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M Pirmohamed

Publications and source records attributed to M Pirmohamed.

At least 55 records · Page 3Linked to original sources
PubMed2000

Induction of metabolism-dependent and -independent neutrophil apoptosis by clozapine.

Clozapine, an atypical antipsychotic used in the treatment of refractory schizophrenia, causes neutropenia and agranulocytosis in 3 and 0.8% of patients, respectively. Clozapine undergoes bioactivation to a chemically reactive nitrenium ion, which has been shown to cause neutrophil cytotoxicity. To define further the mechanism of cell death, we have investigated the toxicity of clozapine, its stable metabolites, and its chemically reactive nitrenium ion to neutrophils and lymphocytes. Clozapine was able to induce neutrophil apoptosis at therapeutic concentrations (1-3 microM) only when it was bioactivated to the nitrenium ion. The parent drug caused apoptosis at supratherapeutic concentrations (100-300 microM) only. Neutrophil apoptosis induced by the nitrenium ion, but not by the parent drug itself, was inhibited by antioxidants and genistein and was accompanied by cell surface haptenation (assessed by flow cytometry) and glutathione depletion. Dual-color flow cytometry showed that neutrophils that were haptenated were the same cells that underwent apoptosis. No apoptosis of lymphocytes was evident with the nitrenium ion or the parent drug, despite the fact that the former caused cell surface haptenation, glutathione depletion, and loss of membrane integrity. Demethylclozapine, the major stable metabolite in vivo, showed a profile that was similar to, although less marked than that observed with clozapine. N-oxidation of clozapine or replacement of the nitrogen (at position 5) by sulfur produced compounds that were entirely nontoxic to neutrophils. 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.

Adult↗
PubMed2000

Immunological principles of adverse drug reactions: the initiation and propagation of immune responses elicited by drug treatment.

Adverse drug reactions account for between 2 to 5% of all hospital admissions and can prevent the administration of an otherwise effective therapeutic agent. Hypersensitivity or immune-mediated reactions, although less common, tend to be proportionately more serious. There is convincing evidence to implicate the immune system in the pathogenesis of hypersensitivity reactions. Our understanding of the way in which the immune system recognises drugs is based on the hapten hypothesis; the onset of hypersensitivity involves drug bioactivation, covalent binding to proteins, followed by uptake, antigen processing and T cell proliferation. Central to this hypothesis is the critical role of drug metabolism, with the balance between metabolic bioactivation and detoxification being one important component of individual susceptibility. The purpose of this review is to classify drug hypersensitivity reactions in terms of their clinical presentation, and also to consider recent advances in our understanding of the chemical, biochemical and, in particular, cellular immunological mechanisms of hypersensitivity. The following topics are reviewed: (i) drug disposition and cellular metabolism; (ii) mechanisms of antigen processing and presentation; (iii) the role of cytokines and co-stimulatory molecules in the induction and maintenance of a polarised immune response; and (iv) the application of the hapten hypothesis, danger hypothesis and serial triggering model to drug hypersensitivity. 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.

Animals↗
PubMed2000

Specialist nurse reporting of adverse drug reactions.

Up to 36% of inpatients experience an adverse drug reaction (ADR) while in hospital. Nurses are well-placed to monitor patients' responses to drugs. Spontaneous reporting of ADRs is the cornerstone of drug safety monitoring and should be the shared responsibility of all health-care staff.

Adult↗
PubMed1999

Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity.

1. Bioactivation of sulphamethoxazole (SMX) to chemically-reactive metabolites and subsequent protein conjugation is thought to be involved in SMX hypersensitivity. We have therefore examined the cellular metabolism, disposition and conjugation of SMX and its metabolites in vitro. 2. Flow cytometry revealed binding of N-hydroxy (SMX-NHOH) and nitroso (SMX-NO) metabolites of SMX, but not of SMX itself, to the surface of viable white blood cells. Cellular haptenation by SMX-NO was reduced by exogenous glutathione (GSH). 3. SMX-NHOH and SMX-NO were rapidly reduced back to the parent compound by cysteine (CYS), GSH, human peripheral blood cells and plasma, suggesting that this is an important and ubiquitous bioinactivation mechanism. 4. Fluorescence HPLC showed that SMX-NHOH and SMX-NO depleted CYS and GSH in buffer, and to a lesser extent, in cells and plasma. 5. Neutrophil apoptosis and inhibition of neutrophil function were induced at lower concentrations of SMX-NHOH and SMX-NO than those inducing loss of membrane viability, with SMX having no effect. Lymphocytes were significantly (P<0.05) more sensitive to the direct cytotoxic effects of SMX-NO than neutrophils. 6. Partitioning of SMX-NHOH into red blood cells was significantly (P<0.05) lower than with the hydroxylamine of dapsone. 7. Our results suggest that the balance between oxidation of SMX to its toxic metabolites and their reduction is an important protective cellular mechanism. If an imbalance exists, haptenation of the toxic metabolites to bodily proteins including the surface of viable cells can occur, and may result in drug hypersensitivity.

Adult↗
PubMed1999

Communication regarding adverse drug reactions between secondary and primary care: a postal questionnaire survey of general practitioners.

GPs are not always informed that their patient suffered an adverse drug reaction (ADR) while in hospital. We have conducted a postal questionnaire survey of 270 GPs in order to elicit their views regarding provision of information from secondary care regarding ADRs. Of the 141 (52.2%) GPs that replied, 127 (90.1%) saw patients that had experienced an ADR in hospital. Of these GPs, 113 (89%) stated that they encountered instances where no record of the ADR existed in patients' discharge documentation. Where written information was absent, GPs are reliant on information given to them by patients. Of those responding, none were 'very confident' of this information, while 92 (78.6%) were 'uncertain' or 'very uncertain' of this information. A sample notification form was developed. GPs were generally satisfied with its content and 110 (82.7%) thought that patients should receive a copy. Almost all GPs (135 (97.8%)) felt that it would be appropriate to provide patients with ADR warning cards. Ensuring that patients and their carers are aware of drugs to which they may be allergic or intolerant through verbal and written methods should minimize the unnecessary risks of inadvertent re-exposure.

Adverse Drug Reaction Reporting Systems↗
PubMed1999

The effect of genetic polymorphisms in CYP2C9 on sulphamethoxazole N-hydroxylation.

Sulphamethoxazole undergoes CYP2C9-mediated bioactivation to a hydroxylamine. In this study, we investigated the effect of the CYP2C9Arg144 to Cys (CYP2C9*2) and CYP2C9Ile359 to Leu (CYP2C9*3) polymorphisms on sulphamethoxazole N-hydroxylation. Human livers were genotyped using polymerase chain reaction amplification and restriction fragment length polymorphism analysis. Formation of sulphamethoxazole hydroxylamine and methylhydroxy tolbutamide in microsomes prepared from cell lines and the genotyped human livers was determined by high-pressure liquid chromatography. Microsomes prepared from the cell line expressing the allelic variants CYP2C9-Cys144 and CYP2C9-Leu359 displayed a threefold and 20-fold decrease in intrinsic clearance (Cl(int)) for sulphamethoxazole, respectively, when compared with the wild-type, CYP2C9-Arg144. A significant decrease (P < 0.05) in Cl(int) was also observed with tolbutamide for both mutations. Of the 26 human livers genotyped, 61.5% were homozygous wild-type, 26.9% were heterozygotes for CYP2C9*2 and 15.4% were heterozygotes for CYP2C9*3. No homozygous mutant livers were detected. There was a good correlation between sulphamethoxazole N-hydroxylation and tolbutamide methyl hydroxylation (r = 0.825). However, there was no difference in the kinetic parameters for either sulphamethoxazole N-hydroxylation or tolbutamide methyl hydroxylation between the wild type livers (n = 6) and either the livers heterozygous for the CYP2C9*2 (n = 5) or the livers heterozygous for the CYP2C9*3 mutation (n = 3). The CYP2C9*2 and CYP2C9*3 polymorphisms may have some influence on the bioactivation of sulphamethoxazole, particularly in individuals who are homozygous mutants, and this could act as a protective factor against sulphamethoxazole hypersensitivity. However, given the rarity of homozygous mutants, it is likely that other metabolic and immunological risk factors will dominate individual susceptibility.

