The aims of this research were to establish the drug use patterns of an elderly population in the southern suburbs of the Cape peninsula and to determine the extent of knowledge with respect to their medicines. In addition, the relationship between drug use patterns and medication knowledge and the socioeconomic status of the elderly, the health care services utilised by them and the amount of information conveyed on medicine container labels was assessed. Two hundred and sixty non-institutionalised Caucasian elderly over the age of 65 years and living in old age residences were interviewed. The interviews were structured with 4 major components: 1. a questionnaire designed to collect participant particulars; 2. an interview schedule to collect information on drug use patterns and to assess participant knowledge of medicines used (Knowledge score). 3. a container label assessment schedule (Label score); 4. a cognitive function test to identify and exclude severely cognitively impaired elderly from the study population. Analysis of the data showed the majority of the participants were English-speaking women of social class 1 or 2. Approximately one fifth of all participants were male. The State-run health care services were utilised by 38% of the participants whilst 73% retained their own general practitioner. A total of 843 medicines were used with an average of 3.2 medicines per capita. Ninety-five percent of all participants took prescribed medicines, with diuretics, non-narcotic analgesics/antipyretics, and tranquillisers the 3 most frequently prescribed classes. A smaller percentage - 41.5% - of participants used self-prescribed medicines, of which non-narcotic analgesics, homeopathic and herbal medicines, and vitamins were taken most frequently. When assessed against container label directions approximitely one third of participants were non-compliant with their dosage regimens. The majority of all medicines had been used on a continuous basis for 1 to 10 years. Average knowledge score was 58%. The majority of participants had very little knowledge about interactions, side effects, and maximum permissible dose for their medicines. Just over one fifth of all participants could correctly state both the name and the strength of their medicine. Average knowledge score was found to decline with increasing age, but no relationships were found to exist with the other patient characteristics. Similarly, no relationship was found to exist between knowledge score and label score. Participants utilising the public health care services tended to have a lower knowledge score than those receiving treatment from the private sector. Twenty-six percent of all labels did not have specific usage directions. The private sector suppliers were most frequently culpable of omitting instructions. Label legibility also proved to be a problem for the elderly participants. The drug use patterns identified in this study are similar to those of the American and British elderly and should be of value in compiling a health care plan for the South African elderly, although further research involving other race and cultural groups is needed.

<p>Prostate cancer is the most frequently diagnosed cancer and the second leading causes of cancer-related death in men in the United States. Despite high overall incidence, the disease is relatively well controlled due to slow progression and early detection. However, surgical resection and external beam radiation therapy, first lines of defense, are the only potentially curative options in the clinic. Radiation resistant and metastatic prostate cancer are treated with androgen signaling inhibition (ASI) therapy to target the major growth/proliferation signaling axis that drives prostate cancer cells, but resistance invariably develops. Further, as ASI therapeutic compounds become more potent and are approved for use as neoadjuvant therapeutic options, up to 25% of prostate cancer patients on ASI therapy develop neuroendocrine prostate cancer (NEPC) that is actually induced by the ASI therapy itself. NEPC is resistant to taxane and platinum-based therapies, has no curative or specific targeting options clinically, results in mean overall survival under 9 months in some patient cohorts, and represents a significant unmet clinical need.