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M Pirmohamed

Publications and source records attributed to M Pirmohamed.

At least 19 recordsLinked to original sources
PubMed2006

Pharmacogenetics of warfarin: current status and future challenges.

Warfarin is an anticoagulant that is difficult to use because of the wide variation in dose required to achieve a therapeutic effect, and the risk of serious bleeding. Warfarin acts by interfering with the recycling of vitamin K in the liver, which leads to reduced activation of several clotting factors. Thirty genes that may be involved in the biotransformation and mode of action of warfarin are discussed in this review. The most important genes affecting the pharmacokinetic and pharmacodynamic parameters of warfarin are CYP2C9 (cytochrome P(450) 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1). These two genes, together with environmental factors, partly explain the interindividual variation in warfarin dose requirements. Large ongoing studies of genes involved in the actions of warfarin, together with prospective assessment of environmental factors, will undoubtedly increase the capacity to accurately predict warfarin dose. Implementation of pre-prescription genotyping and individualized warfarin therapy represents an opportunity to minimize the risk of haemorrhage without compromising effectiveness.

Anticoagulants↗
PubMed2006

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research.

The product of the ABCB1 gene, P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. It is postulated that ABCB1 polymorphisms contribute to variability in PGP function, and that therefore multidrug resistance is, at least in part, genetically determined. However, studies of ABCB1 genotype or haplotype and PGP expression, activity or drug response have produced inconsistent results. This critical review of ABCB1 genotype and PGP function, including mRNA expression, PGP-substrate drug pharmacokinetics and drug response, highlights methodological limitations of existing studies, including inadequate power, potential confounding by co-morbidity and co-medication, multiple testing, poor definition of disease phenotype and outcomes, and analysis of multiple drugs that might not be PGP substrates. We have produced recommendations for future research that will aid clarification of the association between ABCB1 genotypes and factors related to PGP activity.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Which drugs cause preventable admissions to hospital? A systematic review.

AIMS: Previous systematic reviews have found that drug-related morbidity accounts for 4.3% of preventable hospital admissions. None, however, has identified the drugs most commonly responsible for preventable hospital admissions. The aims of this study were to estimate the percentage of preventable drug-related hospital admissions, the most common drug causes of preventable hospital admissions and the most common underlying causes of preventable drug-related admissions. METHODS: Bibliographic databases and reference lists from eligible articles and study authors were the sources for data. Seventeen prospective observational studies reporting the proportion of preventable drug-related hospital admissions, causative drugs and/or the underlying causes of hospital admissions were selected. Included studies used multiple reviewers and/or explicit criteria to assess causality and preventability of hospital admissions. Two investigators abstracted data from all included studies using a purpose-made data extraction form. RESULTS: From 13 papers the median percentage of preventable drug-related admissions to hospital was 3.7% (range 1.4-15.4). From nine papers the majority (51%) of preventable drug-related admissions involved either antiplatelets (16%), diuretics (16%), nonsteroidal anti-inflammatory drugs (11%) or anticoagulants (8%). From five studies the median proportion of preventable drug-related admissions associated with prescribing problems was 30.6% (range 11.1-41.8), with adherence problems 33.3% (range 20.9-41.7) and with monitoring problems 22.2% (range 0-31.3). CONCLUSIONS: Four groups of drugs account for more than 50% of the drug groups associated with preventable drug-related hospital admissions. Concentrating interventions on these drug groups could reduce appreciably the number of preventable drug-related admissions to hospital from primary care.

Adolescent↗
PubMed2006

Exon sequencing and high resolution haplotype analysis of ABC transporter genes implicated in drug resistance.

