No description available.

No description available.

No description available.

No description available.

No description available.

Recent evidence has indicated that NSAIDs might have direct effects on CNS tissue in addition to their classical inhibitory action on COX enzymes. This thesis addresses this hypothesis using electrophysiological and behavioural techniques. The effects of fenamate and other NSAIDs on native neuronal GABA(_A), 5-HT(_3), nicotinic ACh, P2x and strychinine-sensitive glycine receptors, expressed on isolated vagus or optic nerves, was investigated using an extra-cellular recording technique. The fenamate NSAID, mefenamic acid (MFA) potentiated GABA (10µM)- evoked responses in the vagus nerve. Application of MFA also resulted in non-competitive inhibition of 5-HT-and a,βMeATP- evoked responses. Non-competitive like inhibition was also observed with flufenamic acid on DMPP- and a,βMeATP- evoked responses and with meclofenamic acid on GABA- evoked responses. Non-fenamate NSAIDs, including aspirin, did not significantly modulate the GABA(_A), 5-HT(_3), nicotinic ACh, P2x or glycine receptors. The cognitive and behavioural effects of fenamates and other NASIDs were then investigated. MFA (5-20mg/kg) caused a significant dose- and time-dependent enhancement in the non-spatial object discrimination working memory task when compared to saline controls. The enhancement observed with MFA was greater than that of the cognitive enhancer piracetam. This enhancement was not due to a change in non-mnemonic processes such as arousal, anxiety or locomotion. MFA also enhanced rats' performance in the spatial object location working memory task. The fenamate NSAID, meclofenamic acid (20mg/kg) mimicked the effect of MFA, but the non-fenamate NSAIDs aspirin and ibuprofen, did not enhance object discrimination indicating that these cognitive effects are not via inhibition of COX. The GABA(_A) receptor modulators diazepam, bicuculline and loreclezole, did not replicate the effect of MFA on object discrimination, suggesting that its effects do not depend entirely on the GABAa receptor. Scopolamine (0.25-lmg/kg) significantly impaired object discrimination in a dose-dependent manner. This action could be fully reversed by co-treatment with MFA (20mg/kg).In the T-maze task, MFA (20mg/kg) decreased the number of arm entry errors and days taken to reach criterion. The number of arm entry errors made when a 5-minute intra-trial interval was introduced was also significantly reduced by MFA compared with saline treated animals. In the radial maze, MFA (20mg/kg) did not decrease the number of never baited arm entries to reach criterion. However MFA did significantly reduce the number of re-entry errors to baited arms, compared to controls, when an intra-trial delay (10-30 sees) was introduced. These results support the hypothesis that MFA enhances spatial working memory and that these effects are not task-specific. Overall, the data in this thesis show that fenamate NSAIDs can directly modulate native neuronal ligand-gated ion channels and that MFA can enhance working memory in normal and scopolamine-impaired rats. These results suggest additional pharmacological potential for certain fenamate NSAIDs.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to suppress bone formation when administered before, but not if administered after, an acute bout of mechanical load in rats. The NSAID ibuprofen inhibits cyclooxygenase-2 enzyme, effectively reducing loading induced prostaglandin E2. Whether this affects eventual bone mass gains after multiple sessions of a more physiological mechanical loading regimen is unclear. Therefore, the aim of this study was to test the hypothesis that gains in bone mass and size will be diminished in adult rats given ibuprofen before, but not after, each exercise bout during 20 days of simulated resistance training (SRT). Virgin female Sprague-Dawley rats (5-mo-old, n=29) completed 9 SRT sessions using stimulated muscle contractions under anesthesia at 75% peak isometric strength on alternate days; each of 20 contractions included 1 sec isometric + 1 sec eccentric contraction. Animals were blocked assigned by body weight to one of three groups: 1) ibuprofen (30mg/kg) before exercise, placebo after (I:P)(n=9), 2) placebo before, ibuprofen after (P:I)(n=10) and 3) placebo before and after (P:P)(n=10). In vivo pQCT scans measured changes in total volumetric bone mineral density (vBMD) and total bone mineral content (BMC) at the proximal tibia (cancellous), and total vBMD, total BMC and total area at midshaft tibia on days -7 and 21. Dynamic histomorphometry on both midshaft tibiae (exercised and non-exercised legs) determined mineralizing surface (MS/BS), mineral apposition rate (MAR) and bone formation rate (BFR) on the periosteal surface. There were no differences in body weights among groups at baseline or at day 21. There were significant gains due to SRT, but not ibuprofen treatment in total BMC (+10.50 ± S.D. +8.15%) and total vBMD (+5.29 ± 3.41%) at the proximal tibia. The midshaft tibia exhibited significant gains in total vBMD (6.68 ± 3.03%), total BMC (19.18 ± 5.51%) and total area (11.68 ± 5.49%) due solely to SRT. Furthermore, there were significant increases in periosteal BFR (pre 21.89 µm3/µm2/d ±2.63; post 717.81 µm3/µm2/d ±100.57) at the midshaft tibia in the exercised vs. non-exercised legs in all groups but no effect of ibuprofen regimen was detected on these indices of bone formation. In the context of robust increase in BFR and bone mass within this simulated resistance protocol, we were unable to detect any impact of ibuprofen administration on the response to bone loading.

