One of the complications of cancer chemotherapy is an increased risk of secondary treatment-related malignancy. It is believed that secondary cancers arise as a result of mutagenic and genotoxic effects of chemotherapeutic agents. The mechanisms by which these agents induce secondary cancer are not known. This study was designed to investigate the potential genotoxic effects of two agents, etoposide and melphalan, in cancer patients receiving single drug chemotherapy. Both drugs are potent mutagens; and have been implicated as causative agents of secondary acute myeloid leukemia (sAML). Two groups of patients were studied: small cell lung cancer (SCLC) patients who received etoposide and multiple myeloma (MM) patients treated with melphalan. The induction of mutation at the hypoxanthine phosphoribosyl transferase (hprt) gene was investigated in patients' lymphocytes by using the hprt T-cell clonal assay. The results showed that the mean hprt mutant frequency (MF) did not increase after treatment with neither agent, however, a significant elevation of MF was detected in a patient who received the highest melphalan dose. The sequence analysis of mutants revealed a significant enhancement of AT > TA transversions in post-etoposide spectra compared to the control spectra, however, no mechanistic explanation for the induction of such mutation by etoposide can be proposed. Etoposide, a topoisomerase II inhibitor and an inducer of DNA strand breaks, is expected to produce large genomic deletions and rearrangements. No enhancement of large deletions or rearrangements was seen in post-etoposide spectra. The elimination of mutated cells by apoptosis is proposed to explain the negative result. In post-melphalan spectra, a significant enhancement of GC > TA transversions was detected compared to the control spectra. GC > TA transversion is an expected melphalan-induced mutation since alkylating agent melphalan preferentially causes guanine adducts and crosslinks. The results suggest that while single drug chemotherapy does not induce mutation in the majority of patients, exposure to high doses of chemotherapy agents may be associated with the induction of mutation. This correlates with the dose-dependent increase in the risk of secondary malignancy after chemotherapy. The significance of drug-specific changes in the mutational spectra seen in patients' lymphocytes can be evaluated after mutations in proto-oncogenes and/or tumor suppressor genes are identified in secondary cancer cases. Results also suggest that the hprt mutational spectrum might be a more sensitive biomarker of the genotoxic exposure than the hprt MF. To investigate the clastogenic effect of etoposide chemotherapy, blood cells from SCLC patients were screened for the appearance of multiple lineage leukemia (MLL) gene rearrangements using fluorescent in situ hybridization (FISH). MLL gene is rearranged in more than 50% of sAML cases in patients previously treated with etoposide or related compounds. Analysis of the results revealed that FISH is not sensitive enough method for the detection of rare rearrangements. The use of RT-PCR technique is proposed as a more realistic approach for monitoring patients treated with etoposide chemotherapy for the appearance of the MLL gene rearrangements. / Graduate

This thesis explores the perceived relationship between spirituality and psychiatric medication use in individuals living with severe mental health problems. The biological approach to mental health treatment is the dominant paradigm of care across the Western world, which justifies the use of psychopharmacology as a first-line therapy. In the last 30 years, the steady rise in the use of prescription medications has generated much debate and controversy. Historically, much of what we know about psychiatric medication comes from professionals and experts. Comparatively little is known about the perspectives of service users. There is also strong evidence to suggest that religion and spirituality are playing a growing role in addressing mental health problems. Both spirituality and psychiatric medication are known to mediate the processes of wellness and recovery, yet it is not well understood how their interactions may impact upon recovery. The intention of this thesis was to explore this unknown area. The methodology used in this thesis was hermeneutic phenomenology. A purposive sample of twenty people who self-identified as spiritual and/or religious, and were or had in the past taken psychiatric medication participated. Data were collected via in-depth, unstructured interviews, and analysed using a modified approach, based on the works of other researchers. The key finding in this study is that people experienced a multiplicity of interactions between spirituality and psychiatric medication which significantly impacted treatment outcomes, in both positive and negative ways. The overall findings of this research highlights the need for greater awareness of spirituality as a nonpharmacological factor which can impact upon drug treatment outcomes.

