<p>The use of nano- and micro-particulate carriers as delivery systems for oral vaccines has been under investigation for several decades. Surprisingly little is known of their uptake in the human intestine, despite the fact that substantial improvement is required to achieve adequate immune responses in man after oral administration. </p><p>In this thesis, various aspects of particle transcytosis across the human intestinal epithelium were studied, in order to identify strategies for improved uptake of nano- and micro-particulate drug delivery systems. </p><p>The follicle associated epithelium (FAE) overlying Peyer´s patches contains M-cells, which have an increased capacity for uptake of particulate antigens. Therefore, a model of human FAE was developed to study mechanisms of particle uptake and transport.</p><p>Receptors that could be used for targeting to the FAE had previously not been identified in humans. By use of the model FAE, two new targets were identified on human intestinal FAE; CD9 and β1-integrin. Furthermore, studies of isolated human intestinal tissue showed that an integrin-adherent peptide motif, RGD, could be utilized to achieve selective and improved transport of nanoparticles into human Peyer´s patches.</p><p>Studies of factors influencing intestinal particle uptake and transcytosis revealed that two cytokines, TNF-α and LTα1/β2, but also one growth factor, TGF-β1, induced uptake of particles in Caco-2 cells and transcytosis of particles in the model FAE. Furthermore, it was shown that an enteric bacterium, Yersinia Pseudotuberculosis, could trigger uptake and transcytosis of particles across model absorptive epithelial cells.</p><p>In conclusion, this thesis provides a platform for further investigations of particle transcytosis across the human intestinal epithelium. The identification of two new proteins with increased expression in human FAE and a targeting sequence that improves particle uptake into Peyer’s patches, gives new hope for the development of subunit oral vaccines.</p>

<p>The nasal administration of drugs offers advantages over administration by intravenous injection. Drugs can be rapidly absorbed through the nasal mucosa, resulting in a rapid onset of action, and also avoiding degradation in the gastrointestinal tract and first-pass metabolism in the liver. The olfactory receptor cells, which are in direct contact with both the environment and the central nervous system (CNS), are potential routes for drugs into the CNS. The olfactory pathway thus circumvents the blood brain barrier (BBB) which prevents many systemically administered drugs from entering the brain.</p><p>The studies used compounds active in the CNS and the experiments were performed in rodents. The nasal bioavailability of (S)-UH-301, NXX-066 and [³H]-dopamine was investigated in a rat model; uptake into the cerebrospinal fluid (CSF) was compared after nasal and intravenous administration. The concentrations of S-UH-301 and NXX-066 in plasma and CSF were measured with high performance liquid chromatography. The possible transfer of dopamine and neurotensin along the olfactory pathway after nasal administration to mice was studied using brain tissue sampling and autoradiography. The radioactivity content in blood, CSF and dissected brain tissue samples after administration of [³H]-dopamine and [³H]-neurotensin was assessed using liquid scintillation, and thin layer chromatography (TLC) was used to investigate the metabolic fate of [³H]-dopamine.</p><p>The results of this thesis suggest that nasal administration of CNS-active compounds with low oral bioavailability is an interesting and workable alternative to intravenous injection. The small lipophilic compounds (S)-UH-301 and NXX-066 were rapidly and completely absorbed after nasal administration, although hard evidence of direct transfer from the nose remains elusive. Radioactivity measurements in the olfactory bulb following nasal administration of</p><p>[³H]-dopamine and [³H]-neurotensin indicate that transfer occurred. The TLC results showed the presence of unchanged dopamine in the olfactory bulb but it is less clear from initial results with neurotensin, which radioactive products of this molecule reached the olfactory bulb, and further studies are required.</p>

The nasal administration of drugs offers advantages over administration by intravenous injection. Drugs can be rapidly absorbed through the nasal mucosa, resulting in a rapid onset of action, and also avoiding degradation in the gastrointestinal tract and first-pass metabolism in the liver. The olfactory receptor cells, which are in direct contact with both the environment and the central nervous system (CNS), are potential routes for drugs into the CNS. The olfactory pathway thus circumvents the blood brain barrier (BBB) which prevents many systemically administered drugs from entering the brain. The studies used compounds active in the CNS and the experiments were performed in rodents. The nasal bioavailability of (S)-UH-301, NXX-066 and [3H]-dopamine was investigated in a rat model; uptake into the cerebrospinal fluid (CSF) was compared after nasal and intravenous administration. The concentrations of S-UH-301 and NXX-066 in plasma and CSF were measured with high performance liquid chromatography. The possible transfer of dopamine and neurotensin along the olfactory pathway after nasal administration to mice was studied using brain tissue sampling and autoradiography. The radioactivity content in blood, CSF and dissected brain tissue samples after administration of [3H]-dopamine and [3H]-neurotensin was assessed using liquid scintillation, and thin layer chromatography (TLC) was used to investigate the metabolic fate of [3H]-dopamine. The results of this thesis suggest that nasal administration of CNS-active compounds with low oral bioavailability is an interesting and workable alternative to intravenous injection. The small lipophilic compounds (S)-UH-301 and NXX-066 were rapidly and completely absorbed after nasal administration, although hard evidence of direct transfer from the nose remains elusive. Radioactivity measurements in the olfactory bulb following nasal administration of [3H]-dopamine and [3H]-neurotensin indicate that transfer occurred. The TLC results showed the presence of unchanged dopamine in the olfactory bulb but it is less clear from initial results with neurotensin, which radioactive products of this molecule reached the olfactory bulb, and further studies are required.

