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Browsing by master's degree program "Utbildningsprogrammet för provisorsexamen"

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  • Monola, Julia (2022)
    Native nanofibrillated cellulose is wood-derived, animal-free biocompatible biomaterial which has proved the suitability of nanoscale cellulose fiber based hydrogels for 3D cell culturing and wound healing applications. The problem of freeze-drying nanofibrillated cellulose hydrogel (NFCh) has been the aggregation of the hydrophilic fibrils of the NFC during freeze-drying, which leads deformed freeze-dried cake and unsuccessful reconstitution of the sample. Molecular Dynamic (MD) simulations have been earlier applied in formulation design of NFCh for freeze-drying successfully by screening excipients based on their attraction to the surface of NFCh. The weakness of MD simulations is it can only model the fresh formulation system intend to freeze-dry, but not the actual freeze-drying process and the effect of it and the excipients to the material. To evaluate the protecting properties of excipients and therefore the accuracy of the MD simulations detailed information about changes in the physical state and molecular orientation of the formulation before and after freeze-drying is needed. Non-invasive and label-free Raman spectroscopy can be used to determine vibrational modes of molecules to investigate changes in molecular orientation of the material. The aim of this study was to investigate the possible molecular changes induced by freeze-drying of NFCh-based formulations utilizing Raman spectroscopy and evaluate the connection of the results to MD simulations. NFCh with different excipients was freeze-dried and physicochemical properties, rheology and Raman signal were measured before and after freeze-drying and compared to the literature of MD simulations. The principal component analysis (PCA) was done to the Raman spectra and differences evaluated. The spectra of all formulations differed before and after freeze-drying, and more detailed analysis was done to two most potential 0.8% NFCh based formulations, lactose 300 mM and lactose 250 mM + glycine 50 mM. They had great attraction to NFCh in MD simulations and very similar rheological properties before and after freeze-drying and reconstitution. The spectra of different state of both formulations different on areas between 400 - 500 cm-1 and 850 - 900 cm-1 based on PCA analysis contributing the mutarotation of lactose during freeze-drying and reconstitution. Freeze-drying and the absence of water molecules in NFCh formulation favor different ratios of β and α anomers than the fresh hydrated state which could be detected utilizing Raman spectroscopy. Therefore, Raman spectroscopy was confirmed to be a sensitive option to assess subtle changes in molecular orientation in fresh, freeze-dried, and reconstituted NFCh-based formulations, resulting in a detail knowledge of the molecular behavior of excipients which could be applied in MD simulations and design of better freeze-drying formulations in future.
  • Reponen, Sannamari (2021)