BACKGROUND: The ATP-binding cassette (ABC) proteins are a superfamily of efflux pumps implicated as a mechanism for multidrug resistance in cytotoxic chemotherapy, immunosuppressive therapy, HIV and epilepsy. Genetic variation in P-glycoprotein, the product of the ABCB1 gene, is proposed to mediate de novo drug resistance, but associations between polymorphisms in ABCB1 and pharmacoresistance have produced conflicting results. Potential explanations for the inconsistency of results include inadequate characterization of gene structure, variation and linkage disequilibrium (LD) in ABCB1, as well as overlap in substrate specificity between ABCB1 and the various other drug transporters. METHODS AND RESULTS: We undertook a fundamental analysis of gene structure, variation and LD in ABCB1 and four other drug transporter genes implicated in pharmacoresistance: ABCC1, ABCC2, ABCC5 and ABCB4. Manual annotation of the five genes revealed nine shorter alternative transcripts with new untranslated regions and one novel region of coding sequence, demonstrating that on-line annotations are incomplete. Sequencing of exons in 47 Caucasian individuals identified 75 novel single nucleotide polymorphisms (SNPs) previously undescribed in any public database, including 14 new coding sequence SNPs. Genotyping of 502 SNPs in 842 Caucasian individuals across the five genes revealed large blocks of high LD, and low haplotype diversity across all five genes that could be characterized by between 67 and 114 tagging SNPs, depending on the tagging criteria. CONCLUSION: The study illustrates that publicly available data resources on genomic organization of genes and common variation can have important gaps and limitations, and establishes a comprehensive set of tagging SNPs for future association studies in pharmacoresistance.

ATP-Binding Cassette Transporters↗
PubMed2006

Adverse drug reactions in hospital in-patients: a pilot study.

BACKGROUND: About 6.5% of admissions to hospital are related to an adverse drug reaction (ADR). There are no recent large studies, which explore the burden of ADRs on hospital in-patients. The aim of this pilot study was to assess the feasibility of, and establish the methodology for, conducting a large prospective study to fully assess the impact of ADRs on in-patients and the National Health Service (NHS). METHODS: Patients admitted to five wards in a university hospital over a 2-week period were assessed for ADRs through a daily ward visit by a pharmacist. Suspected ADRs were analysed for causality, severity and avoidability using appropriate scales. RESULTS: Twenty-four of 125 patients (19.2%, 95% CI 12-26%) were categorized as having suffered one or more ADRs. A total of 27 ADRs were identified. Patients with ADRs spent longer in hospital than those without ADRs. Causality assessment showed that 17 (63%) ADRs were possibly drug-related, whereas 10 (37%) were classified as probably or definitely related to the drug. Almost two-thirds of reactions were potentially avoidable. Intervention was required in all ADRs and reactions indirectly contributed to the death of two patients. CONCLUSIONS: Almost one-fifth of patients suffered an ADR as an inpatient. Methodology tested using this pilot will enable the design of a larger study, involving over 3000 patients, which will allow the ADR burden and vulnerable patient groups, to be more accurately characterized. This study will aid the development of interventions to reduce the impact of ADRs in hospital in-patients.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Carbamazepine-induced acute liver failure as part of the DRESS syndrome.

Carbamazepine is a widely used drug. It is commonly associated with hepatic abnormalities, ranging from an asymptomatic rise in liver function tests to acute liver failure. The most severe reaction occurs as part of a generalised hypersensitivity reaction, also known as drug reaction, eosinophilia and systemic symptoms (DRESS). We describe a case of a young adult who presented with non-specific symptoms, which progressed to fulminant hepatic failure, displaying the hallmarks of DRESS. We highlight the need for awareness of such an association.

Adult↗
PubMed2004

Intravenous therapy.

Intravenous administration of fluids, drugs, and nutrition is very common in hospitals. Although insertion of peripheral and central cannulae and subsequent intravenous therapy are usually well tolerated, complications that prolong hospitalisation, and in some cases cause death, can arise on occasions. Additionally, many cannulae are inserted unnecessarily. This article seeks to review this area and to outline good medical practice.

Anesthesia, Local↗
PubMed2003

Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones.

