Pharmacogenomics in the treatment of epilepsy

Genetic variability has recently been implicated in the development of familial epilepsy syndromes and in heterogeneous responses of epilepsy patients to drug treatment. Mutations in distinct proteins have been shown to underlie the development of epilepsy, increase propensity for drug resistance, and alter drug metabolism. Improved understanding of how individual genetic variability may alter the efficacy of pharmacological therapeutic interventions is an important and timely goal. The investigation of relationships between genotype and patient responses to drug treatment is termed pharmacogenomics.     

Translational research on prolyl oligopeptidase inhibitors: the long road ahead

Despite the fact that some have passed early phases of clinical trials, no prolyl oligopeptidase inhibitors are currently on the market. Yet, since 2003, there has been a boost in patent applications claiming prolyl oligopeptidase inhibitors for the treatment of Alzheimer's and Parkinson's diseases, and other neurodegenerative and psychiatric disorders. While experts in the field call for innovative scaffolds to develop more potent inhibitors with more favorable properties, they also relate a lack of knowledge of the toxicology, bioavailability, pharmacokinetics and pharmacodynamics of existing compounds that hinders their assessment. Yet, with the current insights, it is difficult to correlate specific inhibitor effects with the postulated functions of prolyl oligopeptidase in the brain.     

Inhaled anti-infective chemotherapy for respiratory tract infections: Successes,challenges and the road ahead

One of the most common causes of illnesses in humans is from respiratory tract infections caused by bacterial, viral or fungal pathogens. Inhaled anti-infective drugs are crucial for the prophylaxis and treatment of respiratory tract infections. The benefit of anti-infective drug delivery via inhalation is that it affords delivery of sufficient therapeutic dosages directly to the primary site of infection, while minimizing the risks of systemic toxicity or avoiding potential suboptimal pharmacokinetics/pharmacodynamics associated with systemic drug exposure. This review provides an up-to-date treatise of approved and novel developmental inhaled anti-infective agents, with particular attention to effective strategies for their use, pulmonary pharmacokinetic properties and safety.     

Therapeutic options to treat sulfur mustard poisoning--the road ahead

For the past 15 years the international research community has conducted a basic and applied research program aimed at identifying a medical countermeasure against chemical threat vesicant, or blistering, agents. The primary emphasis of this program has been the development of therapeutic protection against sulfur mustard and its cutaneous pathology-blister formation. In addition to the work on a medical countermeasures, significant research has been conducted on the development of topical skin protectants and medical strategies for wound healing. This review will focus on the pharmacological strategies investigated, novel therapeutic targets currently under investigation and therapeutic approaches being considered for transition to advanced development. Additionally, we will review the expansion of our understanding of the pathophysiological mechanisms of mustard injury that has come from this research. While great strides have been made through these investigations, the complexity of the mustard insult demands that further studies extend the inroads made and point the way toward better understanding of cellular and tissue disruptions caused by sulfur mustard.     

Pharmacogenomics: questions and concerns

The progressively aging population in the western world, rising socioeconomic expenditure and increasing costs for the treatment of adverse drug reactions, lead to increasing pressure on public spending. The public acceptance of pharmacogenomics is high, therefore, because it promises individualized safe and effective treatment at lower cost. Pharmacogenomics studies the genetic polymorphisms that underlie the variability in drug response between individuals. Despite the great benefits being awaited from this new field, a number of ethical, social and legal concerns arise, which demand rapid strict international regulations in order to prevent discrimination or harm of any kind from society, industry, groups or individuals.     

Pharmacogenomics: questions and concerns

ABSTRACT

The progressively aging population in the western world, rising socioeconomic expenditure and increasing costs for the treatment of adverse drug reactions, lead to increasing pressure on public spending. The public acceptance of pharmacogenomics is high, therefore, because it promises individualized safe and effective treatment at lower cost. Pharmacogenomics studies the genetic polymorphisms that underlie the variability in drug response between individuals. Despite the great benefits being awaited from this new field, a number of ethical, social and legal concerns arise, which demand rapid strict international regulations in order to prevent discrimination or harm of any kind from society, industry, groups or individuals.     

Pharmacogenomics: The implementation phase

Pharmacogenomics makes use of genetic and genomic principles to facilitate drug discovery and development, and to improve drug therapy. Its goal is to attain optimal therapy for the individual patient. This article analyzes current trends in pharmacogenomics and asks how this new science affects drug development in the pharmaceutical industry and the clinical use of drugs.     

