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Alcoholism, Clinical and Experimental... Mar 2015Annually, the use and abuse of alcohol contributes to millions of deaths and billions of dollars in societal costs. To determine the impact of genetic variation on the... (Review)
Review
BACKGROUND
Annually, the use and abuse of alcohol contributes to millions of deaths and billions of dollars in societal costs. To determine the impact of genetic variation on the susceptibility to the disorder and its response to treatment, studies have been conducted to assess the contribution of a variety of candidate genetic variants. These variants, which we review here, were chosen based upon their observed or hypothesized functional relevance to alcohol use disorder (AUD) risk or to the mechanism by which medications used to treat the disorder exert their effects.
METHODS
This qualitative review examines studies in which candidate polymorphisms were tested as moderator variables to identify pharmacogenetic effects on either the subjective response to alcohol or the outcomes of pharmacotherapy.
RESULTS
Although findings from these studies provide evidence of a number of clinically relevant pharmacogenetic effects, the literature is limited and there are conflicting findings that require resolution.
CONCLUSIONS
Pharmacogenetic studies of AUD treatment that use greater methodological rigor and better statistical controls, such as corrections for multiple testing, may help to resolve inconsistent findings. These procedures could also lead to the discovery of more robust and clinically meaningful moderator effects. As the field evolves through methodological standardization and the use of larger study samples, pharmacogenetic research has the potential to inform clinical care by enhancing therapeutic effects and personalizing treatments. These efforts may also provide insights into the mechanisms by which medications reduce heavy drinking or promote abstinence in patients with an AUD.
Topics: Alcohol-Related Disorders; Genetic Variation; Humans; Pharmacogenetics; Randomized Controlled Trials as Topic
PubMed: 25703505
DOI: 10.1111/acer.12643 -
Pharmacological Reviews Dec 1997What have we learned? Pharmacogenetics, heritable variation in response to xenobiotics, is present in all forms of life. Initially, human data perhaps have created the... (Comparative Study)
Comparative Study Review
What have we learned? Pharmacogenetics, heritable variation in response to xenobiotics, is present in all forms of life. Initially, human data perhaps have created the most excitement, and they provide much biochemical detail. However, if we look at pharmacogenetic variation of insects and bacteria, we see it as a characteristic of populations; individuals with inborn resistance to various toxicants can cause the survival of a population by the process of Darwinian selection. Diversity of a population and Darwinian selection are different milestones serving population survival. Variation of drug response may represent variation of drug targets, drug metabolism, and probably drug transport. Metabolic variation appears to be the most prominent; at present, it is not clear whether this prominence has historical or biological causes. It is an interesting exercise to compare pharmacogenetic resistance with intoxication and resistance to infection by invasion of disease-carrying bacteria or other pathogens. The big difference is that pathogens tend to show variabilities that drugs do not have. The immune system is made to deal with the genetic variabilities linked to the short life span of most pathogens. However, there are, besides the immune system, several cases of genetic host resistance associated with the long life span of mammalian hosts. Such genetic host resistances are factors equivalent to pharmacogenetic variation. Current data pertain to resistance against malaria, tuberculosis, cholera, and AIDS. Most pharmacogenetic variants within a population are preadaptive, that is, they are established before xenobiotic exposure. Hence, one must postulate a multiplicity of variants in a population capable of resisting a multiplicity of drugs. The persistence of this multiplicity suggests that most variants are either present in heterozygous form and are thereby advantageous for their carriers, or they are selectively neutral mutants. It means that the biological cost of pharmacogenetic diversity, measured in terms of reduced fertility, should be low in a population. The frequencies of variant genes are usually not the same in different populations. Also the nucleotide substitutions in a variable gene often differ between populations. In other words, pharmacogenetic differences between populations are typical events. Pharmacogenetics is usually thought of as the study of a situation in which a single gene product exerts control over a given drug response so that a failure to respond, or an excessive response, may result. However, one should not forget that random variation is always present, probably reflecting the randomness of mutations plus variation of any environmental factors that might contribute. This underlying randomness of variation will always affect the picture of any all-or-none variation. Future pharmacogenetics must deal with both random and monogenic variation.