    Biologisten lääkkeiden tarjonta ja käyttö ovat lisääntyneet voimakkaasti viimeisen vuosikymmenen aikana. Biologiset lääkkeet voivat parantaa reumasairauksien ja useiden muiden pitkäaikaissairauksien hoitotuloksia. Biologiset lääkkeet ovat yleensä perinteisiä pienimolekyylisiä lääkkeitä kalliimpia, ja siksi biologisen alkuperäislääkkeen kanssa kliinisesti samanarvoiseksi kehitettyjen edullisempien biosimilaarien käyttöä pyritään edistämään osana rationaalista lääkehoitoa. Potilaan näkemyksillä ja niiden huomioimisella on hoitoon sitoutumisen ja hoidon tulosten kannalta suuri merkitys. Potilaiden näkemyksistä ja kokemuksista biologisista lääkkeistä ja niiden vaihdosta on melko vähän tutkimuksia. Tutkimuksen tavoitteena oli tutkia reumapotilaiden tietämystä ja näkemyksiä biologisista lääkkeistä ja biosimilaareista sekä kokemuksia niiden ei-lääketieteellisestä lääkevaihdosta. Lisäksi tutkittiin reumapotilaiden uskomuksia omasta lääkityksestään, halukkuutta osallistua lääkitykseen liittyvään päätöksentekoon lääkärin kanssa ja biologisten reumalääkkeiden käyttäjien lääketiedon lähteitä. Tutkimus toteutettiin sähköisenä kyselynä Yliopiston Apteekin kanta-asiakkaille ja kertomalla siitä Reumaliiton ja IBD- ja muut suolistosairaudet ry:n viestinnässä 18.–30.1.2021. Kohderyhmänä olivat aikuiset avoterveydenhuollon reuma-, IBD- ja muut suolistosairaus-, sekä ihopsoriasispotilaat, jotka käyttivät adalimumabin tai etanerseptin alkuperäistä biologista lääkettä (BA) tai biosimilaaria (BS) tai ainoastaan perinteisiä pienimolekyylisiä lääkeitä (PL). Tässä tutkimuksessa tarkasteltiin vastauksia 260 reumapotilaalta, joista biologisia lääkkeitä oli käyttänyt 75 (BA-käyttäjiä 35, BS-käyttäjiä 40) ja perinteisiä lääkkeitä 185. Ei-lääketieteellisen lääkevaihdon kokeneita oli 17. Tutkimuksen teoreettisena viitekehyksenä käytettiin terveysuskomusmallia. Ensisijaiset lopputulosmuuttujat olivat faktorianalyysillä muodostettuja summamuuttujia. Erot lääkekäyttäjäryhmien (BA, BS, PL) välillä ja taustamuuttujien vaikutukset testattiin tilastollisilla analyyseillä. Vastanneista potilaista 94 % tunnisti biologisen lääkkeen käsitteen, mutta biosimilaari-käsite tunnettiin huonommin (34 %). Suurin osa potilaista (73–78 %) luotti biosimilaarien olevan ominaisuuksiltaan samankaltaisia alkuperäisvalmisteiden kanssa. Lääkärin tekemään biologisten lääkkeiden vaihtoon luotettiin enemmän (89 %) kuin mahdollisesti apteekissa tehtävään vaihtoon (40 %). Tutkimuksessa todetut kokemukset biologisten lääkkeiden vaihdosta biosimilaariin olivat pääosin positiivisia. Tutkimuksen reumapotilailla oli hyvä tietämys biologisista lääkkeistä, mutta he tunsivat huonommin biosimilaarin käsitteen ja mitä biosimilaarit ovat. Heillä oli yleisesti ottaen luottavainen näkemys siitä, että biosimilaari on ominaisuuksiltaan alkuperäisvalmistetta vastaava lääke. Biologisten ei-lääketieteelliseen vaihtoon suhtauduttiin melko myönteisesti, mutta lääkärin toteuttamaan lääkevaihtoon suhtauduttiin luottavaisemmin kuin mahdollisesti apteekeissa tehtävään vaihtoon. Lisää tutkimustietoa tarvitaan muun muassa potilaiden biosimilaareihin kohdistuvan epävarmuuden syistä.
