M Pirmohamed

..These studies show increased activity of Th2 cytokines in CD4+ and CD8+ T cells from individuals with allergic contact dermatitis...

....

....

....

..Carbamazepine hypersensitivity is immune-mediated, although factors determining its occurrence and severity are unknown...

..The overall clinical utility of genotyping in preventing ADRs needs to be proven by the use of prospective randomized controlled clinical trials...

..These standardized criteria will be important in facilitating adequate and accurate patient recruitment in order to advance research in pharmacogenomic, immunological, mechanistic, and epidemiological studies...

....

..Nevertheless, this clinical evidence has to be regarded as being circumstantial and more direct experimental evidence is required to understand the role of 'danger' in the overall pathogenesis of drug hypersensitivity reactions...

..Three phenotypes have been considered in this initial phase: drug-induced liver injury, drug-induced skin injury, and drug-induced torsade de pointes...

....

..In this article, I explore the history of pharmacogenetics, appraise the current state of research in this area, and finish off with suggestions for progressing in the field in the future...

..Further studies that address these deficiencies are urgently needed--only then will prospective P450 genotyping become routine in clinical practice...

..Our results show that genetic polymorphisms in drug metabolizing enzymes are unlikely to be major predisposing factors in determining individual susceptibility to co-trimoxazole hypersensitivity in HIV-positive patients...

..This avenue of research is destined to lead to better preventive strategies...

..To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital...

..Alcohol misuse is a major drain on the resources of the NHS. Strategies that are adequately resourced are urgently needed to be able to cope with the burden of alcohol-related illness...

..The implementation of education, screening and intervention strategies in A&E departments, and employment of key trained personnel, should be considered, to optimize the clinical management of these patients...

..Our findings suggest that HLA testing before carbamazepine therapy would be effective at identifying individuals at risk of hypersensitivity and applicable to multiple populations providing hope for prevention in the future...

..PUD distribution varied (P = 0.024) according to CYP2C19*17 genotype: *1/*1, 490 (64.3%); *1/*17, 304 (71.7%); and *17/*17, 31 (73.8%). CYP2C19*17, a gain-of-function polymorphism, is associated with PUD irrespective of etiology...

..These studies demonstrate the antigenicity of nitroso sulphamethoxazole in vivo and provide evidence for the role of drug metabolism and cell surface haptenation in the induction of a cellular immune response in the rat...

..Further research is required to improve the evidence base and to generate data on clinical validity and clinical utility...

....

..The purpose of this review is to assess critically the evidence to support the hapten mechanism, and also to consider alternative mechanisms by which drugs cause idiosyncratic toxicity...

..This did not affect the kinetic parameters of lymphocyte microsomal epoxide hydrolase. Our results suggest that there is normal HYL1 activity in lymphocytes of hypersensitive patients using cis-stilbene oxide as a substrate...

..Future studies should aim for a more comprehensive assessment of this pathway, while further research is also required in determining the functional effects of these genetic variants...

..Its efficacy is unlikely to be affected by Pgp over-expression in the brain. Furthermore, the interaction of CBZ with drugs that modulate both CYP3A4 and Pgp function such as verapamil is probably due to inhibition of CYP3A4 and not Pgp...

..A greater understanding of the mechanism(s) of hypersensitivity may identify novel therapeutic strategies and help to combat one of the more severe forms of adverse reactions to drugs...

..The objective of this study is to develop methodology to ascertain the current burden of ADRs through a prospective analysis of all unplanned admissions to a paediatric hospital...

..This is rapidly detoxified by microsomal epoxide hydrolase, the efficiency of which can be readily determined by measurement of the ratio of the stable metabolites, naphthalene 1,2-dihydrodiol and 1-naphthol...

..Recent data from Western countries indicate that the aetiology of peptic ulcer disease (PUD) is changing as the prevalence of Helicobacter pylori is decreasing while the use of low-dose aspirin (LDA, ≤325 mg/day) is increasing...

..In conclusion, the findings of the study expand on potential mechanisms of clozapine-induced cytotoxicity, which may be of relevance to the major forms of toxicity encountered in patients taking this drug...

....

..These studies characterize drug-specific T cells in CBZ-hypersensitive patients that are phenotypically different from T cells involved in other serious cutaneous adverse drug reactions...

..The long-term aim of such research is to provide test systems for the evaluation of drug safety and patient susceptibility to idiosyncratic drug toxicity...

..Further work in this area, in combination with other "-omics" technologies, is needed to develop tests that are both clinically useful and cost-effective...

..We therefore conclude that cimetidine may be safely used in patients with RA who are being treated with sulphasalazine...

....

..Our results show that TGZQ as well as TGZ yields reactive metabolites in vivo, and that bioactivation is enhanced by induction of P450 3A. However, hepatotoxicity is unlikely to be due to either TGZQ or its metabolites...

..In summary, our data suggest that the inhibition of the mevalonate pathway by statins may provide a potential therapeutic strategy to prevent AG-induced nephrotoxicity...

..The method can be used as a template for comparative estimations of bioactivation of any drug in patients...

..Our review points out the need for well-designed clinical studies on the efficacy and safety of medicines used in women of childbearing age in order to define the additional utility provided by pharmacogenetic testing...

..We hypothesized that variation in genes regulating adipogenesis, and in those implicated in inherited forms of lipodystrophy, may predispose to the development of HIVLD...

..This study provides a detailed characterisation of sites of chemical modification of an endogenous target and reveals candidate peptides for T-cell and antibody assays of flucloxacillin hypersensitivity...

..This will provide a deeper understanding of potential toxicophores for drug design and define candidate genes for pharmacogenomic approaches to individualized medicines...

....

