Current Pharmaceutical Design - Volume 16, Issue 20, 2010

Pharmacogenomics represents one of the leading emerging translational sciences. It has been rapidly expanding over the past 20 years and especially following the completion of the Human Genome Project and the advent of high-throughput technologies (e.g. microarrays). This has led to a significant accumulation of new information (Fig. 1). Pharmacogenomics, has much to offer to faster drug target identification and evaluation, increasing drug specificity, reducing adverse drug reactions (ADRs) and improving genome-based patient stratification, with direct implications in patient quality of life and viability, clinical practice, drug development and pharmacoeconomics. The U.S.A. Food and Drug Administration (FDA) has already approved a number of pharmacogenomic tests and includes pharmacogenomic information in the labels of ˜10% of its approved drugs, many of which are anti-tumor agents [1]. Indeed, the significant role of pharmacogenomically guided selection of patient treatments is best exemplified in the oncology clinic, such as in the case of molecular targeted therapies. The latest advances in this rapidly evolving area and their clinical implications are presented in this Special Issue by Mountzios et al. [2]. Numerous other patient groups are starting to benefit from the advances in pharmacogenetics. Heart disease is a representative example of an area where significant work on pharmacogenetics is under way and promising findings are arising. For example, numerous genetic variants have been associated with presence/absence or levels of patient response as well as different ADRs to medications for heart disease. However, the biological complexity and multifactorial nature of heart disease together with current limitations in the pharmacogenomic research setting have hindered the transition of pharmacogenomic research findings to the clinic. Vafiadaki et al. are summarizing the latest advances in the field focusing on antihypertensive, antiarrhythmic, anticoagulant, and cholesterol-lowering drugs [3]. Representative large- and small-scale studies are included, the contradictory findings presented and ethnicity is introduced as an important additional parameter to be considered during the integration of pharmacogenetic tests to the cardiology clinic. As our understanding of the drug-genome interplay increases it is likely that environmental parameters will start being introduced to the drug-genome equation. In addition to an individual's ethnic background, sex is emerging as a key component especially in conditions differentially affecting males and females. Pitychoutis et al. are discussing the impact sex could have in pharmacogenetics using the example of depression and antidepressant response [4]. The rapidly accumulating data from phramacogenomic studies raise the need for the establishment of well structured, high-capacity, international pharmacogenomic databases along with clear, globally accepted guidelines. This will not only ensure high quality and comparability of datasets generated across the board, but will further enable easy access to those datasets and form the basis for future large scale metanalysis, ultimately expediting the generation of robust and clinically useful findings. Lagoumintzis et al. are presenting how the existing genetic databases can serve towards this direction [5]. Together with the need for large, carefully selected and well characterized patient cohorts, pharmacogenomic studies must be suitably designed to allow for sufficient statistical power and potentially seek the use of innovative statistical methodologies. Sato et al. highlight some of the important aspects related to the design and statistical analysis for pharmacogenomics studies or clinical trials incorporating biomarkers [6].

Even though treatment of several types of solid tumors has improved in the past few years with the introduction of molecular targeted agents in the therapeutic armamentarium of the medical oncologist, response rates to these agents are generally modest. Increasing evidence is now revealing that genetic factors are affecting patients' response to these therapeutic agents as well as the frequency and intensity of toxic reactions. Importantly, pharmacogenetic analysis is now required for the administration of several molecular targeted agents in clinical practice. For the vast majority of these agents, however, data remain purely experimental. Herein, we provide an overview of the genetic changes (mutations and polymorphisms) that have been associated with response to treatment with anticancer molecular targeted agents. Special emphasis is given on molecules (monoclonal antibodies and tyrosine kinase inhibitors) that target critical mediators in the epidermal growth factor receptor (EGFR), the human epidermal growth factor receptor 2 (HER2/ERBB2/NEU) and the vascular endothelial growth factor receptor (VEGFR) pathways. The true clinical utility of these applications remains to be proven in future prospective, randomized clinical trials in large patient cohorts of all different ethnic backgrounds.

