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Carstens, Bodil Børte (Mastergradsoppgave; Master thesis, 20-May-2009)[+][-]
Abstract: Iron homeostasis is regulated by the interaction between the hormone hepcidin and the iron exporter ferroportin. Hepcidin is a cysteine-rich peptide which is secreted by hepatocytes in response to inflammation, eryhropoietic demand and iron stores. Hepcidin binds to its receptor ferroportin, inducing its internalisation and degradation, thus regulating the export of iron from cells to plasma. One of the aims of this study was to determine the three-dimensional (3D) structure of hepcidin using nuclear magnetic resonance (NMR) spectroscopy. The structure calculated consisted of a β-sheet with a hairpin loop showing a flexible N-terminus. The overall aim of this study was to analyse the interaction between hepcidin and ferroportin. Recently, mutational analysis revealed that hepcidin binds to a 20 residue extracellular loop on ferroportin, called the hepcidin-binding domain (HBD). Techniques including NMR spectroscopy, isothermal titration calorimetry (ITC), circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR) spectroscopy were used. The results from all the assays performed indicate, however, that hepcidin does not bind to the HBD peptide. Three hepcidin analogues was synthesised to elucidate which residues in hepcidin that are important for the binding to ferroportin. The N-terminus of hepcidin is essential for binding to hepcidin and serial deletion of the N-terminal amino acids showed to cause progressive loss of activity when all five residues were deleted. Gly 20 was shown to have a key role in the interaction between hepcidin and ferroportin. This is the first mutation outside the N-terminus region that has activity. URI: http://hdl.handle.net/10037/2178 File(s) in this item: 1
thesis.pdf (1.391Mb) -
Christensen, Marit Bergheim (Master thesis; Mastergradsoppgave, May-2008)[+][-]
Abstract: Background Pharmaceutical care as a health care service has already made its mark and been shown to make an important contribution to the health care system. However, there is still a demand from the NHS among others, that pharmacist to a greater extent must document their provision of pharmaceutical care. Tested out in this project, is the application of a Care Issue Categorisation System. Aims To compare two clinical settings in terms of the profile of pharmaceutical care delivered and the profile of medication use. The findings will be reported in a way which allows quantitative comparison of pharmaceutical care issues addressed by the clinical pharmacy service in a proposed reporting, and a modified categorisation system will be use to accomplish this. Method A literature review were performed on pharmaceutical care, medicines management, common chronic diseases etc. Process maps were produced to describe the delivery of pharmaceutical care at the General Medical Ward at Glasgow Royal Infirmary. An existing categorisation system was modified and a guideline developed and both used for the analysis of documentation made by the pharmacists. Inter rater agreement on the categorisation system was tested and pharmaceutical activity was compared between two wards. Result The existing categorisation system was modified in several parts and tested by four investigators. Process maps and analysis of the care issues documented reveal that there was a inconsistency between the pharmacist’s provision of care and documentation. The comparison between two wards showed that the pharmacists had different priorities and documentation. Conclusion The modified categorisation system is tool that has the potential to aid future documentation of pharmaceutical provision of patient care. Comparison of pharmaceutical care activity between two ward showed that pharmacists are contribution to pharmaceutical care but that there are differences in their priorities and documentation of care issues URI: http://hdl.handle.net/10037/1573 File(s) in this item: 1
thesis.pdf (397.8Kb) -
Dahlheim, Anne-Helene (Master thesis; Mastergradsoppgave, May-2008)[+][-]
Abstract: ABSTRACT Epidemiologic studies have indicated that n-3 polyunsaturated fatty acids (PUFAs) supplementation may reduce the incidence of breast cancer, also in vivo and in vitro studies have shown that n-3 PUFAs have an inhibitory effect on breast cancer cells. One important n-3 PUFA are eiocosapentaenoic acid (EPA), which are metabolized to five regioisomeric epoxyeicosatetraenoic acids (epoxy-EPAs) by the cytochromes P450 system. Further, these epoxides are metabolized by epoxide hydrolase (EH), which can be inhibited by N, N`-dicyclohexylurea (DCU), an epoxide hydrolase inhibitor (EHI). The effect of these five epoxy-EPAs and the combination of epoxy-EPAs and EHI on breast cancer cells is not known. In this study the effect of 8, 9-epoxy-EPA on the human estrogen responsive breast cancer cell line MCF-7 was tested. MCF-7 