PharmGKB: understanding the effects of individual genetic variants

The Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB: http://www.pharmgkb.org) is devoted to disseminating primary data and knowledge in pharmacogenetics and pharmacogenomics. We are annotating the genes that are most important for drug response and present this information in the form of Very Important Pharmacogene (VIP) summaries, pathway diagrams, and curated literature. The PharmGKB currently contains information on over 500 drugs, 500 diseases, and 700 genes with genotyped variants. New features focus on capturing the phenotypic consequences of individual genetic variants. These features link variant genotypes to phenotypes, increase the breadth of pharmacogenomics literature curated, and visualize single-nucleotide polymorphisms on a gene's three-dimensional protein structure.     

PharmGKB: Understanding the Effects of Individual Genetic Variants

The Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB: http://www.pharmgkb.org) is devoted to disseminating primary data and knowledge in pharmacogenetics and pharmacogenomics. We are annotating the genes that are most important for drug response and present this information in the form of Very Important Pharmacogene (VIP) summaries, pathway diagrams, and curated literature. The PharmGKB currently contains information on over 500 drugs, 500 diseases, and 700 genes with genotyped variants. New features focus on capturing the phenotypic consequences of individual genetic variants. These features link variant genotypes to phenotypes, increase the breadth of pharmacogenomics literature curated, and visualize single-nucleotide polymorphisms on a gene's three-dimensional protein structure.     

Pharmacogenetics research network and knowledge base: 1st annual scientific meeting

The National Institute of General Medical Sciences of the National Institutes of Health recently established a collaborative group of scientists, called the Pharmacogenetics Research Network. Central to the network is a shared, state-of-the-art data repository, the Pharmacogenetics Knowledge Base (PharmGKB), which is housed at Stanford University. Network investigators deposit pharmacogenetic data into PharmGKB, after all individually identifying information has been removed. Contents of PharmGKB will be freely accessible to the scientific community, with the goal of forging new links between gene variation and drug response. An open scientific meeting was held recently to introduce the research community to the network and to invite academic and industry-based researchers to deposit data into PharmGKB. Featured at the meeting were summaries of research progress to date, as well as discussions of issues intimately related to pharmacogenetics research, namely ethics and relations with the biotechnology and pharmaceutical industries.     

Pharmacogenetics in drug discovery and development: a translational perspective

The ability to predict a patient's drug response on the basis of their genetic information is expected to decrease attrition during the development of new, innovative drugs, and reduce adverse events by being able to predict individual patients at risk. Most pharmacogenetic investigations have focused on drug-metabolism genes or candidate genes that are thought to be involved in specific diseases. However, robust new genetic tools now enable researchers to carry out multi-candidate gene-association and genome-wide studies for target discovery and drug development. Despite the expanding role of pharmacogenetics in industry, however, there is a paucity of published data. New forms of effective and efficient collaboration between industry and academia that may enhance the systematic collection of pharmacogenetic data are necessary to establish genetic profiles related to drug response, confirm pharmacogenetic associations and expedite the development of new drugs and diagnostic tests.     

Therapeutic drug monitoring and pharmacogenetic tests as tools in pharmacovigilance.

Therapeutic drug monitoring (TDM) and pharmacogenetic tests play a major role in minimising adverse drug reactions and enhancing optimal therapeutic response. The response to medication varies greatly between individuals, according to genetic constitution, age, sex, co-morbidities, environmental factors including diet and lifestyle (e.g. smoking and alcohol intake), and drug-related factors such as pharmacokinetic or pharmacodynamic drug-drug interactions. Most adverse drug reactions are type A reactions, i.e. plasma-level dependent, and represent one of the major causes of hospitalisation, in some cases leading to death. However, they may be avoidable to some extent if pharmacokinetic and pharmacogenetic factors are taken into consideration. This article provides a review of the literature and describes how to apply and interpret TDM and certain pharmacogenetic tests and is illustrated by case reports. An algorithm on the use of TDM and pharmacogenetic tests to help characterise adverse drug reactions is also presented. Although, in the scientific community, differences in drug response are increasingly recognised, there is an urgent need to translate this knowledge into clinical recommendations. Databases on drug-drug interactions and the impact of pharmacogenetic polymorphisms and adverse drug reaction information systems will be helpful to guide clinicians in individualised treatment choices.     

