Thesis (Ph. D. (Pharmacy))--Rhodes University, 2005.

Thesis (M.S.)--University of Toledo, 2010. / Typescript. "Submitted to the Graduate Faculty as a partial fulfillment of the requirement for the Master of Science in Pharmacology and Toxicology." "A thesis entitled"--at head of title. Title from title page of PDF document. Bibliography: p. 68-81.

Increasingly, drug-induced liver injury is one of the main reason for drugs to be withdrawn from the market even after passing toxicity studies in pre-clinical and clinical trials because of risks of toxicity and ineffective treatments. Human immortalised hepatocyte cell lines used in drug testing are widely available, inexpensive and easy to culture. However, these cell lines are commonly known to have poor predictive capabilities and improved in vitro hepatic models are required for predicting hepatotoxicity of large numbers of compounds in drug discovery. In this study, the primary goal was to develop an improved in vitro human hepatic model using a combination of the C3A human hepatic cell line and human umbilical vein endothelial cells (HUVECs), for prediction of acetaminophen (APAP) hepatotoxicity. Initial experiments showed that co-culture of HUVEC:C3A in EGM-2, an endothelial medium, was essential to support both cell types, and that co-cultures maintained the initial cell seeding ratio of 1:1 (HUVEC:C3A) after 3 days. Phenotyping of co-cultured cells using platelet endothelial cell adhesion molecule (PECAM-1/CD31) for HUVECs, and hepatic epithelial (EpCAM) markers for C3As demonstrated that at ratio 1:1 (HUVEC:C3A), there is cross-talk between HUVECs and C3As and cells in co-culture showed properties of self-organisation. This interaction resulted in improved hepatic metabolic activity in vitro in respect of albumin synthesis and cytochrome P450 activity. Treatment with low (5 mM), intermediate (10 mM) and high doses (20 mM) of APAP, showed that prediction of hepatotoxicity using specific kits for cell viability and mitochondria function, was significantly improved in C3As in the presence of HUVECs, thus demonstrating an in vitro human hepatic co-culture could be an invaluable model for drug toxicity studies. We observed that the intermediate APAP dose had no effect on cell viability and mitochondrial function in co-cultures, whilst by comparison both lactate levels and oxidative stress were perturbed in mono-cultures. Co-cultures also up-regulated expression of vascular endothelial growth factor receptor-2 (VEGFR-2) in HUVECs following APAP exposure, which may be important in modulating the toxic effect of APAP on C3As. To further improve the in vitro liver-like model, Matrigel™ was incorporated to promote vascular formation by HUVECs and support hepatic organization, migration and function of C3As. In HUVEC mono-cultures, Matrigel™-promoted vascularization, haptotaxis and self-organization and in HUVEC:C3A co-cultures formation of structures reminiscent of liver sinusoids and maintenance of hepatic albumin synthesis and CYP3A4 activity. Time-lapse imaging showed haptotactic migration of hepatocytes towards endothelial cells, with Matrigel™ likely having a chemotactic effect on HUVECs and C3As, resulting in interconnected vascular network. APAP inhibited angiogenesis in HUVEC mono-cultures whereas APAP had no effect in HUVEC:C3A co-cultures. In conclusion, the development of an in vitro human organotypic co-culture model of HUVECs and C3As significantly enhanced hepatic function, demonstrated by significant improvement in hepatic metabolism, evidence of greater resistance to APAP toxicity, and improved cell-cell communication. Co-cultures markedly modulated APAP hepatotoxicity compared with C3A mono-cultures. Furthermore, co-culture of HUVECs and C3As using a complex basement membrane biomatrix (Matrigel™) produced a self-assembling interconnected vascular network, improved hepatocyte function as well as reproducibility of responses to APAP toxicity. The application of the described co-culture models may improve the accuracy, efficacy and predictive power of drug toxicity testing strategies in drug development.