cells were treated with 8, 9-epoxy-EPA, DCU and a combination of 8, 9-epoxy-EPA + DCU. Both the treatment with 8, 9-epoxy-EPA and the combination of 8, 9-epoxy-EPA + DCU inhibited the growth of MCF-7 cells in the presence of FBS. Treatment with 8, 9-epoxy-EPA in the absence of FBS did not result in a change in cell viability, which indicates that the growth inhibition on MCF-7 cells by 8, 9-epoxy-EPA requires an additional proliferative stimulus. To examine the effects of 8, 9-epoxy-EPA on MCF-7 cell growth flow cytometry was used to monitor cell cycle progression. Cells treated with 8, 9-epoxy-EPA and the combination of 8, 9-epoxy-EPA + DCU for 16 and 24 hours were found to be arrested in G0/G1-phase, and did not progress through the cell cycle at the same rate as control cells. 8, 9-epoxy-EPA treatment for 24 hours also resulted in a corresponding decrease in G2/M-phase. The adding of DCU did not enhance the effect of the 8, 9-epoxy-EPA treatment on cell cycle progression significantly. Treatment in the absence of FBS showed no alteration in the progression of the cell cycle. The growth inhibition effect on MCF-7 cells of 8, 9-epoxy-EPA was further studied by examining changes in expression of different cell cycle regulatory proteins. The protein levels were found to be unaltered after 8, 9-epoxy-EPA treatment. The growth inhibition effect may be due to increased cell apoptosis as an alternative to decreased proliferation in MCF-7 cells. This possibility should be evaluated in further studies. URI: http://hdl.handle.net/10037/1574 File(s) in this item: 1
thesis.pdf (2.001Mb) -
Domingues, Sara; Harms, Klaus; Fricke, W. Florian; Johnsen, Pål Jarle; da Silva, Gabriela J.; Nielsen, Kåre M. (Journal article; Tidsskriftartikkel; Peer reviewed, 2012)[+][-]
Abstract: We have investigated to what extent natural transformation acting on free DNA substrates can facilitate transfer of mobile elements including transposons, integrons and/or gene cassettes between bacterial species. Naturally transformable cells of Acinetobacter baylyi were exposed to DNA from integron-carrying strains of the genera Acinetobacter, Citrobacter, Enterobacter, Escherichia, Pseudomonas, and Salmonella to determine the nature and frequency of transfer. Exposure to the various DNA sources resulted in acquisition of antibiotic resistance traits as well as entire integrons and transposons, over a 24 h exposure period. DNA incorporation was not solely dependent on integrase functions or the genetic relatedness between species. DNA sequence analyses revealed that several mechanisms facilitated stable integration in the recipient genome depending on the nature of the donor DNA; homologous or heterologous recombination and various types of transposition (Tn21-like and IS26-like). Both donor strains and transformed isolates were extensively characterized by antimicrobial susceptibility testing, integron- and cassette-specific PCRs, DNA sequencing, pulsed field gel electrophoreses (PFGE), Southern blot hybridizations, and by re-transformation assays. Two transformant strains were also genome-sequenced. Our data demonstrate that natural transformation facilitates interspecies transfer of genetic elements, suggesting that the transient presence of DNA in the cytoplasm may be sufficient for genomic integration to occur. Our study provides a plausible explanation for why sequence-conserved transposons, IS elements and integrons can be found disseminated among bacterial species. Moreover, natural transformation of integron harboring populations of competent bacteria revealed that interspecies exchange of gene cassettes can be highly efficient, and independent on genetic relatedness between donor and recipient. In conclusion, natural transformation provides a much broader capacity for horizontal acquisitions of genetic elements and hence, resistance traits from divergent species than previously assumed. URI: http://hdl.handle.net/10037/4919 File(s) in this item: 1
article.pdf (530.2Kb) -
Do, Minh-Anh Thuy (Master thesis; Mastergradsoppgave, 19-May-2012)[+][-]
Abstract: In the last decade, the investigation of marine natural products has resulted in a remarkable number of compounds with promising biological activities. Marine natural products have been shown to display antibacterial, antifungal, anticancer, antiviral, antiparasitic, anti-inflammatory activity and several other pharmacological activities of benefit to humankind. In this project, an investigation of the anti-inflammatory and immunostimulatory activities of extracts from two Arctic marine invertebrate species; a bryozoan, Eucratea loricata, and a sea urchin, Echinus esculentus, is presented. Anti-inflammatory activity was analyzed by using the monocyte/macrophage cell lines: THP-1 (accurate monocytic leukemia) and U937 (leukemic monocyte lymphoma). Immunostimulatory activity was analyzed by using THP-1 cell line. Effects on cell culture were monitored as reduced NFκB reporter activity in transfected cell line, and as reduced or increased production of the cytokines TNF-α and IL-1β. Bioassay-guided fractionation of the extracts revealed the presence of anti-inflammatory activity in the Echinus esculentus extracts. The structure of the target compound was partly elucidated using high resolution mass spectrometry, mass spectrometric fragmentation, and nuclear magnetic resonance spectroscopy. In addition, this present project provides background information about natural product research and current anti-inflammatory investigations of marine invertebrate species. URI: http://hdl.handle.net/10037/4323 File(s) in this item: 1
