PGNX in RUM --- AMPLICHIP FURTHER

[Guest guest]

Dear netruminas, please dont take the following material as promotional one. its only for better understanding 'AMPLICHIP' you can get there through http://www.bio-pro.de/en/region/rhein/magazin/01552/index.html A pharmacogenetic chip for clinical application ”This new test provides doctors with access to information that might prove useful in the prevention of adverse drug reactions, and the optimal application of medicine. The test is an important step forward on the way to a more personalised approach to therapy, and has the potential of providing doctors with better therapy results.” (Heino von Prondzynski) New diagnostic technologies, and in particular microarraytechnologies, have enabled the development of pharmacogenetic tests with which it is possible to detect genetic variations that have an effect on the metabolisation of certain drugs. The first test of this kind cleared in the EU and USA for clinical applications is the AmpliChip CYP450 Test from Roche Diagnostics. The test combines the advantage of two industry gold standards - the polymerase chain reaction (PCR) technology patented by Roche, which enables the amplification detection of minute amounts of genetic material, and the Affymetrix high density DNA microarray technology. The GeneChip System 3000Dx instrument used in conjunction with the AmpliChip CYP450 Test was also cleared in the EU and USA for diagnostic purposes. AmpliChip CYP450 Test. Fig.: Roche The AmpliChip CYP450 chip is no larger than a thumbnail and contains more than 15,000 different oligonucleotide probes for the analysis of sense- and antisense strains of an amplified target DNA sample. The chip is inserted into a plastic cassette, which enables easier handling. The test is capable of differentiating between 29 different polymorphisms of the CYP2D6 gene including gene duplication and deletion as well as two important polymorphisms of the CYP2C19 gene. To enable the highly accurate prediction of a patient phenotype,the AmpliChip CYP450 Test

offers the ability to not only detect the presence of CYP2D6 gene duplications, but also to discern which variation of the gene (=allele) has been duplicated. This specificity is important in correctly predicting the ultra-rapid metaboliser phenotype and avoiding potential misclassification of the patients tested. In people with a very fast metabolism it might not be possible to achieve sufficiently high drug levels in the blood using standard dosing. In contrast, slow metabolisers might encounter the risk of having a much too high drug level in the blood or persist over an excessively long time period. In the case of pro-drugs (drugs that require metabolic enzyme activity before they become the active therapeutic compound in the body) poor metabolisers will not obtain any benefit from these drugs. Heino von Prondzynski, CEO of Roche Diagnostics and Member of the Roche Executive Committee commented on the approval of the AmpliChip CYP450 Test by the FDA: “With this

test it will in certain cases also be possible to prevent the selection of a less suitable or even harmful therapy. For patients it is very important to know whether painkillers or anaesthetics are effective or not. In patients who take a long time to metabolise the drugs or are unable to do so, the drugs exert their effect over a much longer period of time. Patients who know about such relationships are able to insist on receiving other or more effective and compatible medications.” Examples Genetic variations of the CYP2C19 and CYP2D6 genes are unequally distributed among people of different geographical origins and their descendents, with some polymorphisms and alleles found virtually in only one racial population.

Numerous case studies in the medical literature underline the importance of such genetic analyses. These include for example the following: An Ethiopian man who was treated in the USA with codeine in order to ease pain experienced hallucinations shortly after ingestion of the drug. It turned out that he had five active copies of the 2D6 gene that enabled the rapid conversion of codeine in the active form of morphine. A female patient who received codeine to ease her pain continued to demand increasingly more and was virtually regarded as a codeine-addict. However, it turned out that she was a member of those 7 percent of American Caucasians who possess an inactive form of the CYP2D6 gene. Codeine did not lead to the alleviation of pain because it could not be converted into morphine. Another patient who was treated with the anti-depressive drug Prozac began to suffer from high blood pressure and other adverse effects because she was unable to metabolise Prozac, which gradually accumulated in the blood. A patient suffering from pneumonia was treated with codeine in order to alleviate heavy coughing. The patient fell into a coma and had to be admitted to the intensive care unit. He possessed an ultra-rapid CYP2D6 genotype, which despite low codeine doses, led to the accumulation of codeine metabolites in the blood. This additional treatment led to costs amounting to nearly 13,000 CHF. These could have been avoided had the AmpliChip CYP450 Test been used for identifying the individual type of metabolism. Affymetrix GeneChipR scan. Fig.: Roche Resource optimisation in healthcare using modern diagnostics The adverse reactions of drugs are an enormous financial burden for the healthcare system. It is estimated that unsuitable drugs are responsible for 5 percent of all hospitalisations or that they prolong hospital stays on an average of two days thereby increasing the healthcare costs per patient by approximately 2,500 USD. In the USA, estimated extra costs arising through unsuitable drug treatment amount to approximately 4 billion USD.

According to WHO estimates, 81 percent of the additional costs arise from therapies, hospital stays and rehabilitation measures; 15 percent need to be spent for new medicines, and only 4 percent account for diagnostic and laboratory services. In view of this relative minor proportion, diagnostics has an enormous potential for supporting the more economic use of financial resources with optimised diagnostics and improved therapies. The CYP450 gene family and the drug metabolism Among the many members of the cytochrome P450 super family, several enzymes are considered to be of particular importance in drug metabolism. The CYP3A4 enzyme is present in much higher abundance in the liver and is involved in the

metabolism of more drugs than others. CYP3A4 enzyme activity is, however, affected more by environmental factors such as diet and concurrent medications than by inherited variations. In contrast, genetic variations play an important role in the CYP2D6 and CYP2C19 isoforms analysed with the AmpliChip CYP450 Test. The tests provide predictive phenotypes: Is a CYP2C19 phenotype patient a poor metaboliser (no enzyme activity) or an extensive (‘normal’ enzyme activity) metaboliser? Is a patient of the CYP2D6 phenotype a poor metaboliser (no enzyme activity), intermediary (reduced enzyme activity), extensive (‘normal’ enzyme activity) or an ultra-rapid (higher than normal enzyme activity) metaboliser? Genetic or environmental factors might also have an effect on these enzymes. The CYP2D6 gene encoded enzyme plays a primary role in the metabolism of drugs that are used to treat severe depression, schizophrenia, cardiovascular disease treated with beta-blockers,

attention deficit/hyperactivity disorder (ADHD) inter alia. The CYP2C19 gene encoded enzyme metabolises many anti-convulsants, proton pump inhibitors, benzodiazepines and anti-malarials. Both the CYP2D6 and CYP2C19 enzymes are involved in the metabolism of certain tricyclic antidepressant drugs that are used to treat depression. EJ - 30.08.05 A list of drugs that are metabolised by different cytochrome P450 enzymes are provided on the website of the "Indiana University Department of Medicine" Regards, Dr Kiran Chaudhari Lecturer, Pharmacology, GMC, Nagpur

Now you can chat without downloading messenger. Click here to know how.