Class of 2012 Abstract / Specific Aims: The objective of this study is to evaluate consumers’ knowledge about over the counter (OTC) products containing acetaminophen (APAP).   Methods: Doctor of pharmacy student researchers set up a booth at consenting community pharmacies and invited consumers to participate in a 10-15 minute knowledge assessment. The booth contained a table displaying several OTC medication bottles/packages. Adult participants: a) answered baseline questions verbally about their APAP knowledge and associated risks; b) identified OTC products at the booth that contain APAP; and c) calculated and demonstrated dosing of APAP. The researchers asked follow-up questions and assessed the accuracy of the dosing. Participants received APAP educational brochures upon completion.      Main Results: Eighty percent of subjects reported not knowing what the abbreviation “APAP” means, and almost half of those who said that they knew what it means were incorrect. Very few participants were able to correctly identify the products containing APAP even with the product packaging information, with the percentage of incorrect responses as to whether a product contains APAP or not varying from 4.9% to 31.6%. More than 40% of the pediatric doses were incorrectly dosed for both of the pediatric formulations, even with the majority of subjects being parents. Conclusions: Consumers are not able to identify which over-the-counter products contain APAP even with the product packaging before them, and they do not know what the abbreviation “APAP” means. Better packaging and product ingredient information should be developed, and the abbreviation “APAP” should be avoided. Pediatric APAP products should be re-evaluated regarding safety and dosing.

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.

No description available.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a mainstay of the management of pain and inflammation associated with musculoskeletal disorders and systemic inflammation in horses. The most utilized NSAIDs in equine practice are non-selective cyclooxygenase (COX) inhibitors, such as flunixin meglumine and phenylbutazone, which act through global inhibition of prostaglandin synthesis and release. While non-selective COX inhibitors are effective as anti-inflammatory agents, they are mired with complications with prolonged or high-dose use, particularly in critically ill patients. Therefore, non-selective COX-inhibitors have been displaced by selective COX-2 inhibitors for many practitioners due to the perceived reduced risk of gastrointestinal complications. It should be noted, however, that the use of COX-2 selective inhibitors in horses is not without risk. Due to the potential for significant adverse events in horses with critical illness treated with traditional NSAIDs, there is clinical need for safe, and effective anti-inflammatories and anti-pyretics for administration in these patients. The studies presented in this dissertation explore the pharmacokinetics, efficacy, and safety of acetaminophen in adult horses for use in musculoskeletal pain and pyrexia. In the first study, the pharmacokinetics and efficacy of oral acetaminophen at two different doses (20 mg/kg and 30 mg/kg) were examined in an experimentally induced lameness model and the analgesic efficacy of acetaminophen was compared to placebo and the non-selective COX inhibitor phenylbutazone. Acetaminophen when administered at 30 mg/kg produced a more rapid onset of greater improvement in subjective lameness scores and heart rate compared to other treatments in this model, and therefore would be more suitable as a monotherapy than acetaminophen dosed at 20 mg/kg. Acetaminophen dosed at 30 mg/kg resulted in a more rapid improvement in lameness scores than phenylbutazone at 2.2 mg/kg and was equivalent to phenylbutazone in lameness score reduction. However, results of this study necessitated further evaluation of the pharmacokinetics and safety of repeated oral dosing of acetaminophen at 30 mg/kg orally every 12 hours to determine clinical utility. In the second study, the pharmacokinetics, efficacy, and safety of oral acetaminophen (30 mg/kg) were examined in adult horses with naturally occurring chronic lameness. In that study, following 21 days of twice daily oral dosing at 30 mg/kg, acetaminophen was found to be safe with no evidence of gastric ulceration or hepatopathy in horses. Acetaminophen at 30 mg/kg twice daily for 21 days provided transient improvement in subjective and objective lameness evaluation when compared to baseline evaluation; however, the study concluded that acetaminophen may not be suitable as a monotherapy for management of moderate to severe orthopedic pain in horses In the third study, the pharmacokinetics and efficacy of oral acetaminophen (30 mg/kg) was examined in adult horses with experimentally induced endotoxemia when compared to placebo and the nonselective COX inhibitor flunixin meglumine. That study found that acetaminophen was superior to placebo and not statistically different from flunixin meglumine in reducing rectal temperature in adult horses with experimentally induced endotoxemia and may be an option for antipyresis in clinical cases, particularly when administration of traditional NSAIDs is contraindicated. Furthermore, acetaminophen administered at 30 mg/kg orally to adult horses with experimentally induced endotoxemia is an effective antipyretic but is unlikely to provide any alteration in systemic inflammatory response. / Doctor of Philosophy / Non-steroidal anti-inflammatory drugs (NSAIDs) are a mainstay of the management of pain and fever in horses. The most used NSAIDs in horses are the non-selective cyclooxygenase (COX) inhibitors flunixin meglumine and phenylbutazone, which are powerful anti-inflammatory agents. However, there are several complications, such as gastric ulcers and kidney damage, that are associated with these drugs – particularly in sick or dehydrated horses. Therefore, to reduce the risk of these complications, COX-2 selective inhibitors, such as firocoxib, have been developed for use in horses. However, there are still safety concerns with COX-2 inhibitors, and a safe, effective option for oral treatment of pain and fevers in horses is still needed. The studies presented in this dissertation explores the use, safety, and pharmacology of acetaminophen in adult horses for treating orthopedic pain and fever. In the first study, the pharmacokinetics and efficacy of oral acetaminophen at two different doses (20 mg/kg and 30 mg/kg) were examined in horses with pressure applied to the bottom of their hoof. The efficacy of acetaminophen at improving lameness in horses was compared to placebo and the non-selective COX inhibitor phenylbutazone. Acetaminophen when administered at 30 mg/kg produced a more rapid onset of greater improvement in lameness and lower heart rate compared to other treatments in this model, and therefore would be more suitable than acetaminophen at a lower dose of 20 mg/kg. Acetaminophen dosed at 30 mg/kg also resulted in a more rapid improvement in lameness scores than phenylbutazone at 2.2 mg/kg and was equivalent to phenylbutazone in lameness score reduction. However, results of this study necessitated further evaluation of the pharmacokinetics and safety of repeated oral dosing of acetaminophen at 30 mg/kg orally every 12 hours to determine if it was clinically useful in horses with orthopedic pain. In the second study, the pharmacokinetics, efficacy, and safety of oral acetaminophen (30 mg/kg) were examined in adult horses with naturally occurring chronic lamenesses (such as arthritis and navicular syndrome). In that study, following 21 days of twice daily oral dosing at 30 mg/kg, acetaminophen was found to be safe with no evidence of gastric ulcers or liver dysfunction in horses. Acetaminophen at 30 mg/kg twice daily for 21 days provided short-lived improvement in lameness when compared to each horse's baseline evaluation; however, the study concluded that acetaminophen may not be suitable alone for management of moderate to severe orthopedic pain in horses In the third study, the pharmacokinetics and efficacy of oral acetaminophen (30 mg/kg) was examined in adult horses with experimentally induced fever when compared to placebo and the nonselective COX inhibitor flunixin meglumine. That study found that acetaminophen was better than placebo and similar to flunixin meglumine in reducing fever in adult horses with experimentally induced fever and may be a suitable option for fever management in clinical cases.