Administration of carbamazepine (CBZ) causes hypersensitivity reactions clinically characterized by skin involvement, eosinophilia, and systemic symptoms. These reactions have an immune etiology; however, the role of T cells is not well defined. The aim of this study was to characterize the specificity, phenotype, and cytokine profile of CBZ-specific T cells derived from hypersensitive individuals. Proliferation of blood lymphocytes was measured using the lymphocyte transformation test. CBZ-specific T cell clones were generated by serial dilution and characterized in terms of their cluster of differentiation and T cell receptor V beta phenotype. Proliferation, cytotoxicity, and cytokine secretion were measured by [(3)H]thymidine incorporation, (51)Cr release, and enzyme-linked immunosorbent assay, respectively. HLA blocking antibodies were used to study the involvement of antigen-presenting cells. The specificity of the drug T cell receptor interaction was studied using CBZ metabolites and other structurally related compounds. Lymphocytes from hypersensitive patients (stimulation index: 32.1 +/- 24.2 [10 microg ml(-1)]) but not control patients (stimulation index: 1.2 +/- 0.4 [10 microg ml(-1)]) proliferated upon stimulation with CBZ. Of 44 CBZ-specific T cell clones generated, 10 were selected for further analysis. All 10 clones were either CD4+ or CD4+/CD8+, expressed the alpha beta T cell receptor, secreted IFN-gamma, and were cytotoxic. T-cell recognition of CBZ was dependent on the presence of HLA class II (DR/DQ)-matched antigen-presenting cells. The T cell receptor of certain clones could accommodate some CBZ metabolites, but no cross-reactivity was seen with other anticonvulsants or structural analogs. 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.

Adult↗
PubMed2003

Herbal medicines.

Explore the source record for details and available documents.

Drug Interactions↗
PubMed2002

Are chemically reactive metabolites responsible for adverse reactions to drugs?

Low molecular weight organic chemicals can be transformed by normal drug-metabolising systems into short-lived metabolites that are inherently reactive towards cellular macromolecules. There is direct evidence that the formation of such chemically reactive metabolites may lead to mutagenesis, carcinogenicity, apoptosis and necrosis in both cell and animal models. A number of drugs associated with non-pharmacological drug toxicities in man have been shown to undergo bioactivation either in vivo or in vitro. 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.

Animals↗
PubMed2001

Short-term exercise training improves body composition and hyperlipidaemia in HIV-positive individuals with lipodystrophy.

Exercise/physical activity is increasingly being advocated as a positive addition to the treatment regimen of HIV-positive individuals. We investigated the effects of 10 weeks' aerobic and resistance training on individuals with HIV-related lipodystrophy. These individuals demonstrated an improvement in exercise tolerance, body composition and blood lipid profiles. Potentially, such changes may contribute to an amelioration of some of the adverse metabolic effects associated with highly active antiretroviral therapy.

Adult↗
PubMed2001

TNFalpha promoter region gene polymorphisms in carbamazepine-hypersensitive patients.

OBJECTIVE: To evaluate whether the major histocompatibility complex contains susceptibility genes for carbamazepine hypersensitivity. Carbamazepine hypersensitivity is immune-mediated, although factors determining its occurrence and severity are unknown. METHODS: Using PCR in 60 carbamazepine-hypersensitive patients, 37 with nonserious (Group I) and 23 with serious (Group II) reactions, and 313 control subjects (63 patients on carbamazepine without adverse effects and 250 healthy volunteers), the association with polymorphisms in the promoter region of the tumor necrosis factor alpha (TNFalpha) gene (positions -308 and -238), and with HLA-DR3 and -DQ2 was determined. RESULTS: The frequency of the variant allele (TNF2) at the -308 position was increased in Group II but not Group I carbamazepine-hypersensitive patients compared with all control subjects (p = 0.01; OR = 2.4), as was the frequency of HLA-DR3 (p = 0.01; OR = 3.3), HLA-DQ2 (p = 0.04; OR = 2.7), and the TNF2-DR3-DQ2 haplotypes (p = 0.02; OR = 3.2). None of the alleles were independently associated with serious carbamazepine hypersensitivity. For the -238 polymorphism, there was a difference in the genotype, but not in the allelic, frequencies between Group II hypersensitive patients and all control subjects. CONCLUSIONS: The TNF2 allele was associated with severe, but not nonserious, carbamazepine hypersensitivity reactions, suggesting that hypersecretion of tumor necrosis factor alpha may be a determinant of the severity of tissue damage. However, the association of the TNF2 allele with carbamazepine hypersensitivity was not independent of HLA-DR3 and -DQ2, and therefore the possibility that it constitutes a passive component of the TNF2-DR3-DQ2 haplotype cannot be excluded.

