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Sökning: hsv:(MEDICIN OCH HÄLSOVETENSKAP) hsv:(Medicinska och farmaceutiska grundvetenskaper) hsv:(Farmaceutiska vetenskaper) > Licentiatavhandling

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1.
  • Larsson, Mikael, 1982 (författare)
  • Heterogeneities in polymer gels: Effects on swelling and mechanical properties
  • 2010
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Polymeric hydrogels is a class of scientifically interesting materials that are being extensively studied. They are found in numerous applications within; drug delivery, hygiene products, food industry, analytical chemistry, etc. In addition, polymeric hydrogels have promising future applications as; cell scaffolds, implants, sensors, etc.One of the critical parameters for the performance of hydrogels in different applications is their structure. One such structural feature is the heterogeneity of the material, where the term heterogeneity applies to many different types of structural variations.The aim of this thesis was to investigate how different kinds of heterogeneities can be introduced into hydrogels, and how the presence of the different heterogeneities can be related to swelling and mechanical properties of such materials. The materials investigated were; polyacrylic acid neutralized with calcium hydroxide, polysodium acrylate superabsorbents with microfibrillated cellulose utilized as a filler and hydroxypropyl methylcellulose with heterogeneous distribution of the substituents.It was found that the presence of calcium ions during the synthesis of crosslinked polyacrylic acid introduces heterogeneities, both in network structure and in the form of phase separation, with dramatic impact on gel properties. Microfibrillated cellulose was found to even in small amounts cause significant changes to the swelling and shear modulus of crosslinked polysodium acrylate superabsorbents. The effect of the microfibrillated cellulose was similar as if an equivalent mass of covalent crosslinker had been used, but with improved resistance to fracture. For hydroxypropyl methylcellulose it was found that a heterogeneous distribution of the substituents causes increased interactions within the material, as determined from the glass transition temperature. Those increased interactions are coherent with earlier reports on solution behaviour for heterogeneously substituted hydroxypropyl methylcellulose.Hopefully the results presented in this thesis can contribute to the field of gel science, and in particular to the design of new multi-component soft materials.
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2.
  • Lundberg, Stina (författare)
  • Examining Female Resilience to Early Environmental Influences : Short- and long-term consequences on behaviour, HPA axis activity and alcohol intake after prolonged maternal separation
  • 2017
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Early-life experiences are an important factor influencing further development of the individual. Adverse experiences early in life, such as various kinds of abuse or neglect, are types of early-life stress that can adversely affect an individuals health, as well as contribute to the development of an array of disorders later in life. Most prominent is the increased risk for psychiatric disorders, primarily depression, anxiety-related and substance use disorders. Many of the implicated disorders also exhibit sex-dependent differences in prevalence and severity. Thus, it is important to consider sex-dependent effects when modeling early-life stress and its consequences. A common animal model for early-life stress is prolonged maternal separation (MS). MS is an umbrella term for different manipulations of the early environment of rodent pups. In this thesis, a prolonged MS condition with separation of rat litters from their dams for six hours per day during the first three weeks of life (MS360) was used. In male offspring MS360 have been associated with early-life stress and negative effects apparent during both adolescence and adulthood. The literature regarding female offspring is not as substantial as for the males, but it seems that females’ exhibit less pronounced or no effect after prolonged MS independent of separation time. In addition, the studies that have examined female offspring have done so in adulthood and thus, short-term consequences of prolonged MS possibly present during adolescence have not been investigated. The aim of this thesis is to provide a broad investigation into the consequences of prolonged MS in female offspring, in both adolescence and adulthood. As stated above, MS360 was used as the adverse rearing condition in this thesis. As control, daily short MS (15 min; MS15) was used; this ensured that all animals were handled equally, except for the length of separation. Any detected differences are thus due to the length of separation only. Three categories of assessments were used to evaluate short- and long-term consequences: 1) hypothalamus-pituitary-adrenal (HPA) axis assessments, 2) behavioral assessments and 3) assessment of voluntary alcohol consumption. HPA axis reactivity was assessed in adolescent and adult offspring by blood sampling before and after challenge. HPA activity was also evaluated after long-term alcohol consumption by measurement of the fecal corticosterone content. Behavior was assessed in adolescence