Topics: Animals; Arthropods; Bacteria; Biological Evolution; Cytochrome P-450 CYP2D6; Drug Resistance; Gene Frequency; Genetic Variation; Humans; Pharmacogenetics; Pharmacokinetics; Xenobiotics
PubMed: 9443163
DOI: No ID Found -
Clinical Pharmacology and Therapeutics Apr 2020Clinical translation of drug-drug interaction (DDI) studies is limited, and knowledge gaps across different types of DDI evidence make it difficult to consolidate and... (Review)
Review
Clinical translation of drug-drug interaction (DDI) studies is limited, and knowledge gaps across different types of DDI evidence make it difficult to consolidate and link them to clinical consequences. Consequently, we developed information retrieval (IR) models to retrieve DDI and drug-gene interaction (DGI) evidence from 25 million PubMed abstracts and distinguish DDI evidence into in vitro pharmacokinetic (PK), clinical PK, and clinical pharmacodynamic (PD) studies for US Food and Drug Administration (FDA) approved and withdrawn drugs. Additionally, information extraction models were developed to extract DDI-pairs and DGI-pairs from the IR-retrieved abstracts. An overlapping analysis identified 986 unique DDI-pairs between all 3 types of evidence. Another 2,157 and 13,012 DDI-pairs and 3,173 DGI-pairs were identified from known clinical PK/PD DDI, clinical PD DDI, and DGI evidence, respectively. By integrating DDI and DGI evidence, we discovered 119 and 18 new pharmacogenetic hypotheses associated with CYP3A and CYP2D6, respectively. Some of these DGI evidence can also aid us in understanding DDI mechanisms.
Topics: Data Mining; Drug Interactions; Humans; Knowledge Discovery; Pharmacogenetics; Translational Research, Biomedical; United States; United States Food and Drug Administration
PubMed: 31863452
DOI: 10.1002/cpt.1745 -
American Journal of Health-system... Apr 2009The basic concepts of pharmacogenetics, pharmacogenetic study approaches, factors to consider when applying pharmacogenetic discoveries to patient care, and potential... (Review)
Review
PURPOSE
The basic concepts of pharmacogenetics, pharmacogenetic study approaches, factors to consider when applying pharmacogenetic discoveries to patient care, and potential roles for pharmacists in pharmacogenetics are discussed.
SUMMARY
The Food and Drug Administration (FDA) has recognized pharmacogenomics as an opportunity to identify new biomarkers that may expedite the drug development process. Currently, there are over 50 drugs with pharmacogenetic discoveries on their labeling. Sequence variations in drug disposition genes can alter the pharmacokinetics of a drug, while sequence variations in drug target genes can change the pharmacodynamics of the drug. The two most common strategies to test a pharmacogenetic question are the candidate-gene approach and genomewide association study. Given the complex interplay among the many factors that influence a drug dose, determination of an appropriate dose of a particular drug for a given patient will eventually require knowledge about both genetic and nongenetic factors that affect drug disposition and pharmacodynamics. Many factors can influence the application of pharmacogenetic discoveries to patient care. Before these discoveries find widespread application in clinical practice, additional work is needed, including randomized clinical trials to evaluate the clinical utility of a pharmacogenetic test, the development of guidelines for the clinical use of various pharmacogenetic tests, and provider education on pharmacogenetics.
CONCLUSION
Pharmacogenetics has made significant progress in the past decade, and many pharmacogenetic discoveries have now been included on FDA-approved drug labeling. Pharmacogenetic discoveries may further promote safe and effective use of medications by more accurately predicting an individual's drug response.
