Institutt for farmasi
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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 Evjens doctoral thesis. 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) -
Berg, Ole Aleksander (Master thesis; Mastergradsoppgave, 20-May-2011)[+][-]
Abstract: Trauma to the skin in the form of severe wound, particularly burns, can facilitate colonization of potentially life threatening bacterial infections. To prevent infections of the wounded area, antimicrobial agents are recommended as standard treatment. Topical administration of antimicrobial agents, such as mupirocin, can provide local therapy, while avoiding the risks of systemic administration. Mupirocin-in-liposomes-in hydrogels were proposed as advanced delivery system for this purpose. Up to now, no liposomal mupirocin for topical administration has been reported. Chitosan was selected as hydrogel matrix due to its biodegradability and in-built antimicrobial and wound healing potentials. Phosphatidylcholine liposomes containing mupirocin, namely non-sonicated and sonicated liposomes, were characterized for vesicle size and size distributions. Non-sonicated vesicles entrapped in average 74 and sonicated 49 % of mupirocin calcium, respectively. Sonication reduced the original vesicle size from around 1 micron down to 135 nm. Liposomes (10 %, w/w) were incorporated in chitosan hydrogels and liposomal hydrogels evaluated for their textural properties. Hydrogels were found to exhibit satisfactory adhesiveness and cohesiveness, with corresponding stability profile. Microbiological assessment confirmed antibacterial properties of liposomally entrapped mupirocin incorporated in hydrogels. In vitro and ex vivo (on pig skin) drug release profiles of various formulations containing mupirocin were performed on Franz diffusion cells. Liposomal hydrogels were compared with marketed mupirocin product, Bactroban® cream. The release studies showed that liposomal size affects the release of the incorporated drug. Liposomal hydrogels were shown to provide sustained release of incorporated mupirocin. In conclusion, liposomal hydrogels developed for mupirocin offer the potential to increase retention time and provide sustained release of a drug, which are important parameters for improved treatment of wounds, including burns. URI: http://hdl.handle.net/10037/3689 File(s) in this item: 1
thesis.pdf (71.30Mb) -
Andersen, Toril (Master thesis; Mastergradsoppgave, 16-Jun-2010)[+][-]
Abstract: Calanus finmarchicus is a vast resource that until recently have been exploited to a minimal degree only. In the last few years harvesting and processing methods have been developed. There is a large market and great interest in products derived from marine oils. Most of the products today are derived from organisms at a high trophic level, i.e. products derived from cod liver oil. One disadvantage with these products is high levels of fat-soluble pollutants that require extensive purification before the products can be released to the market. As C. finmarchicus exists on the first trophic levels it is not polluted and is therefore very interesting as a substitution for cod liver oil, which is the main source for ω-3 fatty acids. In addition to this studies have shown that the oil extracted from the animal, Calanus oil, have beneficial properties and can reduce the risk for coronary heart disease, cancer and inflammation and this could be attributed to the contents of wax esters, high levels of a natural antioxidant, Astaxantine, and high levels of phytosterols. The aim of this thesis was to isolate and characterize the wax esters of the oil, and elucidate their structure. The wax esters were first separated from the Calanus oil with silica SPE and then transesterified to FAME and FAL. The two structures types were separated into two fractions with APS SPE. The FAME were analyzed as their picolinyl esters in GC-MS for structure elucidation and the FAL as their nicotinate esters and TMS ethers. The fractions from various SPE columns were tested by use of TLC and/or GC-MS to confirm that they contained the actual compounds. The FAME found were in a range of 14 to 22 carbon chain length, and there were saturated, monounsaturated and polyunsaturated FAME present. The PUFA were 18:4 (n-5, 7, 9, 11) and 22:5 (n-5, 7, 9, 11, 13). The FAL identified ranged from 16 to 22 carbon atoms in chain length, and were mostly monounsaturated, but one saturated compound was found. The next step would now be to analyze the wax esters in LC-MS to find the complete structure using the pieces of structure found in the FAME and FAL, as there are limited numbers of combinations of the FAME and FAL in a wax ester. URI: http://hdl.handle.net/10037/3526 File(s) in this item: 1
thesis.pdf (6.882Mb) -
Køller, Katrine Sperstad (Master thesis; Mastergradsoppgave, 16-Jun-2011)[+][-]
Abstract: Conotoxins are small disulfide rich peptides derived from the venom of Cone snails. They target different receptors in the nervous system with high selectivity and potency making them valuable as drug leads or drug themselves. One group of conotoxins, α-conotoxins have been shown to have potential as treatment for neuropathic pain. URI: http://hdl.handle.net/10037/3429 File(s) in this item: 1
thesis.pdf (2.180Mb) -
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)
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