Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate.
(65/1551)
BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common mutation of the gene encoding the enzyme that catalyzes reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor in the metabolism of folate, determines a striking reduction in the enzyme activity in carriers of mutation at homozygous status. PATIENTS AND METHODS: We retrospectively analyzed the incidence of MTHFR C677T and the influence of genotype on methotrexate (MTX) toxicity in patients with acute leukemia undergoing maintenance chemotherapy. Seventy-eight patients were analyzed and 61 were evaluable for toxicity. MTX toxicity was assessed on bone marrow, liver and mucosae. RESULTS: The incidence of the C677T mutation was as expected in the general Italian population with 23.08% of patients being TT, 38.46% of patients CT and 38.46% of patients CC. The TT genotype was significantly associated with an increase of toxicity during MTX administration. No specific pattern of toxicity was detected, although in TT patients myelosuppression and liver toxicity were more pronounced. CONCLUSIONS: TT genotype may indicate a need to reduce the dose of MTX during prolonged administration. Considering the high prevalence of homozygous individuals in the Italian population, pretreatment screening may be worthwhile. (+info)
Ethical reflections on pharmacogenetics and DNA banking in a cohort of HIV-infected patients.
(66/1551)
The aim of this study was to analyse ethical issues concerning the storage of human biological samples to be used in genetic analyses and pharmacogenetic research based on a French experience of DNA banking in a cohort of human immunodeficiency virus (HIV)-infected patients started on a protease inhibitor-containing treatment. We describe the ethical issues raised during the establishment of a DNA bank, including questions dealing with autonomy, benefit to the patient, information sharing and confidentiality as well as guarantees concerning the storage and use of DNA. The practical applications of themes illustrated theoretically in the literature are discussed. Most of the points raised are not specific to HIV, but some of them may be more accurate due to the characteristics of the HIV population, which is more involved in the social debate through the community life and the increased risk of stigmatization. Our results are summarized in the memorandum and consent form presented in the Appendices. One issue still open to discussion is the way the results of genetic data will be given to the patients. This work should allow other researchers and members of evaluation committees to enrich their considerations and should stimulate discussion on this topic. (+info)
Will pharmacogenetics allow better prediction of methotrexate toxicity and efficacy in patients with rheumatoid arthritis?
(67/1551)
Methotrexate (MTX) remains the most commonly used disease modifying antirheumatic drug in rheumatoid arthritis (RA) because of its cost and experience in its use, despite the availability of new treatments such as leflunomide and the biological agents. However, a significant number of patients with RA either do not benefit from the drug or are unable to tolerate it. Pharmacogenetic approaches may help optimise treatment with MTX, and also other agents, in RA. (+info)
ADME-AP: a database of ADME associated proteins.
(68/1551)
Drug absorption, distribution, metabolism and excretion (ADME) often involve interaction of a drug with specific proteins. Knowledge about these ADME-associated proteins is important in facilitating the study of the molecular mechanism of disposition and individual response as well as therapeutic action of drugs. It is also useful in the development and testing of pharmacokinetics prediction tools. Several databases describing specific classes of ADME-associated proteins have appeared. A new database, ADME-associated proteins (ADME-AP), is introduced to provide comprehensive information about all classes of ADME-associated proteins described in the literature including physiological function of each protein, pharmacokinetic effect, ADME classification, direction and driving force of disposition, location and tissue distribution, substrates, synonyms, gene name and protein availability in other species. Cross-links to other databases are also provided to facilitate the access of information about the sequence, 3D structure, function, polymorphisms, genetic disorders, nomenclature, ligand binding properties and related literatures of each protein. ADME-AP currently contains entries for 321 proteins and 964 substrates. (+info)
The integration of molecular diagnostics with therapeutics. Implications for drug development and pathology practice.