by registration of social play behavior and in adulthood by generation of behavioral profiles in the multivariate concentric square fieldTM (MCSF). Alcohol consumption was evaluated using the modified intermittent alcohol access schedule with the two- (20% alcohol) and three- bottle (5% and 20% alcohol) free-choice paradigms. Female offspring did not differ depending on rearing condition in HPA reactivity in adolescence or adulthood. However, after the long-term alcohol intake, MS360 females had increased levels of corticosterone in their feces compared to MS15 females. No difference was detected in adolescent social play among female offspring and only a minor alteration was detected in the adult behavioral profile, where MS360 females had increased risk assessment compared to MS15 females. No effect of rearing condition was seen during the two-bottle choice paradigm of alcohol intake, while whole- group differences over time were discovered. Alcohol intake and preference were highest the first week of access and directly after a two-week deprivation period, apart from those time-points, intake and preference were maintained on a stable level. In the three-bottle choice, an interaction with rearing condition was revealed for the total alcohol preference, however this only translated to a minor group-dependent difference. In conclusion, females reared under a prolonged MS paradigm exhibited no or only minor basal changes in HPA axis reactivity, behavior and alcohol consumption. However, after long-term alcohol intake females subjected to prolonged MS had increased corticosterone excretion into feces. That differences only emerge after long-term perturbation can be a sign that females have higher buffering capabilities than males after early-life adversity, as modeled through prolonged MS, and thus require additional challenges before consequences become apparent. This thesis highlights the importance of considering sex when studying the impact of early-life stress, and that the choice of animal model needs to be considered carefully in relation to the research question posed.
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3.
  • Ersson, Lisa, 1985- (författare)
  • β-N-methylamino-L-alanine (BMAA)-induced neurotoxicity : Studies in vitro and in vivo
  • 2020
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • β-N-methylamino-L-alanine (BMAA) is a neurotoxic non-proteinogenic amino acid produced naturally by cyanobacteria, diatoms and dinoflagellates and it has been detected in samples from fresh and marine water from all over the world. It can bioaccumulate in fish and shellfish, and has a potential to biomagnify in a terrestrial food chain. BMAA was first discovered in the search for a neurotoxin related to the amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC) found among the Chamorro people in Guam. This non-proteinogenic amino acid has also been suggested to contribute to sporadic neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). BMAA can induce neurotoxicity via multiple mechanisms. It can act as an excitotoxin by activating glutamate receptors and to induce oxidative stress. It has also been suggested to be misincorporated into proteins leading to misfolded protein aggregates. Previous studies have demonstrated a specific damage in the hippocampus, including intracellular fibril formation, in adult rats following neonatal exposure to BMAA. In this thesis both in vitro and in vivo models were used to characterize the uptake, transport and effects of BMAA in cultured cell lines and in neonatal rodent brain tissue. The uptake of radiolabeled BMAA, as well as the effects of various amino acids and transporter antagonists on the uptake were studied in human mammary epithelial cells, intestinal epithelial cells, glioblastoma and neuroblastoma cells. Based on the obtained results a potential human mother-to-infant transfer of BMAA was suggested. BMAA-induced metabolic changes in a differentiated human neuroblastoma cell line were also characterized. The results revealed a plentitude of altered metabolites, many of them involved in amino acid metabolism and the TCA cycle. Of special interest were the perturbations in alanine, aspartate and glutamate metabolism as this pathway is involved in neurotransmission. The results revealed that BMAA can interfere with fundamental metabolic and neurotransmission pathways. Finally, the levels of free and protein-associated BMAA in the brain and peripheral tissues in neonatal rats exposed to BMAA were analysed. The results revealed high levels of free BMAA in some brain regions, thus demonstrating that the neonatal brain is not protected from BMAA by the blood-brain barrier. The results also revealed a protein-association of BMAA in the neonatal hypothalamus and hippocampus. Although the total amount of BMAA in the hippocampus was not high compared to other brain regions, the percentage of protein-associated BMAA was significantly higher. The results suggest that the protein-association of BMAA may play a role in the long-term effects in the hippocampus following neonatal exposure to BMAA. The studies in this thesis have demonstrated 1) a potential transfer of BMAA via breast milk to the brain of the nursing infant, 2) BMAA-induced metabolic alterations related to neurotransmission in human neuroblastoma cells and 3) that both free and protein-associated BMAA can be detected in the neonatal rat brain.