Pharmacogenetics of antidepressant and mood-stabilizing drugs: a review of candidate-gene studies and future research directions

Heterogeneity of clinical response to antidepressant and mood-stabilizing drugs and susceptibility to adverse effects are major clinical problems. It is reasonable to suggest a genetic contribution to these inter-individual differences. Thus, pharmacogenetic approaches could provide the clinician with tools to individualize pharmacotherapy. In this paper, published reports that address the genetic basis of response to antidepressant drugs and mood-stabilizing drugs are selectively reviewed. There is substantial support for the assumption that genetic factors play a role in response to lithium and a degree of support for a role of such factors in response to antidepressants. Based on a Medline search and access to papers accepted but not yet published, studies on the role of specific candidate genes are comprehensively evaluated. A number of studies from different groups point to a role for polymorphism of the serotonin transporter gene in the therapeutic response to specific serotonin reuptake inhibitors. There are reports of other candidate genes, particularly in the serotonergic system, but these have still to be replicated. There is little evidence thus far that points to a role for specific candidate genes in response to mood-stabilizing drugs. Future research directions including the selection of relevant candidate genes, pivotal issues in the design of studies and high throughput methods of analysis are discussed in the light of the findings. Although pharmacogenetic approaches have great potential in the treatment of major depression and bipolar disorder, substantial further research is needed. Careful attention needs to be paid to research design issues and potential confounding factors such as population stratification. High throughput, genome-wide approaches could greatly accelerate the acquisition of relevant data but their success is dependent on the availability of appropriate clinical samples.     

Applications of pharmacogenetics in psychiatry: personalisation of treatment

In spite of the lack of epidemiological information, pharmacogenetic research has produced evidence of the relationship between genes and treatment response. Genetic variants of metabolic enzymes are related to toxic reactions; polymorphisms in genes coding for drug-targeted neurotransmitter receptors influence therapeutic efficacy. Also, recent studies have shown that response to antipsychotic drugs can be predicted by looking at the individual's pharmacogenetic profile. In addition to providing the first evidence that treatment response can be predicted by looking at a core of key genes, these studies illustrate the feasibility of individualisation of psychiatric treatment.     

Functional analysis of gene expression in risperidone treated cells provide new insights in molecular mechanism and new candidate genes for pharmacogenetic studies

Risperidone is a potent antagonist of both dopamine and serotonin receptors. However, little is known about the underlying molecular mechanism by which risperidone acts. Although a number of genetic variants have been observed to correlate with treatment response there are no definitive predictors of response. We performed a genome-wide gene expression analysis (Human Genome U219 Array Plate) of a human neuroblastoma cell line (SK-N-SH) exposed to risperidone to identify molecular mechanisms involved in the cellular response to risperidone and thus identify candidate genes for pharmacogenetic studies. Our results revealed that cellular risperidone treatment is associated with a range of gene expression changes, which are time (6–48 h) and dose related (0.1–10 μM). We found that functional clusters of these changes correspond to Gene Ontology categories related to neural cell development functions, and synaptic structure and functions. We also identified Canonical Pathways related to these functional categories: neurogenesis and axon guidance; synaptic vesicle; and neurotransmitter signaling (dopamine, serotonin and glutamate). Finally, we identified candidate genes for pharmacogenetic studies related to the main risperidone secondary effects: motor disorders, cardiovascular disorders and metabolic disorders. Our results suggest that risperidone treatment affects the neurogenesis and neurotransmission of neuroblastoma cells, which is in agreement with the “initiation and adaptation” model to explain the mechanism of action of psychotropic drugs.     

Drug receptor/effector polymorphisms and pharmacogenetics: current status and challenges

The pharmacogenetics literature of drug receptors and effector proteins is in its relative infancy compared to that of drug metabolism pharmacogenetics. Nonetheless, in a short time period, numerous studies have demonstrated that receptor/effector polymorphisms contribute to variable drug response. We review the current status, and list challenges that confront drug target pharmacogenetics before we can use genetic information in drug-therapy decision-making. We focus our review on G protein coupled receptors (GPCRs), which represent over 50% of all drug targets, and use specific examples from the beta-adrenergic receptor pharmacogenetic literature to illustrate important issues. Recent resequencing efforts of GPCR genes suggest that they have more coding region and nonsynonymous polymorphisms than non-GPCR genes, thus making GPCRs important foci for pharmacogenetic investigation. Our inability to use drug target genetic information to guide in the selection of drug therapy is due to several factors, including (i) the relatively subtle functional effects of the single gene polymorphisms, which do not account for enough of the drug response variability to accurately predict response and (ii) inconsistencies between studies. The latter may be due to some studies having inadequate sample sizes, studying different drug response phenotypes and patient populations, difficulties in identifying and measuring a valid drug response phenotype, and focusing on single polymorphisms in single genes, rather than haplotypes or multiple genes. To move the field to the point of clinical application, future studies will need to be larger, and will have to consider the complexity of the drug response, either by inclusion of polymorphisms from signal transduction proteins and other proteins relevant to the drug response, or through a genomics approach. Finally, the literature suggests that, for those drugs with multiple pharmacologic effects, or effects in multiple organs, the genetic contribution to each drug response phenotype will have to be considered separately. The knowledge necessary to move forward on all these fronts is not yet available, but will be increasingly accessible over the next few years.     

Pharmacotherapy of obesity: emerging drugs and targets

Background: Obesity and its associated morbidities are the effects of imbalance between energy intake and expenditure. Present drugs either regulate food intake by acting on neural circuits or reduce nutrient absorption from gut. These approaches have shown moderate success, with several safety concerns, leaving an unmet need for effective and safe therapy for obesity. Objective: To provide a brief background on obesity, summarize approved drugs and give an overview of emerging therapeutic targets, their potential benefits and disadvantages. Methods: A review based on information available from medical literature. Conclusions: Potential anti-obesity targets investigated can be classified into five broad categories: i) decreasing appetite through central action; ii) increasing metabolic rate or affecting metabolism through peripheral action; iii) modulating gut peptide receptors; iv) modulating targets to affect overall cardiometabolic parameters; and v) combination therapies directed against several targets.     

Vascular endothelial growth factor pharmacogenetics: a new perspective for anti-angiogenic therapy

The pharmacogenetic approach to anti-angiogenic therapy should be considered a possible strategy for many pathological conditions with high incidence in Western countries, including solid tumors, age-related macular degeneration or endometriosis. While pharmacogenetic studies are building stronger foundations for the systematic investigations of phenotype-genotype relationships in many research and clinical fields of medicine, pharmacogenetic data regarding anti-angiogenic drugs are still lacking. Here we review preclinical and clinical genetic studies on angiogenic determinants such as vascular endothelial growth factor and vascular endothelial growth factor receptor-2. We suggest that pharmacogenetic profiling of patients who are candidates for the currently available anti-angiogenic agents targeting vascular endothelial growth factor and vascular endothelial growth factor receptor-2 may aid the selection of patients on the basis of their likelihood of responding to the drugs or suffering from toxicity.     

Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy

Genetic factors contribute to the phenotype of drug response, but the translation of pharmacogenetic outcomes into drug discovery, drug development or clinical practice has proved to be surprisingly disappointing. Despite significant progress in pharmacogenetic research, only a few drugs, such as cetuximab, dasatinib, maraviroc and trastuzumab, require a pharmacogenetic test before being prescribed. There are several gaps that limit the application of pharmacogenetics based upon the complex nature of the drug response itself. First, pharmacogenetic tests could be more clinically applicable if they included a comprehensive survey of variation in the human genome and took into account the multigenic nature of many phenotypes of drug disposition and response. Unfortunately, much of the existing research in this area has been hampered by limitations in study designs and the nonoptimal selection of gene variants. Secondly, although responses to drugs can be influenced by the environment, only fragmentary information is currently available on how the interplay between genetics and environment affects drug response. Third, the use of a pharmacogenetic test as a standard of care for drug therapy has to overcome significant scientific, economic, commercial, political and educational barriers, among others, in order for clinically useful information to be effectively communicated to practitioners and patients. Meanwhile, the lack of efficacy is in this process is quite as costly as drug toxicity, especially for very expensive drugs, and there is a widespread need for clinically and commercially robust pharmacogenetic testing to be applied. In this complex scenario, therapeutic drug monitoring of parent drugs and/or metabolites, alone or combined with available pharmacogenetic tests, may be an alternative or complementary approach when attempts are made to individualize dosing regimen, maximize drug efficacy and enhance drug safety with certain drugs and populations (e.g. antidepressants in older people).     