No description available.

This study tested the hypothesis that administration of deracoxib, a cyclooxygenase-2 specific (COX-2) inhibitor, would result in lower gastric lesion scores than administration of buffered aspirin and gastric lesion scores similar to placebo when administered to healthy dogs for 28 days. Twenty-four, healthy, random source dogs were divided into three groups. Group I received buffered aspirin, 23.6 mg/kg PO q 8h, group II received deracoxib, 1.6 mg/kg PO q 24h and placebo twice daily PO q 8h after deracoxib administration, and group III received placebo PO q 8h. Gastroscopy was performed on days -7, 6, 14, and 28 of treatment. Four regions of the stomach (pylorus, incisura, cardia, and body) were evaluated separately and lesions scored on a scale of 1 (mucosal hemorrhage) to 12 (perforating ulcer) by an observer unaware of which treatments the dogs received. Dogs were observed every 8 hours for vomiting, diarrhea and anorexia. Feces were scored from 1-5 (scores <4 were considered diarrhea). Lesion scores for each group, at each location, and total scores, at each time period, were evaluated for the effects of time and treatment using a Kruskal-Wallis test. Total dog days of vomiting and dog days of diarrhea in each group were compared using a Wilcoxon rank sums test. Significance was determined at p<0.05. Significantly higher median total gastric lesion scores were found in the aspirin group compared to the deracoxib or placebo groups on days 6, 14, and 28. There were no significant differences in median total gastric lesion scores between the deracoxib or placebo groups at any time during the study. There was no location effect on gastric lesion scores and there was no significant change in gastric lesion scores over time in any of the groups during treatment. Significantly more dog-days of vomiting occurred in the aspirin group as compared to the deracoxib group. No significant differences were found between groups for dog-days of diarrhea. In this study, the administration of deracoxib to healthy dogs resulted in significantly lower gastric lesion scores compared to dogs receiving aspirin and lesion scores similar to those receiving placebo. / Master of Science

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications globally. There are generally two types: selective (COX-2) and traditional NSAIDs (COX-1). They are primarily used for the treatment of pain. They gained attention after a study about their basic mechanisms highlighted their toxicity. Several studies have reported an association between NSAIDs and risk of myocardial infarction (MI). However, the direction of the relationship is not conclusive. Further studies are needed to ascertain the direction of this relationship and evaluate the present situation with available drugs. Due to the seriousness of cardiovascular diseases as one of the leading cause of death, continuous monitoring of the NSAIDs-MI association is needed. The purpose of this dissertation was to investigate the association between NSAIDs and MI in a younger (30-64 years) Kentucky Medicaid population with a 12 year window of data. The three specific aims were: (1) to understand the characteristics of the Kentucky Medicaid population with respect to NSAID use: (2) to evaluate the NSAID-MI relationship with a 12 year follow-up in a young heavily-burdened population for cardiovascular diseases: and (3) to investigate the MI risk of meloxicam, celecoxib and naproxen compared to no exposure. A retrospective study was conducted employing data from January 1st 2000 and December 31st 2012. The data comprised demographic, prescription and medical files. Within this cohort, a nested case control study was conducted. Cases of MI were matched to four controls on race and gender. The results suggested that exposure to COX 2 presented an increased adjusted risk for MI (1.138(0.983, 1.318)). However, this risk was significantly increased for COX-2 only users compared to COX-1 only users (1.221 (1.03, 1.485)) and 30-40 year olds (1.600 (1.082, 2.367)). Meloxicam, celecoxib and naproxen compared to no exposure showed meloxicam presented a non-significant different risk for MI (1.26 (0.98, 1.63)) and celecoxib presented a significantly increased risk for MI (1.52 (1.26, 1.82)). This study considered pattern of use in determining continuous usage by looking at both continuous and sporadic users of NSAIDs and also considered patient switching patterns between classes of NSAIDs.