</p> <p>Protein arginine methyltransferase 5 (PRMT5) is a methyltransferase with histone (epigenetic) and non-histone (non-epigenetic) substrates. PRMT5 is a critical mediator of stemness-associated genes as well as epigenetic regulation of cell fate determination. Further, PRMT5 is a validated therapeutic target in multiple hematological and solid tumor malignancies with multiple clinical trials ongoing. The Hu lab has recently demonstrated that 1) PRMT5 drives androgen receptor (AR) expression in hormone naïve prostate cancer (HNPC) cells, 2) PRMT5 positively regulates DNA damage response gene expression to confer radiation resistance in prostate cancer cells, 3) PRMT5 cooperates with cofactor pICln to drive AR expression in  castration resistant prostate cancer (CRPC) cells, and 4) targeting PRMT5 inhibits development of radiation-induced NEPC development, and that PRMT5 is a valid therapeutic target for prevention of radiation-induced neuroendocrine differentiation (NED). </p> <p>The research presented in this thesis demonstrates that PRMT5 and MEP50 are required for ASI-induced NED in prostate cancer cells, that the PRMT5:MEP50 protein:protein interaction can be pharmacologically targeted, and that ASI-induced NED occurs in an AR-dependent manner. Further, this work contributes a novel class of PRMT5:MEP50 PPI inhibitors in addition to a single-cell, time-resolved model system for interrogating pharmacological targeting of ASI-induced NED <em>in vitro</em>.</p>

<p dir="ltr">Torsades de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia associated with QT interval prolongation. Female sex and age > 65 years are risk factors for QT prolongation and TdP, possibly due to the effect of sex hormones. Progesterone shortens QT interval, while estrogen lengthens QT interval in females. Preclinical and clinical evidence indicates that progesterone has protective effects against drug-induced QT interval prolongation. J-Tpeak (JTp) and Tpeak-Tend (Tpe) intervals are biomarkers of early and late repolarization. Population pharmacokinetic/pharmacodynamic (PK/PD) models can be used to describe exposure-response relationships and identify sources of variability. In this study, data were pooled from four clinical trials with similar study design investigating the effect of progesterone on ibutilide-induced ventricular repolarization lengthening in healthy premenopausal women during menses or ovulation phase and healthy postmenopausal women. A nonlinear mixed effect model of ibutilide - QTc interval was first developed with preliminary data from 33 subjects. The model was then updated with new data from a total of 52 subjects, assessing the effect of progesterone on drug-induced QTc interval lengthening and identifying sources of variability through covariate analysis. Finally, two PK/PD models of ibutilide - baseline corrected JTpc (ΔJTpc) interval and Tpe (ΔTpe) interval were developed to assess the effect of progestogen on ibutilide-induced early and late repolarization lengthening. Progesterone showed protective effect against ibutilide-induced QTc interval lengthening, mainly through the shortening of pre-ibutilide baseline QTc interval. Body weight, age, race, hypertension, electrocardiogram (ECG) type and estradiol concentration were not significant covariates. Progesterone attenuates ibutilide-induced lengthening of late ventricular repolarization but did not show significant effect on ibutilide-induced early repolarization lengthening. Higher estradiol concentration was related to higher ibutilide-induced early repolarization lengthening. Black race was related to lower ibutilide-induced late repolarization lengthening.</p>

<p>Gilbert’s syndrome (GS) occurs in approximately 10% of the European population. The most common cause is homozygosity for UGT1A1*28, which is a TA repeat expansion in the promoter of UGT1A1. It is characterised by intermittent hyperbilirubinemia due to reduced hepatic activity of the  enzyme UDP-glucuronosyl-transferase 1A1(UGT1A1). GS also  alteres the pharmacokinetics of some drugs and increases the risk of drug toxicity. Irinotecan (Camptosar®, Campto®) is used in metastatic colorectal cancer and the active metabolite is inactivated by UGT1A1. Studies have shown that GS can be a risk factor for toxicity during irinotecan therapy.</p><p>Three different methods for genotyping of UGT1A1*28 have been tested.</p><p>PCR with electrophoresis used for size separation, melting temperature analysis and fluorescent PCR followed by fragment analysis on a capillary sequencer.</p><p>The last method was found to be superior. This method was used for genotyping of patients with colorectal cancer treated with irinotecan and 5-fluorouracil in the Nordic VI study. A significant association between UGT1A1 genotype and plasma bilirubin level before the start of irinotecan treatment was seen (ANOVA p<0.0001). Patients with GS had an overall increased risk of adverse drug reactions (Fishers Exact test p=0.02).