Our hypothesis is that the polyamine biosynthetic pathway, a pathway essential in many cellular functions, is modulated by NSAIDs and that this is, at least in part, how NSAID chemoprevention is mediated. An <i>in vitro </i>model of colorectal cancer was used: two cell lines one of which is COX positive and one COX negative to determine the effects of a range of selective and non-selective NSAIDs on various reactions within the polyamine pathway.  NSAIDs are cytotoxic to colorectal cancer cells regardless of their COX expression.  NSAID-mediated inhibition of cell growth is accompanied by inhibition of ODC activity, partial depletion of polyamine concentrations and up-regulation of polyamine catabolism. In order to investigate the importance of polyamine metabolism, a specific polyamine inhibitor α-difluoromethylornithine (DFMO) was used in combination with the NSAIDs.  DFMO <i>per se </i>is not toxic to cells and it does not enhance NSAID mediated toxicity.  DFMO in combination with the NSAIDs did cause increased catabolic activity and more sustained polyamine depletion than either alone, however no additional decrease in ODC activity was observed.  This suggests that NSAID toxicity is not enhanced by DFMO in this <i>in vitro </i>model. Analysis of the mode of death indicated that the NSAIDs caused apoptotic cell death, confirmed through biochemical and morphological studies and that the NSAIDs affected gene expression of key enzymes in the polyamine biosynthetic pathway. Our findings suggest that modulation of the polyamine pathway by NSAIDs is at least part of the mechanism of action involved in cancer chemoprevention. Therefore modulation of the polyamine pathway may be useful for design of new chemopreventative drugs.

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.

No description available.

Dissertation submitted in partial compliance with the requirements for a Masters Degree in Technology: Chiropractic, Durban University of Technology, 2009. / Headaches are one of the most common clinical conditions in medicine, and 80% of these are tension-type headaches (TTH). TTH has a greater socioeconomic impact than any other type of headache due to its prevalence. Within the TTH category, episodic TTH are more prevalent than chronic TTH. The mainstay in the treatment of TTH are simple analgesics and NSAIDs. Unless contraindicated, NSAIDs are often the most effective treatment for ETTH. However patients suffering with TTH tend to relate their headaches to increased muscle stiffness in the neck and shoulders and thus the non-pharmacological treatment of ETTH could be directed at the associated musculoskeletal components of ETTH. It is therefore proposed that the Kinesio Taping® Method may have an effect in the treatment of the muscular component of ETTH. Method: This study was a prospective randomised clinical trial with two intervention groups (n=16) aimed at determining the relative effectiveness of a NSAID and the Kinesio Taping® Method in the treatment of ETTHs. The patients were treated at 5 consultations over a 3 week period. Feedback was obtained using the: NRS – 101, the CMCC Neck Disability Index and a Headache Diary. Results: The Headache Diary showed a reduction in the presence and number, mean duration and pain intensity of ETTH in both groups. These treatment effects were sustained after the cessation of treatment with the exception of mean pain intensity in the Kinesio Taping® Method group. The mean NRS score decreased in both groups but at a slightly faster rate in the Kinesio Taping® Method group. The CMCC showed an improvement in the functional ability of the patients in both groups. Conclusion: There seems to be no significant difference in the relative effectiveness of the treatment modalities. We can thus state that the overall short-term reduction in symptomatology supports the use of NSAIDs or Kinesio Taping® Method in the treatment of ETTH.

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.

Sixty steers were grazed on toxic tall fescue for 104 days to determine the effects of hair coats and steroidal ear implants on physiological measurements. Steers were stratified by body weight and hair coat color for assignment to six, 3.0-ha pastures of 'Kentucky 31' tall fescue. Main plot treatments of either ten clipped or ten unclipped steers were randomly assigned to pastures. Five steers in each pasture were implanted with Synovex-S (200 mg progesterone-20 mg estradiol) and five were implanted with Compudose (25 mg estradiol) as sub-plot treatments. Hair growth rate averaged 0.29 mm/day. Sweating rate declined (P andlt; 0.001) over the grazing period and was higher (Pandlt; 0.10) with the estradiol implant. Rectal temperatures were lower (P andlt; 0.05) in clipped cattle (39.3 vs. 39.5??C) when the highest ambient temperature (33??C) of the study was recorded. At high environmental temperatures, percentage of steers actively grazing was negatively correlated (P andlt; 0.10) with ambient temperature. Winter hair coat retention, continuous hair growth, and reduced sweating caused impaired thermoregulation and thus decreased grazing frequency resulting in poor animal performance.

No description available.

Diss. (sammanfattning) Umeå : Umeå universitet, 2005. / Härtill 4 uppsatser.

Thesis (Ph. D.)--West Virginia University, 1999. / Title from document title page. Document formatted into pages; contains xii, 150 p. : ill. Includes abstract. Includes bibliographical references (p. 124-128).

Thesis (M. Sc.)--University of Toronto, 1996. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.