Topics: Drug Design; Drug Labeling; Drug Therapy; Genotype; Humans; Patient Care; Pharmacists; Pharmacogenetics; Professional Role; United States; United States Food and Drug Administration
PubMed: 19299369
DOI: 10.2146/ajhp080170 -
Nederlands Tijdschrift Voor Geneeskunde Jun 2020With the exception of a few medical specialties, the implementation of pharmacogenetic tests in daily practice has thus far been limited. The Royal Dutch Pharmacists...
With the exception of a few medical specialties, the implementation of pharmacogenetic tests in daily practice has thus far been limited. The Royal Dutch Pharmacists Association (KNMP) has developed pharmacogenetics-based therapeutic doserecommendations for 80 medicinal product combinations on the basis of a systematic literature review. Genotyping of patients can take place on a reactive or pre-emptive basis; the advantage of pre-emptive genotyping is that it provides genetic information the moment a medicinal product is prescribed. Clinical decision support software is crucial to implement pharmacogenetics into daily practice.
Topics: Decision Support Systems, Clinical; Drug Dosage Calculations; Drug Prescriptions; Genotyping Techniques; Humans; Netherlands; Pharmacists; Pharmacogenetics; Pharmacogenomic Testing; Systematic Reviews as Topic
PubMed: 32608920
DOI: No ID Found -
Current Opinion in Pharmacology Oct 2008Considerable interindividual variability exists in patient responses to drug therapy. Differences in DNA sequence can affect the disposition, efficacy, and safety of a... (Review)
Review
Considerable interindividual variability exists in patient responses to drug therapy. Differences in DNA sequence can affect the disposition, efficacy, and safety of a drug. Knowledge of pharmacogenetics may be applied toward understanding and managing such interindividual variability. Increasingly, pharmacogenetic language is being added to drug labels, and genotyping is performed either to select the drug or adjust the dose to an individual. In this article we discuss the current uses of genotyping for managing drug therapy, and issues related to the clinical uptake of pharmacogenetics.
Topics: Animals; Dose-Response Relationship, Drug; Drug Therapy; Humans; Pharmaceutical Preparations; Pharmacogenetics
PubMed: 18762278
DOI: 10.1016/j.coph.2008.07.013 -
Clinical Pharmacology and Therapeutics May 2011Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for... (Review)
Review
Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics-based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).
Topics: Animals; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Pharmacogenetics; Practice Guidelines as Topic
PubMed: 21412232
DOI: 10.1038/clpt.2011.34 -
Current Alzheimer Research 2020Dementia is an important issue in western societies, and in the following years, this problem will also rise in the developing regions, such as Africa and Asia. The most... (Review)
Review
Dementia is an important issue in western societies, and in the following years, this problem will also rise in the developing regions, such as Africa and Asia. The most common types of dementia in adults are Alzheimer's Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD) and Vascular Dementia (VaD), of which, AD accounts for more than half of the cases. The most prominent symptom of AD is cognitive impairment, currently treated with four drugs: Donepezil, rivastigmine, and galantamine, enhancing cholinergic transmission; as well as memantine, protecting neurons against glutamate excitotoxicity. Despite ongoing efforts, no new drugs in the treatment of AD have been registered for the last ten years, thus multiple studies have been conducted on genetic factors affecting the efficacy of antidementia pharmacotherapy. The researchers investigate the effects of variants in multiple genes, such as ABCB1, ACE, CHAT, CHRNA7, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP3A7, NR1I2, NR1I3, POR, PPAR, RXR, SLC22A1/2/5, SLC47A1, UGT1A6, UGT1A9 and UGT2B7, associated with numerous pathways: the development of pathological proteins, formation and metabolism of acetylcholine, transport, metabolism and excretion of antidementia drugs and transcription factors regulating the expression of genes responsible for metabolism and transport of drugs. The most promising results have been demonstrated for APOE E4, dementia risk variant, BCHE-K, reduced butyrylcholinesterase activity variant, and CYP2D6 UM, ultrarapid hepatic metabolism. Further studies investigate the possibilities of the development of emerging drugs or genetic editing by CRISPR/Cas9 for causative treatment. In conclusion, the pharmacogenetic studies on dementia diseases may improve the efficacy of pharmacotherapy in some patients with beneficial genetic variants, at the same time, identifying the carriers of unfavorable alleles, the potential group of novel approaches to the treatment and prevention of dementia.