Pharmaceuticals and personal care products found in the environment pose a significant hazard to human and ecosystem health. While there has been significant work on the fate and remediation of pharmaceuticals and personal care products in wastewater treatment, relatively little work has explored the fate, transport and remediation of these compounds in non-point source input. This is concerning given the increasing use of pharmaceuticals in livestock production and wastewater treatment derived biosolids frequently applied to land. These experiments aimed to quantify the abiotic adsorption and biotic transformation and uptake potential of woodchips and biochar-amended woodchips as a potential sorbent strategy for diffuse acetaminophen (ACT) pollution. Batch reactions were created in triplicate, supplied with 5 mM ACT, and analyzed over an eight hr period using ultraviolet spectrophotometry (298 nm). Ultraviolet absorbance readings for each time step then were compared to standard curves and solution ACT concentration was determined. Decreases in ACT from initial concentrations were the result of either abiotic and/or biotic. Overall, the woodchips and biochar-amended woodchips showed similar removal efficiency (16-21% of initial concentration). Whole model ANOVA analysis showed biologic activity having no significant effect on ACT solution concentration. However, within group ANOVA comparison showed significant differences between abiotic and biotic WC and abiotic and biotic WC treatments (controlling for media). Thus, the media effect could have masked the effect of biology on ACT removal. Species capable of degrading ACT exist and further study into their ability to grow and survive on these sorbents requires further work. / Master of Science

Thesis (Ph. D.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains xi, 147 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 128-143).

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 117-125).