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The Investigation and Application of Individual Antihypertensive Drugs Therapy Related Genotyping Microarray

Author: ZhaoZhenYu
Tutor: ZhouHongZuo
School: Central South University
Course: Journal of Clinical Pharmacology
Keywords: individual medication hypertension microarray gene polymorphism
CLC: R544.1
Type: PhD thesis
Year: 2007
Downloads: 349
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Abstract


The antihypertensive drugs have individual differences on curative effect and adverse affect in the course of medication. The research evolutions of pharmacogenetics and pharmacogenomics have indicated that the major reason of individual drug reaction differences may due to genetic variance of drug metabolic enzymes, transportors, and receptors (the targets of drug action). Establishing the different antihypertension treatment project according to the above genetic variances relating to medication can optimize the administration and relieve the suffering and economic burden of patients, which is meaningful to the society and the economics. Microarray technique is a rapid method for analyzing genes of samples. Fixing abundant known oligonucleotides on the holder and hybridizing with tagged samples, we can select genes from hybridizing message according to their intensity. Microarray has the characters of high-specificity, high-sensitivity, convenience, rapid and high-flux, which makes it possible in clinical speedy genotype detection. Searching feasible medication project according to the correlative genetic messages between the human body and the drug metabolism, doctors can markedly increase the safety, effectively, and economy of medication, and elevate the life quality of patients at the same time.The purpose of present study is to manufacture the detection microarray aim at the genotype of five drug metabolic enzymes and their receptors: CYP2C9~*3, ADRB1(1165G>C), AGTR1(1166A>C), CYP2D6~*10, ACE(I/D) in hypertensive person. These locus of above five genotypes have been proved to closely correlate to the curative effect of common antihypertension treatment. We can make rational prescription in hypertension person according to the genotype result of the microarray. The research designed the special detect probe and prepared the microarray to check above genemutation locus, devised special primer tagged with Cy5, amplify the fragments comprising of CYP2C9~*3, ADRB1(1165G>C), AGTR1(1166A>C), CYP2D6~*10, ACE(I/D), hybridized the PCR products which tagged with Cy5 with microarray, and got the results through scanner.The research had investigated deeply in the techniques of prepare technology and appliance of oligonucleotide microarray and had optimized the experiment work system. The main contents of this research included design and prepare microarray, optimizing PCR reaction and hybriding system, optimizing antipollution system, estimating hybriding signal and validating capability of microarray.The main harvest of this research was that:1. For the first time we had successfully prepared the microarray which can both detect the genotype of drug metabolic enzymes, receptors and angiotensin converting enzymeclosely: CYP2C9~*3、ADRB1(1165G>C), AGTR1(1166A>C)、CYP2D6~*10、ACE(I/D) that have close relationship to individual variation in curative effect of antihypertension treatment.2. The research and the clinical validation had showed that the result of this genotype detecting microarray was exact and the specificity and repeatability were all right. The microarray had the characters of high-automatization, easy and quick operation, comparative low cost during the course of detect, which made it suit for filtrating abundant samples.3. The research had established the flat roof for designing and preparing maciroarray of ripe oligonucleotide.In a word, focus on individual medication in antihypertension treatment, basing on a great deal of research results and combining the microarray technology with the research fruits of pharmacogenetics, the research manufactured the genotyping microarray which had independent intellectual property fight and correlated to the individual medication in antihypertension treatment. This investigation was a beneficial attempt for applying the results of pharmacogenetics in clinical work, and offered important implement in gent oriented individual medication in clinical.

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CLC: > Medicine, health > Internal Medicine > Heart, blood vessels ( circulatory ) disease > Abnormal blood pressure > Hypertension
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