  • Jaakkonen, Liina (2022)
    OATP1B1 is an influx transporter that is predominantly expressed in the liver, and it mediates the uptake of many clinically important endogenous compounds and drugs from portal vein blood into hepatocytes. OATP1B1-mediated uptake affects the rate of hepatic elimination of substrate drugs, directly affecting their plasma concentrations. Some naturally occurring single nucleotide variants (SNVs) in the SLCO1B1 gene encoding OATP1B1 can alter the transport function of the transporter resulting in alterations in pharmacokinetics, efficiency and toxicity of substrate drugs. The aim of this master´s thesis was to examine the effect of four naturally occurring SNVs of the SLCO1B1 gene on transport activity, expression, and localization of the OATP1B1 transporter in vitro. SNVs 170G>A (R57Q), 388A>G (N130D), 452A>G (N151S) and 758G>A (R253Q) were created using site-directed mutagenesis in the SLCO1B1 gene presenting in the pENTR221 plasmid. Recombinante baculoviruses were produced in Sf9 cells using the Bac-to-Bac® Baculovirus Expression System and used to transduce HEK293 cells for the overexpression of OATP1B1 wild type and variant proteins. An uptake assay was used to study the transport activity of the OATP1B1 variants in HEK293 cells. Western blotting was used to study the expression of OATP1B1 proteins in membrane vesicles. Immunofluorescence staining was used to determine the localization of OATP1B1 wild type and variants in HEK293 cells. Transport activity of the OATP1B1 variants R57Q and R253Q was significantly decreased compared to wild type. In contrast, transport activity of the N130D ja N151S variants was not significantly altered. The reasons for the changes in transport activity could not be reliably estimated due to the failure to measure the expression levels of OATP1B1 proteins by Western blotting. However, immunofluorescence microscopy revealed that the localization and expression of the all the studied OATP1B1 in baculovirus transduced HEK293 cells were comparable to the wild type. The results of this master´s thesis indicate that SNVs 170G>A and 758G>A can impair the transport activity and substrate uptake functions of OATP1B1 in vitro. Additional in vitro studies of transport activity, expression and localization of the variants R57Q and R253Q will be required to confirm these results. In the future, the R57Q and R253Q variants should be also studied for their possible clinical significance in pharmacokinetics and pharmacodynamics of substrate drugs, as SNVs 170G>A and 758G>A may increase the exposure and the risk for adverse effects of OATP1B1 substrate drugs.
  • Liimatta, Janne (2021)
    During co-processing, magnesium stearate can induce surface coating on carrier particles in powders which contain at least one other component in addition to magnesium stearate. Magnesium stearate is sometimes added to powder mixtures as it is known to have beneficial effects on powder characteristics, such as physical and chemical stability, and flowability. In order to fully optimize and control the coating/mixing process, it is necessary to be able to characterize the quality of surface coating. Various methods can be used in determining the coating of powder particles. They can roughly be divided into two different categories: direct and indirect methods. For example, spectrophotometric instruments, which are used to visually express the element distribution on particle surface, are considered direct methods. Indirect methods include methods in which coating parameters are inferred using other properties such as water sorption and powder flowability. Principally direct methods have been used in previous studies to determine the quality of coating. Therefore, the area of interest was especially to study indirect methods and compare them to results obtained using direct methods. Having knowledge of the suitability of indirect methods would be interesting as they might have many benefits compared to direct methods, such as quicker analysis speed and cost-efficiency. The aim of the study was to examine the suitability of direct and indirect methods in studying the surface of powders containing magnesium stearate and active pharmaceutical ingredients (APIs) or lactose, more closely how magnesium stearate was placed on carrier particles as well as the uniformity and the thickness of coating layer. The used methods were selected using literature and own consideration while taking the available equipment into account. The powders containing API (d50 < 10 μm) or lactose (d50 > 80 μm) with magnesium stearate had substantially differing characteristics and thus behaved differently. Therefore, there were differences in the suitability of analytical methods in determining surface of powders. Powders containing lactose and magnesium stearate were able to be examined using direct methods (SEM-EDS and ToF-SIMS) and several indirect methods. Samples with API and magnesium stearate were able to be studied with fewer methods. Validation of the suitability of these methods need more research. However, according to the results from this study, it is probable that surface characterization of studied co-particles can be achieved with direct, but also with indirect methods.
