>Magister Scientiae - MSc / Non-steroidal anti-inflammatory drugs (NSAIDs) are amongst the most commonly used medications globally, as they are highly effective and easily accessible. The NSAIDs are indicated for mild to moderate pain management. The increasing incidence of NSAID related side effects and hospitalisations has raised a concern about these medications’ safety. The prevalence of these side effects has drastic consequences to a challenged South Africanpublic healthcare system. The implications of not treating severe, potentially preventable upper gastrointestinal complications attributed to NSAIDs’ consumption continue to be a significant problem that healthcare professionals (HCP) face.

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The purpose of this study was to determine the safety and pharmacokinetic profile of firocoxib in healthy neonatal foals. Foals are more sensitive to the side effects of nonsteroidal anti-inflammatory drugs, (NSAIDs), particularly due to immature renal clearance mechanisms and ulcerogenic effects on gastric mucosa. Firocoxib, a novel second generation NSAID, is reported to have reduced side effects due to its COX-2 selectivity. The pharmacokinetic profile of firocoxib in neonates has not been established, making reliable dosing difficult. We hypothesized that firocoxib given per os at the labeled dose to neonatal foals would be absorbed and not be associated with clinically significant adverse events. Seven healthy American Quarter Horse foals of mixed gender were administered 0.1mg/kg firocoxib orally q24h for nine consecutive days, commencing at 36h of age. Blood samples were collected for firocoxib analysis using high pressure liquid chromatography with fluorescence detection at 0 (dose #1 only), 0.25, 0.5, 1, 2, 4, 8, 16 and 24 hours after doses #1, 5 and 9. For all other doses (2, 3, 4, 6, 7 and 8) blood was collected immediately prior to the next dose (24 hour trough). Elimination samples (36, 48, 72, 96, 120 and 144 hours) were collected after dose #9. Safety was assessed via physical examinations, changes in body weight, gastroscopy, complete blood count, serum biochemistry and urinalysis. Firocoxib was rapidly absorbed following oral administration with minimal accumulation after repeat dosing. After the initial dose, an average peak serum concentration (Cmax) of 89.50 ° 53.36 ng/mL (mean ° SD) was achieved (Tmax) in 0.54 ° 0.65 hours. Steady state was obtained after approximately 4 doses and the average maximum concentration (Cavg) in serum was 39.1 ° 8.4 ng/mL. After the final dose, the mean terminal half-life (T½?») was 10.46 ° 4.97 hours. Firocoxib was not detected in plasma 72 hours after the final dose (<2ng/mL). Bioavailability could not be determined as currently, there is no accompanying intravenous dose of firocoxib for this age group to permit the calculation. No significant abnormalities were noted on blood work, urinalysis or gastroscopy. This study demonstrated that firocoxib is absorbed after oral administration in neonatal foals with no observable adverse effects after multiple doses. / Master of Science

Ziel der Dissertation war die Überprüfung der klinischen Wirksamkeit von Natriumsalicylat bei respiratorischen Erkrankungen von Mastputen unter Feldbedingungen. Bisher existieren keine konkreten Richtlinien bzw. Modelle zum Versuchsaufbau beim Geflügel, und explizit bei der Pute, zur Durchführung einer derartigen Studie. Daher stellten sowohl die Konzeption als auch die Implementierung eines Studiendesigns zur Untersuchung der Wirksamkeit eines Antiphlogistikums bei der Mastpute unter Feldbedingungen eine zusätzliche elementare Zielsetzung dieser Promotion dar. Die in dieser Dissertationsschrift entwickelten Feldstudien orientieren sich an den Leitlinien der good clinical practice sowie der guideline for the conduct of efficacy studies for non-steroidal anti-inflammatory drugs und entsprechen der Wertigkeitsklasse Ia der evidenzbasierten Veterinärmedizin. Jede der drei Feldstudien wurde als kontrollierte, randomisierte und verblindete Parallelgruppenstudie in verschiedenen Regionen Deutschlands durchgeführt und gliederte sich in eine viertägige experimentelle Phase (EP) und eine siebentägige postexperimentelle Phase (PoP). Die zunächst definierten Arbeitshypothesen bekamen entsprechende Beurteilungskriterien zugewiesen. Unter deren Nutzung erfolgte die spätere Evaluierung, inwieweit die entzündungshemmende Wirkung von Natriumsalicylat imstande war, den Heilungsprozess der respiratorischen Grunderkrankung zu beschleunigen und eine verbesserte restitutio ad integrum hervorzurufen.