thesis.pdf (2.884Mb) -
Dyrhaug, Sara Ann (Master thesis; Mastergradsoppgave, 20-May-2011)[+][-]
Abstract: Abstract Background– All solid organ transplanted patients are treated with immuno suppression medications to keep the immune system from rejecting the transplanted organ. Unfortunately the suppressed immune system makes the body more exposed for cancer and opportunistic infections. Among the most important viruses that causes one of these opportunistic infections is cytomegalovirus (CMV). A local project showed that not all transplanted patients on CMV prophylaxis get the right dose according to creatinine clearance (CrCl), and that the patients who had not been prescribed the recommended dose according to CrCl had a higher incident of CMV disease than those adjusted as recommended. The Quality improvement team for the transplant unit therefore suggested that a project could further investigate these issues. Aim and objectives – The aim of this project was to critically review and evaluate the processes in the prescribing and administration of valganciclovir for cytomegalovirus prophylaxis in liver, kidney or pancreas transplantation. Methods – Semi-structured one-to-one interviews with 2 nurses and 6 prescribers were conducted to establish current practice in prescribing, administration and monitoring of valganciclovir. A review of the local protocols at the transplant unit was conducted. To assess the harm a database analysis on the incident reporting system and a retrospective review of clinical records of 4 patients was undertaken. A questionnaire was developed for staff to self-assess the risk of harm of the whole process of CMV prophylaxis treatment. Pharmaceutical care issues relevant to CMV prophylaxis were recorded prospectively by clinical pharmacists over a two month period. Results – The semi-structured interviews with prescribers indicated that: 1) Prescribers often fail to recognise that the valganciclovir dose should be adjusted with changing CrCl. 2) That the laboratory test results taken at the clinic do not come back until the evening and are therefore not available at the time of prescribing, 3) There are gaps of knowledge, especially in the junior doctors. Reviews of local protocols suggested a need for update of the protocols and inclusion of detailed dosing guidance. The one incident reported in the database in terms of valganciclovir involved a missed dose. Case note reviews of four patients identified that dose adjustments are appropriate in 2 cases, 1 case was borderline and the other was a complex case but was judged to be appropriate. The questionnaire identified that there was agreement among healthcare professionals that there is a risk of errors that might lead to harm associated with all stages of valganciclovir use. Two clinical pharmacists recommended adjustment of valganciclovir 12 times in 7 patients in a time period of approximately two months. Conclusion – the outcomes from the interviews and pharmaceutical care issues analysis confirm the previous observation that the dose of valganciclovir is not always adjusted according to CrCl. Recommendations for improvement are to ensure modified guidelines are implemented to ensure all prescribers are aware of need for dose adjustment. Further work can be undertaken to measure the benefit after implement of the recommendations to assess improvement. URI: http://hdl.handle.net/10037/3420 File(s) in this item: 1
thesis.pdf (2.545Mb) -
Elvheim, Iselin Sørstad (Master thesis; Mastergradsoppgave, Jun-2011)[+][-]
Abstract: The relaxin family of peptides consists of seven structurally related peptides, with a wide variety of biological functions, ranging from involvement in reproductive processes to functions as neuroendocrine modulators. Because of the complex, two-chained structure of the relaxins, and their lack of specificity for the various relaxin family receptors (RXFPs), design of simpler, more selective analogues is important for further investigation of their biological functions and as potential drug leads. The aim of this project was to introduce a helical structure around the receptor-binding region of single-chain relaxin analogues. This was approached by utilising helix capping sequences on truncated relaxin B-chains and by grafting of residues important