  • Saksa, Mari (2022)
    There are certain characteristics in children’s medication process, such as weight or body surface area-based drug dosing and off-label use of medications, that expose children to medication errors. Small children especially are prone to physical injuries resulting from medication errors. High-alert medications bear a heightened risk of causing significant, even life-threatening harm to a patient when used in error. The aim of this study was to promote children's medication safety by identifying medication errors and contributing factors to errors associated with the use of high-alert medications in pediatric medication process in a hospital environment. The data of this retrospective register study consisted of voluntary medication error reports (HaiPro) made in the pediatric and adolescent units at Helsinki university hospital (HUS). ISMP's (Institute for Safe Medication Practices) list of high-alert medications in acute care settings was used to limit the data. The data was analyzed by using both quantitative and qualitative methods. The aim of the quantitative analysis was to report the frequencies (n) and proportions (%) of high-alert medications and routes of administration and the aim of the qualitative analysis was to identify the types of medication errors and contributing factors in the data. ISMP’s high-alert medications accounted for approximately one-fifth (19.7%) of all medication error reports made in pediatric and adolescent units in 2018–2020. Twelve medications and intravenous route covered approximately 65.0% of all high-alert medications and routes of administration mentioned in the data. Medication errors were mostly identified in medication administration stage (43.3%) and administration errors were often preceded by prescribing errors. Dosing errors (20.5%) and documenting errors (16.8%) were the most common medication error types in the data. Errors associated with dosing and infusion rate were most often involved in severe medication errors. The most frequently identified contributing factors in the data were associated with the work situation and conditions, documenting and information transfer or medications. More detailed risk analysis considering high-alert medications and the intravenous medication process and targeting preventive barriers to identified risk areas are recommended in pediatric and adolescent units in the future. Barriers should be planned to cover the entire medication process. Among different types of medication errors, multiple dosing errors and errors during the programming of infusion rate require special attention in the future.
  • Jaskari, Iida (2022)
    Multiple sclerosis is a progressive inflammatory disease of the central nervous system that affects young adults. The pathological hallmark of MS is the degradation and loss of oligodendrocytes resulting in demyelination. Damage to axons caused by demyelination severely impairs physical function. Currently there is no cure for MS, but current drugs aim to modify the course of the disease and relieve symptoms. However, they are unable to promote the repair of damaged myelin sheaths, and thus new therapies are needed. In this study, the effect of V-MANF on remyelination was investigated in two commonly used experimental toxin models. V-MANF is a modification of the endoplasmic reticulum located protein MANF, which has been found to have neuroprotective and regenerative properties. Additionally, MANF can regulate ER stress, which contributes to demyelination in MS. The effect of V-MANF on lysolecithin-induced demyelination was examined in organotypic cerebellar brain sections from C57B/6 mice. The study was conducted exceptionally using the brains of adult mice because they are a better model for neurodegenerative diseases. However, when analyzing the results, it was found that there was no demyelination in the tissue cultures, so the effect of V-MANF could not be analyzed. In the other study, C57B/6 mice were given dietary cuprizone for six weeks, followed by daily intranasal administration of either V-MANF or vehicle for seven days. Mice were subjected to behavioral experiments, in which a light/dark box test showed that V-MANFs had a potential anxiolytic effect in mice receiving cuprizone. No significant demyelination was observed by immunohistochemical analysis and therefore the effect of V-MANF on remyelination could not be assessed. However, the results of the study can be utilized in the design of further studies.
  • Ruutiainen, Henna (2022)
    In health care, the most patient safety incidents occur from medication errors, to which pediatric patients in particular are susceptible. According to James Reason's Theory of Human Error, errors inevitably occurs in an individual's actions, causing potential harm. The prescribing phase has been identified as a specific risk point in the pediatric medication-use process, and therefore defences must be established to prevent or stop errors before they reach the patient. Such system-centric barriers are, for example, electronic health record (EHR) systems that can include computerized physician order entry (CPOE) systems where e.g., medication orders and prescriptions can be made. Knowledge-based clinical decision support (CDS) tools such as dose range check or dose calculator can be integrated into the CPOE system to assist in the prescribing process. The objective of this systematic review was examine the effects of CPOE systems with CDS functions on preventing wrong dose errors in pediatric inpatient orders