Class of 2005 Abstract / Objectives: The objectives of this study were to assess the number of antihypertensive prescriptions by therapeutic class including beta-blockers, calcium channel blockers (CCBs), diuretics, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs), dispensed in the fiscal years 2002 through 2004. Methods: The project was a retrospective analysis of pharmacy data for medications used to treat hypertension from October 2002 through December 2004 (FY02 through the first quarter of FY05). Drug classes used to treat hypertension were obtained from the VA Integrated Service Network 18 (VISN 18). Within the drug classes, only drugs within the class having at least 100 prescriptions were included for the class. Rates of prescriptions dispensed by quarter over the three-year period of interest were obtained. Descriptive statistics were used to compare the before and after ALLHAT and JNC-7 time periods. Results: After the publication of The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), The Australian National Blood Pressure Study 2 (ANBP2), and Joint National Committee (JNC-7) guidelines, dihydropyridine CCB use declined to from 1.80% to 1.65% and non-dihydropyridine CCB use declined from 0.99% to 0.83% of all prescriptions from the first quarter 2002 to the first quarter 2004. In addition, after the publication of ALLHAT, hydrochlorothiazide use increased from 1.42% to 1.83% and ACE-inhibitor use increased from 4.26% to 4.79% of all prescriptions. Implications: The findings have several implications for encouraging our prescribing patterns to follow national guidelines and clinical studies more closely. Health care providers need to accept some responsibility through continuous education to be able to maintain appropriate therapy.

No description available.

No description available.

In this project, an extensive range of benzodiazepine analogues have been synthesised via Schmidt reaction of specially prepared flavanone, 4-quinolone and l-thioflavanone precursors; nitrogen insertion being effected by use of trimethylsilyl azide in trifluoroacetic acid. In some cases, several of the benzodiazepine analogues have also been prepared by alternative cyclisation routes. A detailed kinetic-mechanistic study of the Schmidt reaction of flavanones has been carried out using 'H NMR spectroscopy to explain the observed regiochemistry of nitrogen insertion. The reaction rates, for the formation of both amide and tetrazolo derivatives have been found to be influenced by the electronic effects of the A- and B-ring substituents. A series of benzodiazepine analogues have been shown to undergo regioselective A-ring chlorination with t-butylhypochlorite; the products being characterised by 'H NMR, IR and mass spectroscopy. The mass spectrometric fragmentation patterns of series of 2-aryl-4-quinolones, and 2-aryl-l ,4-benzodiazepinones and their tetrazolo[l ,5-dl analogues have been elucidated using a combination of low-resolution, high-resolution and metastable-peak analyses. The binding affinities of various benzodiazepine analogues for rat brain benzodiazepine receptors have been evaluated using a radioreceptor assay technique. Structure-activity relationships were investigated to establish the effects of various A-, B- and Coring substituents on binding affinity. The conformational preferences of selected systems have been studied using a combination of multi-pulse 'H NMR spectroscopy, X-ray crystallography and computer modelling techniques with a view to establishing the influence of conformation on binding affinity.

In this study the metabolism of the anti-arthritic drug, phenylbutazone, was investigated in female Wistar rats, and the results compared with those of other workers in this field. Two interrelated projects were undertaken. The first covered the pattern of excretion, isolation and characterisation of the metabolites and decomposition products of phenylbutazone in rats dosed post-orally with the drug. It was found that the major route of excretion was via the urine and over 50% of the administered dose was excreted in the first 24 hours by this route. A small percentage of the dose was excreted in the faeces. The following compounds were identified using chromatographic and autoradiographic techniques: p-Hydroxy derivative of phenylbutazone γ-Hydroxy derivative of phenylbutazone in both its molecular forms (ring lactone and straight chain hydroxyl) 4-Hydroxy derivative of phenylbutazone p-γ-Dihydroxy derivative of phenylbutazone p-4-Dihydroxy derivative of phenylbutazone Hydrolysable conjugates (possibly glucuronides) Water soluble non-hydrolysable conjugates. The second project dealt with the quantitation of the water insoluble compounds isolated in the initial work. Using a unique technique, combining inverse isotope dilution assay and spectrophotometric analysis, it was found that the major metabolite was the γ-hydroxy derivative of phenylbutazone, present in both its molecular forms. Oxyphenbutazone was a minor metabolite and the p-γ-dihydroxy derivative of phenylbutazone was present only in very low concentration. These results did not conform with those of previous workers in this field who reported the γ-hydroxy derivative of phenylbutazone, in one molecular form only, as the major metabolite and the dihydroxy derivative as the second metabolite with a higher concentration in the urine than oxyphenbutazone. This disparity could be due to the fact that these workers took no account of the presence of the two molecular forms of the γ-hydroxy derivative of phenylbutazone with their different polarities and different Rf values. The present study showed that the straight chain hydroxyl isomer was probably mistakenly identified as the p-γ-dihydroxy derivative of phenylbutazone. This theory is supported by the fact that the percentage dose recovered by the previous workers of the γ-hydroxy and p-γ-dihydroxy derivatives together equalled the percentage dose recovered in this study of the two molecular forms of the γ-hydroxy derivative. / KMBT_363 / Adobe Acrobat 9.54 Paper Capture Plug-in