for binding onto a stable peptide scaffold. Helix capping enhanced the helical properties compared to previous single- chain analogues, but was unable to introduce a sufficiently stable helix. Despite the increased helical tendencies, no high-affinity analogues were found. As a result, the importance of Arg8 was investigated, and we have demonstrated that this residue might be more involved in binding than previously thought. We successfully synthesised a relaxin-3/chlorotoxin analogue, which appeared to fold correctly. However, the yield following oxidation was poor, and no bioactivity data or structural data confirming the correct fold was obtained within the time limits of the project. A secondary aim was to probe for favourable mutations around the receptor- binding region by synthesising a combinational library. We were able to successfully synthesise a library of peptides with mutations in one position by inserting a mixture of amino acids at this coupling step in the solid phase peptide synthesis (SPPS) procedure. Although no significant improvement in binding was seen for the analogues generated, important methodological advances were made that will be used to scan different positions for new contact points with the receptor. URI: http://hdl.handle.net/10037/3428 File(s) in this item: 1
thesis.pdf (11.68Mb) -
Engeland, Anders; Bjørge, Tone; Daltveit, Anne Kjersti; Skurtveit, Svetlana; Vangen, Siri; Vollset, Stein Emil; Furu, Kari (Journal article; Tidsskriftartikkel; Peer reviewed, 2011)[+][-]
Abstract: This study aimed to use a population-based Prescription Database to explore later development of diabetes in women registered with gestational diabetes mellitus (GDM) and/or preeclampsia in the Medical Birth Registry of Norway (MBRN) during 2004–8. We used two nationwide Norwegian registries, the Norwegian Prescription Database and the MBRN, to explore the onset of later diabetes after pregnancy complications, indicated by receiving prescriptions of drugs used to treat diabetes, in 230,000 women giving birth in 2004–8. The mean follow-up of the study cohort was 3.7 years. Five years after pregnancy, about 19 and 2% of women with GDM and preeclampsia, respectively, received drugs used to treat diabetes, compared to 0.5% of those without these complications. The risk of being dispensed drugs used to treat diabetes within the first years after pregnancy was estimated to be 41 times (95% CI: 35–47) and 3.0 times (95% CI: 2.4–3.6) higher in women with GDM and preeclampsia, respectively, compared to women without these pregnancy complications. Women with pregnancies complicated with preeclampsia or GDM had an increased risk of later diabetes, especially those having GDM. If the increase in frequency of GDM observed inMBRN in recent years is real, a further increase in diabetic women can be expected. URI: http://hdl.handle.net/10037/3901 File(s) in this item: 1
article.pdf (240.9Kb) -
Engesland, André (Master thesis; Mastergradsoppgave, 20-May-2010)[+][-]
Abstract: Hydrogels made of chitosan has a well-established place in drug delivery for the skin. Our particular interest were hydrogels for wound healing. Hydrogels from low, medium and high molecular weight were prepared in different concentrations for texture and release characterization incorporating liposomes and chloramphenicol as a model drug. A method for comparing viscosity between gels was established with a Texture analyser and back-extrusion method. The method proved to be able to distinguish differences between gels with standard deviations varying with less than 2%. Different liposomal chitosan hydrogels were prepared with or release studies with the model drug chloramphenicol. The release study proved that liposomal hydrogels could act as vehicles for antibiotics in depot formulations. Chitosan preparations were also tested under both accelerated stability testing and freeze-thaw test. Stability was improved with glycerine in the hydrogels. Stability seemed to be dependant on molecular weight and concentration of chitosan. The low molecular weight chitosan gels were the least stable, and higher concentrations can give more stable gels. URI: http://hdl.handle.net/10037/2750 File(s) in this item: 1
thesis.pdf (2.452Mb) -
Engesæter, Birgit Øvstebø; Engebråten, Olav; Flørenes, Vivi Ann; Mælandsmo, Gunhild (Journal article; Tidsskriftartikkel; Peer reviewed, 2012)[+][-]
