ABSTRACT The non-steroidal anti-inflammatory drug (NSAID), diclofenac, has been associated with a high risk for cardiovascular events in observational studies. However, majority of studies identifying this association were conducted when diclofenac was the only NSAID that could be obtained as a combination product (i.e., formulated with misoprostol). As a result, channelling bias might have resulted if prescribers selected the combination of diclofenac/misoprostol (Diclo-Miso) in patients with poor health status frequently than other NSAID products. The main purpose of this study was to identify evidence for channelling bias in a cohort of patients with coronary heart disease (CHD) prescribed NSAIDs. Three independent, retrospective analyses were carried out using Saskatchewan’s health administrative databases. Patients were eligible if they were hospitalized with CHD event between January 1, 1994 and December 31, 2008. In the first analysis, a time series was conducted to examine trends in the use of NSAIDs following discharge from original hospitalization. In the second analysis, multivariate logistic regression models were constructed to identify characteristics of patients prescribed with Diclo-Miso in comparison to single-entity diclofenac. Finally, a nested case-control study was conducted to examine the risk for recurrent myocardial infarction (MI)/ Unstable Angina (UA) or death among patients prescribed with Diclo-Miso versus single-entity diclofenac. For each case, up to five controls were matched by age and sex. Between 1994 and 2008, NSAIDs were used by 20.1% (3,099/15,393) of patients in the year following discharge from their original MI/UA hospitalization. Use of these agents was relatively stable until 2004 when the COX-2 selective agent rofecoxib was withdrawn from the market. Following this date (i.e., September 30, 2004), the use of Diclo-Miso and single-entity diclofenac appeared to follow different trends. However, available patient and disease specific factors could not explain diverging utilization trends. Further, no differences were observed in the risk of experiencing recurrent MI/UA between patients receiving Diclo-Miso (OR 0.88, 95% CI 0.72-1.08, p=0.22) or single-entity diclofenac (OR 0.78, 95% CI 0.60-1.00, p=0.06) versus patients not exposed to NSAIDs. Based on the study’s result, channelling bias does not appear to be a major threat to the analysis of cardiovascular toxicity of diclofenac products.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for systemic control of acute and chronic pain and inflammation (Lin et ah, 2000:1129), but usage problems and side-effects that occur during the post-marketing phase of these drugs are well documented (Thiefin & Beaugerie, 2005:287). Following the demonstration of the value of anti-inflammatory therapy in diseases like rheumatoid arthritis (Boardman & Dudley Hart, 1967:268), new NSAIDs appeared on the market (Dieppe et al., 2004:867), and the indications steadily broadened from inflammatory diseases to almost any painful condition. Studies have indicated that NSAID-associated serious upper gastro-intestinal (GI) adverse events result in 103 000 hospitalisations (Bombardier, 2002:4) and 165 000 deaths per year in the United States. A study in South Africa in 2002 indicated that NSAID utilisation contributed considerably to the total cost of all medicine items from a medicine claim database in the private health care sector (Joubert, 2002:260). The objective of this study was to determine the prevalence and cost of non-steroid anti-inflammatory drugs in a section of the private health care sector, and specifically to determine the prevalence, usage and cost of Coxib (Specific cyclo-oxygenase-2 inhibitor) medicine items before and after the withdrawal of Vioxx® from the market in September 2004 (Merck, 2004). Data from two medicine claim databases for the years 2004, 2005 and 2006 (medicine claim database I) and the years 2005 and 2006 (medicine claim database M), were analysed by means of a retrospective drug utilisation review (DUR) study. The usage of Coxib medicine items was determined, and compared for the periods before and after the withdrawal of Vioxx® in September 2004. It was found that between 9 and 10.5 per cent of prescriptions dispensed through both medicine claim database I and medicine claim database M during the study period were NSAID prescriptions. NSAID medicine items on medicine claim database I represented between 3.9 % (R25 942 986) and 2.9 % (R8 073 034) of the total cost of all medicine items claimed from 2004 to 2006. NSAIDs represented 3.1 % (R58 290 412) and 2.8 % (R57 752 267) of the cost of all medicine items claimed through medicine claim database M during 2005 and 2006 respectively, indicating