Pharmacogenomics: Bridging the gap between science and practice

ObjectiveTo educate pharmacists about principles and concepts in pharmacogenomics, clinical applications of pharmacogenomic information, and the social, ethical, and legal aspects of pharmacogenomics and to describe a Centers for Disease Control and Prevention (CDC)-supported pharmacogenomics education program for pharmacists and other health professionals.Data sourcesPrimary literature from PubMed, recommendations from the Food and Drug Administration and Evaluation of Genomic Applications in Practice and Prevention Working Group, prescribing information, websites of government agencies and professional organizations, and relevant textbooks.Study selectionNot applicable.Data extractionNot applicable.Data synthesisPrinciples and concepts of pharmacogenomic nomenclature, polymorphism types, and systematic approach to understanding polymorphisms were reviewed. Drug therapy for select therapeutic areas that highlight the applicability of pharmacogenomics are presented, including abacavir, selective serotonin reuptake inhibitors, tamoxifen, and warfarin. Challenges of translating pharmacogenomics into clinical practice included ethical, social, legal, and economic issues. We have developed a pharmacogenomics education program to disseminate evidence-based pharmacogenomics information and provide a resource for health professionals, including pharmacists.ConclusionPharmacists play a critical role in the education of patients and health professionals in the area of pharmacogenomics.     

Pharmacogenomics and Children

Pharmacogenomic research promises to permit the development and delivery of safer and more effective drugs. If children are to receive these benefits, as justice would demand that they should, children must be included in trials that assess the impact of genetic variation, changing patterns of gene expression over time, and the effects of administering drugs. The ethical and legal challenges to conducting the necessary research include concerns about vulnerability and issues of consent, the scientific validity of the studies and the larger policy question of priority setting. Proposed strategies for ensuring the appropriate conduct of this research include analysis of the ethics based on risks and harms rather than presence or absence of a disorder, the development of model substrates to conduct physiological testing more safely, and the consideration of the disposition and impact of individual study results. With appropriate study, ultimately the use of pharmacogenomic testing can become available for children in the clinical setting.     

Pharmacogenomics: implications and considerations for pharmacists

The Renaissance period of world history is analogous to the renewal of healthcare that will arise from pharmacogenomic discoveries. Just as geography, science, art and communication were reawakened by the works of Columbus, da Vinci, Michelangelo and Gutenberg; genetic science will revitalize the clinical role of pharmacists and generate new interest in pharmacy research and education.     

Pharmacogenomics: bench to bedside

Pharmacogenetics is the study of the role of inheritance in inter-individual variation in drug response. Since its origins in the mid-twentieth century, a major driving force in pharmacogenetics research has been the promise of individualized drug therapy to maximize drug efficacy and minimize drug toxicity. In recent years, the convergence of advances in pharmacogenetics with rapid developments in human genomics has resulted in the evolution of pharmacogenetics into pharmacogenomics, and led to increasing enthusiasm for the 'translation' of this evolving discipline into clinical practice. Here, we briefly summarize the development of pharmacogenetics and pharmacogenomics, and then discuss the key factors that have had an influence on - and will continue to affect - the translation of pharmacogenomics from the research bench to the bedside, highlighting the challenges that need to be addressed to achieve this goal.     

QSAR, diagnostic statistics and molecular modelling of 1,4-dihydropyridine calcium antagonists: a difficult road ahead.

Quantitative structure-activity relationships of a series of substituted 1,4-dihydropyridine calcium channel antagonists were studied. The analysis is difficult because of the problem of multicollinearity of substituent parameters, a high-leverage point, and position-dependent grouped observations. Canonical regression appears to be the method of choice. With respect to a maximum activity, it was shown that the following rank order of substituent parameters exists: Lipophilicity approximately ortho-position > inductivity > minimum width > meta-position. The molecular conformation of antagonists does not differ markedly (with exception of nifedipine derivatives and nimodipine), but differences seem to exist between the antagonists and the activator BAY K 8644.     

Pharmacogenomics and breast cancer

Germline variants can be used to study breast cancer susceptibility as well as the variable response to both drug and radiation therapy used in the treatment of breast cancer. In addition to germline high-penetrance mutations important in familial and hereditary breast cancer, a substantial component of breast cancer risk can be attributed to the combined effect of many low-risk germline polymorphisms involved in relevant pathways like those of DNA repair, adhesion, carcinogen and estrogen metabolism. Additionally, the identification of sequence variants in genes involved in response to chemotherapy and radiation treatment, has created the opportunity to apply genomics to individualized treatment. The continued insight into the molecular pathways involved in drug and radiation response has enabled progress in tailoring therapies in such a way as to both maximize efficacy and minimize toxicity. Polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters and drug targets can be used to predict toxicity and response to pharmacologic agents used in breast cancer treatment. Similarly, germline variants in genes involved in DNA repair, radiation-induced fibrosis and reactive oxygen species may be used to predict response to radiation therapy. As a result, pharmacogenomics is rapidly evolving to affect the entire spectrum of breast cancer management, influencing both prevention and treatment choices.