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4.
  • Andersson, Helene, 1983 (författare)
  • Mass Transport through Phase Separated Films - Effects of Ethyl Cellulose Molecular Weight on Cellulose Derivative Blends for Pharmaceutical Coatings
  • 2012
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Polymer blends are utilized for a variety of applications, not least in pharmaceutical coatings for controlled release of drugs. For instance, blends of ethyl cellulose (EC) and the water-soluble hydroxypropyl cellulose (HPC) can be used to coat drug pellets for oral extendedrelease formulations. Although EC and HPC can be co-dissolved in ethanol, they tend to phase separate during solvent evaporation in the coating process. If a substantial amount of HPC is present in the coating, pores form when the coating is subjected to water. The HPC-rich phase may then serve as a template for the pore geometries that transport the drug. Phase separated microstructures can have a variety of morphological features. However, polymer phase separation is a complex process and much is still left to be understood regardingthe underlying mechanisms that drive structure evolution. A range of physical and chemical parameters are known to affect phase separation, including the molecular weight (MW) of polymers. If the morphology of phase separated structures is affected by the MW, then drugrelease through a phase separated coating is likely to be affected as well. The major aims of this work were to study the effects of the MW of EC, on the mass transport and microstructure in films made of 70% EC and 30% HPC, and to understand the underlying mechanisms behind different release profiles from coated pharmaceutical pellets. A wide range of batches of EC were investigated, with weight average MWs from 19·10^3 to 68·10^3. Overall, the effects on solvent cast films, sprayed films and spray coated pellets were investigated. The MW showed substantial influence on the phase separated morphology, as well as effects on the pore structures in sprayed freestanding films. A decrease in mass transfer ratewith increasing MW of EC was found by permeability measurements on free films and drug release from coated pellets. The observed trend in permeability was mainly affected by the geometries of pores, while drug release was affected by both HPC-leakage and the film structure.As a result, it was concluded that the MW of EC affects the phase separated structure of EC/HPC-films, which has profound effects on diffusion mediated release from coated pellets.
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5.
  • Bender, Johanna, 1975 (författare)
  • ALA and m-ALA in bicontinuous lipid formulations: -Characterization and Transdermal Delivery
  • 2004
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • δ-Aminolevulinic acid (ALA) and its methyl ester (m-ALA) are both used in photodynamic therapy (PDT) of certain non melanoma skin cancers as the basal cell carcinoma (BCC). In PDT the cancer cells are destroyed by a photochemical reaction that occurs when a photosensitive molecule is irradiated with light of a certain wavelength. The topically delivered ALA or m-ALA is, through the heme biosynthesis, transformed into the photosensitizer and accumulated in the chosen area.In this thesis ALA and m-ALA (as hydrochloride salts) were incorporated in the monoolein/propylene glycol/water (MO/PG/water) sponge phase. The addition of up to 16% of the methyl ester made the samples more or less anisotropic dependent on the amount added. Isotropic liquids were reformed when water was added and the samples were characterized with nuclear magnetic resonance diffusometry (NMRD) and small angle X-ray scattering (SAXS) in order to confirm the reformation of the bicontinuous sponge phase. Highly obstructed self-diffusion coefficients were found for every component, which is a clear signal of the presence of a bicontinuous structure such as the sponge phase. Moreover, the diffusion coefficients of MO were evidently slower than for the other components indicating that the lipid by itself constitutes the structural skeleton, the bilayer of the phase. Small angle X-ray scattering confirmed the presence of the sponge phase by the presence of diffuse Bragg peak in the diffractograms. The passive and iontophoretic transdermal delivery from sponge phases with added ALA and m-ALA were also studied. The sponge phase might have an optimal composition of the three components revealed from iontophoresis with 0.25% (w/w) ALA. The resulting fluxes from the two techniques with sponge phases incorporated with 16% m-ALA were comparable to fluxes received from clinically used formulations in both cases. Therefore, the MO/PG/water sponge phase can be regarded as a potential drug delivery vehicle for both passive diffusion and iontophoresis.