similar trends in the two medicine claim databases. The prevalence of Coxibs on medicine claim database I decreased from almost 20 % (47 938) in 2004 to 8.4 % (13 276) in 2005, but showed an increase again to 10.9 % (12 355) in 2006. The prevalence of both cyclo-oxygenase (COX) inhibitors, and Coxibs demonstrated a change during 1 September 2004 to 31 December 2004 when COX-inhibitors showed an increase in use, while Coxibs showed and almost equal but opposite trend with a decrease in use. This could possibly be related to perceptions of providers and public with regard to Coxibs and their related safety after the withdrawal of Vioxx® on 30 September 2004 (Merck, 2004) and other Coxibs such as Bextra® (FDA, 2005) in 2005 in USA. It is concluded that most patients who were using Coxibs before the withdrawal of Vioxx®, substituted Coxibs for COX-inhibitors, that are known for their possible gastro-intestinal side-effects. Recommendations for future research regarding NSAID use were also made, and included an investigation of the usage of Coxibs in different age groups, as well as the combination of NSAIDs with gastro-protective medicines in long-term use. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2009.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for systemic control of acute and chronic pain and inflammation (Lin et ah, 2000:1129), but usage problems and side-effects that occur during the post-marketing phase of these drugs are well documented (Thiefin & Beaugerie, 2005:287). Following the demonstration of the value of anti-inflammatory therapy in diseases like rheumatoid arthritis (Boardman & Dudley Hart, 1967:268), new NSAIDs appeared on the market (Dieppe et al., 2004:867), and the indications steadily broadened from inflammatory diseases to almost any painful condition. Studies have indicated that NSAID-associated serious upper gastro-intestinal (GI) adverse events result in 103 000 hospitalisations (Bombardier, 2002:4) and 165 000 deaths per year in the United States. A study in South Africa in 2002 indicated that NSAID utilisation contributed considerably to the total cost of all medicine items from a medicine claim database in the private health care sector (Joubert, 2002:260). The objective of this study was to determine the prevalence and cost of non-steroid anti-inflammatory drugs in a section of the private health care sector, and specifically to determine the prevalence, usage and cost of Coxib (Specific cyclo-oxygenase-2 inhibitor) medicine items before and after the withdrawal of Vioxx® from the market in September 2004 (Merck, 2004). Data from two medicine claim databases for the years 2004, 2005 and 2006 (medicine claim database I) and the years 2005 and 2006 (medicine claim database M), were analysed by means of a retrospective drug utilisation review (DUR) study. The usage of Coxib medicine items was determined, and compared for the periods before and after the withdrawal of Vioxx® in September 2004. It was found that between 9 and 10.5 per cent of prescriptions dispensed through both medicine claim database I and medicine claim database M during the study period were NSAID prescriptions. NSAID medicine items on medicine claim database I represented between 3.9 % (R25 942 986) and 2.9 % (R8 073 034) of the total cost of all medicine items claimed from 2004 to 2006. NSAIDs represented 3.1 % (R58 290 412) and 2.8 % (R57 752 267) of the cost of all medicine items claimed through medicine claim database M during 2005 and 2006 respectively, indicating similar trends in the two medicine claim databases. The prevalence of Coxibs on medicine claim database I decreased from almost 20 % (47 938) in 2004 to 8.4 % (13 276) in 2005, but showed an increase again to 10.9 % (12 355) in 2006. The prevalence of both cyclo-oxygenase (COX) inhibitors, and Coxibs demonstrated a change during 1 September 2004 to 31 December 2004 when COX-inhibitors showed an increase in use, while Coxibs showed and almost equal but opposite trend with a decrease in use. This could possibly be related to perceptions of providers and public with regard to Coxibs and their related safety after the withdrawal of Vioxx® on 30 September 2004 (Merck, 2004) and other Coxibs such as Bextra® (FDA, 2005) in 2005 in USA. It is concluded that most patients who were using Coxibs before the withdrawal of Vioxx®, substituted Coxibs for COX-inhibitors, that are known for their possible gastro-intestinal side-effects. Recommendations for future research regarding NSAID use were also made, and included an investigation of the usage of Coxibs in different age groups, as well as the combination of NSAIDs with gastro-protective medicines in long-term use. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2009.