Heart disease represents the primary cause of death worldwide, with mortality rates being predicted to remain constant within the next couple of decades. Cardiac disease treatment currently includes the administration of drugs, predominantly aiming at improving heart performance, through controlling heart rhythm, blood pressure, as well as reducing cholesterol and blood clotting. Despite, however, the medical advances that have led towards a better understanding of heart disease pathophysiology and the development of new therapeutic approaches, the degree of success of the available drug therapies varies among patients. Polymorphisms in a number of genes have been shown to result in differences in pharmacokinetics, pharmacodynamics and drug metabolism and have therefore been associated with response to drug treatment. The occurrence of adverse drug reactions represents another factor influencing the outcome of therapeutic treatments. While the influence of genetic polymorphisms in patient's response to heart disease drugs is being unveiled, the rapidly evolving field of pharmacogenetics is promising to aid clinicians in choosing the best suited drug/dose for each patient and the pharmaceutical companies in the design of better targeted, more effective new chemical compounds. In the near future individualized, targeted therapy will become part of clinical care routine maximizing patient therapeutic benefits and minimizing risks of adverse effects.

It is known that the frequency of men and women suffering from stress-related neuropsychiatric disorders is all but proportionally distributed. Notably, women are far more susceptible than men in the precipitation of depressive symptomatology. Some studies attribute this sex-specific vulnerability to the pronounced genetic predisposition that women may present towards the development of depressive disorders. Furthermore, clinical evidence support the notion that antidepressant response is also characterized by sex-specific manifestations; women may have a better outcome when treated with selective serotonin re-uptake inhibitors, in comparison to tricyclic antidepressants. Despite the fact that the contribution of the “genome” remains elusive when it comes to major depression, intriguing evidence has recently emerged pointing to sexually dimorphic influences of certain polymorphisms in genes related to the pathophysiology of major depression and antidepressant response, such as the serotonin transporter (5-HTT), serotonin 1A (5-HT1A) receptor, monoamine oxidase A (MAO-A) and others. Given that the ultimate goal of pharmacogenetics is to provide “tailor-made” pharmacotherapies based on the genetic makeup of an individual, the factor of “sex” needs to be carefully addressed in disorders that are characterized by sexspecific manifestations. The aim of the present article is to highlight the impact of sex in depression and in antidepressant pharmacoresponse by providing intriguing insights from the field of pharmacogenetics.

The completion of the human genome sequencing project and the establishment of new methods for the detection of point mutations have lead to a remarkable increase of sequence variants identification in a growing number of genes. As a result of this, a new field of research has emerged, pharmacogenomics, which deals with the influence of genetic variation on drug response by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. Genetic databases are continuously updated online repositories of mutation data, described for a single or more genes or specifically for a population or ethnic group. Genetic databases can also fulfil the mission of pharmacogenomics by helping elucidate gene function, estimate the prevalence of genes in populations, differentiate among subtypes of diseases, trace how genes may predispose to or protect against illnesses, and improve medical intervention. Therefore, it is expected that genetic databases will gradually assume an increasing importance in all aspects of genome medicine. This article aims to provide an update of the current and emerging types of genetic databases relevant to the field of pharmacogenomics. Moreover, the key elements that are holding back the field as well as the challenges that should be addressed in the near future are also commented.

Inter-individual variations in drug response are all-too common and, throughout medical history have often posed problems, many of them serious ones. The variations could stem from multiple factors, which include those of both the host (age, genetic and environmental factors) and disease (pathophysiological phenotypes, somatic mutations in case of cancers). The complex interplay of these factors can influence pharmacodynamic responses, such as adverse effects and efficacy, as well as pharmacokinetic manifestations through variability in drug absorption, distribution, metabolism and excretion. Recently, several potentially powerful tools to decipher such intricacies are emerging in various fields of science, and the translation of such knowledge to personalized medicine, called, in general, pharmacogenomics, has been promoted and has occasioned strong expectations from almost every sector of health care. However, at present, few biomarkers can predict which group of patients will respond positively, which will be non-responders and who might experience adverse reactions from the same medication and dosage. This review highlights several important aspects related to the design and statistical analysis for pharmacogenomics studies or clinical trials, which incorporate biomarkers. First, we review biomarker development: how biomarkers may be used as targets and the difference between prognostic and predictive markers. Second, in confirmatory clinical trials, we focus on issues related to study design for evaluating biomarkers and how they can be used to determine which patients might optimally benefit from a specific therapy. Finally, we review exploratory statistical screening techniques for detecting biomarkers in Phase I or pharmacokinetics studies.

