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No description available.

Allergic drug reactions are immune-mediated idiosyncratic reactions. The main problem in the clinical management of drug allergic patients is the unpredictable nature of the reaction and a lack of understanding of the relationship between drug exposure, drug antigen formation and the stimulation of a pathogenic immune response. Drug-responsive T lymphocytes are thought to play a crucial role in the pathogenesis of many forms of allergic drug reactions, especially reactions that develop in the skin. Studies have shown that cytotoxic CD4+ and CD8+ T cells migrate to the skin of allergic patients and directly kill autologous keratinocytes following drug stimulation. The objective of these studies was to further investigate the role of T cells in (1) patients with cystic fibrosis presenting with allergic reactions to the β-lactam antibiotic piperacillin and (2) a patient that developed severe hepatitis following exposure to trimethoprim. Cloned T cells responsive against the culprit drugs were utilized to define mechanisms of drug antigen presentation, cross-reactivity at individual T cell receptors and the cellular pathophysiology of different forms of allergic reaction. Mass spectrometric methods were employed to detect and fully characterize the nature of piperacillin derived-epitopes on protein which can function as an antigen to stimulate T cells. Albumin modification was time- and concentration- dependent, with selective modification of Lys541 observed at low concentrations, whereas at higher concentrations up to 13/59 lysine residues were modified. Piperacillin-specific T lymphocyte responses (proliferation and cytokines) were detected ex vivo with cells from hypersensitive patients, and analysis of incubation medium showed that modification of the same lysine residues in albumin occurred in situ. The antigenicity of piperacillin-modified albumin was confirmed by stimulation of T lymphocytes with characterized synthetic conjugates. Analysis of minimally-modified T cell stimulatory albumin conjugates revealed peptide sequences incorporating Lys 190, 432 and 541 as principal functional epitopes for T cells. Over 400 piperacillin-responsive CD4+, CD4+8+ or CD8+ T cell clones were generated from five allergic patients. The T cell response was highly specific; clones were stimulated with piperacillin, but not structurally-related compounds. The synthetic piperacillin albumin conjugate stimulated clones via a MHC- restricted pathway involving processing. Flucloxacillin, which modifies essentially the same Lys residues on albumin as piperacillin and occupies non- covalent albumin binding sites, reduced piperacillin albumin binding and the piperacillin-albumin conjugate-specific T cell response. Piperacillin also stimulated T cells in the absence of processing and when antigen presenting cells

At the present, researchers are not able to predict which individual patients might be susceptible to developing AML. Current research carried out in various laboratories is focused on identifying potential markers that would allow for identification of such patients. The analysis of gene expression profiles of cells treated with the FAC drug regime gave an insight on the impact that the chemotherapeutics have on non-cancerous cells. Exposure to the FAC drug regime caused many changes in gene expression profiles of treated cells. Experiments examining the impact of single doses treatments and combined FAC regime showed variations in gene expression responses to the xenobiotics. Gene expression profiles varied depending on the amount of time that the cells were exposed to the FAC drugs. Shorter exposure to FAC drugs generated more overexpresed genes. During the microarray analysis, synergistic interactions between FAC drugs were discovered. Such synergistic interactions could be very important for future drug discovery and population studies. Two candidate biomarkers were also investigated as potential indicators of susceptibility to developing secondary leukaemias. Minisatellite MS1 and MLL/AF4 translocations were analysed. Minisatellites are highly sensitive repeat regions in human genome that might be susceptible to changes induced by xenobiotics. MS1 has a highly variable internal structure, because of its variability and unstable nature, it was chosen to act as biomarker. An alternative method to detect DNA damage by identification of MLL/AF4 translocations was explored in this project. Chromosomal aberrations between those genes may cause secondary leukaemeia in cancer patients. PCR based techniques were utilised to detect any MLL/AF4 translocations present both in cell lines and in patients' DNA. Both minisatellites MS1 and MLL/AF4 translocations proved not to be suitable candidates as biomarkers.

There are limited data on incidences of drug related problems (DRPs) including adverse drug reactions (ADRs) in children. The aim of this thesis is to increase knowledge of the incidence of ADRs and other DRPs and to enhance the understanding of risk factors for ADRs across several countries. This should facilitate the development of appropriate prevention strategies. Two large prospective cohort studies were conducted; ADVISE" recruited patients from five countries to investigate the incidence and characteristics of ADRs. Multivariable regression analysis was conducted to identify risk factors associated with ADRs in hospitalised children. The second study investigated DRPs in children attending the A&E department and/or admitted to a hospital in the Kingdom of Saudi Arabia (KSA) and the UK. ADRs and other DRPs were identified using intensive chart review. In the ADVISE study, 1278 children were included (Australia n=149, Germany n=376, UK n=313, HK n=143, Malaysia n=300). The overall ADR incidence was 18.5% (95% Cl, 16.3- 20.9). There was significant variation in incidence between countries (p<0.001), the highest was in the UK (34.9%). The use of ~five low risk drugs per patient or ~three high risk drugs (e.g. opioids) were strong predictors for ADRs (OR 4.7,95% CI, 2.4-9.3; OR 6.5,95% CI, 2.7-16.0; respectively, p<0.001). In the second study, 990 children were included (KSA n=507, UK n=483). The overall incidence of DRPs was 39.2% (95% Cl, 36.1-42.3). Incidence was highest in the paediatric intensive care units (59.7%; 95% CI, 47.0-71.5). Dosing problems were the most frequent DRP (n=303, 55.5%).80.0% (n=437) of DRPs were preventable. Using standardised methods in both studies enabled comparison of incidences of ADRs and DRPs between countries. The variation between countries was considered to be mainly due to differences in treatment strategies. These studies indicated that improvements to current procedures could reduce DRPs and hence improve patients' health. Also, a focus on paediatric pharmacology and pharmacotherapy within paediatric medical education is important to improve prescribing practices and paediatric patient safety.

