Background: Acute postoperative pain can develop into chronic pain if not managed well. Nurse anesthetists consider many factors when developing an anesthetic plan to provide optimal postoperative pain management. Multimodal pain management is recommended for managing pain in the perioperative period and this may include administering medications such as intravenous (IV) acetaminophen and IV non-steroidal anti-inflammatory drugs (NSAIDs) to the patients if not contraindicated. Even though these are valuable and daily considerations for nurse anesthetists, there is not a standard of care for addressing postoperative pain management in adult abdominal surgical procedures. Objective: The purpose of the project is to determine the perspectives of nurse anesthetists for developing postoperative pain management in adult patients having abdominal surgical procedures. Design: This is a descriptive study designed to determine if current nurse anesthetist practices are being guided by evidence-based practices and if the findings can be used to develop a standard of care. Participants: Nurse anesthetists from a local Tucson, AZ health care facility Measurements: Nurse anesthetists were interviewed in-person. They were asked six semi-structured questions and the answers were recorded and transcribed into the program NVivo. Each answer was then coded and compared for emerging common themes. Results: Five out of eleven nurse anesthetists participated in this project. Thirty-five themes were discovered and three main categories developed: 1. Nurse anesthetists consider multimodal pain management an integral part of the anesthetic plan. IV acetaminophen and IV NSAIDs are considered for every surgical patient if they are not contraindicated; 2. IV acetaminophen is used more frequently for abdominal procedures compared to IV NSAIDs because of risks for bleeding associated with IV NSAIDs; and 3. Each anesthetic plan is individualized to safely address both the patient and surgical factors. Conclusion: A multi-center study should be considered for a future project to determine if these common themes would be found consistently across health care facilities. Eventually, this information could be used to develop a standard of care for managing postoperative pain in adults having abdominal surgery. Other methods for addressing multimodal pain management such as regional blocks should be considered for future studies as well.

Prostaglandins (PGs) are important signalling factors for bone mechanotransduction. The inhibition of cyclooxygenase, responsible for the synthesis of PGs, with non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to influence bone formation induced by mechanical stimulation. The purpose of this study was to examine the timing effects of NSAID administration on: 1) bone formation induced by multiple mechanical loading events in a rat model and 2) the PGE2 response of MLO-Y4 osteocyte like cells stimulated by fluid shear stress. The rat forelimb compression model was used to induce bone formation in male and female rats using a 1-month loading protocol (12 loading sessions). The right forelimbs were loaded and the left forelimbs served as non-loaded controls. NSAIDs were administered orally either before or after loading. Fluorochrome labels were administered to the rats to determine mineral apposition rate (MAR). The NSAIDs examined (indomethacin, NS-398 and ibuprofen) did not significantly affect periosteal MAR, administered either before or after loading, suggesting NSAIDs do not affect bone adaptation to multiple mechanical loading events. To examine in vitro effects of NSAIDs on PGE2 production, an orbital shaker was used to apply fluid shear stress to MLO-Y4 cells seeded in 6-well culture plates. Indomethacin was added to the culture media either before or after loading and media PGE2 concentrations were determined at various time points by enzyme immunoassay. Fluid shear stress increased PGE2 production of MLO-Y4 cells and indomethacin administration inhibited that response when administered both before and after fluid flow. However, PGE2 production was influenced by the media changes that occurred in the in vitro experiments, making it difficult to differentiate between indomethacin effects and media change effects. The in vitro experiments revealed the difficulties of modeling the timing effects of NSAID administration on MLO-Y4 PGE2 production in response to fluid flow. / Thesis / Doctor of Philosophy (PhD) / Bone is a dynamic tissue that can adapt to mechanical loading. Prostaglandins (PGs) are important signalling factors produced by osteocytes, the bone mechanosensing cells, that help to activate various cells and cell processes leading to changes in bone structure. Blocking PG signalling with non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to influence bone formation induced by mechanical stimulation in animals and humans. The purpose of this study was to examine the timing effects of NSAID administration on: 1) bone formation induced by multiple mechanical loading events in rats and 2) the PG production of osteocyte like cells in response to fluid flow stimulation. The results of this study suggest that NSAIDs, administered either before or after loading, do not affect bone responses to multiple mechanical loading events. Further investigation is needed to determine the translatability of these findings to NSAID use around the time of exercise in humans.