The use of a handheld Raman analyser for the positive identification of raw materials in a manufacturing pharmaceutical company was evaluated using paracetamol as test raw material to evaluate whether such a system would meet Aspen’s regulatory requirements. The approach involved subjecting the chosen raw material to identification tests under a variety of conditions so as to evaluate robustness, and specificity of the system. Thus, raw material provided by different suppliers, different packages of one manufacturing batch, and raw materials subjected to different storage conditions were evaluated. Specificity was evaluated by deliberately contaminating a sample of paracetamol with either acetanilide, or 4-aminophenol, or both at varying concentration levels. The results obtained from these investigations showed that the handheld Raman analyser can correctly identify the selected raw material (paracetamol) under a wide range of conditions, but could not correctly identify the presence of the selected contaminants at lower concentration levels (< 10 – 20 mass percent). Finally, a cost-benefit analysis was carried out in which a scenario of an existing FTIR-ATR system is used for the analysis of a specific number of raw material samples per year as opposed to a scenario in which a new handheld Raman analyser has to be purchased, set up, and used for the analysis of the same number of raw material samples. This comparison showed that the handheld Raman analyser had a pay-back time of approximately 6 months and gave a return on investment of approximately the same value as the actual purchase cost.

Antipsychotic drugs are the mainstay of treatment for psychotic disorders according to the Standard Treatment Guidelines (2012). However, these drugs are associated with multiple severe adverse drug reactions. In order to limit the effect of adverse drug reactions on patient care, documentation is necessary. Documentation of adverse drug reactions entails recording the reaction experienced, as well as supplementary information. Proper documentation can prevent future occurrences of the same or similar adverse drug reactions. The aim of this study was to determine the effects of an educational intervention targeting increasing documentation of the adverse effects of antipsychotic drugs. The objectives of the study were: to determine the pre-intervention extent and frequency of documentation of antipsychotic-related adverse drug reactions in the patient medical record; to implement an intervention aimed at educating the relevant healthcare professionals, focusing on the adverse drug reactions of antipsychotic drugs and how to record or document these reactions; to assess the post-intervention extent and frequency of documentation of antipsychotic-related adverse drug reactions in the patient medical record; and to assess the attitude of healthcare providers towards the documentation of antipsychotic related adverse drug reactions before and after the intervention.

Rheological characterization of pharmaceutical semisolids is of importance as it provides fundamental information required for the assessment of some of the final properties of a product such as viscosity, elasticity, quality and storage stability. The effect of formulation variables on product characteristics such as consistency and correlation of consumer evaluation of consistency can also be attained. (Ramachandran et al., 1999) This study focussed on using rheological techniques to fully characterize the properties of various semisolid formulations being developed or produced at a South African-based generic pharmaceutical company. Various tests were employed to characterize the semisolid dosage forms (creams and ointments), including continuous shear tests such as flow and viscosity curves and yield point measurements, oscillatory tests such as amplitude and frequency sweeps, as well as step and temperature ramp tests. A method to determine justifiable and meaningful viscosity specifications was developed, where excellent reproducibility of results were obtained when compared to the single-point viscosity determinations usually used. An evaluation as to whether rheology can be utilized as an assessment tool for product stability revealed varying results, with the oscillation-frequency sweep test displaying modest predictive capabilities. Observable differences in rheological character were found when evaluating ointment formulations exhibiting deviating quality characteristics. When analysing the effect of varying processing parameters, namely, cooling rate and mixing speed, during the manufacture of a cream, statistically significant rheological differences were obtained, while a thorough characterization of a scale-up procedure was also achieved upon analysis of various rheological properties.