..The reasons for this appear to be complex, though they may include insufficient guidelines from the nursing regulatory bodies, local political difficulties and a lack of consistency between educational establishments...

..5 +/- 0.06%, respectively. These data indicate that clozapine undergoes bioactivation in the heart to a chemically reactive nitrenium metabolite that may be important in the pathogenesis of myocarditis and cardiomyopathy observed in man...

..5 and 1 microM and 5 to 10 microM, respectively. The potential of SMX-NO to generate a potent antigen and cause cytotoxicity may in combination provide the signals necessary to induce a hypersensitivity reaction to SMX...

..Our data show that CD4(+) T-cells are involved in the pathophysiology of phenindione hypersensitivity. There may be cross-sensitivity with warfarin in some phenindione hypersensitive patients...

..0) with UV detection at 285 nm. The method is selective, reproducible and precise with a limit detection of 45 ng/ml and is suitable for the determination of CBZ in murine brain after intra-peritoneal administration...

..The growth response to recombinant human growth hormone (rhGH) in GH deficient (GHD) patients may be influenced by polymorphisms in the growth hormone receptor (GHR) gene...

..This study will aid the development of interventions to reduce the impact of ADRs in hospital in-patients...

..A variant in the CYP4F2 gene, rs2108622, has been recently shown to determine stable warfarin dose requirements. CYP4F2 has also been shown recently to metabolize vitamin K...

..In addition, it is necessary to advance our knowledge of hypersensitivity mechanisms through functional studies, which will lead to the development of predictive and diagnostic tests...

..We have therefore examined the evidence for the role of reactive metabolites in the three most common drug-induced toxicities: hepatotoxicity, skin reactions and blood dyscrasias...

..These data provide evidence of a link between localized metabolism, dendritic cell activation, and drug immunogenicity...

..These results highlight important differences in T-cell recognition of drug (metabolite) antigens in animals that have been sensitized against a drug metabolite and patients with hypersensitivity to the drug...

..The "danger signal" might result from chemical, physical, or viral stress...

....

..Furthermore, identification of large numbers of Vbeta 5.1(+) T cells suggests that polymorphisms within T-cell receptor genes might act as determinants of susceptibility...

..Amantadine/prazosin primed TKI cytotoxicity in vitro may be a useful test for the level of ER-releasable calcium, and may be of prognostic value...

..Additionally, many cannulae are inserted unnecessarily. This article seeks to review this area and to outline good medical practice...

..Further understanding of the pathogenesis of NSAID-induced ulcers is important to enable the development of novel and effective preventive strategies...

....

....

..The aim of this survey was to determine what measures general hospital NHS Trusts in England had in place to deal with alcohol-related problems, including the employment of dedicated alcohol specialist nurses...

..The various aspects of clinical pharmacology discussed make a strong case for this field as the backbone of optimising and promoting safe development and use of drugs...

..This paper reviews the epidemiology of ADRs in hospitals and evaluates the research that has been undertaken to date to prevent ADRs...

....

..The aim of the study was to determine whether functional polymorphisms in TNF, LTA, HSPA1L and HLA-DRB1 genes influence the risk of cotrimoxazole hypersensitivity in HIV-infected patients...

..The heat shock protein (HSP70) gene cluster is located in the MHC class III region...

..Our aim was to investigate whether single-nucleotide polymorphisms (SNPs) in 19 candidate genes were associated with tacrine-induced liver damage...

..Attempts to characterize drug-specific CD8(+) T cells have been largely unsuccessful...

..To test the role of acetylator status, and to investigate the reported discrepancy between acetylator phenotype and genotype in HIV-positive patients with sulphamethoxazole (SMX) hypersensitivity...

..Our aim was to confirm the presence of this genetic factor in our patients, and to determine whether genotyping for HLA B*5701 would be a cost-effective use of healthcare resources...

..4-15.0, z=2.3, p=0.02). Our findings suggest that nurses, who form the largest proportion of health-care staff in the UK, can play a valuable part in improvement of pharmacovigilance...

..CLINICAL IMPLICATIONS: Some patients with a history of carbamazepine hypersensitivity possess T cells that cross-react with oxcarbazepine, providing a rationale for cross-sensitivity between the 2 drugs...

....

..Larger numbers of patients need to be studied to fully evaluate the role of T cells in nevirapine-induced hepatitis and nevirapine hypersensitivity syndrome...

....

..These data identify Cys as the single target for PPD-HSA binding, and show that PPD protein adducts are antigenic determinants in patients with contact dermatitis...

..BB-specific T cells are found in both allergic patients and volunteers, but not in cord blood. Their presence seems to reflect an acquired immune response, which is not translated into an allergic reaction...

..The treatment of this condition with the antiviral agents ganciclovir, valganciclovir, foscarnet and cidofovir, can also be associated with significant systemic toxicity...

....

..A strong pharmacogenetic association has been reported in Chinese patients between human leukocyte antigen (HLA)-B*1502 and carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)...

..CONCLUSIONS: There is substantial variability in the expression of Pgp in human liver, but this is not due to the presence of C3435T and G2677T(A) polymorphisms in the ABCB1 gene, although our study is limited by a small sample size...

..This review focuses on issues that will need to be considered in the scientific assessment of pharmacogenetic testing...

..The objective of this study was to investigate CYP2B6 haplotype structure and functional consequences in a Latin American population...

..25 days/patient admission episode. The overall burden of ADRs on hospitals is high, and effective intervention strategies are urgently needed to reduce this burden...

..Incorporation of genetic and environmental factors could help in the prediction of more individualized loading and maintenance doses for safer anticoagulation therapy...

....

..To examine the adequacy of instructions to monitor for haematological adverse drug reactions in the Summary of Product Characteristics...