Systems biology has emerged as a major trend in biological research during the past decade. As living organisms are described in more and more detail, it aims at filling the gap between understanding basic molecular processes and complex biological systems in which new properties often emerge from the combination of these elementary processes. This approach culminates in the development of computer-based mathematical models of physiological and pathophysiological processes. We review the state of the art in dynamic modelling, with emphasis on two complementary approaches: the modelling of small systems that is mostly developed by academic teams and aims at understanding generic biological properties, and the modelling of large systems that is mostly implemented by industrial companies and aims at the generation of new therapeutic strategies. We also provide an example of such large-scale modelling applied to the identification of drug targets for neurodegeneration.

Understanding of the roles of RNAs within the cell has changed and expanded dramatically during the past few years. Based on fundamentally new insights it is now increasingly possible to employ RNAs as highly valuable tools in molecular biology and medicine. At present, the most important therapeutic strategies are based on non-coding regulatory RNAs inducing RNA interference (RNAi) to silence single genes, and on modulation of cellular microRNAs (miRNAs) to alter complex gene expression patterns in diseased organs. Only recently it became possible to target therapeutic RNAi to specific organs via organotropic viral vector systems and we discuss the most recent strategies in this field, e.g. heart failure treatment by cardiac-targeted RNAi. Due to the peculiar biochemical properties of small RNA molecules, true therapeutic translation of results in vitro is more demanding than with small molecule drugs or proteins. Specifically, there is a critical requirement for extensive studies in animal models of human disease after pre-testing of the RNAi tools in vitro. This requirement likewise applies for miRNA modulations which have complex consequences in the recipient dependent on biochemical stability and distribution of the therapeutic RNA. Problems not yet fully solved are the prediction of targets and specificity of the RNA tools. However, major progress has been made to achieve their tissue-specific and regulatable expression, and breakthroughs in vector technologies from the gene therapy field have fundamentally improved safety and efficacy of RNA-based therapeutic approaches, too. In summary, insight into the molecular mechanisms of action of regulatory RNAs in combination with new delivery tools for RNA therapeutics will significantly expand our cardiovascular therapeutic repertoire beyond classical pharmacology.

Carbohydrates have been revealed to play fundamental roles in diverse biological phenomena, such as being recognition sites and biomarkers. Recently, ample nucleic acid aptamers guided for carbohydrate recognition have already been isolated and characterized through SELEX methodology. This review would like to present and discuss these aptamers toward recognizing various carbohydrate targets: monosaccharides, oligosaccharides, polysaccharides, aminoglycoside antibiotics and glycans from glycoproteins. High affinity carbohydrate aptamers that we survey herein might shed light on the development of a tool to augment drug discovery creations.

Since the 1960's much research has focused on biofilms, i.e. microbial-derived populations irreversibly attached to a surface and embedded in a self-produced polymeric matrix. In this matrix, microbial cells are protected from detrimental external factors such as heat, UV radiation and the host immune system. The most relevant biofilm-related property is the unusual high resistance to antimicrobial therapy, although the origin of this extreme resistance is still the subject of debate. Besides an overview of the main characteristics of biofilms, this review discusses the different resistance mechanisms that lead to increased biofilm-related morbidity and mortality. Adherent communities are involved in at least 65% of all human bacterial infections, particularly in cystic fibrosis and several nosocomial device- related infections. Even in healthy immunocompetent individuals, biofilm infections are rarely resolved and usually persist until the colonized surface is removed from the body. Fundamental research aiming to develop new anti-biofilm strategies will largely depend on the availability of appropriate in vitro models for production and quantification of biofilms. This review describes the most frequently used in vitro biofilm models with respect to the different pitfalls that can emerge from in vitro biofilm research. Despite extensive efforts, no antimicrobial drug has yet been found that completely eradicates adherent microbial populations. The advantages and disadvantages of the currently available therapies are described with a particular focus on antibiotics and biocides. The options and benefits of future antibiofilm therapies are discussed.