Adverse drug reactions are a significant burden on industry and healthcare providers. They account for approximately 5 % of hospital admissions and are a considerable cause of morbidity and mortality in patients. While it is widely considered that an individual's susceptibility to idiosyncratic reactions is caused by a variety of factors; ADRs are thought to be linked to the formation and accumulation of reactive drug metabolites rather than the parent drug. Of the patients administered carbamazepine 30-50 % are subject to the development of some form of adverse drug reaction. Carbamazepine is metabolized extensively in vivo and hypersensitivity reactions have been hypothetically linked to the formation of chemically reactive arene oxide or iminoquinone metabolites. In order to understand the mechanisms behind such ADRs it is important to synthesize a variety of chemical probes to observe changes in pharmacokinetic and pharmacodynamic properties of the compounds. The overall theme of this thesis is the synthesis and the examination of the structure-metabolism relationships for halogenated analogues of carbamazepine. It is divided into three main sections; a general introduction introduces the reader to the basics of drug metabolism from how drugs are metabolized to the implications of halogen substitution on the metabolism of drugs. It next covers the synthetic strategies employed in the formation of halogenated carbamazepine analogues before ending on a discussion of the key findings of the structure-metabolism relationships that may be derived from in vitro investigations

Adverse drug events (ADEs), whether from drug-drug or drug-disease interactions, inappropriate prescribing, errors in administration, therapeutic failures, poor patient adherence to medication regimens, or insufficient inter-sector communication, can lead to serious negative outcomes for hospitalised patients. Epidemiological studies indicate that ADEs are relatively common in hospitalised patients and many are considered preventable. In the present research, two types of ADEs were assessed in hospitalised patients i.e. those resulting in extrinsic toxicity (preventable ADEs; pADEs), and those resulting in intrinsic toxicity (adverse drug reactions; ADRs). Furthermore, the present research explored the factors associated with the development of ADEs in hospitalised patients. The application of trigger tool methodology in detecting and preventing ADEs was also investigated. The assessment of ADEs retrospectively in the cardiology ward in the Antrim Area Hospital, N. Ireland, using trigger tool methodology, indicated that pADEs and ADRs are frequently encountered in hospitalised cardiovascular patients and ADEs continue to be an important risk of hospitalisation. ADEs were identified in 18.4 % of admissions, of which 51.9% were preventable and 48.1 % were ADRs. Approximately 54% of ADEs were identified at admission. The outcomes of the ADEs ranged from temporary harm (47.4%) to severe harm (11.3%). In a further evaluation of cardiovascular patient data and medication-related incident reports, collected by spontaneous/voluntary reporting (incident reporting system) in N. Ireland, were analysed with a focus on risk factors for individual cardiovascular medicines and factors involved in the occurrence of pADEs. The most frequently implicated variables in ADEs were related to age, the number of medications prescribed, length of stay, renal insufficiency, drug-drug interactions and laboratory values, whereas A&E, surgical wards, the action of nurses, antibiotics, anticoagulants and wrong dose administration had a significant positive association with the occurrence of pADEs. An evaluation of the application of trigger tool methodology demonstrated that this approach had clear benefits in identifying ADEs during a manual chart review. The results indicated that the sensitivity of the trigger tools used for identifying ADEs, pADEs and ADRs was 0.75, 0.8 and 0.71 respectively when compared to manual health record review. The trigger tool approach was also used to develop a targeted injury detection system (TIDS) which was evaluated by clinical pharmacists working on cardiovascular wards in the King Fahd Military Medical Complex in Saudi Arabia. This research demonstrated that concurrent and real-time triggers had clear benefits in guiding clinical pharmacist interventions in order to prevent emerging or mitigate actual ADEs in hospitalised cardiovascular patients. Application of the TIDS resulted in a clear trend of reduced incidence of ADEs (from 50.0% to 36.3% per alert), an increased number of clinical pharmacist interventions and a reduced time taken on the pharmacist rounds (with reduced time taken per clinical intervention). Trigger tools were also shown to have a potential role in evaluating and driving quality improvement in warfarin management within the Antrim Area Hospital (N. Ireland). The exploration of risk factors in hospitalised patients, together with the development of clinical event monitoring approaches, will help maximise the detection of ADEs and inform the further development of efficient clinical pharmacy services to patients at risk of drug-related problems.