and outpatient prescriptions. This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 criteria and Synthesis Without Meta-analysis (SWiM) items as an extension to PRISMA criteria. The Joanna Briggs Institute’s (JBI) recommendations from JBI Manual for Evidence Synthesis on mixed methods was used as a guide to conduct this review. Additionally, Cochrane Handbook for Systematic Reviews of Interventions was utilized to conduct the synthesis examining the wrong dose error effectiveness. The study protocol according to the prior defined eligibility criteria was registered in PROSPERO. The literature search was implemented in four databases (MEDLINE Ovid, Scopus, Web of Science and EMB Reviews), reference lists and grey literature in January 2022. Two independent reviewers conducted the study selection and data extraction of the eligible studies using a Covidence software platform. Vote counting method was used to describe and analyze the quantitative findings of the studies exploring the characteristics of CPOE-CDS systems reducing wrong dose errors and regarding their effectiveness on error prevention. JBI’s critical appraisal tools and Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach were used to define the quality of the studies. A total of 18 studies met the inclusion criteria. The studies had been published in 2007–2021 and majority (13/18) considered only inpatient orders. Almost all (n=16) studies had customized or homegrown CPOE-CDS system and the most used CDS tools were dose range check (78%, 14/18), dose calculator (45%, 8/18) and dosing frequency check (45%, 8/18). When implementing new or customizing the used CPOE-CDS system usually alert functions were added (n=9) and in total alerts were present in 15 studies. Statistically significant reduction in wrong dose errors (overall, overdosing or underdosing errors) was reported in eight studies. None of the studies (n=18) found an overall increase of wrong dose errors. CPOE systems with CDS functions have a great potential to reduce wrong dose errors and promote pediatric medication safety. CPOE-CDS system customization for pediatric population, implementing CDS alerts and the use of dose range check tool seem to be most advantageous when aiming to prevent wrong dose errors. However, CPOE-CDS systems cannot prevent all wrong dose errors as human errors continue to occur and the implemented CPOE-CDS systems can pose new risks such as alert fatigue. Therefore, systematic actions are needed to optimize the safe use of CPOE-CDS systems in pediatrics. More studies are needed particularly on the effectiveness on wrong dose error prevention comparing basic and advanced CDS tools and the effects of different individual CDS functions on wrong dose errors.
  • Lillsved, Iida (2022)
    For their good clinical value and supply the use of biological medicines has increased in the treatment of inflammatory bowel disease (IBD). However, biological medicines are often more expensive compared to traditional small molecule medicines. More inexpensive biosimilars, shown to be clinically equal to the corresponding biological original products, can be used to reduce medication costs as part of rational pharmacotherapy. Although patients’ perceptions about biosimilars may affect the treatment adherence and outcomes of the use of these medicines, only a few studies have been published on this area. The primary aim of the study was to study IBD patients’ perceptions of the features of biosimilars and biosimilars’ suitability for their own treatment. The secondary aim was to study biological medicine users’ perceptions of the suitability of biosimilar switch by a physician for their own treatment. In addition, sources of medicines information of the users of biological medicines were studied. The data of the study were based on a cross-sectional survey conducted by the University Pharmacy and University of Helsinki in January 2021. Research Newsletter and response link were delivered per an email to University Pharmacy’s loyal customers and electronically communicated via the Association of Rheumatism and the Association of IBD and other intestinal diseases. The study comprised of the responses of adult outpatients with IBD (n=979) who were using original biological medicines (n=120), biosimilars (n=30) or traditional small molecule medicines (n=829) (medicine user groups). The sum variables constructed by factor analysis based on the study aims were used as outcome variables. Differences between medicine user groups and the effects of other background variables were analyzed by bivariate and multivariate analysis using SPSS Statistics software. Most of the patients (70–97 % depending on the medicine user group) trusted biosimilars’ features to be equal to the corresponding original biological medicines. However, more than half of the patients (53–67%) did not know whether they would like to physician to prescribe biosimilar to them rather than the original biological medicine. Of the users of original biological medicines, 71 % did not want to be switched to a biosimilar if the current medication was working well. Biosimilar users had more positive perceptions about biosimilars and switching compared to other medicine user groups. Physician’s perception played an important role in biologic switching. Several factors that may affect perceptions about the features of biosimilars and their use in patient’s own treatment were identified. These included, in particular, previous user experience with biosimilars and having information about them. