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Doi:10.1016/j.drudis.2010.03.004

Drug Discovery Today  Volume 15, Numbers 9/10  May 2010 The inaugural London Genetics Pharmacogenetic Conference,‘Harnessing Genetic Knowledge To Improve Clinical Develop-ment and Patient Care’, was held last autumn in the UK. Withspeakers from the biopharmaceutical industry, academia, regula-tors and health care organizations, the place of pharmacogeneticsin the future of drug development was debated. Pharmacogeneticsis the study of how our genetic make-up affects our response to drugs and leads to the area of stratified (or personalized) medicine,in which drugs are given to those who are expected to be respon-ders or not suffer from side-effects. The discipline is all aboutfinding the right drug for the right patient at the right dose.
Challenges to the industryApart from the challenges of increasing innovation and produc-tivity, at the same time as increasing drug safety, the fourth hurdleof cost-effectiveness is becoming increasingly high profile for the industry as a result of countries (particularly the USA) focusing onhealthcare budgets. Pharmacogenetics is seen as one of the leadingemerging translational sciences to help meet these challenges ,which no company involved in drug discovery and clinical devel-opment can afford to ignore. Although it is clear that genetics andpharmacogenetics have much value to add in the areas of findingdrug targets, increasing specificity, reducing side-effects andimproving patient selection, the question appears to be how weuse the myriad of genetic and pharmacogenetic data that is Pharmacogenet- becoming available to us.
ics—pivotal to the Pharmacogenetics progress so far Stratified medicine has arrived to a certain extent, and oncology isthe poster child. In this area, the advent of pre-treatment genetic future of the bio- testingtoidentifyrespondersandnon-respondersdrivesthepre- scription of both Herceptin and Erbitux. There has also beenprogress in the HIV area, with genetic testing to identify those pharmaceutical in- most at risk of severe skin hypersensitivity reactions to Ziagen.
Results from clinical studies also support the importance of genetic dustry variation in our response to drugs such as Plavix and warfarin.
These examples in fact encapsulate some of the potential ofpharmacogenetics—the ability to select responder populations, 1359-6446/06/$ - see front matter ß 2010 Elsevier Ltd. All rights reserved. doi: Drug Discovery Today  Volume 15, Numbers 9/10  May 2010 most susceptible to side-effects, pharmacogenetics has a key part  The biopharmaceutical industry faces an unprecedented set of Many commentators noted that with the regulators interested in pharmacogenetics as well as the industry, the need for  Genetics and pharmacogenetics offer great potential in meeting collaboration is great. Looking at how the industry does clinical trials now, we use Phase III populations that consist of non-  Use in the clinical trial process, not just diagnostics and genetic tests responders to the drug, partial responders and responders. In a  Can lead to more effective, safer drugs and increased research ‘utopian’ industry, Phase III trials would consist of just responders.
If we used pharmacogenetics to identify them by Phase IIb, then  Genetics and pharmacogenetics are an important part of the puzzle later studies could potentially be smaller and drugs with higher  Their exact role and place in research needs to be clarified response rates would result because non-responders would not be  Early collaboration between academia, industry, regulators and able to ‘dilute’ the response rate. Pharmacogenetics could also be used to rule out those susceptible to side-effects.
 The need to show cost-effectiveness is hugely important In addition, given that Phase IIb trials are designed to refine dosing, their smaller size means that they might not be able to flagup the smaller incidence, but serious, side-effects that often come the potential ability to exclude those most at risk of side-effects to light only when a drug is on the market and taken by millions of and the ability to tailor dosing to individuals. However, most of patients. It was postulated that we could have larger Phase IIb this evidence was generated from studies conducted after drug trials, scrapping Phase III and moving straight on to Phase IV.
approval. The challenge ahead is to use this technology early in theclinical trial process to increase effectiveness and efficiency and to deliver more effective and safer drugs, with increased chance of Professor Munir Pirmohamed, the NHS Chair of Pharmacoge- gaining regulatory approval and, importantly, reimbursement.
netics, University of Liverpool discussed his work . A prospec- Evidence of the increasing big company interest in this area has tive study investigating the cause of admission in two hospitals come in the acquisition by Qiagen of the UK personalized med- found that 6.5% (n = 1225) of admissions were due to adverse drug icine company DxS, just as the London Genetics conference reactions; death caused by adverse drug reactions occurred in started. The LGL conference highlighted many of the pertinent 0.15% of admissions, equivalent to 5700 deaths per year with issues in pharmacogenetics at the moment, which are discussed an associated cost of more than £446 million per annum to the NHS. Looking at the data in another way, he noted that seven 800-bed hospitals are occupied by patients brought in with adverse In a provocative after-dinner speech at the conference, Steve Continuing his comments on the theme of the costs of side- Arlington of PriceWaterhouse Coopers discussed the need for effects associated with drugs, he noted that the NHS in the UK prevention and cure to be the new industry focus for healthcare could save money and improve patient care by testing for HLA-B*- costs to be kept at a reasonable level. Saying that the industry is 5701 before Ziagen therapy in HIV-positive patients. Patients with ‘not incentivized’ to provide prevention and cure because long- this genetic variant suffer severe skin hypersensitivity reactions, term treatments are reimbursable, he suggested that the payers and the strong association has been demonstrated in both retro- ‘don’t want (insurance) claims’ and the industry will now be spective and prospective studies. In a study, incidence of hyper- forced to ‘prove drugs work’. We can expect ‘high costs’ for sensitivity was reduced from 7%, 12% and 7.8% to <1%, 0% and ‘specialized drugs that prevent and cure’ and the need to sell 2% in clinics in Australia, France and UK, respectively. Use of ‘pills by outcome’. What part can pharmacogenetics play in this abacavir also increased by approximately eightfold. Factors con- area? The message from the conference was that with the tributing to the successful adoption of this approach include the potential to select responsive patient populations, as well as strength of the association, physicians in this area being amenable to exclude those whose genetic make-up means that they are to change, an organized patient lobby and the availability of a test.
