Assessing the cost-effectiveness of pharmacogenomics.
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The use of pharmacogenomics to individualize drug therapy offers the potential to improve drug effectiveness, reduce adverse side effects, and provide cost-effective pharmaceutical care. However, the combinations of disease, drug, and genetic test characteristics that will provide clinically useful and economically feasible therapeutic interventions have not been clearly elucidated. The purpose of this paper was to develop a framework for evaluating the potential cost-effectiveness of pharmacogenomic strategies that will help scientists better understand the strategic implications of their research, assist in the design of clinical trials, and provide a guide for health care providers making reimbursement decisions. We reviewed concepts of cost-effectiveness analysis and pharmacogenomics and identified 5 primary characteristics that will enhance the cost-effectiveness of pharmacogenomics: 1) there are severe clinical or economic consequence that are avoided through the use of pharmacogenomics, 2) monitoring drug response using current methods is difficult, 3) a well-established association between genotype and clinical phenotype exists, 4) there is a rapid and relatively inexpensive genetic test, and 5) the variant gene is relatively common. We used this framework to evaluate several examples of pharmacogenomics. We found that pharmacogenomics offers great potential to improve patients' health in a cost-effective manner. However, pharmacogenomics will not be applied to all currently marketed drugs, and careful evaluations are needed on a case-by-case basis before investing resources in research and development of pharmacogenomic-based therapeutics and making reimbursement decisions. (+info)
Genetic variations in human G protein-coupled receptors: implications for drug therapy.
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Numerous genes encode G protein-coupled receptors (GPCRs)-a main molecular target for drug therapy. Estimates indicate that the human genome contains approximately 600 GPCR genes. This article addresses therapeutic implications of sequence variations in GPCR genes. A number of inactivating and activating receptor mutations have been shown to cause a variety of (mostly rare) genetic disorders. However, pharmacogenetic and pharmacogenomic studies on GPCRs are scarce, and therapeutic relevance of variant receptor alleles often remains unclear. Confounding factors in assessing the therapeutic relevance of variant GPCR alleles include 1) interaction of a single drug with multiple closely related receptors, 2) poorly defined binding pockets that can accommodate drug ligands in different orientations or at alternative receptor domains, 3) possibility of multiple receptor conformations with distinct functions, and 4) multiple signaling pathways engaged by a single receptor. For example, antischizophrenic drugs bind to numerous receptors, several of which might be relevant to therapeutic outcome. Without knowing accurately what role a given receptor subtype plays in clinical outcome and how a sequence variation affects drug-induced signal transduction, we cannot predict the therapeutic relevance of a receptor variant. Genome-wide association studies with single nucleotide polymorphisms could identify critical target receptors for disease susceptibility and drug efficacy or toxicity. (+info)
The prevalence of avascular necrosis in patients treated with chemotherapy for testicular tumours.
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To study the prevalence of avascular necrosis in patients receiving chemotherapy for testicular cancer we invited 103 consecutive patients treated by chemotherapy to attend for MRI scan of the hips. Four of 47 (9% (CI 2-20%)) patients scanned and 4/103 (3.8% (CI 1-10%)) of patients invited to participate in the study had evidence of avascular necrosis. As not all patients in the study had completed the at risk period this equates to a 3-year actuarial risk of 6.3% (95% confidence limits (CI) 2.4-16.1). These data suggest that avascular necrosis is an uncommon but significant complication of chemotherapy including steroids as anti-emetics. (+info)
PharmGKB: the Pharmacogenetics Knowledge Base.
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The Pharmacogenetics Knowledge Base (PharmGKB; http://www.pharmgkb.org/) contains genomic, phenotype and clinical information collected from ongoing pharmacogenetic studies. Tools to browse, query, download, submit, edit and process the information are available to registered research network members. A subset of the tools is publicly available. PharmGKB currently contains over 150 genes under study, 14 Coriell populations and a large ontology of pharmacogenetics concepts. The pharmacogenetic concepts and the experimental data are interconnected by a set of relations to form a knowledge base of information for pharmacogenetic researchers. The information in PharmGKB, and its associated tools for processing that information, are tailored for leading-edge pharmacogenetics research. The PharmGKB project was initiated in April 2000 and the first version of the knowledge base went online in February 2001. (+info)
TTD: Therapeutic Target Database.
