Thesis (MSc(Med)(Pharmacy)) -- University of Limpopo, 2012. / The role of the pharmacist has evolved over the last two decades beyond the traditional functions of dispensing and stock control. The focus has shifted toward patient-oriented functions, in which the pharmacist assumes responsibility for the patient’s drug- and healthcare needs as well as the outcome of treatment. The aim of this research was to assess the need for pharmaceutical care to the Surgical Intensive Care Unit of Steve Biko Hospital. The surgical and trauma ICU is a 12 bed unit to which the researcher rendered pharmaceutical care over an eight week period, from 14 February to 26 March 2011. Interventions to assess drug therapy and achieve definite outcomes to improve patients’ quality of life were documented for 51 study patients according to the system developed by the American Society of Health-System Pharmacists (1992). Of the 51 patients, 35 were male and 16 were female. The age of the patients ranged from 12 years to 86 years, with most patients admitted to the unit in the age groups 21 to 30 years, and 51 to 60 years. The patients’ estimated weights ranged from 40kg to 120kg with older patients, from age 41 upwards, weighing more. The average stay in the unit was 8.7 days, with the minimum stay for one patient being only one day, and the maximum stay for one patient was 26 days. In the study, the HIV status of only 13 of the 51 patients was tested. Of the 13 patients, six were HIV positive, while seven tested negative. All the patients admitted to the unit were not tested for HIV, because they were not admitted to the unit for HIV-related causes, and test results would not have had an effect on their outcome. Diagnoses encountered most frequently in the unit were trauma (21 patients), skeletal involvement or fractures (16 patients), infections or sepsis (15 patients) and gastro-intestinal bleeds (14 patients). In most cases more than one diagnosis applied to the same patient, since patients admitted with trauma also had skeletal or gastro-intestinal involvement. An Assessment of the need of Pharmaceutical Services in the Intensive Care Unit and High Care Unit of Steve Biko Academic Hospital viii The medications prescribed most frequently were enoxaparin (49 patients), sucralfate (41 patients) and multivitamin syrup (47 patients); in accordance with the standard ward protocol for prophylactic regimens. The drug class most often used was the anti-infectiveshaving124 items prescribed during the study period. Of these, the broad spectrum antibiotics were used most frequently, e.g. piperacillin/tazobactam (22 patients), meropenem (11 patients) and imipenem (11 patients). An average of 12 medications was prescribed for each patient in the ward. A total of 181 interventions were suggested for the 51 patients during the study period, of which 127 (70%) were accepted and implemented by the medical and nursing staff. The average number of interventions per patient ranged from 0 to 13 with a median of 3.5 interventions per patient. The four most frequent problem types were untreated medical conditions (15.5%), length or course of therapy inappropriate (13.8%), investigations indicated or outstanding (12.2%) and prescribed doses and dosing frequency appropriate (11%). Interventions were also made regularly to address system errors or non-compliance and factors hindering achievement of therapeutic effect. The perceived need for pharmaceutical care by healthcare professionals in the SICU was measured by questionnaires before and after the study period. The feedback by staff regarding the pharmacist working in the ward was very positive. They appreciated the researchers input on ward rounds, as well as assistance with problems encountered with the pharmacy. Of the total time spent in the ward, the researcher spent 28% of her time on patient evaluation. Ward rounds also took up a great deal of time (21.7%), since ward rounds were done with different members of the multidisciplinary team. Most interventions were suggested during ward rounds. The costs saved during the study period were enough to justify the appointment of a pharmacist to the ward on a permanent basis, albeit for limited hours daily. The researcher designed an antibiotic protocol for the unit. The protocol was designed according to international standards, and after discussion with the microbiologists, adapted for use in the specific unit. An Assessment of the need of Pharmaceutical Services in the Intensive Care Unit and High Care Unit of Steve Biko Academic Hospital ix In conclusion, the study results have demonstrated that a pharmacist’s contribution to patient care at ward level in a surgical ICU resulted in clinical outcomes that improved the patient’s quality of life. Drug-related problems were identified and addressed. Medical staff in the S-ICU accepted the pharmacist’s interventions and even welcomed her contribution to other ward functions, for instance managing medication and providing education. Pharmaceutical care should be rendered on a permanent basis to the Surgical ICU and the pharmacist should increasingly become a key part of the multidisciplinary team, taking responsibility for patients’ medication needs.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1954. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1951. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1954. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 88-90).

Thesis (M.A.)--Rowan University, 2006. / Typescript. Includes bibliographical references.

Univ., Diss. u.d.T.: Poget, Cédric Julien: Parallel imports of pharmaceuticals: evidence from Scandinavia and policy proposals for Switzerland--Basel, 2007.

Thesis (Ph. D.)--Victoria University (Melbourne, Vic.), 2008. / Includes bibliographical references.

