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 Use of these agents was relatively stable until 2004 when the COX-2 selective agent rofecoxib was withdrawn from the market.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.

Master of Science / Department of Clinical Sciences / Gregory F. Grauer / Prostaglandins play many important roles in the kidney including regulation of renal blood flow, glomerular filtration, renin release, and sodium excretion. Upon activation of the renin angiotensin aldosterone system (RAAS), prostaglandin upregulation becomes critical to offset the vasoconstrictive effects of norephinephrine, angiotensin II, and vasopressin. Nonsteroidal anti-inflammatory drugs (NSAIDs) produce both their beneficial and detrimental effects through inhibition of the cyclooxygenase enzyme and subsequent interference with prostaglandin production. Healthy canine kidneys express both COX-1 and COX-2, although basal COX-2 expression in dogs is significantly higher than in other species. Nonsteroidal anti-inflammatory drugs that spare COX-1 have exhibited less gastrointestinal toxicity, but no NSAID has been proven safe for the kidney. The kidney is the organ with the second highest reports of adverse drug events, which is usually manifested as functional changes. However, structural changes including renal papillary necrosis, can occasionally be observed. Dogs with chronic kidney disease could be expected to be at increased risk for NSAID-related adverse drug effects. As nephrons and renal reserve are lost in chronic kidney disease, the canine kidney becomes more dependent on COX-2 for production of prostaglandins. Inasmuch as the prevalence of both CKD and OA increases with age, it is expected that many dogs being treated with NSAIDs for OA will have loss of renal reserve and/or early stage CKD. If administration of an NSAID is required for long term treatment of osteoarthritis, frequent monitoring of blood pressure and renal parameters, as well as hepatic enzymes are recommended.

Twenty-four healthy, mixed breed dogs were divided into four groups. Group I received a placebo PO BID, group II received an average 16.5 (range, 15.1-17.8) mg/kg buffered aspirin PO BID, group III received an average 2.2 (range, 2.0-2.4) mg/kg carprofen PO BID, and group IV received an average 12.8 (range, 11.7-13.8) mg/kg etodolac PO QD (with a placebo in the P.M.). All treatments continued for 28 consecutive days. Gastroduodenal endoscopy was performed on days – 9, 0, 5, 14 and 28. Multiple gastric biopsies were obtained endoscopically on day – 9 to determine each dog's Helicobacter spp. status. Five areas, consisting of four regions in the stomach and one in the proximal duodenum, were evaluated endoscopically, and each was assigned a score from 1 to 11 based on qualitative assessment of submucosal hemorrhage, erosion, or ulceration. These scores for each region were then summed to give a total score for each endoscopic evaluation. Erosions and submucosal hemorrhages were seen in all dogs receiving aspirin. Only minor gastric lesions were observed in the carprofen, etodolac, and control groups. No adverse clinical signs were noted in any dog given any treatment during the course of the study. There was no predilection site for lesion development in any group. Median total score on days 0, 5, 14, and 28 were as follows: group I, 5.0, 5.0, 5.0, 5.0; group II, 5.0, 27.0, 26.0, 27.5; group III, 5.0, 5.0, 6.0, 5.0; group IV, 5.0, 7.0, 5.0, 5.0, respectively. There was no significant difference between dogs receiving carprofen, etodolac, or placebo. The administration of carprofen, etodolac, or placebo to healthy dogs resulted in significantly less gastroduodenal lesion development than in dogs receiving buffered aspirin. Thirty healthy, random source, dogs were evaluated to determine the prevalence of Helicobacter spp., and to compare the ‘Campylobacter-like organism’ test (CLOtest®) to histopathologic identification of Helicobacter spp. organisms. Gastric mucosal biopsies from each of four gastric regions (cardia, pyloric antrum, greater curvature, and angularis incisura) were obtained endoscopically for use in the CLOtest® and for histopathologic evaluation. Twenty-seven of 30 dogs (90%) were positive for spiral bacteria suspected to be Helicobacter spp. by histopathologic evaluation in at least one of the four gastric regions. Three dogs (10%) were negative for Helicobacter spp. in all gastric regions by histopathologic evaluation. The CLOtest® was found to have a sensitivity, specificity, and positive predictive value of 84%, 81%, and 92%, respectively, when compared to histopathologic evaluation. When only the angularis incisura was evaluated, the sensitivity, specificity, and positive predictive value increased to 92%, 94%, and 96%, respectively. The angularis incisura had the highest, whereas the pyloric antrum had the lowest, prevalence of positive test results when compared to dogs determined to be overall Helicobacter spp. positive (histopathologic positive in at least one gastric region). The results of this study suggest the prevalence of Helicobacter spp. in apparently healthy dogs is high. For accurate and economical detection of Helicobacter spp. in a dog undergoing upper gastrointestinal endoscopy, a tissue sample should be taken from the angularis incisura for CLOtest® sampling. / Master of Science

Chronic inflammation is intimately linked with cancer development and progression and therefore reducing or eliminating inflammation represents a logical treatment and prevention strategy. Studies have shown that anti-inflammatory agents have anti-tumour effects in cancers, with reduced metastases and mortality. Current use of anti-inflammatory agents in the treatment and prevention of cancer is limited by their toxicity and side effects. The emerging field of nanotechnology allows the fundamental properties of a drug to be altered, creating a product with improved reactivity and bioavailability, leading to more targeted treatments and reduced dosage. In the present study, the genotoxic effects of three commonly used anti-inflammatory drugs; aspirin, ibuprofen and hydrocortisone, in their bulk and nano forms were evaluated on peripheral blood lymphocytes of healthy donors using the comet assay and the micronucleus assay. In order to determine any anti-cancer effects, these agents were also tested in peripheral blood lymphocytes in patients with haematological cancers. The glucocorticoid hydrocortisone was also evaluated for anti-oxidant capacity. Our results demonstrate that the nano versions of each drug produced a different response than the bulk counterpart, indicating that a reduction in particle size had an impact on the reactivity of the drug. Our results also indicate that the nano versions of each drug were less genotoxic than the bulk formulation, further emphasising the potential of nanoparticles as an improvement to current treatment options. We also found an anti-oxidant effect with hydrocortisone, with a more profound effect seen with the nano formulation.

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most used drugs in equine medicine, mainly used to treat inflammation, endotoxemia, pain or fever. NSAIDs inhibit cyclooxygenases which induce to synthesize prostanoids. But NSAIDs have side effects to renal functions too. Objectives: The current study was carried out to investigate the effects of the most common used NSAIDs on urinary parameters in horses. Materials and Methods: Thirty healthy horses were used as a control group and 20 horses with left dorsal displacement, left ventral impaction or lameness of using either flunixin meglumine (FM), metamizole (MZ) or phenylbutazone (PHZ) have been assigned to groups 1, 2 or 3, respectively. Creatinine, urea nitrogen, glucose, protein and electrolytes were measured in serum and urine including GGT using an automatic analyzer. Fractional excretions (FE) of sodium, chloride, potassium, calcium, magnesium and inorganic phosphate, in addition to urinary protein (U-Pro):U-Cr and urinary gamma glutamyl transferase (U-GGT):U-Cr ratios were calculated. Urinary mucus and IgA concentrations were measured and their ratios to the urinary creatinine were calculated. The data were statistically analyzed using Shapiro-Wilks test, descriptive statistics, Kruskal-Wallis one-way analysis of variance and Dunn’s test. Significance was set at P £ 0.05. Results: The FEMg was significantly higher in group 3 (P < 0.033) compared to the control group. The U-GGT:U-Cr ratio was also significantly higher in group 3 (P < 0.001) compared with the control group. The U-Pro:U-Cr ratio was significantly higher in groups 1 and 2 (P < 0.007 and P < 0.001, respectively) than in the control group. PHZ group had a significantly increase in mucus:U-Cr ratio (P < 0.005). Significant increases were observed regarding the IgA:U-Cr ratio in groups 1 (P < 0.007) and 2 (P < 0.014). Conclusions: Long-term use of PHZ has an influence on the renal ascending limb of the loop of Henle, and all these drugs could have effects on the proximal tubules. Phenylbutazone causes an increase in urinary mucus secretion, probably as a protective mechanism against the necrotic effect in renal pelvis of PHZ. Parameters such as U-Pro:U-Cr and U-GGT:U-Cr ratios and FEMg are helpful in detecting these renal abnormalities.