</p><p>Gilbert’s syndrome can be diagnosed by genotyping UGT1A1*28 with a fragment analysis method. Genotyping of UGT1A1*28 can be used to identify patients with an increased risk of adverse reactions to irinotecan.<strong> </strong></p><p><strong> </strong></p> / <p>Gilberts syndrom (GS) drabbar upp till 10% av befolkningen i Västeuropa. GS beror på nedsatt aktivitet av enzymet UDP-glukuronosyltransferas 1A1 (UGT1A1) i levern. Den vanligaste orsaken är att individen är homozygot för en insertion av två baser i promotorn för genen UGT1A1. Denna genvariant kallas (TA)7TAA  eller UGT1A1*28. GS leder till intermittent stegring av bilirubin vid infektioner, men bilirubinstegring kan förekomma även utan utlösande agens. GS kan också leda till bilirubinstegring vid viss läkemedelsbehandling. Irinotekan (Campto®) används vid metastaserande colorektal cancer och dess aktiva metabolit inaktiveras av UGT1A1. Det finns rapporter om att GS ger ökad risk för toxiska biverkningar av irinotekan.</p><p>Tre metoder för att bestämma UGT1A1 har jämförts: PCR med elfores, PCR med smältpunktsanalys och PCR med fragmentanalys på sekvensator. Den sista metoden var bäst och användes för att genotypa UGT1A1 hos patienter med colorektal cancer från Nordic VI-studien. De behandlades med irinotekan i kombination med bolusinjektion eller infusion av 5-fluorouracil. Vi fann att  patienter med GS hade signifikant högre S-bilirubin före behandling jämfört med övriga patienter. De hade även ökad frekvens biverkningar av irinotekan (Fishers exakta test p=0,02).</p><p>Genotypning av UGT1A1 kan således användas för att diagnostisera Gilberts syndrom hos patienter med oförklarad bilirubinstegring. Det kan även användas för att identifiera patienter med ökad risk för biverkningar av irinotekan.</p>

Ovarian cancer is one of the most common female cancer diseases in the world today and in Sweden more than 800 new cases are diagnosed every year. The standard treatment consists of chemotherapy with paclitaxel in combination with carboplatin after initial cytoreductive surgery. The response to treatment and the severity of adverse drug reactions after chemotherapy varies greatly among individuals, and one of the most important factors responsible for these differences is now recognized to be the genetic variability. One of the major obstacles to successful treatment is drug resistance. Several potential mechanisms have been suggested for the resistance to paclitaxel, such as mutations in the target protein β-tubulin, single nucleotide polymorphisms (SNPs) in the gene ABCB1, which encodes the transport protein P-glycoprotein. P-glycoprotein can mediate efflux of various drugs from cancer cells as well as from the circulation into the intestinal lumen, and overexpression and/or high activity leads to drug resistance and/or increased elimination. Another reason might be the high interindividual variability of paclitaxel plasma concentrations, which has been suggested to be influenced by variability in metabolic enzymes, such as CYP2C8 and CYP3A4, and transport proteins e.g. P-glycoprotein. In the studies constituting this thesis we have investigated the possibilities of predicting the pharmacokinetics of paclitaxel as well as the tumor response and adverse drug reactions after chemotherapy in the preparation of personalized chemotherapy. We studied the correlation between the response and the presence of mutations in the dominant β-tubulin gene and SNPs in ABCB1. DNA from 40 ovarian tumors was screened for sequence variations in the β-tubulin gene without finding any, showing that β-tubulin mutations are rare and unlikely to be a clinically relevant resistance mechanism for paclitaxel. The SNPs G2677T/A and C3435T in the ABCB1 gene were determined in 53 ovarian cancer tumors from patients with poor (progressive disease or relapse within one year) or good (disease-free survival of more than one year) response to paclitaxel-carboplatin chemotherapy. Patients homozygously mutated for G2677T/A had a higher probability of responding to chemotherapy. There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment. No correlation was found for the C3435T variant. By using a newly developed quantitative LC/MS method for the simultaneous determination of paclitaxel and its hydroxymetabolites in human plasma we assessed the individual elimination of paclitaxel in 33 ovarian cancer patients. The patients were genotyped for SNPs in the ABCB1, CYP2C8 and CYP3A4 genes and their in vivo CYP3A4 enzyme activity, tumor response and toxicity, especially the neurotoxicity, were determined. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than patients with the wild type or homozygously mutated, but not compared to patients carrying the G/T alleles. A lower clearance of paclitaxel was also found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. The CYP3A4 enzyme activity in vivo affected the relative influence of CYP2C8 and CYP3A4 on the metabolism, but not the total clearance of paclitaxel. The exposure to paclitaxel was correlated to the neurotoxicity, but not to the treatment response. In conclusion, our findings suggest that the SNP G2677T/A in the ABCB1 gene, but not β-tubulin mutations, might be a predictor for paclitaxel response and that the interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy. / Ovarialcancer (äggstockscancer) är en av de vanligaste cancerformerna hos kvinnor i Sverige idag. Behandlingen består vanligen av tumörreducerande kirurgi följd av kemoterapi med paklitaxel och karboplatin. Målsättningen med detta avhandlingsarbete har varit att förbättra cytostatikabehandlingen (cellgiftsbehandlingen) med framförallt paklitaxel vid ovarialcancer genom att lägga grunden för individualisering av doser och förutsäga tumörsvaret vid behandlingen. Ett problem med dagens cancerbehandling är att många cancerceller så småningom blir resistenta mot olika cytostatika. För att angripa den mest resistenta cellen innan den induceras att öka uttrycket av, eller utveckla, fler resistensmekanismer vore det en fördel om vi före behandlingen kunde prediktera vilken dos av cytostatika som är bäst lämpad för individen samt om tumören kommer att reagera på behandlingen eller ej. En av de viktigaste faktorerna för skillnader i behandlingseffekt tros vara genetiska variationer mellan olika individer. I våra studier har vi använt genetiska metoder för att studera om vi kan prediktera tumörsvaret vid behandlingen genom att bestämma mutationer i genen för paklitaxels målprotein, β-tubulin, samt bestämma genetiska variationer i ABCB1-genen, kodande för transportproteinet P-glykoprotein. Tanken är att ett förändrat målprotein eller en förändrad förmåga hos cancercellerna eller kroppen att transportera ut paklitaxel skulle leda till en skillnad i påverkan på tumören. DNA från 40 ovarialtumörer analyserades utan att en enda sekvensvariation hittades i genen för β-tubulin, vilket tyder på att genetiska förändringar i genen för β-tubulin sannolikt inte är en klinisk relevant resistensmekanism. De normalt förekommande genetiska variationerna G2677T/A och C3435T i ABCB1-genen bestämdes i DNA från 53 ovarialtumörer där behandlingen endera givit en bra (tumörfri minst ett år) eller dålig (progression av tumören eller tumörfri mindre än ett år) anti-tumöreffekt. Patienter som var dubbelmuterade i position 2677 dvs hade endera T/T eller T/A (A/A hittades inte i materialet) i denna position hade en högre sannolikhet att få ett bra anti-tumörsvar vid behandlingen. Även antalet muterade baser påverkade utfallet, ju fler muterade baser i position 2677, desto högre sannolikhet att få ett bra svar på behandlingen. Andelen T eller A var också högre i den grupp av patienter som fått en lyckad behandling. För att kunna prediktera patientens individuella förmåga att bryta ner paklitaxel studerade vi inverkan av sekvensvariationer i generna för de nedbrytande enzymerna, CYP2C8 och CYP3A4, och transportproteinet P-glykoprotein (genen ABCB1) på eliminationen av läkemedlet i kroppen. Vi utvecklade en metod för att mäta paklitaxelkoncentrationerna i blodet och använde den för att studera hur snabbt 33 ovarialcancer patienter eliminerade cytostatikat från blodbanan. Hos dessa patienter bestämde vi förekomsten av kända genetiska variationer i generna ABCB1, CYP2C8 och CYP3A4 samt deras CYP3A4 enzymaktivitet i kroppen. Biverkningarna och tumörsvaret vid behandlingen utvärderades också. Eliminationen av paklitaxel hos dessa patienter var beroende av vilken bas som fanns i position 2677 i ABCB1-genen och förekomsten av den genetiska varianten CYP2C8*3. Enzymaktiviteten hos CYP3A4 kunde inte påvisas påverka eliminationen av paklitaxel utan snarare vilket enzym, CYP2C8 eller CYP3A4, som var relativt dominant i respektive patient. Exponeringen av paklitaxel korrelerade till den neurologiska påverkan som patienten orsakades av cytostatikat, men kunde inte korreleras till tumörsvaret vid slutet av cytostatikabehandlingen. Sammanfattningsvis ger patientens genetiska variationer i ABCB1, men inte β-tubulin, information om behandlingsutfallet. Genetiska variationer i CYP2C8 och ABCB1 påverkar patientens förmåga att eliminera paklitaxel och kan förhoppningsvis användas för att individualisera doserna. Vår förhoppning är att resultaten i denna avhandling skall kunna användas för att individualisera och ytterligare förbättra cytostatikabehandlingen vid ovarialcancer.

