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    ABSTRACT: Several laboratories use the lymphocyte transformation test for the diagnosis of delayed-type drug hypersensitivity reactions. Recently, the availability of multiple readouts has improved our ability to diagnose reactions. It is important to note that most published studies characterizing the usefulness of diagnostic tests utilize blood samples from well-defined test and control patient groups. The purpose of this article is to briefly summarize the cellular and chemical basis of delayed-type drug hypersensitivity reactions and to review in vitro assays that are available for drug hypersensitivity diagnosis.
    Full-text · Article · Aug 2014 · Immunology and Allergy Clinics of North America
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    ABSTRACT: Understanding the chemical mechanisms by which drugs and drug metabolites interact with cells of the immune system is pivotal to our knowledge of drug hypersensitivity as a whole.In this chapter, we will discuss the currently accepted mechanisms where there is scientific and clinical evidence to support the ways in which drugs and their metabolites interact with T cells. We will also discuss bioanalytical platforms, such as mass spectrometry, and in vitro test assays such as the lymphocyte transformation test that can be used to study drug hypersensitivity; the combination of such techniques can be used to relate the chemistry of drug antigen formation to immune function. Ab initio T cell priming assays are also discussed with respect to predicting the potential of a drug to cause hypersensitivity reactions in humans in relation to the chemistry of the drug and its ability to form haptens, antigens and immunogens in patients.
    No preview · Article · Jan 2014 · EXS
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    ABSTRACT: We modelled nevirapine (NVP) pharmacokinetics in HIV-infected Malawian patients to assess the relationship between drug exposure and patient characteristics, genetic polymorphisms and development of hypersensitivity reaction (HSR). 1117 patients were prospectively recruited and followed for 26 weeks with multiple or single serum samples obtained in a subset of patients for NVP quantification. Single nucleotide polymorphisms (SNP) within CYP2B6 and CYP3A4 genes were typed. Non-linear mixed effects modelling was utilised to assess the influence of patient characteristics and host genetics on NVP apparent oral clearance (CL/F), and explore the relationship between NVP CL/F and HSR. Published haplotype distributions were used to simulate NVP concentrations in Caucasians vs. Africans. 180 patients (101 female) were included in the model; twenty-five experienced HSR. No associations between patient demographics or HSR and NVP CL/F were evident. A significant relationship between CYP2B6 c.983T>C and CYP2B6 c.516G>T and NVP CL/F was observed (p<0.01). NVP CL/F was reduced by 23% and 36% in patients with CYP2B6 983TT/516TT and 983TC/516GG or GT, respectively compared to reference genotype. Simulated exposures suggested similar proportions (13-17%) of patients with subtherapeutic NVP amongst Caucasians and an African population. Influence of CYP2B6 polymorphisms on NVP CL/F in this population is in agreement with other reports. Our data indicate a lack of association between NVP exposure and HSR. Based on these data, dose optimisation based solely on ethnicity (without individual gene testing) is unlikely to impact on risk of treatment failure or toxicity even in an African population with high carriage of poor metaboliser mutations.
    Full-text · Article · Nov 2013 · Antimicrobial Agents and Chemotherapy
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