Anti-emetic drugs in oncology: pharmacology and individualization by pharmacogenetics

Objective Nausea and vomiting are the most distressful side effects of cytotoxic drugs in cancer patients. Antiemetics are commonly used to reduce these side effects. However, the current antiemetic efficacy is about 70?C80% in patients treated with highly-emetogenic cytotoxic drugs. One of the potential factors explaining this suboptimal response is variability in genes encoding enzymes and proteins which play a role in metabolism, transport and receptors related to antiemetic drugs. Aim of this review was to describe the pharmacology and pharmacogenetic concepts of of antiemetics in oncology. Method Pharmacogenetic and pharmacology studies of antiemetics in oncology published between January 1997 and February 2010 were searched in PubMed. Furthermore, related textbooks were also used for exploring the pharmacology of antiemetic drugs. The antiemetic drugs which were searched were the 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs), dopamine antagonists, corticosteroids, benzodiazepines, cannabinoids, antihistamines and neurokinin-1 antagonists. Result The 5-HT3RAs are widely used in highly emetogenic chemotherapy in combination with dexamethasone and a neurokinin-1 antagonist, especially in acute phase. However, the dopamine antagonists and benzodiazepines were found more appropriate for use in breakthrough and anticipatory symptoms or in preventing the delayed phase of chemotherapy induced nausea and vomiting. The use of cannabinoids and antihistamines need further investigation. Only six articles on pharmacogenetics of the 5-HT3RAs in highly emetogenic chemotherapy are published. Specifically, these studies investigated the association of the efficacy of 5-HT3RAs and variants in the multi drug resistance 1 (MDR1) gene, 5-HT3A,B and C receptor genes and CYP2D6 gene. The pharmacogenetic studies of the other antiemetics were not found in this review. Conclusion It is concluded that pharmacogenetic studies with antiemetics are sparse. It is too early to implement results of pharmacogenetic association studies of antiemetic drugs in clinical practice: confirmation of early findings is required.     

Risk classification systems for drug use during pregnancy: are they a reliable source of information?

BACKGROUND: In several countries, risk classification systems have been set up to summarise the sparse data on drug safety during pregnancy. However, these have resulted in ambiguous statements that are often difficult to interpret and use with accuracy when counselling patients on drug use in pregnancy. OBJECTIVES: The objective of this study was to compare and analyse the consistency between and the criteria for risk classification for medications used during pregnancy included in 3 widely used international risk classification systems. All 3 systems use categories based on risk factors to summarise the degree to which available clinical information has ruled out the risk to unborn offspring, balanced against the drug's potential benefit to the patient. METHODS: Drugs included in the risk classification systems from the US Food and Drug Administration (FDA), the Australian Drug Evaluation Committee (ADEC) and the Swedish Catalogue of Approved Drugs (FASS), were reviewed and compared on basis of the risk factor category to which they had been assigned. Agreement between the systems was calculated as the number of drugs common to all 3 and assigned to the same risk factor category. In addition, evidence on teratogenicity and adverse effects during pregnancy was retrieved using a MEDLINE search (from 1966 up to 1998) for common drugs classified as teratogenic. RESULTS: Differences in the allocation of drugs to different risk factor categories were found. Risk factor category allocation for 645 drugs classified by the FDA, 446 classified by ADEC and 527 classified by FASS was compared. Only 61 (26%) of the 236 drugs common to all 3 systems were placed in the same risk factor category. Analysis of studies on the safety of common drugs during pregnancy of drugs classified as X by the FDA indicated that the variability in category allocation was not only attributable to the different definitions for the categories, but also depended on how the available scientific literature was handled. CONCLUSIONS: Differences in category allocation for the same drug can be a source of great confusion among users of the classification systems as well as for those who require information regarding risk for drug use during pregnancy, and may limit the usefulness and reliability of risk classification systems.     

Personalized medicine: is it a pharmacogenetic mirage?

