The organic anion transporter family: from physiology to ontogeny and the clinic. (25/1551)

The organic anion transporter (OAT) family handles a wide variety of clinically important compounds (antibiotics, nonsteriodal anti-inflammatory drugs, etc.) and toxins. However, little is known about their appearance during development despite documented differences in the handling of anionic drugs among neonates, children, and adults. A similar spatiotemporal pattern of mRNA expression of the OATs (OAT1-4) during kidney development suggests that OAT genes may be useful in understanding the mechanisms of proximal tubule maturation. Moreover, OAT expression in unexpected extrarenal sites (e.g., spinal cord, bone, skin) has also been detected during development, possibly indicating a role for these transporters in the formation or preservation of extrarenal tissues. The cloning of these transporters also paves the way for computer-based modeling of drug-transporter interactions at the molecular level, potentially aiding in the design and assessment of new drugs. Additionally, increased understanding of single nucleotide polymorphisms in OATs and other transporters may eventually allow the use of a patient's expression profile and polymorphisms to individualize drug therapy.  (+info)

The shifting functional balance of patents and drug regulation. (26/1551)

Patents are often portrayed as the necessary reward to compensate pharmaceutical firms for the huge costs and risks associated with Food and Drug Administration (FDA)-mandated clinical trials of new drugs. But the relationship between the patent system and other regulation of drugs is more complex than this simple formulation suggests. Drug regulation operates in tandem with patents to make proprietary products profitable, and patents themselves increasingly threaten to limit profitability by diverting profits elsewhere. At the same time, resistance to high drug prices is prompting new state and federal regulatory initiatives that threaten to reduce the value of drug patents. The distinctive intertwining of patents with other regulatory regimes and the shifting role of patents in the biopharmaceutical sector call into question how this singular success story for innovation policy will play out in the future.  (+info)

High-throughput genomic and proteomic analysis using microarray technology. (27/1551)

BACKGROUND: High-density microarrays are ideally suited for analyzing thousands of genes against a small number of samples. The next step in the discovery process is to take the resulting genes of interest and rapidly screen them against thousands of patient samples, tissues, or cell lines to further investigate their involvement in disease risk or the response to medication. METHODS: We used a microarray technology platform for both single-nucleotide polymorphisms (SNPs) and protein expression. Each microarray contains up to 250 elements that can be customized for each application. Slides contained either a 16- or 96-microarray format (4000-24,000 elements per slide), allowing the corresponding number of samples to be rapidly processed in parallel. RESULTS: Results for SNP genotyping and protein profiling agreed with results of restriction fragment length polymorphism (RFLP) analysis or ELISA, respectively. Genotyping analyses, using the microarray technology, on large sample sets over multiple polymorphisms in the NAT2 gene were in full agreement with traditional methodologies, such as sequencing and RFLP analysis. The multiplexed protein microarray had correlation coefficients of 0.82-0.99 (depending on analyte) compared with ELISAs. CONCLUSIONS: The integrated microarray technology platform is adaptable and versatile, while offering the high-throughput capabilities needed for drug development and discovery applications.  (+info)

Pharmacogenetics. (28/1551)

Pharmacogenetics is the variability of drug response due to inherited characteristics in individuals. Drug metabolizing enzymes have been studied for decades, first as chemical reactions and, more recently, as specific polymorphisms of known molecules. With the availability of whole-genome single-nucleotide polymorphism (SNP) maps, it will soon be possible to create an SNP profile for patients who experience adverse events (AEs) or who respond clinically to the medicine (efficacy). Proof-of-principle experiments have demonstrated that high density SNP maps in chromosomal regions of genetic linkage facilitate the identification of susceptibility disease genes. Whole-genome SNP mapping analyses aimed at determining linkage disequilibrium (LD) profiles along an ordered human genome backbone are in progress. SNP 'fingerprints' or SNP PRINTs(sm) will be used to identify patients at greater risk of an AE, or those patients with a greater chance of responding to a medicine. As LD maps for various ethnic populations are constructed, the number of SNPs necessary to measure for an individual will decrease. Standardized pharmacogenetic maps for drug registration and post-marketing surveillance will result in safer, more effective and more cost-efficient medicines. The timing of these pharmacogenetic applications will occur over the next 5 years. In contrast, the benefits of pharmacogenomic applications such as the identification of new tractable targets will not be visible as new medicines for 7-12 years, due to the lengthy drug development and registration processes.  (+info)