Studies of intestinal drug permeability have traditionally been performed in the colon-derived Caco-2 cell model. However, the permeability of these cell monolayers resembles that of the colon rather than that of the small intestine, which is the major site of drug absorption following oral administration. One aim of this thesis was therefore to develop a new cell culture model that mimics the permeability of the small intestine. 2/4/A1 cells are conditionally immortalized with a temperature sensitive mutant of SV40T. These cells proliferate and form multilayers at 33°C. At cultivation temperatures of 37 – 39°C, they stop proliferating and form monolayers. 2/4/A1 cells cultivated on permeable supports expressed functional tight junctions. The barrier properties of the tight junctions such as transepithelial electrical resistance and permeability to hydrophilic markers resembled those of the human small intestine in vivo. These cells lacked functional expression of drug transport proteins and can therefore be used as a model to study passive drug permeability unbiased by active transport. The permeability to diverse sets of drugs in 2/4/A1 was comparable to that of the human jejunum for both incompletely and completely absorbed drugs, and the prediction of human intestinal permeability was better in 2/4/A1 than in Caco-2 for incompletely absorbed drugs. The small intestinal-like paracellular permeability of 2/4/A1 thus enables better predictions of drug permeability in the small intestine than does Caco-2. The studies of the paracellular route and its importance for intestinal drug permeability was also in focus in the second part of this thesis, in which a new principle for tight junction modulation was developed, based on the primary structure of the extracellular tight junction protein occludin. Peptides corresponding to the N-terminus of the first extracellular loop increased the permeability of the tight junctions, but lacked apical effect. This problem was solved by conjugation of one peptide to a lipoamino acid, resulting in two diastereomers with different effects. The L-isomer had a sustained apical effect, while that of the D-isomer was transient. In conclusion, conjugated occludin peptides constitute a new class of tight junction modulators that can enhance the tight junction permeability.

The use of nano- and micro-particulate carriers as delivery systems for oral vaccines has been under investigation for several decades. Surprisingly little is known of their uptake in the human intestine, despite the fact that substantial improvement is required to achieve adequate immune responses in man after oral administration. In this thesis, various aspects of particle transcytosis across the human intestinal epithelium were studied, in order to identify strategies for improved uptake of nano- and micro-particulate drug delivery systems. The follicle associated epithelium (FAE) overlying Peyer´s patches contains M-cells, which have an increased capacity for uptake of particulate antigens. Therefore, a model of human FAE was developed to study mechanisms of particle uptake and transport. Receptors that could be used for targeting to the FAE had previously not been identified in humans. By use of the model FAE, two new targets were identified on human intestinal FAE; CD9 and β1-integrin. Furthermore, studies of isolated human intestinal tissue showed that an integrin-adherent peptide motif, RGD, could be utilized to achieve selective and improved transport of nanoparticles into human Peyer´s patches. Studies of factors influencing intestinal particle uptake and transcytosis revealed that two cytokines, TNF-α and LTα1/β2, but also one growth factor, TGF-β1, induced uptake of particles in Caco-2 cells and transcytosis of particles in the model FAE. Furthermore, it was shown that an enteric bacterium, Yersinia Pseudotuberculosis, could trigger uptake and transcytosis of particles across model absorptive epithelial cells. In conclusion, this thesis provides a platform for further investigations of particle transcytosis across the human intestinal epithelium. The identification of two new proteins with increased expression in human FAE and a targeting sequence that improves particle uptake into Peyer’s patches, gives new hope for the development of subunit oral vaccines.