The notion of personalized medicine has developed from the application of the discipline of pharmacogenetics to clinical medicine. Although the clinical relevance of genetically-determined inter-individual differences in pharmacokinetics is poorly understood, and the genotype-phenotype association data on clinical outcomes often inconsistent, officially approved drug labels frequently include pharmacogenetic information concerning the safety and/or efficacy of a number of drugs and refer to the availability of the pharmacogenetic test concerned. Regulatory authorities differ in their approach to these issues. Evidence emerging subsequently has generally revealed the pharmacogenetic information included in the label to be premature. Revised drugs labels, together with a flurry of other collateral activities, have raised public expectations of personalized medicine, promoted as 'the right drug at the right dose the first time.' These expectations place the prescribing physician in a dilemma and at risk of litigation, especially when evidence-based information on genotype-related dosing schedules is to all intent and purposes non-existent and guidelines, intended to improve the clinical utility of available pharmacogenetic information or tests, distance themselves from any responsibility. Lack of efficacy or an adverse drug reaction is frequently related to non-genetic factors. Phenoconversion, arising from drug interactions, poses another often neglected challenge to any potential success of personalized medicine by mimicking genetically-determined enzyme deficiency. A more realistic promotion of personalized medicine should acknowledge current limitations and emphasize that pharmacogenetic testing can only improve the likelihood of diminishing a specific toxic effect or increasing the likelihood of a beneficial effect and that application of pharmacogenetics to clinical medicine cannot adequately predict drug response in individual patients.     

Pharmacogenetics in transplant patients: can it predict pharmacokinetics and pharmacodynamics?

Pharmacogenetics holds the potential to allow individualized dosing of immunosuppressive agents to optimize their therapeutic effect while minimizing adverse effects. As more pharmacogenetic information accumulates, the prospect of reducing or discontinuing the intensive therapeutic drug monitoring of immunosuppressants looks attractive. However, the long process of developing useful clinical information from basic information on the genes of interest is at a very early stage, and our present information does not supercede pharmacokinetic or blood concentration monitoring of immunosuppressants. The most extensive blood concentration/dose information available is on tacrolimus and its dosing related to CYP3A5 and ABCB1 gene polymorphisms. Although CYP3A5 genotype is definitely associated with tacrolimus dosing, the only recommendation presently published is for an arbitrary doubling of the starting tacrolimus dose in CYP3A5 expressors. For cyclosporine, sirolimus, and corticosteroids, the presently available pharmacogenetic information does not permit pharmacokinetic predictions. The pharmacodynamics of immunosuppressants, as evidenced by effects on acute rejection or adverse drug effects, have considerably more potential for prediction by pharmacogenetic models. Drug-resistant rejection, nephrotoxicity, steroid resistance and osteonecrosis, and even patient survival may ultimately be predicted by models incorporating multiple gene polymorphisms and other critical patient information. At this point, treatment algorithms can be developed that will allow us to individualize a transplant patient's immunosuppressive therapy.     

Pharmacogenetics and immunosuppressive drugs

Several candidate genes have been proposed as potential biomarkers for altered pharmacodynamics or pharmacokinetics of immunosuppressive drugs. However, there is usually only limited clinical evidence substantiating the implementation of biomarkers into clinical practice. Testing for thiopurine-S-methyltransferase polymorphisms has been put into routine clinical use quite widely, while the other pharmacogenetic tests are much less frequently used. Relatively good evidence appeared for tacrolimus-related biomarkers; thus, their utilization may be envisaged in the near future. Although the biomarkers related to mycophenolate, sirolimus or other drugs in the therapeutic class may be promising, further research is necessary to provide more robust evidence. The present review focuses on immunosuppressive drugs, excluding biological treatment.     

眼科药物合理应用的研究

目的综合分析各影响因素，为眼科药物的合理应用提供参考。方法对治疗眼疾药物进行分类研究，探索眼器官各部位对眼药的生物利用度，进而综合评价眼药的合理应用。结果根据眼疾发作的多因性，可将眼药按治疗功能划分为五大类，眼睛中各部位对眼药的生物利用度存在一定的差异，所以针对不同的病因及发病情况，选用合适的眼药进行治疗。结论选择合适的治疗药物及治疗方法，对眼疾进行针对性治疗。     

Drug interaction management

Although thousands of articles on drug interactions have been published and numerous computerized screening systems have been developed, patients continue to suffer from adverse drug interactions. Possible methods for reducing the risk of drug interactions include improving the knowledge of health care providers, improving computerized screening systems, providing information on patient risk factors, increased use of pharmacogenetic information, more attention to drug administration risk factors, and improving patient education on drug interactions.