Chronic inflammation is intimately linked with cancer development and progression and therefore reducing or eliminating inflammation represents a logical treatment and prevention strategy. Studies have shown that anti-inflammatory agents have anti-tumour effects in cancers, with reduced metastases and mortality. Current use of anti-inflammatory agents in the treatment and prevention of cancer is limited by their toxicity and side effects. The emerging field of nanotechnology allows the fundamental properties of a drug to be altered, creating a product with improved reactivity and bioavailability, leading to more targeted treatments and reduced dosage. In the present study, the genotoxic effects of three commonly used anti-inflammatory drugs; aspirin, ibuprofen and hydrocortisone, in their bulk and nano forms were evaluated on peripheral blood lymphocytes of healthy donors using the comet assay and the micronucleus assay. In order to determine any anti-cancer effects, these agents were also tested in peripheral blood lymphocytes in patients with haematological cancers. The glucocorticoid hydrocortisone was also evaluated for anti-oxidant capacity. Our results demonstrate that the nano versions of each drug produced a different response than the bulk counterpart, indicating that a reduction in particle size had an impact on the reactivity of the drug. Our results also indicate that the nano versions of each drug were less genotoxic than the bulk formulation, further emphasising the potential of nanoparticles as an improvement to current treatment options. We also found an anti-oxidant effect with hydrocortisone, with a more profound effect seen with the nano formulation.

No description available.

<b>Background:</b> Comparative assessments of the vascular and upper gastrointestinal risks of different regimens of non-steroidal anti-inflammatory drugs (NSAIDs) are required. <b>Methods:</b> Meta-analyses were conducted, using individual participant data where possible, of placebo-controlled trials of a selective cyclo-oxygenase [COX]-2 inhibitor ('coxib') or traditional NSAID, or randomised trials of a coxib versus traditional NSAIDs. A prespecified subdivision of traditional NSAID regimens of those with antiplatelet activity (mainly naproxen) and those without (mainly diclofenac) was made. Primary outcomes were major vascular events (MVEs; nonfatal myocardial infarction, nonfatal stroke or vascular death) and upper gastrointestinal complications (UGICs; perforation, obstruction or bleed). <b>Findings:</b> Searches identified 788 trials: 200 comparisons of a coxib vs placebo (88,604 participants, mean follow-up 0.60 years), 206 comparisons of a traditional NSAID vs placebo (43,482 participants, 0.46 years) and 149 comparisons of a coxib vs traditional NSAID (137,466 participants, mean follow-up 0.95 years). Compared to placebo, allocation to a coxib increased the risk of MVEs (rate ratio 1.38, 95&percnt; CI 1.14-1.66), vascular mortality (1.58, 1.11-2.24) and UGICs (1.81, 1.17-2.81). Overall, in the population studied, coxibs were associated with three additional major vascular events (one fatal) and two (rarely fatal) upper gastrointestinal complications per 1000 person-years exposure. There was no evidence of heterogeneity by duration of follow-up, coxib type, dose (other than for celecoxib), or patient characteristics, for the primary outcomes. The risk of MVEs for traditional NSAIDs without antiplatelet activity (mostly diclofenac 75mg bd or ibuprofen 800mg tds) were comparable to coxibs (1.40, 1.15-1.72); but the risk of UGICs (1.98, 1.39-2.84) was significantly greater. For traditional NSAIDs with antiplatelet activity (mostly naproxen 500mg bd) there were no significant excess of MVEs (0.84, 0.66-1.08), but UGICs were substantially increased (4.06, 2.85-5.78). Both coxibs and traditional NSAIDs increased risk of hospitalisation for heart failure by about two-fold. <b>Interpretation:</b> The vascular and upper gastrointestinal risks of coxibs and high-dose tNSAID regimens can be predicted, allowing the choice of analgesia to be tailored for particular patients.