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6.
  • Boge, Lukas, 1987 (författare)
  • Lipid-based liquid crystals as drug delivery vehicles for antimicrobial peptides
  • 2017
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The development of antimicrobial resistance is a great challenge within the health sector around the world. The demand for new efficient treatments is alarming in order to treat various bacterial infections in the near future. Antimicrobial peptides (AMPs) are a group of novel antibiotics that have gain more and more attraction the past decade. However, AMPs suffers from relatively low stability due to proteolytic and chemical degradation. As a consequence, carrier systems protecting the AMPs are highly needed for achieving efficient treatments. In this thesis, lyotropic liquid crystalline (LC) structures consisting of cubic glycerol monooleate/water and hexagonal glycerol monooleate/oleic acid/water have been examined as carriers for three AMPs (AP114, DPK-060 and LL-37). Both bulk gels and discrete dispersed structures, i.e. cubosomes and hexosomes have been studied. Moreover, two different peptide loading approaches for the cubosomes were tested and compared; pre- and post-loading. Characterization of the LC structures was performed using small-angle x-ray scattering (SAXS), dynamic light scattering, ζ-potential, and cryogenic transmission electron microscopy (Cryo-TEM) and peptide loading efficacy by liquid chromatography. The antimicrobial effect of the AMP loaded LC nanoparticles (LCNPs) was studied in vitro using minimum inhibitory concentration (MIC) and time-kill assays. Proteolytic protection was investigated by incubating the formulations with two elastases and the antimicrobial effect after proteolysis was studied using radial diffusion assay (RDA). Results showed that the most hydrophobic peptide (AP114) was prone to induce an increase in negative curvature of the bulk cubic LC gel, hence pushing the system towards a hexagonal structure. The most polar peptide (DPK-060) induced a decrease in negative curvature while LL-37 did not change the LC phase at all. The hexagonal LC phase was not affected by any of the AMPs. The cubic pre- and post-loaded LCNPs displayed promising antimicrobial activity, and sometimes could a synergetic effect be observed, resulting in a slightly better activity than the unformulated AMP. The hexagonal LCNPs were found to be very efficient in encapsulating the AMPs, but did not display any antimicrobial effect, indicating insufficient delivery of peptide to the bacteria. Moreover, cubosomes post-loaded with LL-37 was found to protect the peptide from proteolytic degradation, resulting in a significant better bactericidal effect after proteolysis.
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7.
  • Cardilin, Tim, 1989 (författare)
  • Data-driven modeling of combination therapy in oncology
  • 2016
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • This thesis contains two manuscripts: Tumor Static Concentration Curves in Combination Therapy and Extending the Tumor Static Concentration Curve to Exposure - A Combination Therapy Example with Radiation Therapy. There is also an introductory chapter presenting some basic facts necessary to understand the appended manuscripts. The manuscripts share the common goal of developing model-based data-driven tools and techniques to quantitatively assess the effectiveness of anticancer combinations. The first paper presents a dynamical systems model for combination therapy with the anticancer drugs cetuximab and cisplatin. Using a mixed-effects approach the model is shown to adequately describe a preclinical dataset. The model is then analyzed by introducing the Tumor Static Concentration (TSC) curve, a curve of cetuximab-cisplatin concentration pairs all of which, if maintained, result in tumor stasis. The TSC analysis reveals a modest gain from combining the compounds. The variability of the TSC curve across the population is also explored. In the second paper we develop a dynamical systems model for combination therapy with ionizing radiation and a test compound. For this combination we introduce an extension of the TSC curve called the (average) Tumor Static Exposure (TSE) curve based on average, as opposed to pointwise, tumor stasis. The TSE analysis for combinations of radiation and the test compound demonstrates a large synergistic effect.