Preclinical testing is an important part of cancer drug development. The aim of this thesis was to establish and evaluate preclinical in vitro methods useful in the development of new anticancer drugs. In paper I, the development of non-clonogenic assays (FMCA-GM) using CD34+ stem cells for assessment of haematological toxicity was described. A high correlation was seen when comparing the 50% inhibitory concentrations (IC50) from FMCA-GM with the IC50 from the established clonogenic assay (CFU-GM). In paper II, FMCA-GM was complemented with additional cell models, establishing a normal cell panel. In vitro toxicity towards the five normal cell types was compared with known clinical adverse event profiles. The normal cell panel roughly reflected the tissue specific toxicities but was most useful in the prediction of therapeutic index. In paper III the use of peripheral blood lymphocytes from human, dog, rat and mouse to detect species differences in cellular drug sensitivity was described. Good agreement between our method and the established CFU-GM assay was observed. In paper II the benefit of using primary tumour cells from patients to predict cancer diagnosis-specific activity was studied. The in vitro activity of fourteen anticancer drugs was tested in tumour samples of both haematological and solid tumour origin. In general, clinical activity was well reflected. In paper IV, the efficacy and toxicity models were applied for experimental follow-up of a novel inhibitor of the ubiquitin-proteasome system, CB3 (Phosphoric acid, 2,3-dihydro-1,1-dioxido-3-thienyl diphenyl ester). In the preliminary characterization of CB3, antitumour activity and a favourable toxicity profile were displayed, although the exact mechanism of action remains to be elucidated. CB3 will therefore be further investigated. In conclusion, the work presented here contributes to different parts of the preclinical drug development and the methods may aid in the characterization of anticancer compounds

Intervertebral discs (IVD) degenerate earlier than many other musculoskeletal tissues and will continue to degenerate with aging. IVD degeneration affects up to 80 percent of the adult population and is a major contributing factor to low back pain. Anti-sclerostin antibody is an FDA-approved treatment for osteoporosis in postmenopausal women at high-risk for fracture and, as a systemic stimulant of the Wnt/LRP5/b-Catenin signaling pathway, may impact the IVD. Stabilization of b-Catenin in the IVD increases Wnt signaling and is anabolic to the extracellular matrix (ECM), while deletion of b-catenin or LRP5 decreases Wnt signaling and is catabolic to the ECM. Here, we hypothesized that a reduction of Sost would stimulate ECM anabolism. Lumbar and caudal (tail) IVD and vertebrae of Sost KO and WT (wildtype) mice (n=8 each) were harvested at 16 weeks of age and tested by MRI, histology, immunohistochemistry, Western Blot, qPCR, and microCT. Compared to WT, Sost KO reduced sclerostin protein and Sost gene expression. Next, Sost KO increased the hydration of the IVD and the proteoglycan stain in the nucleus pulposus and decreased the expression of genes associated with IVD degeneration, e.g., heat shock proteins. However, deletion of Sost was compensated by less unphosphorylated (active) b-Catenin protein in the cell nucleus, upregulation of Wnt signaling inhibitors Dkk1 and sFRP4, and catabolic ECM gene expression. Consequently, notochordal and early chondrocyte-like cells (CLCs) were replaced by mature CLCs. Overall, Sost deletion increased hydration and proteoglycan protein content, but activated a compensatory suppression of Wnt signaling that may trigger chondrogenesis and may potentially be iatrogenic to the IVD in the long-term.