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A number of proteins and nucleic acids have been explored as therapeutic targets. These targets are subjects of interest in different areas of biomedical and pharmaceutical research and in the development and evaluation of bioinformatics, molecular modeling, computer-aided drug design and analytical tools. A publicly accessible database that provides comprehensive information about these targets is therefore helpful to the relevant communities. The Therapeutic Target Database (TTD) is designed to provide information about the known therapeutic protein and nucleic acid targets described in the literature, the targeted disease conditions, the pathway information and the corresponding drugs/ligands directed at each of these targets. Cross-links to other databases are also introduced to facilitate the access of information about the sequence, 3D structure, function, nomenclature, drug/ligand binding properties, drug usage and effects, and related literature for each target. This database can be accessed at http://xin.cz3.nus.edu.sg/group/ttd/ttd.asp and it currently contains entries for 433 targets covering 125 disease conditions along with 809 drugs/ligands directed at each of these targets. Each entry can be retrieved through multiple methods including target name, disease name, drug/ligand name, drug/ligand function and drug therapeutic classification. (+info)
Analysis of 20 mature ovarian cystic teratoma cases in postmenopausal women.
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OBJECTIVE: To study the incidence of malignant change, diagnosis and management of mature cystic teratomas in postmenopausal women. METHODS: Twenty cases of mature cystic teratoma in postmenopausal women admitted to our hospital between January 1977 and January 1997 was retrospectively reviewed and evaluated. RESULTS: The number of postmenopausal patients with mature cystic teratoma (20) accounted for 7.6% of the total number of patients with benign ovarian teratomas (263). There were 3 cases of malignant change, which were squamous carcinoma, carcinosarcoma, and digestive gland epithelial carcinoma. The incidence of malignant change was 15%. CONCLUSION: In postmenopausal women, mature ovarian cystic teratoma should be treated as lowly malignant and should be paid much attention. (+info)
Influence of clinical factors, diet, and drugs on the human upper gastrointestinal glutathione system.
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BACKGROUND: Glutathione (GSH) and the cytosolic glutathione S-transferases (GSTs) protect the gastrointestinal mucosa against the toxic effects of a wide variety of compounds, such as reactive oxygen species and electrophiles. AIMS: We wished to investigate the distribution along the upper gastrointestinal mucosa and the influence of clinical variables on components of the GSH system to learn more about factors which control its cytoprotective properties. METHODS: Antral and duodenal biopsies of normal appearing mucosa were collected from 202 patients (104 males, 98 females; mean age 62 years) undergoing upper gastrointestinal endoscopy. GSH content was examined by high pressure liquid chromatography, GST enzyme activity by 1-chloro-, 2, 4-dinitrobenzene conjugation, and levels of the GST classes alpha, pi, and theta by western blot. RESULTS: GSH, GST enzyme activity, and GST alpha levels were significantly lower (p<0.001) in the antrum than in the duodenum (antrum v duodenum: GSH 23.0 (0.7) v 35.0 (1.0) nmol/mg protein; GST activity 626 (19) v 832 (22) nmol/mg protein/min; GST alpha 4.5 (0.5) v 20.0 (0.7) microg/mg protein) while GST pi content was significantly higher (p<0.001) in antral than in duodenal biopsies (16.5 (0.7) v 11.2 (0.5) microg/mg protein). Antral GSH and GST activities were markedly lower in males compared with females (p<0.01). Some drugs (cisapride, diuretics, cortisol, analgesics) increased GST pi and GST alpha content but cytostatic drugs suppressed duodenal GST activity. High intake (>3 days a week) of vegetables enhanced duodenal GST alpha and GST pi and high intake of fruits the antral content of GST theta 1. CONCLUSIONS: The gastrointestinal GSH system represents the antitoxic barrier of the mucosa; its activity is influenced by localisation, sex, and drugs, and its enzymes are stimulated by a high intake of vegetables and fruits. (+info)
Exploring medication use to seek concordance with 'non-adherent' patients: a qualitative study.
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BACKGROUND: 'Concordance' has been proposed as a new approach towards sub-optimal medication use; however, it is not clear how this may be achieved in practice. AIM: To develop a strategy for understanding sub-optimal medication use and seek concordance during primary care consultations. DESIGN: A developmental qualitative study using a modified action research design. SETTING: Three Scottish general practices. METHOD: Patients using treatment sub-optimally and having poor clinical control were offered extended consultations to explore their situation. Their authority to make treatment decisions was made explicit throughout. Clinicians refined a consultation model during ten 'Balint-style' meetings that ran in parallel with the analysis. The analysis included all material from the consultations, meetings, and discussion with patients after the intervention. RESULTS: Three practitioners recorded 59 consultations with 24 adult patients. A six-stage process was developed, first to understand and then to discuss existing medication use. Understanding of medication use was best established using a structured exploration of patients' beliefs about their illness and medication. Four problematic issues were identified: understanding, acceptance, level of personal control, and motivation. Pragmatic interventions were developed that were tailored to the issues identified. Of the 22 subjects usefully engaged in the process, 14 had improved clinical control or medication use three months after intervention ceased. CONCLUSIONS: A sensitive, structured exploration of patients' beliefs can elucidate useful insights that explain medication use and expose barriers to change. Identifying and discussing these barriers improved management for some. A model to assist such concordant prescribing is presented. (+info)