogenomic markers 1)Linkage study: Genotyping families with micro satellite-markers to correlate inheritance of particular chromosomal region with inheritance of disease in family members. Eg. Malignant hyperthermia But it is impractical. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 Respected members, 2)Association studies Correlate the presence of chromosomal region and trait in unrelated individuals of a population. Eg. Apo E4 is strongly associated with Alzheimer's disease Dr. Amruta Dawari JR1 Dept. of Pharmacology, GMCH, Nagpur Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 Respected members, 3)DNA micro arrays (DNA chips)is anevolving technology, by this method it is possible to examine patients for presence of specific SNP's quickly and affordably. Microarray solid-phase bound DNA molecules to simultaneously genotype large numbers of SNPs (up to more than a million) in a single sample. Used in the genome-wide association studies. Dr. Amruta Dawari JR1 Dept. of Pharmacology, GMCH, Nagpur Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 27, 2011 Report Share Posted January 27, 2011 Respected members, Genomics versus epigenomics We (scientists and physicians engaged in pharmacogenetics and genomics) have learned and repeatedly taught the following: analyzing inherited genetic variation has the big advantage that analysing the genome of one cell of an organism provides reliable information on all the other cells independent of age, tissue localization or environmental factors. However, there are somatic cell mutations as well as tissue-specific epigenetic effects, such as DNA methylation, histone modification or micro-RNA expression, that significantly and constantly can change the pattern of gene expression of the cell. Such changes can significantly modify drug efficacy or initiate adverse effects and, therefore, they have to be taken into account in future clinical pharmacology. Dr. Amruta Dawari JR1 Dept. of Pharmacology, GMCH, Nagpur Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 28, 2011 Report Share Posted January 28, 2011 Respected members, The concept of personalized medicine evolves from pharmacogenomics. What is personalized medicine? Developing drugs on the basis of individual genetic differences How does it work? -Tailoring therapies to genetically similar subpopulations results in improved efficacy and less toxicity. Regards, Dr. Amruta Dawari JR 1, Dept of pharmacology, GMCH, Nagpur. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 28, 2011 Report Share Posted January 28, 2011 Respected members, In personalized medicine with the help of genetic information we can give drug to only those patient who are likely to respond to drug & avoid giving drug to non responders & patients likel to have toxicity of that drug. Regards, Dr. Amruta Dawari JR 1, Dept of pharmacology, GMCH, Nagpur. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 28, 2011 Report Share Posted January 28, 2011 Respected members, Chalanges to be met by pharmacogenomics are, 1. Cost of gene tasting e.g. a simple test for CYP may cost you 200-1000 $ 2.Polygenic nature of diseases 3.Tests for genetic polymorphism are not standardized. Most of them lack specificity. 4.Physicians lack awareness. 5.Complexity during prescription 6.There is no regulation regarding genetic testing 7.Patients have fear regarding genetic testing Regards, Dr. Amruta Dawari JR 1, Dept of pharmacology, GMCH, Nagpur. Quote Link to comment Share on other sites More sharing options...
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