Abstract: Mapatumumab and lexatumumab (targeting death receptor 4 (DR4) and 5 (DR5), respectively) are agonistic TRAIL receptor antibodies that induce apoptosis in a wide range of cancer cells. The potency of mapatumumab and lexatumumab was assessed in mono therapy protocols, and the ability to sensitize for dacarbazine (DTIC) treatment was explored in ten different melanoma cell lines. Our data indicated that melanoma cell lines tend to be resistant to mapatumumab, most likely due to low expression of DR4, while a dose dependent response to lexatumumab was observed. Combining DTIC and lexatumumab induced an additive or synergistic effect on cell death in the various melanoma cell lines. The synergistic effect observed in the FEMX-1 cell line was related to enhanced cleavage of Bid in parallel with elevated expression of the pro-apoptotic proteins Bim, Bax and Bak. Furthermore, the anti-apoptotic proteins Bcl-XL, cIAP-1, XIAP and livin were down regulated. Cleavage of Bid and down regulation of cIAP-2 and livin were observed in vivo. Altogether, these data suggest a change in the balance between pro- and anti-apoptotic proteins favoring induction of apoptosis. In the more therapy resistant cell line, HHMS, no changes in the pro- and anti-apoptotic proteins were observed. FEMX-1 xenografts treated with DTIC and lexatumumab showed reduced growth and increased level of apoptosis compared to the control groups, providing arguments for further evaluation of this combination in melanoma patients. URI: http://hdl.handle.net/10037/4920 File(s) in this item: 1
article.pdf (1.861Mb) -
Erdal, Hilde (Master thesis; Mastergradsoppgave, May-2008)[+][-]
Abstract: Innledning: Apotekloven slår fast at legemidler skal utleveres nøyaktig etter resept og rekvisisjon. Studier viser imidlertid at feil og mangler forekommer ved 2,0 % av reseptene som blir levert inn ved vanlige apotek i Norge, og forskrivningsavvik forekommer ved 8,5 % av ordinasjonene på resepter utskrevet av leger ved Haukeland Universitetssykehus. Forskrivningsavvik kan medføre fare for klinisk signifikante effekter på pasientens legemiddelbehandling og uønskede legemiddelhendelser. Hensikten med studien var å undersøke hvor stor andel av forskrivningsavvikene som hadde en klinisk relevans for pasientens legemiddelbehandling, og hvor alvorlig den kliniske relevansen var. Metode: Det ble i en studie fra 2007 registrert 867 forskrivningsavvik ved Haukeland Sykehusapotek, Vitusapotek Nordstjernen Bergen og Tønsberg Sykehusapotek. Et ekspertpanel med åtte deltakere, hvorav fire farmasøyter og fire leger, klassifiserte 119 potensielt klinisk relevante avvik i henhold til en modifisert versjon av Safety Assessment Code (SAC)-score med fire kategorier av klinisk relevans. Klassifiseringen ble gjennomført individuelt. Inter-rater reliabilitet ble vurdert i forhold til grad av enighet beregnet ved kappa-statistikk. Resultater: Ekspertpanelet viste svært lav enighet, κ=0,115-0,093, noe som henspeiler lav inter-rater reliabilitet. Dette må tas hensyn til ved tolkning av resultatene. Det er tendenser til at ekspertpanelet vurderte interaksjoner og avvik i forbindelse med dosering, samt legemidler i ATC-gruppe N 02 Analgetika, som mest klinisk relevant. Forskrivningsavvik men klinisk relevans forekom ved 1,29 % av resepter skrevet ut av sykehusleger, og ved 0,33 % av resepter skrevet ut av leger utenfor sykehus. Konklusjon: Klinisk relevante forskrivningsavvik forekommer hyppgere ved resepter skrevet ut av sykehusleger enn resepter utskrevet av leger utenfor sykehus. Metoden som ble benyttet for klassifisering av klinisk relevans av forskrivningsavvik hadde ikke tilfredsstillende reliabilitet og validitet. URI: http://hdl.handle.net/10037/1575 File(s) in this item: 1
thesis.pdf (1.287Mb) -
En legemiddeløkonomisk analyse av acetylsalisylsyre som primærprofylakse mot hjerte- og karsykdommerEriksen, Heidi-Mirelle (Master thesis; Mastergradsoppgave, May-2009)[+][-]
Abstract: Verdens helseorganisasjon (WHO) anbefaler primærforebyggende behandling med acetylsalisylsyre (ASA) hos pasienter med forhøyet risiko for utvikling av hjerte- og karsykdom. Per i dag ytes det ikke generell refusjon til forebyggende behandling med lavdosert ASA. Det var behov for å kartlegge hvorvidt primærforebygging av kardiovaskulære sykdommer med ASA viste seg å være en god utnyttelse av samfunnets begrensede ressurser. Hensikten med oppgaven var å belyse hvorvidt Albyl-E® oppfylte de faglige kriteriene for refusjon ved primærforebygging av hjerte- og karsykdommer. For å belyse det fjerde faglige kriteriet i Legemiddelforskriftens § 14-13, ble det utført tre legemiddeløkonomiske analyser. Den overordnede konklusjonen fra denne oppgaven er at ASA er et refusjonsverdig behandlingsalternativ for primærforebyggende behandling av pasienter med forhøyet risiko for hjerte- og karsykdommer. URI: http://hdl.handle.net/10037/2214 File(s) in this item: 1
thesis.pdf (2.005Mb) -
Eriksen, Sureeporn Aemsangthum (Master thesis; Mastergradsoppgave, 20-May-2012)[+][-]