NSAIDs are among the most used drugs in the world. It is estimated that 30 million people take NSAIDs daily world-wide, without including drugs sold over the counter. They are effective in alleviating pain and inflammation. Even though they are very common there does not appear to be any clear-cut guidelines to when which NSAID should be used. It has therefore been the purpose of this thesis to analyze if there is a need to differentiate between different NSAIDs according to contemporary evidence. Since the withdrawal of rofecoxib in 2004 there has been a general idea that coxibs as a group are cardiotoxic, recent evidence suggests that this holds true for all NSAIDs however. As such this work included 5 drugs, three common over the counter non-selective NSAIDs; naproxen, ibuprofen and diclofenac as well as the two coxibs currently on the Swedish market; celecoxib and etoricoxib. Pubmed and google scholar were searched for relevant studies on the subject. The results showed that there is a need to differentiate between NSAIDs, however the clinical setting is complex and a one-size fits all solution is difficult to come by. Naproxen and moderate doses of celecoxib (100 mg b.i.d.) show the best cardiovascular profiles whilst etoricoxib, celecoxib and diclofenac show the best gastrointestinal profiles. Coxibs show similar upper GI-profiles as tNSAIDs if combined with PPI however PPI are not without adverse events and the lower GI is not affected by PPI. Longer half-life is in general the better option in situations with lasting pain since it has been shown that lower dosing intervals increase adherence. In terms of pain management there does not appear to be any differences in efficacy amongst different NSAIDs

Master of Science / Department of Clinical Sciences / Elizabeth Davis / The first aim of the current study was to investigate the pharmacokinetics of oral meloxicam tablets and the gastrointestinal and renal effects after a 14-day treatment period. Meloxicam was orally administered to six adult horses once daily at a dosage of 0.6 mg/kg for 14 consecutive days. Blood was collected prior to each administration and at 20 and 40 min, and 1, 2, 4, 8, 12, and 24 hours after administration on days 1, 7, and 14 for the determination of meloxicam plasma concentrations by mass spectrometry. In addition, trough samples were taken on days 3 and 10. Complete blood count, serum biochemical analysis, urinalysis, and gastroscopy were performed at baseline and conclusion of the investigation. Complete blood count, serum chemistry, and urinalysis results were unchanged through the study period. Gastroscopy scores were not significantly increased. The Cmax was 1.82 ± 0.80 µg/mL at Tmax 3.48 ± 3.30 hr on day 1, 2.07 ± 0.94 µg/mL at Tmax 1.24 ± 1.24 hr on day 7, and 1.81 ± 0.76 µg/mL at 1.93 ± 1.30 h on day 14 (p = 0.30). The mean half-life was 4.99 ± 1.11 h. The second aim of the study was to compare the analgesic effects and gastrointestinal and renal adverse effects of oral meloxicam tablets (0.6 mg/kg) to oral phenylbutazone tablets (4.4 mg/kg) orally once daily for 4 days in induced and naturally occurring lameness in adult horses. The study was performed on 4 healthy but lame adult horses. Complete blood count, serum biochemistry, urinalysis, and gastroscopy were performed prior to entrance to the study. Lameness was exacerbated in two horses using lipopolysaccharide (LPS; E. coli O55:B5) injected into the right metacarpophalangeal joint. The remaining two horses had Grade 3 or Grade 4 lameness due to naturally occurring laminitis. Meloxicam or phenylbutazone was administered to two horses each in a blinded, randomized manner once daily for four days. Lameness was evaluated using a pressure mat system and contact pressure, force, and stride length were evaluated at baseline and twice daily. Complete blood count, serum chemistry, and urinalysis were unremarkable for all four horses except one horse with an increased GGT. This horse experienced hepatic rupture secondary to amyloidosis the final day of the study. Gastric ulcer scores did not change during the study period. Phenylbutazone administration resulted in a greater response (force and contact area) in the right front and left hind limbs compared to meloxicam administration. There were not enough data points to evaluate the other two limbs. A third aim of the study was two-fold and first evaluated the effects of ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with LPS on cyclooxygenase (COX) messenger RNA (mRNA) expression. The second portion documented the effects of LPS-induced joint inflammation and treatment with non-steroidal anti-inflammatory drugs on the mRNA and protein expression of COX-2 in PBMCs. The results indicate that LPS upregulates COX-2 gene expression in PBMCs. Additionally, injection of LPS into the metacarpophalangeal joint increases both COX-2 mRNA and protein expression in PBMCs at 24 hours after injection. The relative expression of COX-2 after treatment with meloxicam or phenylbutazone indicates a stronger inhibition with phenylbutazone; however, further study with additional horses is needed. Pharmacokinetic analysis of the oral tablet formulation of meloxicam indicates the pharmacokinetics are similar to the oral suspension formulation. Meloxicam appears to be inferior to phenylbutazone in its analgesic properties for induced lameness and naturally occurring laminitis, however the small sample size used in the study makes interpretation difficult.