Adolescent↗
PubMed2001

Toxicogenetics in drug development.

The major progress made in the understanding of the genetic basis of inter-individual variation in drug response, alongside the rapid advances in technology, provides major new opportunities to ensure the safe introduction of a new chemical entity into clinical practice. In essence, the aim is to get the right drug into the right patient using knowledge of factors that influence both benefit and risk. The stage of the drug development process at which genetic analysis needs to be undertaken is dependent on the frequency of the event, and the availability of clinical samples. Thus, common adverse events, or assessment of efficacy, will be feasible for testing in phases I-III. However, when a rare event is being studied, for example idiosyncratic toxicity, prospective analysis becomes impossible. Thus, retrospective studies using available drugs is important as it may provide paradigms for future drug development. Additionally, prospective collection of samples will be important so that rare adverse events identified during phase IV can then be analysed using toxicogenetic approaches. Ultimately, information obtained from toxicogenetics must be included in the Specific Product Characteristics (SPC) and thus formally translated into clinical practice in order to contraindicate the drug in specific patients with a genetically determined susceptibility to drug toxicity.

Carbamazepine↗
PubMed2001

Metabolic activation in drug allergies.

Drug allergies are a major problem in the clinic and during drug development. At the present time, it is not possible to predict the potential of a new chemical entity to produce an allergic reaction (hypersensitivity) in patients in preclinical development. Such adverse reactions, because of their idiosyncratic nature, only become apparent once the drug has been licensed. Our present chemical understanding of drug hypersensitivity is based on the hapten hypothesis, in which covalent binding of the drug (metabolite) plays a central role in drug immunogenicity and antigenicity. If this theory is correct, then it should be possible to develop in vitro systems to assess the potential of drugs to bind to critical proteins, either directly or indirectly after metabolic activation to protein-reactive metabolites (bioactivation) and initiate hypersensitivity. 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.

Animals↗
PubMed2001

Genetic susceptibility to adverse drug reactions.

Adverse drug reactions (ADRs) are a major clinical problem. Genetic factors can determine individual susceptibility to both dose-dependent and dose-independent ADRs. Determinants of susceptibility include kinetic factors, such as gene polymorphisms in cytochrome P450 enzymes, and dynamic factors, such as polymorphisms in drug targets. The relative importance of these factors will depend on the nature of the ADR; however, it is likely that more than one gene will be involved in most instances. In the future, whole genome single nucleotide polymorphism (SNP) profiling might allow an unbiased method of determining genetic predisposing factors for ADRs, but might be limited by the lack of adequate numbers of patient samples. The overall clinical utility of genotyping in preventing ADRs needs to be proven by the use of prospective randomized controlled clinical trials.

Animals↗
PubMed2001

LC determination of carbamazepine in murine brain.

A reversed phase HPLC method for the determination of carbamazepine (CBZ) in the brain of adult mice is described. CBZ was recovered from murine brain by solvent-extraction with ethyl acetate and resolved from imipramine (internal standard) and brain endogenous material using a Lichrospher RP select B column with a linear gradient of acetonitrile (40-80 v/v, 25 min) in ammonium acetate buffer (25 mM, pH 4.0) 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.

Animals↗