Abstract: Nasjonalt råd for ernæring anbefaler å spise fisk og sjømat fordi de innholder de flerumettede omega-3 fettsyrene eikosapentaensyre (EPA: 20:5n-3) og dokosahekaensyre (DHA: 22: 6n-3). Mye forskning viser kobling mellom omega-3 fettsyrene og helsegevinster. Helsegevinstene er at disse fettsyrene er betennelsesdempende, de reduserer risiko for å utvikle sykdommer som revmatoid artritt, hjerte -kar sykdommer, psoriasis, og de virker hemmende på utvikling av enkelte mentale lidelser og de reduserer tilfeller prostatakreft. Omega-3 fettsyrer er nødvendig for normal utvikling av fosteret under svangerskapet og er også spesielt viktig for normal nevrologisk utvikling. Mange av verdens kostholdsorganisasjoner anbefaler at man spiser fisk 1-2 ganger i uken eller får i seg 0,2-0,5 g EPA og DHA. Alternative kilder til EPA og DHA er helsekostprodukter. EPA og DHA i produktene bør være av god kvalitet og i riktig mengde for å dekke kroppens behov. Det er derfor viktig at produktdeklarasjon samsvarer med innholdet i produktene. Målet med min oppgave var å undersøke fettklassesammensetningen av Omega-3 produktene; Lofot tran, Trippel Omega-3, Nordic Light krill & fiskeolje, Omega-3 med krillolje (blanding av krill og fiskeolje) og Complete Krillolje (krillolje). I et av blandings produktene av krill & fiskeolje (Nordic Light krill & fiskeolje) ble fettsyresammensetningen undersøkt i noen av fettklassene i produktet. Tilslutt ble det målt frie fettsyrer av de to krill & fiskeoljeproduktene i 2 perioder for å se stabilitet ved lagring. Resultatene viste at Lofot tran inneholdt triacylglyserider; Trippel Omega-3 innehold metyl- og etylestere; Nordic Light krill & fiskeolje innholdt polare lipider, kolesterol, diacylglyserider, frie fettsyrer og triacylglyserider; Omega-3 med krillolje (blanding av krill og fiskeolje) inneholdt triacylglyserider, metyl og etylester. Det siste produktet som ble undersøkt var Complete Krilloljeproduktet som inneholdt tilsvarende fettklasser som Nordic light krill & fiskeolje, men med mer polare lipider og frie fettsyrer. Ved undersøkelse av fettsyresammensetningen i Nordic Light krill & fiskeolje, viste denne et innhold av omega-3 (n-3) 63.9 %, omega-6 (n-6) 3.2 %, og langkjedede flerumettede omega-3 (Lc n-3) 63,2 %. EPA var 31,8 % og DHA 26 %. Ved lagring av Krill & fiske olje produktene i romtemperatur i ca 2 måneder vistes en viss forskjell i verdiene av de frie fettsyrene, men ikke noe som kan karakteriseres som dramatisk økning. URI: http://hdl.handle.net/10037/4325 File(s) in this item: 1
thesis.pdf (1.382Mb) -
Eriksen, Øystein (Master thesis; Mastergradsoppgave, 16-Jun-2008)[+][-]
Abstract: CXCR4 is a GPCR that by activation of its ligand CXCL12 is involved in the pathology of several diseases, examples being cancer and rheumatoid arthritis. It has also shown to play a crucial role for HIV-1 entry into T-cells and the development of AIDS. Several cyclopentapeptides (CPPs) based on the sequence D-Tyr-Arg-Arg-2-Nal-Gly of the lead compound FC131 have shown to have antagonistic activity. These CCPs are therefore targets for drug research. In this thesis a previously published 3-point pharmacophore for these CCPs is reproduced and a new 4-point pharmacophore is presented. Structural similarities of low-energy conformations of CPPs that fit these pharmacophores have been identified. A set of new conformational stabilized CPPs based on these findings have been designed and synthesized. A set of citrulline based analogs of FC131 have been synthesized as they will serve as probes to determine the nature of the Arg residues interaction with CXCR4 URI: http://hdl.handle.net/10037/1580 File(s) in this item: 1
thesis.pdf (2.189Mb) -
Evjen, Tove Julie; Nilssen, Esben A.; Barnert, Sabine; Schubert, Rolf; Brandl, Martin; Fossheim, Sigrid L (Journal article; Tidsskriftartikkel; Peer reviewed, 2011)[+][-]
Abstract: Novel sonosensitive doxorubicin-containing liposomes comprising dioleoylphosphatidylethanolamine (DOPE) as the main lipid constituent were developed and characterized in terms of ultrasound-mediated drug release in vitro. The liposome formulation showed high sonosensitivity; where approximately 95% doxorubicin was released from liposomes after 6 min of 40 kHz US exposure in buffered sucrose solution. This represented a 30% increase in release extent in absolute terms compared to liposomes comprising the saturated lipid analogue distearoylphosphatidylethanolamine (DSPE), and a 9-fold improvement in release extent when compared to standard pegylated liposomal doxorubicin, respectively. Ultrasound release experiments in the presence of serum showed a significantly reduction in sonosensitivity of DSPE-based liposomes, whilst the release properties of DOPE-based liposomes were essentially maintained. Dynamic light scattering measurements and cryo-transmission electron microscopy of DOPE-based liposomes after ultrasound treatment indicated liposome disruption and formation of various lipid structures, corroborating the high release extent. The results point to the potential of DOPE-based liposomes as a new class of drug carriers for ultrasound-mediated drug delivery. Description: This article is part of Tove Julie Evjen's doctoral thesis. Available in Munin at http://hdl.handle.net/10037/3373 URI: http://hdl.handle.net/10037/4485 File(s) in this item: 1
article.pdf (395.3Kb) -
Evjen, Tove Julie; Brandl, Martin (Journal article; Tidsskriftartikkel; Peer reviewed, 2011)[+][-]