Aryl Hydrocarbon Hydroxylases↗
PubMed1999

The adverse effects of drugs.

Adverse drug reactions vary in presentation and severity, and can mimic almost any disease. The article explores the importance of adverse drug reactions in modern clinical practice, highlighting the mechanisms and how to manage patients.

Decision Making↗
PubMed1998

Adverse drug reactions.

Explore the source record for details and available documents.

Adverse Drug Reaction Reporting Systems↗
PubMed1998

Metabolism-dependent neutrophil cytotoxicity of amodiaquine: A comparison with pyronaridine and related antimalarial drugs.

Life-threatening agranulocytosis and hepatotoxicity during prophylactic administration of amodiaquine have led to its withdrawal. Agranulocytosis is thought to involve bioactivation to a protein-reactive quinoneimine metabolite. The toxicity of amodiaquine and the lack of cheap drugs have prompted a search for alternative antimalarial agents. The aim of this study was to determine the metabolism and neutrophil toxicity of amodiaquine, pyronaridine, and other related antimalarial agents. Horseradish peroxidase and hydrogen peroxide were used to activate drugs to their respective quinoneimine metabolites. Metabolites were trapped as stable glutathione conjugates, prior to analysis by LC/MS. Amodiaquine was metabolized to a polar metabolite (m/z 661), identified as a glutathione adduct. Tebuquine was converted to two polar metabolites. The principal metabolite (m/z 686) was derived from glutathione conjugation and side chain elimination, while the minor metabolite gave a protonated molecule (m/z 496). Only parent ions were identified when chloroquine, cycloquine, or pyronaridine was incubated with the activating system and glutathione. Calculation of the heat of formation of the drugs, however, demonstrated that amodiaquine, tebuquine, cycloquine, and pyronaridine readily undergo oxidation to their quinoneimine. None of the antimalarial compounds depleted the level of intracellular glutathione (1-300 microM) when incubated with neutrophils alone. Additionally, with the exception of tebuquine, no cytotoxicity below 100 microM was observed. In the presence of the full activating system, however, all compounds except chloroquine resulted in depletion of the level of glutathione and were cytotoxic. Pretreating the cells with glutathione and other antioxidants inhibited metabolism-dependent cytotoxicity. In summary, our data show that amodiaquine and related antimalarials containing a p-aminophenol moiety undergo bioactivation in vitro to chemically reactive and cytotoxic intermediates. In particular, pyronaridine, which is currently being investigated in humans, was metabolized to a compound which was toxic to neutrophils. Thus, the possibility that it will cause agranulocytosis in clinical practice cannot be excluded, and will require careful monitoring.

Adult↗
PubMed1998

Expression of cytochrome P4502E1 in human liver: assessment by mRNA, genotype and phenotype.

Cytochrome P4502E1 (CYP2E1) is constitutively expressed in human liver and is responsible for the metabolic bioactivation of a wide variety of xenobiotics, including a number of protoxins and procarcinogens. CYP2E1 expression is regulated at several levels including pre-transcriptional, transcriptional and post-transcriptional levels, and any variation in enzyme concentration and hence activity may represent increased risk of toxicity or carcinogenicity. We have investigated variability in the levels of CYP2E1 mRNA, protein and functional activity in a human liver bank, and attempted to relate these parameters to the RsaI restriction fragment length polymorphism in the 5'-flanking region. Variation in CYP2E1 mRNA (18-fold) was greater than the variation seen in CYP2E1 protein (twofold) and functional activity (fourfold) determined using two probe substrates, chlorzoxazone and p-nitrophenol. Although protein and functional activity showed a significant correlation (r = 0.93 and r = 0.83 for chlorzoxazone and p-nitrophenol, respectively), there was no correlation between any of these parameters and mRNA levels. Also, the variation in CYP2E1 activity could not be directly accounted for by the RsaI polymorphism in our samples. In conclusion, our results are consistent with a complex regulation of CYP2E1 and the fact that it is highly conserved in the human population. The absence of a relationship between the RsaI polymorphism and CYP2E1 activity is consistent with other studies performed in Caucasians, but does not exclude an effect of this polymorphism on inducibility of CYP2E1.

Adult↗