The effect of reduced frequency of administration of misoprostol on its ability to prevent aspirin-induced gastric injury was evaluated. Twenty-four random-source dogs were divided into 4 groups which received aspirin and misoprostol as follows: Group I, 25 mg/kg aspirin PO TID and placebo PO TID; Group II, 25 mg/kg aspirin PO TID and misoprostol 3 ug/kg PO TID; Group III, 25 mg/kg aspirin PO TID, misoprostol 3 ug/kg PO BID and placebo PO QD; and Group IV, 25 mg/kg aspirin PO TID, misoprostol 3 ug/kg PO QD and placebo PO BID for 28 days. Groups were stratified to contain an equal number of dogs positive or negative for Helicobacter spp. based on results of ‘CLO test’. Gastroscopy was performed on days –9, 5, 14 and 28. Each region of the stomach was evaluated separately and visible lesions were scored on a scale of 1 (submucosal hemorrhage) to 11 (perforating ulcer). The scores for each region were summed and the median total score for each group at each day and median total score within each group between days was compared using a Kruskal-Wallis test. No difference in total score was identified between Group I and IV on any day. Median total scores for Groups II and III were significantly(p < 0.05) lower compared to Groups I and IV on day 5. Significant difference was observed on Day 14 between the total score of Group III and Group IV. Group III had a significantly lower score (p < 0.05) than Groups I, II and IV on day 28. Gastric erosions were present in all groups in the study. This study suggests that misoprostol 3 ug/kg PO BID dosing is as effective as misoprostol 3 ug/kg PO TID dosing at preventing aspirin-induced gastric injury in this model. However, misoprostol 3 ug/kg PO TID dosing was less effective in preventing aspirin-induced gastric injury on days 14 and 28 than in previous studies. The lack of efficacy of TID dosing on days 14 and 28 may be related to higher salicylate concentrations in Group II dogs or individual variation within the small study population. / Master of Science

Photoallergic contact dermatitis (PACD) is a clinical problem that has often been poorly understood and neglected by dermatologists over recent years. This can be partly attributed to its investigation by photopatch testing (PPT) falling between the expertise of photobiologists and contact dermatitis clinicians. One result of this situation was that no European Baseline PPT series had been agreed on. To redress this, the European multi centre photopatch test study (EMCPPTS) was conceived to provide up to date information on which photoallergens are of greatest clinical relevance. Its conduct and results form the core research project of this thesis. To enable the EMCPPTS to proceed and its results to be viewed in a wider context, the other Chapters of this thesis explore important related aspects of PACD and PPT in Europe. The introduction examines the nature of PACD and PPT and reviews current photoallergens. Then, the investigation of the two photoallergens carprofen and chlorproethazine by PPT is recounted. These studies highlight deficiencies within the current European regulatory system for preventing photoallergens from reaching the marketplace, as well as providing templates for the investigation of new photoallergens in the human environment. This is followed by a pilot PPT study which provides new information on the optimum non-irritating concentration of the 19 ultraviolet sunscreen absorbers to be used in the EMCPPTS. The issue of attempting to determine the photoallergenic potential of the EMCPPTS agents with respect to exposure patterns is addressed by conducting a sunscreen survey in the UK. The EMCPPTS itself is then detailed, as well as the difficulties that can be encountered when conducting a large clinical study of this nature. The results from the EMCPPTS and other presented studies were shown to be of importance in deciding upon a new European Baseline PPT series. The process involved in deciding this series, as well as its content are described before overall conclusions and possible future studies in the domain of PACD and PPT are discussed.

Alzheimer's disease (AD) has multiple factors that contribute to the disease process. Among these is a state of chronic inflammation that is endured by the brain during the aging process. The use of non-steroidal anti-inflammatory drugs (NSAIDs) decreases the amount of neuroinflammation sustained by the brain, and greater levels of NSAID use have been demonstrated to be associated with decreased probability of developing AD. This study looked at whether greater rates of NSAID use were also associated with decreased rates of cognitive and funtional decline and survival in a population-based sample of persons with AD.