Abstract: Ultrasound sensitive (sonosensitive liposomes) are drug delivery systems designed for releasing their drug load upon exposure to ultrasound (US). Inclusion of dioleoylphosphatidylethanolamine (DOPE) in liposome membranes was previously shown to induce sonosensitivity. For efficient US mediated drug delivery to solid tumours, a long blood circulation time of the liposomal drug providing high tumour uptake is required. In this study, blood pharmacokinetics of DOPE-based liposomal doxorubicin (DXR) were evaluated in mice. A markedly faster blood clearance of DXR was observed for DOPE-rich liposomes compared to Caelyx! (standard liposomal DXR). Subsequently, liposome membrane composition was altered to improve drug retention in the bloodstream, while maintaining sonosensitivity. Formulations with reduced blood clearance of DXR were obtained by reducing the content of DOPE from 62 to 32 or 25 mol%. These formulations showed long blood circulation time, as approximately 20% of the administered DXR dose was present in the bloodstream 24 h after intravenous injection. The reduction in liposomal DOPE content did not significantly reduce US mediated DXR release in vitro, indicating that DOPE is a potent modulator to sonosensitivity. The novel liposome formulations, containing moderate amounts of DOPE, displayed similar blood pharmacokinetic profiles as standard liposomal DXR, but a markedly improved sonosensitivity. Description: This article is part of Tove Julie Evjen's doctoral thesis, which is available in Munin at http://hdl.handle.net/10037/3373 URI: http://hdl.handle.net/10037/3756 File(s) in this item: 1
article.pdf (1.353Mb) -
Evjen, Tove Julie (Master thesis; Mastergradsoppgave, May-2007)[+][-]
Abstract: Bendamustin is an alkylating anticancer agent which is currently in routine use for the treatment of different types of cancer. The drug is very unstable in serum due to hydrolysis; the half life of the first part of the serum elimination curve is about 6-10 minutes. The rapid degradation of the drug in serum impairs its cytostatic action within a short period of time, and frequent application of relatively high doses is required. This, in turn, leads to dose-limiting systemic toxicity. Incorporation of bendamustin into liposomes might be a promising way to prolong its half life in plasma, and thus improve the efficiency and toxicity profile of the drug. Up to now only a few attempts to incorporate bendamustin into liposomes are found in literature. However, none of these have been successful and reached clinical practice. Recently, a new technique for liposome preparation, dual asymmetric centrifugation (DAC), has been suggested which is suitable for making liposomes immidiatly prior to application (bed-side preparation). In a previous study a protocol for liposomes made of phosphatidyl choline and cholesterol was developed and used for direct entrapment of bendamustin. However, the formulation turned out to be unstable in terms of rapid efflux of bendamustin out of the liposomes. In this study, a new liposomal formulation of bendamustin was developed using the DAC. The intention was to improve the stability of the liposome formulation by obtaining a reduced leakage of drug. Liposome release of incorporated drug was investigated by incubation of liposomes under physiological conditions; 37 °C, with further assay of the samples with respect to loss of incorporated drug over time. For this, cation-exchange chromatography and RP-HPLC was used. It turned out that bendamustin in its zwitterionic form tended to diffuse through the lipid-membrane more readily than both the cationic and anionic forms. In order to reduce the amount of zwitterionic molecules, and hence efflux, a buffered system with a pH of 2.0 in the liposome interior was chosen. Compared to the previous formulation, the new formulation showed an increase in encapsulation efficiency as well as a slower efflux of drug when incubated in phosphate buffered saline pH 7.4 at 37 ºC; EE= 61% ± 2 as compared to 44 % ± 3 and t1/2= 3 h as compared to 1.5 h. Stability of the new formulation was assayed with respect to intact bendamustin as well as lipid at 23 °C over 24 hours. For this RP-HPLC and HPTLC were used, respectively. The results showed that the formulation is stable enough to be used within the same day as a bed-side preparation. Furthermore, stability of the new bendamustin-liposomes was compared to the free drug in cell culture medium at 37 ºC. Unfortunately, the bendamustin-liposomes showed a minor improvement in stability as compared to the free bendamustin only; the half life was prolonged to 20 minutes for the liposomes (14 minutes for the solution). Finally, an attempt of active loading of bendamustin was performed by the means of a pH gradient between the liposome interior and exterior. An EE of 14 % was observed. Further optimization of the protocol will be needed to render active loading an attractive alternative. URI: http://hdl.handle.net/10037/1177 File(s) in this item: 1
