Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Ohio State University, 2009. / Title from first page of PDF file. Includes bibliographical references (p. 202-241).

Thesis (Ph. D.)--Ohio State University, 2005. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 May 26.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xix, 94 p.; also includes graphics (some col.). Includes bibliographical references (p. 87-94). Available online via OhioLINK's ETD Center

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 178-204).

Metabolomic Insights into the Pharmacological and Genetic Inhibition of Cyclooxygenase-2 William T. E. Briggs The cyclooxygenase (COX)-2 inhibitors, or “coxibs,” are excellent anti-inflammatory agents, but their reputation has been tarnished by the adverse cardiovascular (CV) events, including heart failure (HF), with which they are associated. Whilst the risk of HF represents the greatest adverse CV event signal seen with these compounds, it is also perhaps the least well understood and has often been explained away as a consequence of the thrombotic risk with which the coxibs are also associated. One recent hypothesis, put forward by Ahmetaj-Shala et al., suggests that asymmetric dimethylarginine (ADMA) may serve as a mechanistic bridge between COX-2 inhibition and HF. However, the ADMA-COX-2 hypothesis was developed based on findings in a constitutive mouse model of COX-2 knock-out (KO), which is compromised by severe developmental cardio-renal pathology, and pharmacological studies which may not accurately reflect coxib use in clinical practice. Various studies have explored the metabolic changes induced by coxib treatment. However, these studies have been limited in scope and have tended to focus on specific pathways or certain tissues/bio-fluids. This has left large regions of the metabolome, in the context of coxib-treatment, unexplored. Given that metabolic remodelling is a key feature of HF, changes in these metabolites may hold the key to understanding the pathogenesis of coxib-induced HF. L-Carnitine shuttles activated long-chain fatty acids (FAs) across the inner mitochondrial membrane to the mitochondrial matrix, where they are oxidised by β-oxidation. This is especially important in the heart, which derives the majority of its energy from the metabolism of FAs. Changes in carnitine metabolism are also seen in HF. It is therefore biologically plausible that derangements in carnitine metabolism may contribute to the pathogenesis of coxib-induced HF. This thesis employs a combination of targeted and untargeted metabolomic techniques, stable isotope labelling and quantitative reverse transcription polymerase chain reaction (RT-qPCR) to i) profile the metabolic changes induced by celecoxib and rofecoxib, in the mouse; ii) specifically interrogate the effect of celecoxib, rofecoxib and global COX-2 gene deletion on carnitine synthesis, metabolism and shuttling, and iii) explore the advantages and disadvantages of the inducible post-natal global (IPNG) COX-2 KO (COX-2-/-) mouse, an alternative to the constitutive COX-2-/- mouse used by Ahmetaj-Shala et al. The results of this thesis demonstrate that i) celecoxib and rofecoxib have similar metabolomic consequences in the mouse; ii) carnitine metabolism may be affected by celecoxib, rofecoxib and dietary composition, via a peroxisome proliferator-activated receptor-alpha (PPAR-α) mediated effect on hepatic carnitine synthesis and iii) the IPNG COX-2-/- mouse neither exhibits the severe developmental cardio-renal pathology nor the altered ADMA metabolism observed in the constitutive COX-2-/- mouse. These findings contradict those of Ahmetaj-Shala et al., oppose the ADMA-COX-2 hypothesis and highlight a potential role for carnitine metabolism and diet in coxib induced HF.

Indiana University-Purdue University Indianapolis (IUPUI) / Adolescent alcohol abuse is a global problem that initiates lifelong addiction. Alcohol use during adolescence is associated with subsequent Meth dependence in humans. Specifically, female adolescents are particularly vulnerable to serial alcohol and Meth use. However, it is unknown if prior voluntary alcohol drinking impacts subsequent Meth-taking in female adolescent rats. Both alcohol and Meth increase the prostaglandin synthesis enzyme cyclooxygenase-2 (COX-2) in the brain but the effect of serial exposure to alcohol and Meth on COX-2 has not been determined. The first study uses a novel method of serial voluntary alcohol drinking and Meth self-administration in female adolescent rats to model human patterns of co-abuse. Prior alcohol drinking did not affect subsequent Meth self-administration, but it reduced the cue-primed reinstatement of Methseeking after abstinence from Meth. Rats with a history of adolescent alcohol drinking also had increased COX-2 in the dorsal striatum, regardless of subsequent Meth selfadministration. These findings demonstrate that a history of adolescent alcohol drinking does not alter Meth self-administration but persistently reduces cue-primed Meth seeking and increases COX-2 after prolonged abstinence from alcohol. To further examine the role of COX-2 in alcohol drinking, the second study found that adolescent alcohol drinking not only increased COX-2 after four weeks of alcohol abstinence, but also increased endothelin-1 (ET-1) and prostaglandin E2 (PGE2) in the dorsal striatum. Furthermore, adolescent alcohol drinking increased alcohol drinking after abstinence, and this increase was attenuated by treatment with the COX-2 inhibitor nimesulide during abstinence. Antagonism of the interaction between PGE2 and its receptor 1 (EP1) also attenuated the increase in relapse drinking and restored alcohol drinking to the rate of alcohol naïve rats. Overall, these experiments identified a prostaglandin-mediated mechanism that is a putative target for the treatment of alcohol relapse following abstinence in individuals with a history of adolescent alcohol abuse.

Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is primarily limited by renal and gastrointestinal adverse effects. Rebamipide suppresses gastric mucosal injury when administered with NSAIDs. This study aimed to determine rebamipide's influence upon renal effects following concomitant use with celecoxib or diclofenac. On day 0, rats were randomly divided into 6 groups (n≥6). On days 1 and 2, three groups received placebo and three groups were administered rebamipide (30 mg/kg) twice daily. On day 3, the rats treated with placebo received another dose of placebo and ten minutes later a single dose of celecoxib (40 mg/kg), diclofenac (10 mg/kg), or placebo, respectively. The rats treated with rebamipide received one more dose of rebamipide and ten minutes later one single dose of celecoxib, diclofenac, or placebo, respectively. Urine and blood samples were collected on days 0, 2, and 3. Sodium and potassium excretion rates decreased significantly in the rats treated with celecoxib, diclofenac, rebamipide plus celecoxib, or rebamipide plus diclofenac on day 3. Blood urea nitrogen (BUN) levels significantly increased in placebo plus diclofenac and rebamipide plus diclofenac groups on day 3. Comparing the two groups, the levels of BUN was significantly higher in the rebamipide plus diclofenac group compared to that of placebo plus diclofenac group. Concomitant administration of rebamipide with either NSAID caused a rise in concentrations of urinary kidney injury molecule-1. Histopathological evaluations revealed an intensified NSAID-induced tubular necrosis by rebamipide. Based upon the results obtained, concomitant administration of rebamipide with NSAIDs enhances the effect of NSAIDs on tubular injury.

Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is primarily limited by renal and gastrointestinal adverse effects. Rebamipide suppresses gastric mucosal injury when administered with NSAIDs. This study aimed to determine rebamipide's influence upon renal effects following concomitant use with celecoxib or diclofenac. On day 0, rats were randomly divided into 6 groups (n≥6). On days 1 and 2, three groups received placebo and three groups were administered rebamipide (30 mg/kg) twice daily. On day 3, the rats treated with placebo received another dose of placebo and ten minutes later a single dose of celecoxib (40 mg/kg), diclofenac (10 mg/kg), or placebo, respectively. The rats treated with rebamipide received one more dose of rebamipide and ten minutes later one single dose of celecoxib, diclofenac, or placebo, respectively. Urine and blood samples were collected on days 0, 2, and 3. Sodium and potassium excretion rates decreased significantly in the rats treated with celecoxib, diclofenac, rebamipide plus celecoxib, or rebamipide plus diclofenac on day 3. Blood urea nitrogen (BUN) levels significantly increased in placebo plus diclofenac and rebamipide plus diclofenac groups on day 3. Comparing the two groups, the levels of BUN was significantly higher in the rebamipide plus diclofenac group compared to that of placebo plus diclofenac group. Concomitant administration of rebamipide with either NSAID caused a rise in concentrations of urinary kidney injury molecule-1. Histopathological evaluations revealed an intensified NSAID-induced tubular necrosis by rebamipide. Based upon the results obtained, concomitant administration of rebamipide with NSAIDs enhances the effect of NSAIDs on tubular injury.

With the beginning of the Human Genome Project, an emerging field of science was brought to the forefront of the pharmaceutical community. Pharmacogenetics facilitates optimization of the current patient-centered care model and pharmacotherapy as a whole. Utilizing these ever-expanding branches of science to nonsteroidal anti-inflammatory drugs (NSAIDs) can provide novel opportunities to affect patient care. With a wide range of NSAID choices available as treatment options for relieving pain and/or reducing inflammation or fever, a more systematic way of selecting the ideal agent for the patients based upon their genetic information could spare them from a potentially permanent health-care condition. Furthermore, if a patient possesses or lacks certain alleles, serious adverse events can be anticipated and avoided. The tailoring of drug therapy can be achieved using the published data and cutting-edge genetic testing to attain a higher standard of care for patients.