<p>As we have been actively involved in various teaching programmes for many years, we wanted to enquire how the students and teachers understood their school and compare it to how we experienced it.  Do the students fully understand the knowledge they are receiving and can they learn from it? Do the teachers believe what they are teaching is understood by the students? What is the underlining knowledge of social practices in the school, which can inspire students in different ways? The aim of the study, as the title suggests, is to convey and describe the various methods practiced in a specific social practice.</p><p>Our project is a quality study.  We have used observation, specific intense individual and group interviews. In the result, arrives a different message through what there is possible for the students to learn about the matter. These messages are visible in the different attitudes the teacher, the school and the organisation have vis-à-vis the matter. In the discussion, we have focussed on what has arrived in the result around the teacher's and the organisation's attitudes. How can these attitudes influence the students' attitude to the matter and how will one work in order to become aware about the messages that are sent.</p>

<p>En stor del av Sveriges befolkning över 65 år får sina läkemedel expedierade via Apotekets dosdispenserade läkemedel, ApoDos. E-dos är ett förskrivarverktyg som nu används vid förskrivning till dessa patienter. Införandet av e-dos är tänkt att förenkla hanteringen av ordinationer, att öka graden av automatisering av produktion av doser och att öka säkerheten i processerna. Trots detta så kommer en stor del av ordinationerna fortfarande till DosApoteken via fax.</p><p>Syftet med denna studie är att öka förståelsen för den underliggande problematik som ligger till grund för att e-dos inte används i större utsträckning än cirka 50-60 % vid ordination av läkemedel till ApoDos-patienter.</p><p>Studien har ett kvalitativt tillvägagångssätt där intervjuer med läkare från Kalmar kommun har genomförts. Data samlades in från så väl öppen- som slutenvårdsläkare under ett par veckor i april 2010.</p><p>Resultaten visar att läkarna tycker att e-dos är ett bra system, som ger en god helhetsbild över patientens samtliga läkemedel. Men på grund av att journalsystemet Cosmic och e-dos inte automatiskt delar information mellan sig så gör det att läkarna utsätts för ett tidskrävande dubbelarbete. En integrering av dessa system skulle med största sannolikhet minska läkarnas arbetsbörda och därmed leda till en ökad användning av e-dos. E-dos grafiska utformning upplevdes som komplicerad och svåröverskådlig. För att genomföra ändringar i patientens läkemedelsbehandling så krävs en stor mängd bakgrundsinformation och att läkaren genomför många moment innan en ordinationsförändring godkänns. Ledtiden och låsningen av e-dos är en orsak till att även vana e-dosanvändare väljer att gå utanför systemet, framförallt vid akuta och tillfälliga ordinationer.  </p><p>Majoriteten av läkarna ansåg att användandet av e-dos är en säkerhet för patienten men under intervjuerna så framkom det att behovet av en integrering mellan journalsystemet och e-dos är stort. Läkarna upplevde att avsaknaden av en integrering var en riskfaktor för patienten och att det ökade på läkarnas arbetsbörda. En enklare utformning av e-dos önskades också, då ett stort antal läkare upplevde systemet som svåranvänt.</p> / <p><em>Objective</em>. The aim of this study is to increase the understanding of why physicians don’t use e-dos (a computerized prescription system) to a greater extent than about 50-60 % when prescribing medicine to patients within the specific medication dispensing system (ApoDos).</p><p><em>Methods.</em> This study has a qualitative approach. Data was collected via interviews with general practitioners and physicians from a hospital in the municipality of Kalmar during a couple of weeks in April 2010.</p><p><em>Results.</em> The physicians feel that e-dos is a good system, that provides a complete picture of the patient’s prescriptions. But because the electronic medical record systems “Cosmic” and e-dos aren’t able to share the same information in between them, this leads to an extra workload for the physicians. An integration of these two systems would decrease the workload and maybe also increase the use of e-dos. The graphic design is experienced as complicated and difficult to grasp. To make a change in a patient’s medication within e-dos requires a great quantity of information. Physicians are required to carry out a number of steps before a change is completed. Even experienced users choose not to use e-dos in some circumstances, i.e. then the prescription is urgent or temporary, and they use ordinary prescriptions instead.  After a change in a patient’s medication is prescribed, the system is locked until the change is approved by a pharmacist. This is a course of irritation among the physicians.   </p><p><em>Conclusion. </em>The majority of physicians considered the use of e-dos as safe for the patient.  They also pointed on the need of integration between the electronic medical record system, “Cosmic” and e-dos. Physicians expressed that the lack of integration was a risk factor for medical errors and that it increased the physicians’ workload. Several physicians also described the system as difficult to handle and wished a simpler design.  </p>