thesis.pdf (680.4Kb) -
Fazelpour, Maryam (Master thesis; Mastergradsoppgave, 06-Jun-2008)[+][-]
Abstract: Natural transformation is recognaized as a major horizontal gene transfer mecahnism which impacts the genetic adaptaion , diversity and evolution of prokaryotes. Natural ransformation is uptake of extracellular DNA and its integration in a host genome. The fact that species take up foregin nucleotide sequences is believed to be followed by elimination of non-adventageous DNA sequence since bacterial genome do not grow in size.Transfer of gene from one species into the gene pool of another by backcrossing of hybid transformants with one parents is defined as intrgression. In this study the hypothesis that bacteria during introgrssion might regulate aquisition of foreign DNA by non-selected sequence by recombination was examined. The thesis contribute to earlier (Ray 2007)and ongoing projects investigating the fate of non-selected DNA during introgression of a choromsomal antibiotic resistance gene (nptII) in the bacterium A. baylyi. Hybrid transormants f A.baylyi ADP17021 contained a kanamycin resistance gene ande a mutS-gene deletion and an undeteramined amount of the donor strain A.sp.62A1. In this study DNA sequencing technologies and the Acinetobacter baylyi BD413 (ADP1) published geneome sequence was used to achive important results as identifying putative recombination junctions in ten back-transformants among the 10th and first generation and the effect of methyl-directet mismatch repair (mutS-deletion) on flanking DNA aquired by the recipient. The generation of the initial heterogamic transformation and ten subsequent backcross transformants were performed in a previous study (Ray, 2007). The aim of this study was identifying recombination junctins and the insert size of flanking DNA. It was clear that back-cross transformants harboured a significantly shorter donor sequence when compared to the initial genration. This indicates that during introgression, the non selected sequence will be gradually eliminated. URI: http://hdl.handle.net/10037/1569 File(s) in this item: 1
thesis.pdf (1.524Mb) -
Forsberg, Kristian Lund (Master thesis; Mastergradsoppgave, Jun-2009)[+][-]
Abstract: Til påvisning av selektive serotonin reopptakshemmere (SSRI) i sjøvann har det tidligere blitt benyttet ulike teknikker; væske-væske mikroekstraksjon (LPME) og tradisjonell fast faseekstraksjon (SPE). Disse metodene har vært begrenset av henholdsvis prøvevolum og tidkrevende ekstraksjon. Det har derfor vært et mål å utvikle en SPE-metode som er rask og effektiv, og som samtidig ved hjelp av store prøvevolum kan senke deteksjons- og kvantifikasjonsgrensene. Polymersorbentene XAD 2 og XAD 7HP har i et tradisjonelt SPE-oppsett blitt benyttet til å ekstrahere sjøvannsprøver med volum på 10 l. Prøvene ble analysert ved hjelp av UPLC-MS/MS. Innledende tester viste at XAD 7HP ga bedre gjenvinning enn XAD 2 og at begge sorbentene hadde gode fysiske egenskaper som tillot hurtig ekstraksjon av store prøvevolum. Ved oppskalering av sorbentmengde og prøvevolum kunne imidlertid ikke gode kromatografiresultater oppnås, og det ble konkludert med at dette mest trolig ble forårsaket av forurensninger fra sorbenten. Innenfor gitte tidsrammer har det derfor ikke vært mulig å utvikle en fungerende metode, og videre utvikling vil være nødvendig. Forutsatt utvikling av en effektiv metode for rensing av sorbentmaterialet vil metoden kunne være brukbar for både sure, nøytrale og basiske forbindelser fra sjøvann. URI: http://hdl.handle.net/10037/2213 File(s) in this item: 1
thesis.pdf (5.825Mb) -
Gjerde, Anne Marie (Master thesis; Mastergradsoppgave, 06-Jun-2008)[+][-]
Abstract: Masteroppgaven er en del av prosjektet ” Legemiddelgjennomgang ved utskriving fra St. Olavs hospital til sykehjem i Trondheim kommune”. Som har som mål å vinne praktisk kunnskap om og erfaring med en integrert intervensjon for legemiddelgjennomgang, overføring av legemiddelinformasjon og opplæring i legemiddelbruk for eldre pasienter som skrives ut fra St. Olavs hospital til sykehjem i Trondheim kommune. Formålet med masteroppgaven var å utarbeide en mal for pasientsamtalen, gjennomføre pasientsamtaler i rehabiliteringsinstitusjon og i hjemmet, og evaluere effekten av gitt legemiddelinformasjon på pasientens kunnskap om egen legemiddelbruk. Hensikten med pasientsamtalen er å oppnå at pasientene bruker legemidlene sine riktig når han/hun kommer tilbake i hjemmebasert omsorg. Resultatene fra denne studien tyder på at samtlige av pasientene kunne hatt behov for mer informasjon, og at flere av pasientene ønsket mer informasjon. Intervju med pasienter, pasientsamtaler og hjemmebesøk ser ut til å være nyttige tiltak, for å nå målet om riktig legemiddelbruk. URI: http://hdl.handle.net/10037/1647 File(s) in this item: 1
thesis.pdf (616.5Kb)
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