Searching for pharmacogenomic markers: the synergy between omic and hypothesis-driven research. (29/1551)

With 35,000 genes and hundreds of thousands of protein states to identify, correlate, and understand, it no longer suffices to rely on studies of one gene, gene product, or process at a time. We have entered the "omic" era in biology. But large-scale omic studies of cellular molecules in aggregate rarely can answer interesting questions without the assistance of information from traditional hypothesis-driven research. The two types of science are synergistic. A case in point is the set of pharmacogenomic studies that we and our collaborators have done with the 60 human cancer cell lines of the National Cancer Institute's drug discovery program. Those cells (the NCI-60) have been characterized pharmacologically with respect to their sensitivity to >70,000 chemical compounds. We are further characterizing them at the DNA, RNA, protein, and functional levels. Our major aim is to identify pharmacogenomic markers that can aid in drug discovery and design, as well as in individualization of cancer therapy. The bioinformatic and chemoinformatic challenges of this study have demanded novel methods for analysis and visualization of high-dimensional data. Included are the color-coded "clustered image map" and also the MedMiner program package, which captures and organizes the biomedical literature on gene-gene and gene-drug relationships. Microarray transcript expression studies of the 60 cell lines reveal, for example, a gene-drug correlation with potential clinical implications--that between the asparagine synthetase gene and the enzyme-drug L-asparaginase in ovarian cancer cells.  (+info)

Candidate genes and single nucleotide polymorphisms (SNPs) in the study of human disease. (30/1551)

The genomic revolution has generated an extraordinary resource, the catalog of variation within the human genome, for investigating biological, evolutionary and medical questions. Together with new, more efficient platforms for high-throughput genotyping, it is possible to begin to dissect genetic contributions to complex trait diseases, specifically examining common variants, such as the single nucleotide polymorphism (SNP). At the same time, these tools will make it possible to identify determinants of disease with the expectation of eventually, tailoring therapies based upon specific profiles. However, a number of methodological, practical and ethical issues must be addressed before the analysis of genetic variation becomes a standard of clinical medicine. The currents of variation in human biology are reviewed here, with a specific emphasis on future challenges and directions.  (+info)

Invited review: Pharmacogenetics of estrogen replacement therapy. (31/1551)

There are a number of genetic factors that likely modulate both the beneficial and adverse effects of estrogen. An important domain of consideration is the relationship of estrogen and thrombosis risk. Gene polymorphisms among the key elements of the coagulation and fibrinolytic cascade appear to influence the effects of estrogen on risk for venous thromboembolic events and possibly arterial thrombosis as well. Emerging data also suggest that allelic variants in the estrogen receptor-alpha may modulate estrogen's effects, especially with respect to bone and lipid metabolism.  (+info)

Pharmacogenetics of anticancer drugs in non-Hodgkin lymphomas. (32/1551)

The variability of tumour responses to chemotherapeutic agents is a topic of major interest in current oncology research. Advances in the knowledge of molecular pathology of cancer make available strategies by which tumour cells can be profiled for their genetic background in order to select anticancer agents that might selectively kill cells in a molecular context that matches the mechanism of action of drugs. The next generation of anticancer treatments might thus be tailored on the basis of the numerous molecular alterations identified in tumour cells of a particular patient. However, to exploit these alterations, it is necessary to understand how they influence the cellular pathways that control the sensitivity or, conversely, resistance to chemotherapeutic agents. The aim of this article is to outline major genetic abnormalities in non-Hodgkin lymphomas that can be used to streamline anticancer drug selection and to underscore the major role of pharmacogenetics, which studies the interactions between genetic background and drug activity, to the prediction of likelihood of response and identification of potential new targets for pharmacological intervention.  (+info)