Precision Medicine and Adverse Drug Reactions Related to Cardiovascular Drugs
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Cardiovascular disease remains the leading global cause of death. Early intervention, with lifestyle advice alongside appropriate medical therapies, is fundamental to reduce patient mortality among high-risk individuals. For those who live with the daily challenges of cardiovascular disease, pharmacological management aims to relieve symptoms and prevent disease progression. Despite best efforts, prescription drugs are not without their adverse effects, which can cause significant patient morbidity and consequential economic burden for healthcare systems. Patients with cardiovascular diseases are often among the most vulnerable to adverse drug reactions due to multiple co-morbidities and advanced age. Examining a patient's genome to assess for variants that may alter drug efficacy and susceptibility to adverse reactions underpins pharmacogenomics. This strategy is increasingly being implemented in clinical cardiology to tailor patient therapies. The identification of specific variants associated with adverse drug effects aims to predict those at greatest risk of harm, allowing alternative therapies to be given. This review will explore current guidance available for pharmacogenomic-based prescribing as well as exploring the potential implementation of genetic risk scores to tailor treatment. The benefits of large databases and electronic health records will be discussed to help facilitate the integration of pharmacogenomics into primary care, the heartland of prescribing.Keywords:
Pharmacogenomics
Individual variation in response to drugs is an important clinical problem, which ranges from failure to respond to the drug, over adverse reactions to drugs, to interactions among drugs being administered concurrently. Numerous findings indicate that the differences in the patients response on the same drug are caused by genetic variations. This is the subject of pharmacogenetics. Although pharmacogenetics generally equated with the concept of pharmacogenomics, pharmacogenetics is primarily related to variations in a single gene that influence the on drug response, while pharmacogenomics is a broader term, which studies how all of the genes (the genome) can influence responses to drugs. In focus of this paper will be individual variation in response to drugs arising from single nucleotide polymorphisms in genes encoding the drug target proteins, enzymes that metabolize drugs, drug transporters, and polymorphisms of genes responsible for toxicity and hypersensitivity to drugs. Determination of pharmacogenetic profile of patients could point out patients who are at increased risk of adverse drug effects (for which drug should be applied at lower doses or other drugs can be used) and those in which are likely to achieve the desired therapeutic effect, and so to enable individualization of therapy.
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For more than 60 years, genetic variation had been recognized as an important determinant of inter-individual variability in drug efficacy and drug safety. Pharmacogenomics, studying the variations of DNA sequence and gene expression related to drug responses, is the whole genome application of pharmacogenetics. The aim of PGt/PGx is to elucidate functionally relevant genomic determinants for drug metabolism, transport and response in order to optimize drug therapy including therapy response prediction, appropriate drug selection and individualization based on the patient's genomic profile. This article describes and surveys the international landscape on recent PGt/PGx applications in clinical practice. A topline list of drugs in personalized medicine is highlighted together with the cutting edge initiatives such as the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group. Keywords: Collective innovation, drug efficacy and safety, drug metabolizing enzyme, drug receptor, drug transporter, personalized medicine, pharmacogenetics, pharmacogenomics.
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Individuals respond differently to drugs and sometimes the effects are unpredictable. Differences in DNA that alter the expression or function of proteins targeted by drugs can contribute significantly to the variation in the individuals responses. The use of pharmacogenomics is to identify genetic polymorphisms that predispose patients to adverse drug effects that, although they may occur in only a small subset of the people treated with a new medication, are sufficiently toxic to jeopardise further development of the drug for all patients. Given the potential value of knowing all the possible factors that influence the effects of new agents, it is likely that pharmacogenomics will have an increasingly important role in drug discovery and development. This article briefly reviews concepts that underlie the emerging fields of pharmacogenetics and pharmacogenomics, with an emphasis on the pharmacogenetics of drug metabolism. Although only a few examples will be provided to illustrate concepts and to demonstrate the potential contribution of pharmacogenetics to medical practice, it is now clear that virtually every pathway of drug metabolism will eventually be found to have genetic variation. Key words: Drug; genotype; pharmacogenetics; pharmacogenomics DOI: 10.3126/kumj.v7i2.2716 Kathmandu University Medical Journal (2009) Vol.7, No.2 Issue 26, 172-176
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Large differences among normal human subjects in the efficacy and safety of many therapeutic agents are caused by genetically controlled polymorphisms of drug‐metabolizing enzymes, drug transporters, and drug receptors. Development of pharmacogenomics as a new field has accelerated progress in pharmacogenetics by elucidating at the level of the human genome the inherited basis for those large interindividual variations. Examples discussed in this review illustrate how this approach can be used not only to guide new drug discovery but also to individualize therapy. Adverse drug reactions, often attributable to large differences among subjects in drug response, constitute a leading cause of death in the USA. Such high morbidity and mortality could be reduced by application of the principles of pharmacogenetics and pharmacogenomics, defined broadly as the study of genetically caused variability in drug response.