Regulatory guidance and reflection papers related to pharmacogenetics Diabetes Mellitus—evaluating cardiovascular risk in new anti-diabetic therapies Pharmacogenomic (PG) Biomarker Qualification: Format and Data Standards Use of genomics in cardiovascular clinical intervention trials Use of pharmacogenetics in the pharmacokinetic evaluation of medicinal products Drug Discovery Today  Volume 15, Numbers 9/10  May 2010 This means early engagement by pharmaceutical and biotechnol- Another topic that was much discussed was patient samples. This ogy companies with genetics experts so that the full potential of is a very basic part of the puzzle about which to be concerned, and to do large-scale pharmacogenetics studies, large and reliablecollections are needed. These are often taken routinely in clinical Is pharmacogenetics welcomed by the industry? trials but not often interrogated for genetic information. The The biopharmaceutical industry is struggling to fill the revenue questions were raised of whether companies can afford to inter- gaps caused by massive patent expiries—so much so that many rogate the samples, and if they can, is it clear yet what genetic commentators are starting to believe that the age of the mega- questions are they asking? In addition, do companies take and blockbuster is over, to be replaced by that of the ‘minibuster’. The store samples consistently so that any data obtained is compar- minibuster would still generate sales of billions of dollars, but only able? There are also issues around informed consent, and the in the population in which it is known to be effective—and in the difficulty of exporting samples from territories such as China— new cost-effectiveness-driven world, would be reimbursed. Initi- territories that are expected to drive much of the future growth of ally, though, will industry welcome technologies that mean that the pharmaceutical sector and whose populations are expected to their drugs are directed at smaller markets? have significant genetic differences to those of the West.
Not all genetic variants have a large effect Other issues addressed at the conference include bioinformatics Professor Patricia Munroe from Bart’s and The London, in her and subgroup analysis of clinical data. The increasing amounts of comments on the genetics of hypertension, highlighted how there genetic and pharmacogenetic data generated need to be managed is a lot of work to be done before genetic research provides easy by improved bioinformatics tools, so that they can be used effi- answers to cardiovascular disease. In this area, there is a need both ciently by all players. To obtain subgroup analysis data from early for new drugs and for a better understanding of cardiovascular clinical development studies, these need to be designed statisti- genetics, and it is interesting to note that heart conditions are, in cally to be sufficiently powered and will also need to use innova- general, 30–50% influenced by our genetic make-up and 50%–70% tive statistical methodologies. Sustainability for pharmaceutical influenced by lifestyle factors. Studies have found genetic variants companies will only come from effective networking, partnering associated with hypertension, with the genes encoding relevant and collaborations in order to gain the expertise and access to the proteins such as ion channels and calcium ATPase, but the key resources they need to exploit the enormous knowledge emerging question is how much these variants contribute to disease. She from genetic studies, and the importance of strengthening inter- described how, via the work (including genome-wide association actions between academia and industry has been recommended in studies) of the Global Blood Pressure Gene consortium and others, 13 genetic variants related to blood pressure were identified, basedon the analysis of many thousands of samples. However, each of those variants only explained a small proportion of the total Although genetics and pharmacogenetics are not the cure to all variation in systolic and diastolic blood pressure. They were the ills that ail the industry, they are a powerful piece of the jigsaw.
responsible for around 0.5–1.0 mm Hg of change. Given that achange of 2 mm Hg results in a 6% reduction in stroke, the effect of these variants is minimal at a population level but might be 1 Challenge and opportunity on the critical path of new medical products. FDA White significant at an individual level. New therapeutic targets, there- 2 Pirmohamed, M. et al. (2004) Adverse drug reactions as cause of admission to fore, are needed, as are more predictive biomarkers for drug dis- hospital: prospective analysis of 18820 patients. BMJ 329, 15–19 covery and patient selection, and there is a clear need for 3 Hughes, D.A. et al. (2004) Cost-effectiveness analysis of HLA B*5701 genotyping in identification of variants that have a greater effect on clinical preventing abacavir hypersensitivity. Pharmacogenetics 14, 335–342 4 The stratification of disease for personalised medicines. ABPI White Paper April 2009 5 Genomic Medicine. House of Lords, Science and Technology Committee Report July ‘Early’ is a key wordThe need to engage early was one of the themes to recur frequently throughout the conference. It will be a key factor in the new paradigm, with early consideration of factors likely to impact drug London Genetics Ltd, BioIncubator Unit, Imperial College, Prince Consort response (efficacy or risk of adverse events), early engagement with key stakeholders (regulators and reimbursement authorities) and building responder analyses into early clinical development plans.

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