Topics: Constitutive Androstane Receptor; Gene Editing; Humans; Neurocognitive Disorders; Pharmacogenetics
PubMed: 32321403
DOI: 10.2174/1567205017666200422152440 -
Clinical Pharmacology and Therapeutics Aug 2023Pharmacogenetics can improve clinical outcomes by reducing adverse drug effects and enhancing therapeutic efficacy for commonly used drugs that treat a wide range of...
Pharmacogenetics can improve clinical outcomes by reducing adverse drug effects and enhancing therapeutic efficacy for commonly used drugs that treat a wide range of cardiovascular diseases. One of the major barriers to the clinical implementation of cardiovascular pharmacogenetics is limited education on this field for current healthcare providers and students. The abundance of pharmacogenetic literature underscores its promise, but it can also be challenging to learn such a wealth of information. Moreover, current clinical recommendations for cardiovascular pharmacogenetics can be confusing because they are outdated, incomplete, or inconsistent. A myriad of misconceptions about the promise and feasibility of cardiovascular pharmacogenetics among healthcare providers also has halted clinical implementation. Therefore, the main goal of this tutorial is to provide introductory education on the use of cardiovascular pharmacogenetics in clinical practice. The target audience is any healthcare provider (or student) with patients that use or have indications for cardiovascular drugs. This tutorial is organized into the following 6 steps: (1) understand basic concepts in pharmacogenetics; (2) gain foundational knowledge of cardiovascular pharmacogenetics; (3) learn the different organizations that release cardiovascular pharmacogenetic guidelines and recommendations; (4) know the current cardiovascular drugs/drug classes to focus on clinically and the supporting evidence; (5) discuss an example patient case of cardiovascular pharmacogenetics; and (6) develop an appreciation for emerging areas in cardiovascular pharmacogenetics. Ultimately, improved education among healthcare providers on cardiovascular pharmacogenetics will lead to a greater understanding for its potential in improving outcomes for a leading cause of morbidity and mortality.
Topics: Humans; Pharmacogenetics; Cardiovascular Agents; Cardiovascular Diseases; Drug-Related Side Effects and Adverse Reactions; Health Personnel
PubMed: 37303270
DOI: 10.1002/cpt.2957 -
Annual Review of Genomics and Human... 2006Pharmacogenetics and pharmacogenomics involve the study of the role of inheritance in individual variation in drug response, a phenotype that varies from potentially... (Review)
Review
Pharmacogenetics and pharmacogenomics involve the study of the role of inheritance in individual variation in drug response, a phenotype that varies from potentially life-threatening adverse drug reactions to equally serious lack of therapeutic efficacy. This discipline evolved from the convergence of rapid advances in molecular pharmacology and genomics. Originally, pharmacogenetic studies focused on monogenic traits, often involving genetic variation in drug metabolism. However, contemporary studies increasingly involve entire "pathways" encoding proteins that influence both pharmacokinetics--factors that influence the concentration of a drug reaching its target(s)--and pharmacodynamics, the drug target itself, as well as genome-wide approaches. Pharmacogenomics is also increasingly moving across the "translational interface" into the clinic and is being incorporated into the drug development process and the governmental regulation of that process. However, significant challenges remain to be overcome if pharmacogenetics-pharmacogenomics is to achieve its full potential as a major medical application of genomic science.
Topics: Drug Design; Genetic Variation; Genome, Human; Humans; Pharmacogenetics
PubMed: 16948615
DOI: 10.1146/annurev.genom.6.080604.162315