Activation of the transcription factor Nrf2 regulates expression of phase II enzymes and other adaptive responses to electrophile and oxidant stress. Nrf2 concentrations are regulated by the thiol-rich sensor protein Keap1, which is an adaptor protein for Cul3-dependent ubiquitination and degradation of Nrf2. However, the links between site-specificity of Keap1 modification by electrophiles and mechanisms of Nrf2 activation are poorly understood. We studied the actions of the prototypical Nrf2 inducer tert-butylhydroquinone (tBHQ) and two biotin-tagged, thiol-reactive electrophiles N-iodoacetyl-N-biotinylhexylenediamine (IAB) and 1-biotinamido-4-(4'-[maleimidoethyl-cyclohexane]-carboxamido)butane (BMCC). Both IAB and tBHQ induce expression of ARE-directed GFP expression in ARE/TK-GFP HepG2 cells and both initiatednuclear Nrf2 accumulation and induction of heme oxygenase 1 in HEK293 cells. In contrast, BMCC produced none of these effects. Liquid chromatography tandem mass spectrometry (LC-MS-MS) analysis of human Keap1 modified by IAB or BMCC in vitro indicated that IAB adduction occurred primarily in the central linker domain, whereas BMCC modified other Keap1 domains. Treatment of FLAG-Keap1 transfected HEK293 with the Nrf2-activating compounds IAB and tBHQ generated high molecular weight Keap1 forms, which were identified as K-48-linked polyubiquitin-conjugates by immunoblotting and LC-MS-MS. Keap1 polyubiquitination coincided with Nrf2 stabilization and nuclear accumulation. In contrast, BMCC did not induce Keap1 polyubiquitination. Our results suggest that Nrf2 activation is regulated through the polyubiquitination of Keap1, which in turn is triggered by specific patterns of electrophile modification of the Keap1 central linker domain. These results suggest that Keap1 adduction triggers a switching of Cul3-dependent ubiquitination from Nrf2 to Keap1, leading to Nrf2 activation.The chemopreventive agent sulforaphane is an isothiocyanate, which was isolated from broccoli. Sulforaphane was demonstrated to induce ARE-regulated genes by stimulating the Keap1-Nrf2 system. This agent is a powerful electrophile that can react with thiols to form thionoacyl adducts. A specific sulforaphane modification pattern on Keap1 may trigger the activation of Nrf2. However, thionoacyl adducts are labile to hydrolysis and transacylation reactions, which prevent the identification of the sulforaphane modification patten on Keap1. In this study, we have developed a LC-MS-MS method to map sulforaphane modification sites formed on Keap1 in vitro. Our studies indicate that sulforaphane displays a different pattern of Keap1 modification than ARE/ERE inducers that modify Keap1 by alkylation. Moreover, the modification of Keap1 in vivo by sulforaphane does not trigger the ubiquitination of Keap1, which suggests a novel mechanism for Nrf2 stabilization by sulforaphane thionoacyl adduct formation.

Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United Kingdom (UK) and the United States (US). Most of the cases are diagnosed in the metastatic stage (MPC) and the disease is associated with a significant economic and quality of life burden. Chemotherapy with gemcitabine (GEM) is the standard of care. Combination regimens such as cisplatin plus GEM (CIS+GEM), capecitabine plus GEM (CAP+GEM), nab-paclitaxel plus gemcitabine (NAB-P+GEM), FOLFIRINOX (FFX), and oxaliplatin plus GEM (OX+GEM) showed an improvement in the survival outcome when compared to GEM alone. The purpose of the pharmacoeconomic research program included in this dissertation-by-articles was to assess the benefits of these regimens as first-line treatment relative to their costs in the management of metastatic pancreatic cancer for the UK and the US-doing so by building upon a critical review of pharmaco-economic studies of treatments for MPC and using a newly developed algorithm for parametric model selection. The four objectives of this research program were: (1) to identify and critique previous economic evaluation studies that have been done in the pancreatic cancer setting; (2) to propose a transparent algorithm to justify parametric model selection in economic evaluation studies; (3) to conduct an economic evaluation of systemic chemotherapies as first-line treatment of MPC from the payer perspective for the UK; and (4) to conduct an economic evaluation of systemic chemotherapies as first-line treatment of MPC from the payer perspective for the US. This dissertation begins with an orientation to MPC, treatment options, innovation, and dissertation outline. From the critical review (Chapter 2) we concluded that no comprehensive economic evaluations for all treatment options for the UK and the US have been published; overall survival was the key driver for most of the economic evaluations; economic analyses were country-specific, not generalizable across countries, inconsistent in their use of model inputs and utility estimates; and their justification for selecting a specific parametric model. The latter led us to the development of a quantitative algorithm (Chapter 3) for objectively selecting parametric models to extrapolate the data beyond the time horizon reported in the clinical trials; showing also that the application of different parametric models impacted the economic evaluation estimates. Considering the likelihood of between-country differences, we then performed pharmacoeconomic evaluations of GEM alone, CAP+GEM, OX+GEM, CIS+GEM, NAB-P+GEM and FFX for the UK (Chapter 4), with its single-payer system, and for the US (Chapter 5), with its multiple-payer system. The UK analyses revealed that compared to CAP+GEM, OX+GEM and CIS+GEM were more costly but less effective. Treatment with either FFX or CAP+GEM was more costly but more effective than with GEM alone. In contrast, the US analyses showed that OX+GEM, CAP+GEM, NAB-P+GEM and FFX were found to be costlier and more effective than GEM alone. Compared to GEM alone, NAB-P+GEM was found to have the smallest incremental cost-effectiveness and utility ratio among all other regimens. We synthesize and examine the implications of these findings in Chapter 6.

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