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This chapter contains sections titled: Introduction Definition of Terms Pharmacogenomics Pharmacogenetics Pharmacogenomics: Finding New Medicines Quicker and More Efficiently Pharmacogenetics: More Targeted, More Effective Medicines for our Patients Genes and Environment An Attempt at a Systematic Classification Pharmacogenetic Testing for Drug Efficacy vs. Safety Ethical – Societal Aspects of Pharmacogenetics
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Abstract Pharmacogenetics and pharmacogenomics are related areas of research that aim to determine the relationship between genotypic variation, including changes in gene expression, and variations in drug response seen across patient groups. Understanding the genetic bases of variability in drug response due to altered pharmacokinetics (e.g., drug absorption, distribution, metabolism, excretion) or pharmacodynamics (e.g., drug receptor up- or downregulation) is essential for the practitioner to fully anticipate, recognize, and mitigate potential drug toxicity or ineffectiveness. The ultimate goal of pharmacogenetics and pharmacogenomics is to develop personalized medicine for individuals by leveraging knowledge of phenotypic variation in drug response due to genetic mutations, polymorphisms, or gene expression.
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Problems pertaining to the development of individual therapy based on the achievements of modern pharmacogenetics and pharmacogenomics, as well as the safety of using drugs from various pharmacological groups in patients belonging to different ethnical groups (with the corresponding features of metabolism) are considered. The terms "pharmacogenetics" and "pharmacogenomics" are discussed in connection to the significance of genetic polymorphism (or single nucleotide polymorphism) in determining of the individual sensitivity with respect to certain drugs.
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Aim: To determine the availability of pharmacogenetic and pharmacogenomic information for healthcare professionals in France during 2009 for anticancer drugs. Materials & methods: We searched in the informatic version of the VIDAL dictionary which is currently used by healthcare professionals in France. We then compared this with data available in the PubMed database. Results: Among the 109 anticancer molecules available in France during 2009, 13 have pharmacogenomic or pharmacogenetic information in their monographs. In the scientific literature, we found numerous pharmacogenomic and pharmacogenetic biomarkers concerning 43 of the 109 anticancer agents. Some are pharmacogenomic biomarkers related to drug effectiveness, others are pharmacogenetic biomarkers related to drug toxicity. Conclusion: We believe that the lack of pharmacogenomic and pharmacogenetic information in drug monographs reflects the relative newness of the discipline. However, pharmacogenetics and pharmacogenomics can offer valuable information for improving the safety of drugs, reducing toxicity and predicting nonresponders. The drugs might then be incorporated into clinical practice through several strategies, including increased drug labeling and better education of healthcare professionals.
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Abstract Pharmacogenetics and pharmacogenomics (PGx) are rapidly growing fields that aim to elucidate the genetic basis for the interindividual differences in drug response. PGx approaches have been applied to many anticancer drugs in an effort to identify relevant inherited or acquired genetic variations that may predict patient response to chemotherapy and targeted therapies. In this article, we discuss the advances in the field of cancer pharmacogenetics and pharmacogenomics, driven by the recent technological advances and new revolutionary massive sequencing technologies and their application to elucidate the genetic bases for interindividual drug response and the development of biomarkers able to personalize drug treatments. Specifically, we present recent progress in breast cancer molecular classifiers, cell-free circulating DNA as a prognostic and predictive biomarker in cancer, patient-derived tumor xenograft models, chronic lymphocytic leukemia genomic landscape, and current pharmacogenetic advances in colorectal cancer. This review is based on the lectures presented by the speakers of the symposium “Pharmacogenetics and Pharmacogenomics as Tools in Cancer Therapy” from the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF), held in Madrid (Spain) on April 21, 2015.
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