This thesis investigates the biological activity of selected non-steroidal analogues of sex steroid hormones by examining two different effects of analogues on endogenous sex hormone activity. Non-steroidal analogues of sex hormones were synthesised to study their biological interactions with a sex steroid receptor and a sex steroid metabolising enzyme. Chapter One introduces the steroid hormones and their physiology, which leads to a review of the mechanisms by which steroids exert their effects. Their implication in disease is discussed, with particular emphasis on the sex steroids. As the biological activity of steroids is related to their chemical structure, the important features of steroid structure are identified, including the cyclopentanoperhydrophenanthrene nucleus, arrangement of ring substituents and ring junction conformation. The concept of non-steroidal analogues of steroids is introduced, and the harmful or beneficial effects analogues have on endogenous steroid activity are considered. Alteration of steroid activity and its consequences are focussed on two main areas; the potential adverse effects of environmental chemicals which mimic sex steroid activity, and the use of non-steroidal analogues in medicinal chemistry for treating sex steroid related disease. Chapter Two describes an investigation into the 17β-estradiol mimicking activity of non-steroidal analogues. Exogenous chemicals that mimic estradiol are of concern as they may alter endogenous estradiol activity and disrupt endocrine systems. Firstly, an introduction to the field of research concerned with environmental chemicals that mimic steroid hormones is given. The interaction of xenoestrogens with the estrogen receptor is described, as are the methods available for assessing the estrogen mimicking activity of xenoestrogens. The concern for insecticides mimicking estrogen activity is described by reviewing reported activities of insecticides, which leads into a discussion of work carried out as part of this thesis. Metabolites of the pyrethroid insecticides permethrin and cypermethrin, 2.14, 2.15, and 2.16 were synthesised while others were commercially obtained. The interaction of pyrethroid insecticide metabolites with the human estrogen receptor expressed in recombinant yeast (Saccharomyces cerevisiae) was studied, following the establishment and validation of the assay. Metabolites 2.11, 2.12, and 2.14 were found to weakly stimulate estrogen receptor-mediated estradiol responsive gene expression in the yeast assay (105 less active than 17β-estradiol). Since the activity of the metabolites using the yeast assay was greater than for the parent compounds, metabolic pathways need to be considered when assessing the impact of exposure to environmental estrogens. The low estrogenic activity suggests these compounds are not individually contributing significantly to the xenoestrogenic impact on humans, but will add to total xenoestrogen exposure. Chapter Three describes the inhibition of a sex steroid metabolising enzyme, steroid 5a-reductase, by novel non-steroidal compounds. Inhibitors of this enzyme are potentially useful therapeutic agents for regulating the activity of an androgen in prostate disorders. A review of the literature on non-steroidal inhibition of 5a-reductase identified three key structural features known to enhance inhibitor potency; ring substitution, position and nature of ring unsaturation and angular methyl group presence. These features were taken into account in the design of inhibitors synthesised in this thesis (3.55-3.57, 3.59, 3.61, 3.62, 3.110 and 3.111). Inhibitors consisting of non-steroidal 5- or 1-aryl pyridone scaffolds were synthesised to investigate SAR for 4'-substituents. The 5-aryl 1-methyl-2-pyridone/piperidone scaffold of compounds 3.55-3.57 and 3.59 was constructed by Suzuki cross coupling methodology, while the 1-aryl 2-methyl 2,3-dihydro-4-pyridone scaffold of 3.61 and 3.62 was constructed by aza Diels-Alder methodology. Long carbon chain olefin containing tethers 3.107 and 3.108 were synthesised for conjugation to inhibitor 3.57 by cross metathesis to give conjugates 3.110 and 3.111. Compounds 3.55-3.57, 3.59, 3.61, 3.62, 3.110 and 3.111 inhibited the type 1 5a-reductase isozyme expressed by HEK-I cells, with activities comparable to those of related literature compounds. The 1-aryl 2,3-dihydro-4-pyridone 3.62 inhibited both the type 1 and 2 isozymes (expressed by HEK-II cells) of 5a-reductase. The presence of bulky hydrophobic groups (benzoyl, long chain tethers) at the 4' position enhanced the potency of type 1 inhibition by 5-aryl pyridone type compounds in comparison to N,N-diisopropyl- and N-allylacetamide groups. This information provides further understanding of SAR within and across different classes of non-steroidal inhibitors of steroid 5a-reductase towards improved drug design.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (M.Sc.). / Written for the Dept. of Epidemiology, Biostatistics and Occupational Health. Title from title page of PDF (viewed 2008/07/30). Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 186-207).

Thesis (M.S.)--West Virginia University, 2005. / Title from document title page. Document formatted into pages; contains viii, 59 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 33-38).

Thesis (M.S.)--University of Louisville, 1997. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.