Introduction: The effect of electrical stimulation on muscle degeneration and regeneration is largely unknown and it has not been studied in conjunction with telomeres. The consumption of non-steroidal anti-inflammatory drugs (NSAIDs) is widespread in athletes and the general population when faced with muscle soreness or injury. Furthermore, the effect of NSAIDs on muscle regeneration is controversial and its effect on telomere lengths is also unknown. Methods: Young adult males performed 200 electrically stimulated maximal isokinetic contractions with one leg (ES) and the other worked as a control (CON). They received either 1200mg ibuprofen (IBU) per day or placebo (PLA) from 21 days pre- to 30 days post-exercise. Muscle biopsies were obtained from the vastus lateralis of the CON leg at baseline (H0) and ES leg at 2.5h (H2.5) and both legs at 2, 7 and 30 days post-exercise. Blood samples were obtained at the same time points and at day 4 post-exercise. Afterwards the muscle and blood specimen were analysed for skeletal muscle and peripheral blood telomere lengths by Southern blot and signs of muscle degeneration and regeneration were quantified histologically. Results: Histological changes occurred in the ES leg, including; increased proportion of damaged myofibres (2.1±2.8%) and infiltrated myofibres (5.0±6.0%) at day 7, small myofibres (3.0±4.4%) and internally located myonuclei (2.9±3.1%) at day 30. The IBU group had significantly less internally located myonuclei at day 30 compared to PLA (1.7±2.4% vs. 4.1±3.8%). No significant differences were observed in skeletal muscle mean and minimum telomere lengths between ES and CON leg, between IBU and PLA group or between time points. Peripheral blood mean telomere lengths were not significantly different between IBU and PLA group, but between time points; H0 (9.6±1.2kb) and H2.5 (9.1±1.1kb) were significantly shorter than day 4 (10.3±1.6kb) and day 7 (10.1±1.5kb) (P&lt;0.05). Conclusion: Electrically stimulated contractions caused significant muscle degeneration and regeneration in the 30 days post-exercise. Electrical stimulation also appeared to cause fluctuations in peripheral blood telomere lengths, but not skeletal muscle telomeres. The intake of ibuprofen appeared to interfere with muscle regeneration, but did not seem to affect the peripheral blood or skeletal muscle telomeres. However, due to marked individual variations and the small participant group it is difficult to conclude on the effects of electrical stimulation and ibuprofen on proliferative potential. Further studies are warranted to elucidate the effects of electrical stimulation and ibuprofen on blood and skeletal muscle telomeres.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently prescribed classes of drugs worldwide. Due to their excellent effects for analgesic, anti-inflammatory and antipyretic, most elder population used frequently for osteoarthritis. Gastrointestinal symptoms and ulceration associated with NSAIDs are common. Such ulcers may cause pain, bleeding, or perforation. It leads to other medical problems. The aim of this study was to examine the utilizations of medical resources associated with inpatients with NSAID related peptic ulcer disease and compared to non-NSAID related peptic ulcer disease. The study used the database from a teaching hospital in southern Taiwan. Inpatients who were identified ICD-9 CM codes as peptic ulcer diseases from January 1st of 2008 to December 31 of 2008 were included in this study. We also examined the indications for usage of NSAIDs, the date of prescription before the index date. The results showed 17.6% of inpatients with peptic ulcer disease related to NSAIDs. Inpatients with NSAIDs related peptic ulcer disease compared with inpatients with non-NSAIDs related peptic ulcer disease had significant difference in age and comorbidity. Although rapid urease test positive rate for Helicobacter pylori was higher in group of non-NSAID related peptic ulcer disease, it seemed underestimate because of the test number of patients was low. The average total direct medical cost of inpatients with NSAID related peptic ulcer was NT$ 36,491 and non-NSAID related peptic ulcer was NT$ 37,266.1. There were no significant difference in medical costs of standard care , intensive care , blood products,endoscopy, endoscopic hemostasis, surgery, CT scan , ultrasound, laboratory tests,medications, doctor¡¦s service between the two groups. Diagnostic and therapeutic procedures were no statistically significant difference, including blood transfusion,CT scan, endoscopic hemostasis, surgery, symptoms presentations, and intensive care. In this study, the duration for using NSAID was within 30 days for inpatients associated with NSAID related peptic ulcer, which had a substantial excess numbers of ulcer hospitalization. Since the common disease for using NSAID is osteoarthritis,which is very popular in elderly, therefore, we suggested that the policy makers of the National Health Insurance should be aware that preventive usage of proton pump inhibitors for the elder population who need frequent use of NSAIDs might decrease NSAID related ulcer complications.