La fibrose kystique (FK) est une maladie qui affecte principalement les systèmes respiratoires, digestifs et reproducteurs et rend les personnes atteintes plus susceptibles aux surinfections bronchiques et aux exacerbations pulmonaires. Le dosage initial et les ajustements de dose des antibiotiques sont difficiles en raison des altérations pharmacocinétique (PK), la grande variabilité PK et l'émergence de résistance aux antibiotiques dans cette population. En guise d’introduction, le premier chapitre de ce mémoire présente la pathologie de la fibrose kystique, des principes de base en pharmacologie et en modélisation compartimentale. Le deuxième chapitre présente une revue systématique de la littérature sur les modèles PK de population des antibiotiques développés dans la population FK adulte. Cette étude a mis en évidence les facteurs démographiques et cliniques ayant le plus d'impact sur la PK des antibiotiques en FK. Par exemple, le poids corporel maigre était la covariable la plus fréquemment utilisée pour estimer les paramètres PK des β-lactamines. Le troisième chapitre montre comment les modèles PK de population peuvent être utilisés pour proposer des stratégies de dosage alternatives aux cliniciens. Les résultats ont montré que la normalisation des doses de tobramycine par la taille (à une dose de 3,4 mg/cm) permet d'obtenir des concentrations maximales et minimales de tobramycine adéquates pour un patient médian. Le quatrième chapitre présente une évaluation méthodologique de l’impact du temps de prélèvement à 8h post-dose sur la performance prédictive de modèles PK de population pour la tobramycine. Il a été démontré que les paramètres PK du deuxième compartiment sont biaisés lorsqu’estimés en utilisant des concentrations simulées issues de temps de prélèvement divergents du modèle analysé. Le cinquième chapitre illustre le développement et l’évaluation d'un nomogramme de doses initiales pour la tobramycine basé sur la taille. Les doses dérivées du nomogramme entraînent une réduction significative de la variabilité des concentrations maximales prédites par rapport à ce qui est observé en clinique, ce qui pourrait potentiellement améliorer les issues cliniques en FK. Ce mémoire a donc démontré l'importance et la pertinence de la modélisation et des simulations dans un contexte clinique afin d’améliorer la prise en charge des patients atteints de FK. / Cystic fibrosis (CF) is a progressive, hereditary disease that primarily affects the respiratory, digestive, and reproductive systems and makes patients more likely to develop bronchial bacterial infections, and subsequently experience acute pulmonary exacerbations. Effective antibiotic use is in part responsible for the decreased respiratory burden observed over the past decades. However, initial dosing and dose adjustments of antibiotics, particularly of tobramycin, is challenging due to altered pharmacokinetics (PK), high PK variability, and emergence of antibiotic resistance. The first chapter of this dissertation presents the pathology of cystic fibrosis, basic principles in pharmacology and compartmental modeling. The second chapter presents a systematic literature review of population PK models of antibiotics developed for adult patients with CF. This study highlighted the demographic and clinical factors most impacting the PK of prescribed antibiotics in this population. For example, lean body weight was the most frequently used covariate for estimating PK parameters of β-lactams. The third chapter of this memoire shows how previously developed population PK models can be leveraged to propose alternative dosing strategies to clinicians. It was found that dose normalization of tobramycin using height rather than body weight at a 3.4 mg/cm dose resulted in tobramycin maximum and residual concentrations within the target range found in published guidelines for a median patient. The fourth chapter presents a methodological evaluation of the impact of 8h post-dose sampling times on the predictive performance of tobramycin population PK models. It was shown that the PK parameters of the second compartment are biased when estimated using simulated concentrations from divergent sampling times of the analyzed model. The fifth chapter shows the development and evaluation of an initial tobramycin dosing nomogram based on height rather than body weight to further individualize antibiotic therapy for CF patients. It was found that doses derived from the proposed nomogram resulted in significantly reduced variability in predicted peak concentrations values in comparison to what is observed in clinical practice, which could potentially improve clinical outcomes for CF patients. This memoire has therefore demonstrated the importance of modeling and simulations in a clinical setting to improve the management of CF in adult patients.