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8.
  • Held, Felix, 1990 (författare)
  • Modelling of drug-effect on time-varying biomarkers
  • 2018
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Model-based quantification of drug effect is an efficient tool during pre-clinical and clinical phases of drug trials. Mathematical modelling can lead to improved understanding of the underlying biological mechanisms, help in finding shortcomings of experimental design and suggest improvements, or be an effective tool in simulation-based analyses. This thesis addresses the modelling of time-varying biomarkers both with and without drug-treatment. Pharmacokinetic/pharmacodynamic models were used to describe observed drug concentrations and biomarkers. These are modelled in the framework of compartmental modelling described by ordinary differential equations. This thesis contains two papers in manuscript-form. In the first paper, a metaanalysis was performed of an existing model and previously published data for the stress-hormone cortisol and the drug dexamethasone. Cortisol exhibits a circadian rhythm, resembling oscillations, and is therefore a time-varying target for treatment. The aim was to utilize the model for prediction of the outcome of a medical test used in veterinary treatments on horses. In addition to model parameters, inter-individual variability was modelled and estimated in a Bayesian framework. This allowed simulation of test outcomes for the whole population, which in turn were used to evaluate available test protocols and suggest improvements. In the second paper, an improved model was constructed for the cytokine TNFα after challenge with LPS in addition to intervention treatment. TNFα is not measurable in healthy subjects but release into blood plasma can be provoked by challenge with LPS. The result is a short-lived turnover of TNFα. A test compound targeting intervention of TNFα release was included in the study. Comprehensive experimental data from two studies was available and allowed to model features of TNFα release, that were not addressed in previously published models. The final model was then used to analyse the current experimental design and correlations between LPS challenge and test compound effectiveness. The paper provides suggestions for future experimental designs.
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10.
  • Zayny, Ahmad (författare)
  • Vitamin D metabolism in osteoblast-like cells : effects of drugs on inactivation by CYP24A1
  • 2018
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Vitamin D is essential for bone function, and deficiency in active vitamin D hormone can lead to bone disorders. Long-term treatment with glucocorticoids and antiretroviral drugs used to treat HIV infection, results in osteoporosis and increased risk of fractures. Much remains unclear regarding the effects of these compounds in bone cells. In the current study, human osteosarcoma Saos-2 cells and primary human osteoblasts were found to express mRNA for the vitamin D receptor as well as activating and deactivating enzymes in vitamin D3 metabolism. These bone cells exhibited CYP24A1-mediated 24-hydroxylation, involved in deactivation of the active vitamin form. However, bioactivating vitamin D3 hydroxylase activities were not detected in either of these cells, indicating that local vitamin D bioactivation is not significant in osteoblasts.Several glucocorticoids and antiretroviral drugs, including prednisolone, efavirenz and ritonavir, down regulated CYP24A1 mRNA expression. Prednisolone and ritonavir also down regulated CYP24A1-mediated 24-hydroxylase activity in both Saos-2 and primary human osteoblasts.Also, prednisolone significantly suppressed a human CYP24A1 promoter-luciferase reporter gene in Saos-2 cells co-transfected with the glucocorticoid receptor. Thus, the results of the present study show suppression by glucocorticoids on CYP24A1 mRNA, CYP24A1-mediated metabolism and CYP24A1 promoter activity in human osteoblast-like cells. Interestingly, ritonavir markedly potentiated the induction of CYP24A1 mRNA expression by 1,25-dihydroxyvitamin D3 suggesting that ritonavir may have different regulatory effects depending on the vitamin D3 metabolite levelsAs part of this study, we examined if glucocorticoids are formed locally in Saos-2 cells. The experiments indicate formation of 11-deoxycortisol, a steroid with glucocorticoid activity, which can bind the glucocorticoid receptor. Our findings showing effects of glucocorticoids and antiretroviral drugs on CYP24A1 expression in human osteoblasts indicate a previously unknown mechanism for effects of glucocorticoids and antiretroviral drugs in human bone, where effects of these drugs may lead to altered levels of active vitamin D3.
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