(69/1551)
It is widely anticipated that during the next 5 years the molecular diagnostic industry will continue to grow at double-digit pace to meet increasing demand for personalized medicine. A wide variety of drugs in late preclinical and early clinical development are being targeted to disease-specific gene and protein defects that will require coapproval of diagnostic and therapeutic products by regulatory agencies. An increasingly educated public will demand more information about their predisposition for serious diseases and how these potential illnesses can be detected in an early stage when they can be arrested or cured with new therapies custom-designed for their individual clinical status. To respond to this demand, major pharmaceutical companies will partner with diagnostics companies or develop their own in-house capabilities that will permit efficient production of more effective and less toxic integrated personalized medicine drug and test products. For clinical laboratories and pathologists, this integration of diagnostics and therapeutics represents a major new opportunity to emerge as leaders of the new medicine, guiding the selection, dosage, route of administration, and multidrug combinations and producing increased efficacy and reduced toxicity of pharmaceutical products. (+info)
The heritability of antinociception: common pharmacogenetic mediation of five neurochemically distinct analgesics.
(70/1551)
The heritability of nociception and antinociception has been well established in the mouse. The pharmacogenetics of morphine analgesia are fairly well characterized, but far less is known about other analgesics. The purpose of this work was to begin the systematic genetic study of non-mu-opioid analgesics. We tested mice of 12 inbred mouse strains for baseline nociceptive sensitivity (49 degrees C tail-withdrawal assay) and subsequent antinociceptive sensitivity to systemic administration of (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate (U50,488; 10-150 mg/kg), a kappa-opioid receptor agonist; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzox azin-6-yl]-1-naphthalenylmethanone (WIN55,212-2; 0.5-480 mg/kg), a synthetic cannabinoid receptor agonist; epibatidine (7.5-150 microg/kg), a nicotinic receptor agonist; clonidine (0.1-5 mg/kg), an alpha(2)-adrenergic receptor agonist; and, for purposes of comparison, the prototypic mu-opioid receptor agonist, morphine (5-200 mg/kg). Robust interstrain variability was observed in nociceptive sensitivity and in the antinociceptive effects of each of the drugs, with extreme-responding strains exhibiting antinociceptive potencies differing up to 37-fold. Unexpectedly, we observed moderate-to-high genetic correlations of strain sensitivities to the five drugs (r = 0.39-0.77). We also found moderate-to-high correlations between baseline nociceptive sensitivity and subsequent analgesic response to each drug (r = 0.33-0.68). The generalizability of these findings was established in follow-up experiments investigating morphine and clonidine inhibition of formalin test nociception. Despite the fact that each drug activates a unique receptor, our results suggest that the potency of each drug is affected by a common set of genes. However, the genes in question may affect antinociception indirectly, via a primary action on baseline nociceptive sensitivity. (+info)
Functional genomics and gene microarrays--the use in research and clinical medicine.
(71/1551)
In the year 2000, the Human Genome Project Consortium presented the first complete draft of the human genome together with Celera Genetics. Since then, the so-called "post-genome era" has started. Microarrays are capable of profiling gene expression patterns of tens of thousands of genes in a single experiment and thus allow a systematic analysis of DNA and RNA variation. They seem likely to become a standard tool of both molecular biology research and clinical diagnostics. These prospects have attracted great interest and investment from both the public and private sectors. This review introduces the principle of microarray technology and gives an overview of its current and future potential in clinical medicine. (+info)
Privacy issues in personalized medicine.
(72/1551)
Pharmacogenomics is the emerging study of why individuals respond differently to drugs. It aims to replace the current 'one size fits all' therapeutic approach with 'personalized medicine' that will use pharmacogenomic tests to predict drug response. In a simple conceptualization, these tests challenge privacy as a result of two factors: how comprehensive is the test and how is the access to samples or digital information controlled. Point-of-care tests are likely to be limited in scope, fit seamlessly into medical records and do not raise qualitatively new ethical and privacy challenges. In order to define practically relevant pharmacogenomic predictive patterns however, large-scale clinical trials and research on human specimens will be required, resulting in large databases of genomic information. The genomic scans' magnitude, stability, implications to kin and ease of dissemination together represent a qualitatively different challenge compared to traditional, self-limited and often temporally transient medical information. (+info)