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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.
    Immunology and Allergy Clinics of North America. 08/2014; 34(3):691–705.
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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.
    EXS 01/2014; 104:137-163.
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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.
    Antimicrobial Agents and Chemotherapy 11/2013;
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    Neuropeptides 10/2013;
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    ABSTRACT: The regulation of neuropeptide gene expression and their receptors in a tissue specific and stimulus inducible manner will determine in part behaviour and physiology. This can be a dynamic process resulting from short term changes in response to the environment or long term modulation imposed by epigenetically determined mechanisms established during life experiences. The latter underpins what is termed 'nature and nurture, or 'gene×environment interactions'. Dynamic gene expression of neuropeptides or their receptors is a key component of signalling in the CNS and their inappropriate regulation is therefore a predicted target underpinning psychiatric disorders and neuropathological processes. Finding the regulatory domains within our genome which have the potential to direct gene expression is a difficult challenge as 98% of our genome is non-coding and, with the exception of proximal promoter regions, such elements can be quite distant from the gene that they regulate. This review will deal with how we can find such domains by addressing both the most conserved non-exonic regions in the genome using comparative genomics and the most recent or constantly evolving DNA such as repetitive DNA or retrotransposons. We shall also explore how polymorphic changes in such domains can be associated with CNS disorders by altering the appropriate gene expression patterns which maintain normal physiology.
    Neuropeptides 10/2013;
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    ABSTRACT: With the licensing of the direct acting antivirals telaprevir and boceprevir the topic of drug-drug interactions has come to the forefront. These first generation hepatitis C virus protease inhibitors are metabolized by and inhibit the key drug metabolizing enzyme CYP3A4, which means that knowledge of drug-drug interactions has become an essential component of the evaluation of a patient starting triple therapy. The number of potential co-medications means that many drugs will be used in hepatitis C virus patients where there are no pharmacokinetic study data. Here we have to use the data that are available and seek to extrapolate to unstudied drugs using key principles of clinical pharmacology (disposition characteristics, concentration-effect relationships, therapeutic window) in order to give some guidance for management of patients. This is a rapidly moving area in hepatitis C therapy, both in terms of understanding the drug interaction profile of telaprevir and boceprevir, interaction mechanisms that sometimes appear counterintuitive and that may involve enzymes other than CYP3A4 or transporters, but then seeking to understand the interaction potential of the next wave of drugs that will soon be with us.
    Digestive and Liver Disease 09/2013; 45S5:S343-S348.
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    ABSTRACT: Rifampicin is a potent inducer of cytochrome (CYP) P450 enzymes and transporters. Drug-drug interactions during tuberculosis treatment are common. Rifapentine and rifabutin induction is understudied. Rifampicin and rifabutin significantly induced CYP3A4 (80-fold and 20-fold, respectively) in primary human hepatocytes. Induction was concentration-dependent. Rifapentine induced CYP3A4 in 3 of 6 donors. Data were also generated for ABCB1, ABCC1, ABCC2, OATP1B1 and OATP1B3. This work serves as a basis for further study into the extent to which rifamycins induce key metabolism and transporter genes.
    Antimicrobial Agents and Chemotherapy 09/2013;
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    ABSTRACT: Triazoles are first-line agents for treating aspergillosis. The prevalence of azole resistance in Aspergillus fumigatus is increasing, and cross-resistance is a growing concern. In this study the susceptibility of 40 A. fumigatus clinical isolates was tested by CLSI method against amphotericin B, itraconazole, voriconazole, posaconazole, and the new triazole isavuconazole. Isavuconazole MICs were higher in strains with reduced susceptibility to other triazoles, mirroring changes in voriconazole susceptibility. Isavuconazole MICs differed depending on the Cyp51A substitution.
    Antimicrobial Agents and Chemotherapy 09/2013;
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    ABSTRACT: This study is motivated by understanding and controlling the key physical properties underlying internalisation of nano drug delivery. We consider the internalisation of specific nanometer size delivery vehicles, comprised of self-assembling amphiphilic block copolymers, called polymersomes that have the potential to specifically deliver anticancer therapeutics to tumor cells. The possible benefits of targeted polymersome drug delivery include reduced off-target toxic effects in healthy tissue and increased drug uptake by diseased tissue. Through a combination of in vitro experimentation and mathematical modelling, we develop a validated model of nanoparticle uptake by cells via the clathrin-mediated endocytotic pathway, incorporating receptor binding, clustering and recycling. The model predicts how the characteristics of receptor targeting, and the size and concentration of polymersomes alter uptake by tumor cells. The number of receptors per cell was identified as being the dominant mechanism accounting for the difference between cell types in polymersome uptake rate.
    Nanomedicine: nanotechnology, biology, and medicine 09/2013;
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    ABSTRACT: Rilpivirine is a non-nucleoside reverse transcriptase inhibitor approved for treatment of HIV-1 infection in antiretroviral-naive adult patients. Potential interactions with drug transporters have not been fully investigated. Transport by and inhibition of drug transporters by rilpivirine was analysed to further understand mechanisms governing rilpivirine exposure and determine the potential for transporter-mediated drug-drug interactions.The ability of rilpivirine to inhibit or be transported by ABCB1 was determined using ABCB1-overexpressing CEMVBL100 cells and Caco-2 monolayers. The Xenopus laevis oocyte heterologous protein expression system was used to clarify if rilpivirine was either transported by or inhibited the function of influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A2, SLC22A6 and SLC22A8. The ability of rilpivirine to inhibit or be transported by SLC22A1 was determined using SLC22A1-expressing KCL22 cells.Rilpivirine showed higher accumulation in SLC22A1-overexpressing KCL22 cells versus control cells (27% increase, p=0.03) and inhibited functionality of SLC22A1 and SLC22A2 transport with an IC50 of 28.5 μM and 5.13 μM, respectively. Inhibition of ABCB1-mediated digoxin transport was determined for rilpivirine, which inhibited B-to-A digoxin transport with an IC50 of 4.48 μM.The maximum rilpivirine concentration in plasma in patients following a standard 25 mg dosing regimen is 0.43 μM, lower than that necessary to substantially inhibit ABCB1, SLC22A1 or SLC22A2 in vitro. However, these data indicate that SLC22A1 may contribute to variability in rilpivirine exposure and interactions of rilpivirine with substrates of SLC22A1, SLC22A2 or ABCB1 may be possible.
    Antimicrobial Agents and Chemotherapy 09/2013;
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