Master of Science / Department of Animal Sciences and Industry / Barry Bradford / During the transition period, 3 wk before to 3 wk after calving, dairy cows experience a variety of sudden hormonal and metabolic shifts that could result in metabolic disorders or diseases, which can be detrimental to the productive life and longevity of the cow. Cows undergo a negative energy balance, where they cannot consume enough feed to meet their energy requirements. To make up this deficit, cows mobilize adipose tissue in the form of non-esterified fatty acids (NEFA) which are transported to the liver and are either used for fuel or stored as triglycerides. High levels of circulating NEFA can lead to endoplasmic reticulum (ER) stress, which is linked to inflammation. This low-grade inflammation can compromise cell function. To mitigate this inflammation, sodium salicylate, a non-steroidal anti-inflammatory drug (NSAID), was given to mature (3+ parity) cows for 7 d after parturition via their drinking water. Blood was collected daily and a glucose turnover assay was performed. Liver, muscle, and adipose tissue was collected on d 7. Overall, it appeared that SS increased insulin sensitivity and depressed gluconeogenesis post-transcriptionally. Multiple in vitro studies were performed on immortalized bovine mammary epithelium (MAC-T) cells to determine the action of SS when ER stress was induced with palmitate (PALM). Treatment with SS did not mitigate, and in some cases exacerbated, the ER stress response. The addition of bovine serum albumin (BSA), a common component of cell culture media, may alter reactive oxygen species (ROS) measurements due to its antioxidant property. Overall, SS seems to alter metabolic processes and the cellular response to stress.

The overall objective of this research was to investigate the status of tumor necrosis factor-α (TNF-α), and molecules associated with its signaling, in the pathological state of hepatic steatosis. The effect of NSAID piroxicam, a cancer preventive agent also known to affect TNF-α signaling on hepatic steatosis, was also investigated. The biological state of the tissue was assessed by examining the expression of TNF-α signaling molecule in whole tissue, as well as in hepatic lipid raft. Lipid rafts are dynamic assemblies of cholesterol and sphingolipids, microdomains that form in the exoplasmic leaflet of the biological membranes shown to play a role in compartmentalization, modulation and integration of the cell signaling. In the present research, Zucker obese rats were used as a model of human obesity and insulin resistant state. These rats exhibit hepatic steatosis in adulthood similar to those noted in obese individuals. Female Zucker obese and lean rats (5 weeks old) were fed a semisynthetic diet with or without piroxicam (150 ppm). Zucker lean counterparts served as control. After 8 weeks of feeding, rats were euthanized and liver from each animal was collected. Liver tissue from each animal was processed for histology and biochemical analysis which included lipids and proteins (COX-1 and 2, TNF-α, TNF-RI and RII, IKK-β, IκB-α and NF-κB). Liver histology and the level of total lipids confirmed that Zucker obese rats had hepatic steatosis, which was further augmented by piroxicam treatment. Whole tissue protein expression, using western blot, showed that the steatotic liver differed from non-steatotic livers by having lower levels of TNF-RII. TNF-RII showed a trend which was inversely proportional to the pathological state of the tissue. The obese-piroxicam liver had the lowest level of TNF-RII and lean livers had the highest (p<0.05). The total NF-κB level was higher in the obese and obese-piroxicam groups compared to the lean or lean-piroxicam groups (p<0.05). Piroxicam treatment lowered the level of NF-κB in obese and lean livers. IκB-α was higher in obese livers than in lean livers. The nuclear level of NF-κB by western blot analysis showed the same pattern as noted in the whole tissue homogenate. However, the difference in the level between obese and lean was marked. The obese nuclei contained two to three fold higher levels of NF-κB protein than the lean liver nuclei. IκB-α level was significantly higher in the obese liver tissues and nuclei than their lean counterparts. While transcriptionally active NF-κB was higher (p<0.05) in the obese livers than in the lean livers, the difference between obese and lean groups was not as significant as that noted for the level of NF-κB assessed by western blot. This suggests that the proportion of active NF-κB present in the nuclear fraction is much higher in the lean than in the obese nuclei. Lipid raft was extracted and identified successfully from obese and lean livers. The total caveolin and flotillin levels were significantly higher in the liver lipid rafts of the obese-piroxicam than that of the other groups. This is the group that also exhibited higher steatosis. Piroxicam treatment significantly decreased the level of caveolin in the lean liver and significantly increased the level of flotillin in the obese liver. While COX-1 was not detectable, however, the level of COX-2 and TNF-RII in lipid raft was opposite to the level noted in the whole tissue homogenate. TNFRII was highest in the obese-piroxicam lipid raft and lowest in the lean-piroxicam lipid raft. TNF-RII, COX-2, IκB-α and NF-κB proteins were the molecules profoundly affected by the pathological state of the tissue and piroxicam treatment. This research is the first to report the presence of IκB-α in the nuclear compartment with a higher level in the nuclei and whole tissue in the obese liver than in the lean liver. This research demonstrates that TNF-α to NF-κB axis is altered in steatotic liver, and analysis of lipid rafts in steatotic and non-steatotic liver demonstrates that lipid rafts play a distinct role in modifying the biological availability of key proteins in the pathological state of liver steatosis.

This thesis is an investigation of the impact of abdominal surgeries and assisted parturition in dairy cows on physiological and behavioural parameters, and the potential management of pain through the use of non-steroidal inflammatory drugs (NSAIDs) or a mechanical brush. This research is novel and necessary because of the paucity of pain research in dairy cows. Three abdominal surgery studies were conducted. The first was a randomized clinical field trial, conducted on commercial dairy herds in southern Ontario, Canada, to evaluate the effect of ketoprofen following correction of left displaced abomasum. The second and third studies were randomized clinical trials evaluating NSAIDs following the first stage of a two-stage fistulation surgery. The second tested ketoprofen versus saline, while the third compared ketoprofen and meloxicam. The key findings from these studies were that there were indicators of pain following surgery (such as decreased milk production, dry matter intake, and changes in lying behavior) and that there were beneficial effects of administering NSAIDs following abdominal surgery(improved eating and lying behavior), although these effects were not sufficient to alleviate all of the surgical pain. Two trials were conducted in parturient cows. The first trial examined the effects of meloxicam administration 24 h following assisted calving. There were beneficial effects of NSAID on feeding behavior, however, further research is needed to investigate the full potential of providing an NSAID as a post-calving pain therapy. The second trial described the use of a mechanical brush by parturient cows. This study yielded insight on the brush use of these cows, as well as on their maternal, auto-grooming, and scratching behaviors. Cows used the brush before parturition, and when the calf was present, auto-grooming and scratching behaviors were significantly reduced, and calf licking time was greater in the brush group compared to the no brush group. The findings described in this dissertation provide insights into the expression and assessment of pain and its management following abdominal surgery in dairy cattle. This study has also identified areas of future research for both assessment and management of pain following abdominal surgery and following assisted calving. / NSERC IPS II, Boehringer-Ingelheim (Canada) Ltd., OMAFRA, Merial Canada Inc.

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