<p dir="ltr">Previous research shows that the prevalence rates for alcohol use disorder, opioid use disorder, and chronic pain are high worldwide. Additional work has demonstrated that the most used pain medications are potentially addictive and not suitable for chronic use. Recent research suggests that inhibiting adenylyl cyclase type 1 (AC1) may be an alternative, non-addictive, method for reducing pain. The purpose of this study was to explore the effects of a novel AC1 inhibitor (CMPD84) on pain threshold and alcohol reward-related behavior in high-alcohol preferring male and female mice (HAP). No research to date has investigated the effects of AC1 inhibition on pain threshold and alcohol-induced conditioned place preference (CPP) in HAP mice, making this the first study to do so. Two manual von Frey experiments were run to explore the effects of CMPD84 (compared to alcohol and morphine) on pain threshold. Three CPP experiments were run to assess the effects of CMPD84 on the expression and acquisition of alcohol-induced CPP. Brain samples were taken from the NAc shell and vlPAG to assess levels of PKCε after the pain threshold experiments and the acquisition CPP experiment. PKCε has previously been shown to be linked to alcohol reward-behavior and pain relief. Results show that CMPD84 was more efficacious in increasing pain threshold in HAP mice compared to morphine and alcohol. CMPD84 also reduced the acquisition and expression of alcohol-induced CPP. AC1 inhibition reduced levels of PKCε in the brain, which matched behavioral results that reduced the expression and acquisition of alcohol-induced CPP, as well as increased pain threshold. These results suggest that PKCε may be linked to AC1 inhibition, pain threshold, and alcohol reward-related behaviors. </p>

This thesis is a user study within library and information science on participatory practices of a professional group in work activity. This has been investigated only to a minor extent in previous library and information science research. The qualitative empirical focus alternates between physicians‟ engagements in work practice and workplace learning within patient care. The overall research problem was to learn how people in workplaces interacted with information that was embedded, intricately intertwined, and tightly bound to the ongoing routines of their everyday work. This thesis aims at understanding information practices of professionals in occupational settings as exemplified by a team of physicians in a Nigerian teaching hospital. In this thesis, the focus was on the collective work activity, and the specific goals identified include how physicians interact and make meaning in the context of the social activities in the workplace, how professionals individually or collectively gather, understand, produce, share and use information, and how workplace learning influences information practices. Information practices are viewed as sociocultural practices that occur inside other practices. The thesis focuses on a nuanced, contextualized understanding of the interplay between the participating actors in activity, the activity per se, and the intermediary role of tools and artefacts. The epistemological point of departure is the sociocultural perspective that emphasizes the dynamic interdependence of the individual with the social and collective development focusing on mediation through tools and artefacts in cultural, institutional, and historical situations. I have chosen cultural-historical activity theory and the practice theories to analyse the dynamic processes in the context of patient care. Their underlying principles guided the empirical study, facilitating extrapolations and illustrations in the analysis. The cultural-historical activity theory was used to understand contextual issues that influence information practices in work activity: the object and subject of activity, division of labour, rules and norms, community, tools and artefacts, as well as the activity system itself and the hierarchical structure of the activity. Theories and concepts employed from a practice perspective on learning were considered useful for understanding the participatory modes in workplace and the influence of social learning communities on diverse information processes. In so doing, the study strives to provide a holistic understanding of information practices, workplace learning, and the relationships between them.The empirical data was gathered through a qualitative case study that lasted over a period of two years. Direct observation was the dominant data collection technique 5 used throughout the preliminary and main empirical studies to capture physicians‟ information practices and experiences. The observation focused on the Clinical Pharmacology and Therapeutics (CPT) team‟s encounters with patients; the interactions they had amongst themselves, and events and situations surrounding patient care. During the main study, other data collection techniques were employed alongside the observation method. In-depth open-ended interviews were conducted with 17 physicians and 9 non-physicians who were selected to provide rich and varied descriptions of the phenomena under study. The interview time totalled at 1,535 minutes. Physical artefacts were another data collection technique employed: 30 patients‟ medical records were assessed during the empirical study. Finally, informal interactions in the research setting were an additional data collection technique used continuously throughout the two empirical periods. The results were analyzed through a combination of inductive and deductive methods of analysis. There are four parts to the empirical results in this thesis. In the first, contextual elements that showed how work environment can be an influencing factor in the information practices of a professional group are described from the perspective of cultural historical activity theory. In the second part, the nature of information access in the real-world information environment was portrayed. It was found that information sources and strategies contributed to the overarching goal of restoring patient health to normalcy. The information sources and strategies were also found useful for mediating the information environment both subjectively and intersubjectively. An equally important result concerns the authority issues related to information sources and strategies. In the third part, available tools and artefacts were presented as useful information aids that also played a mediating role. Tools were categorised into physical tools and language. Language was categorized according to the social situations or classes of speakers. The case notes were seen as useful artefact and occupied a central niche in the studied work activity. These tools and artefacts enabled affordances around which social practices were built on in the work activities. In the last part of the results, various information practices that mirror the participatory practices rather than those of isolated individuals are highlighted. Six dimensions made up and covered the most vital spectrum of the information processing: information gathering, meaning making, information sharing, information use, reading, and documentation. Furthermore, the study revealed that learning took place simultaneously with the work activity and that it influenced information practices at the same time. / <p>Academic dissertation for the Degree of Doctor of Philosophy in Library and Information Science at the University of Borås to be publicly defended on Friday 19 October 2012 at 13.00 in lecture room D 211, University of Borås, Allégatan 1, Borås.</p>