<p>Biografmarknaden är i dagsläget i en situation där marknadsledaren har en monopolliknande ställning. Detta påverkar i hög grad de mindre biografernas existens då man inte kan konkurrera på samma villkor. Detta i sin tur leder till att biografbesökarna försvinner till de större biograferna med större produktutbud. Mindre biografer måste hitta nya lösningar för att kunna behålla sina kunder på en konkurrensutsatt marknad. Denna uppsats tar därför upp vilka faktorer som är viktiga för att kunna skapa lojala och återkommande kunder. </p><p>Syftet med uppsatsen är att göra en fallstudie för att analysera och utvärdera två stora och en liten biograf. Detta sker genom enkätundersökningar av biografbesökarna på de tre olika biograferna som är Heron City, Kistabiografen och Roxybiografen.</p><p>Denna uppsats är skriven utifrån den mindre biografen Roxybiografens perspektiv för att se vilka faktorer som skapar lojala biografbesökare. Uppsatsen använder sig av en fallstudie för att skapa en stor förståelse och inblick för objektets situation.</p><p>Det som framkommit av studien är att en mindre biograf måste differentiera sig genom att erbjuda något annat än vad konkurrenterna gör vilket är grundläggande för att en liten biograf ska överleva.</p><p>Som underlag till denna undersökning ligger teorin involvement theory och marknadsföringsstrategier som kostnadsöverlägsenhet, differentiering och fokusering.</p>

New approaches quantifying the effect of treatment are needed in oncology to improve the drug development process and to enable treatment optimization for existing therapies. This thesis focuses on the development of pharmacometric models for biomarkers, side effects and efficacy in order to identify predictors of clinical response in anti-cancer drug therapy. The variability in myelosuppression was characterized in six different cytotoxic anticancer treatments to evaluate a model-based dose individualization approach utilizing neutrophil counts as a biomarker. The estimated impact of inter-occasion variability was relatively low in relation to the inter-individual variability, indicating that myelosuppression is predictable from one treatment course to another. The approach may thereby be useful for dose optimization within an individual. To further study and to identify predictors for the severe side effect febrile neutropenia (FN), the relationship between the shape of the myelosuppression time-course and the probability of FN was characterized. Patients with a rapid decline in neutrophil counts and high drug sensitivity were identified to have a higher probability of developing FN compared with other patients who experience grade 4 neutropenia. Predictors of clinical response in patients receiving sunitinib for the treatment of gastro-intestinal stromal tumor (GIST) were identified by the development of an integrated modeling framework. Drug exposure, biomarkers, tumor dynamics, side effects and overall survival (OS) were linked in a unified structure, and univariate and multivariate exposure variables were tested for their predictive capacities. The soluble biomarker, sVEGFR-3 and tumor size at start of treatment were found to be promising predictors of overall survival, with decreased sVEGFR-3 levels and smaller baseline tumor size being predictive of longer OS. Also hypertension and neutropenia was identified as predictors of OS. The developed modeling framework may be useful to monitor clinical response, optimize dosing in sunitinib and to facilitate dose individualization.

Chemotherapy plays an important role in the treatment of cancer. However, these drugs also cause death of non-malignant cells, resulting in severe side-effects. In addition, drug resistance may exist. Predictive tools for dose and drug selection are therefore warranted. In this thesis predictive pharmacometric models were developed for the main dose-limiting side-effect, neutropenia, and for treatment response following chemotherapy. Neutropenia is associated with a high risk for life-threatening infections and leads frequently to reduced dose delivery and thereby suboptimal treatment of the tumor. A better characterization of the dynamics of docetaxel induced neutropenia was obtained by simultaneous analysis of neutrophils and leukocytes. The fraction of neutrophils was shown to change over the time-course, hence leukocytes and neutrophil counts are not interchangeable biomarkers. Sometimes neutrophil count is reported as categorical severity of neutropenia (Grade 0-4). A method was developed that allowed analysis of these data closer to its true continuous nature. The main regulatory hormone of neutrophils is granulocyte colony stimulating factor (G-CSF). Although recombinant G-CSF is used as supportive therapy to prevent neutropenia, little is known of how the endogenous G-CSF concentrations vary in patients following chemotherapy. A prospective study was carried out and simultaneous analysis of endogenous G-CSF and neutrophils following chemotherapy enabled a more mechanistic model to be developed that also could verify the self-regulatory properties of the physiological system. Patient characteristics were investigated using a pharmacokinetic-myelosuppression model for docetaxel in patients with normal and impaired liver function. The model was a useful tool in evaluating different dosing strategies and a reduced dosing scheme was suggested in patients with poor liver function, thereby enabling docetaxel treatment in this patient population which has previously been excluded. Treatment of acute myeloid leukemia with daunorubicin and cytarabine is associated with drug resistance and high variability in pharmacokinetics, which was partly explained for daunorubicin by peripheral leukocyte count. An integrated model of the in vitro drug sensitivity and treatment response showed that in vitro drug sensitivity was predictive for treatment outcome in this patient population and may therefore be used for choice of drug. The developed pharmacometric models in this thesis may be useful in the optimization of treatments schedules for existing and new drugs as well as to assist in drug and dose selection to improve therapy in an individual patient. The models and methods presented may also facilitate pooled analysis of data and demonstrate principles which could be useful for the pharmacometric community.