The main goals of this research were to synthesize nitrogen oxide releasing diazeniumdiolates and their prodrugs and to evaluate their pharmacological effects. The different projects and their results are described below. i. Comparison of HNO and NO donating properties of cyclic amine diazeniumdiolates Diazeniumdiolates are an attractive class of donor compounds as they can be tuned to release NO or both NO and HNO depending upon the amine backbone. Isopropylamine (IPA/NO) and cyclohexylamine (CHA/NO) diazeniumdiolates are currently the only examples of primary amine based diazeniumdiolates. A series of structurally related cyclic amine based diazeniumdiolates were synthesized and characterized. An acetoxymethyl derivative was also synthesized to facilitate cellular uptake and to achieve higher HNO levels in cells. ii. Nitrogen oxide releasing diazeiumdiolate based adducts of N-des-methyl-tamoxifen Nitrogen oxide (NO/HNO) donating diazeniumdiolate adducts of N-desmethyltamoxifen (a key metabolite of the breast cancer drug tamoxifen) were synthesized. DEA/NO-AcOM, an NO donor was also synthesized to monitor the effect of NO on breast cancer cell survival. Derivatives of N-desmethyltamoxifen were found to be effective towards estrogen receptor positive (ER+) cells only. DEA/NO-AcOM was found to be cytotoxic towards estrogen-dependent and independent cell lines, in combination with tamoxifen, or by itself. iii. Synthesis and characterization of nitrogen oxide adducts with non-steroidal anti-inflammatory drugs (NSAIDs) Our group has shown HNO releasing diazeniumdiolate derivatized aspirin to be comparably effective in preventing gastric ulceration to NO-releasing diazeniumdiolate based aspirin analogues. Series of such NSAID adducts were further extended by synthesizing such derivatives of indomethacin and niflumic acid. NO/HNO releasing analogues of aspirin and indomethacin were cytotoxic towards two different breast cancer cell lines, irrespective of estrogen dependence.iv. Chlorambucil analogue of PABA/NOChlorambucil, an alkylating agent is used in leukemia treatment. Tumor cells resistant to alkylating agents often have increased glutathione levels and increased activity of glutathione-S-transferase (GST). PABA/NO is an NO donor with a promising anticancer profile. The chlorambucil analogue of PABA/NO was synthesized to utilize GST for releasing NO and to potentially overcome cellular resistance.

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.

Non-steroidal anti-inflammatory drugs (NSAIDs) and their NO derivatives (NO-NSAIDs), and synthetic analogs are highly effective as anticancer agents that exhibit relatively low toxicity compared to most clinically used drugs. However, the mechanisms of action for NSAIDs and NO-NSAIDs are not well defined and this has restricted their clinical applications and applications for combined therapies. Earlier studies from our laboratory reported that specificity protein (Sp) transcription factors (Sp1, Sp3 and Sp4) are overexpressed in several types of human cancers including colon cancer and many Sp-regulated genes are pro-oncogenic and individual targets for cancer chemotherapy. Based on published results showing that NSAIDs downregulate several putative Sp-regulated genes, we hypothesized that the anticancer properties of NSAIDs may be due, in part, to downregulation of Sp transcription factors. NSAIDs including aspirin and tolfenamic acid (TA) and nitro derivatives of NSAIDs such as GT-094 have been investigated in colon cancer cells and in vivo xenograft models. Aspirin and TA induced apoptosis and decreased colon cancer cell growth and tumor growth in vivo and downregulated genes associated with cell growth, survival, and angiogenesis. Previous RNA interference studies in this laboratory have shown that many of these genes are regulated, in part, by Sp transcription factors Sp1, Sp3 and Sp4 that are overexpressed in colon and other cancer cell lines. Not surprisingly, these NSAIDs also decreased Sp1, Sp3 and Sp4 proteins and Sp-regulated gene products in colon cancer cells and this was due to caspase-dependent proteolysis of Sp1, Sp3 and Sp4 proteins. Aspirin-induced activation of caspases and degradation of Sp1, Sp3 and Sp4 was due to sequestration of zinc and could be reversed by addition of zinc sulphate, whereas TA mediated induction of caspases was independent of zinc ions and is currently being investigated. GT-094 is a novel NO chimera-containing NSAID, which also inhibited colon cancer cell proliferation and induced apoptosis; these effects were accompanied by decreased mitochondrial membrane potential (MMP) and induction of reactive oxygen species (ROS), and were reversed after cotreatment with the antioxidant glutathione. GT-094 also downregulated Sp and Sp-dependent gene products and was due to decreased expression of microRNA-27a (miR-27a) and induction of ZBTB10, an Sp transcriptional repressor that is regulated by miR-27a in colon cancer cells. Moreover, the effects of GT-094 on Sp1, Sp3, Sp4, miR-27a and ZBTB10 were also inhibited by glutathione suggesting that the anticancer activity of GT-094 in colon cancer cells is due, in part, to ROS-dependent disruption of miR-27a:ZBTB10. The importance of ROS induction in targeting Sp transcription factors was also confirmed using pro-oxidants such as ascorbic acid, hydrogen peroxide and t-butyl hydroperoxide and similar results have been observed in collaborative studies with other ROS inducers in colon cancer cells. Many cancer cell lines and tumors exhibit addiction to non-oncogenes such as Sp1, Sp3 and Sp4 for maintaining the oncogenic phenotype and future research will focus on the mechanisms of ROS-mediated targeting of Sp transcription factors which represents a novel approach for cancer chemotherapy.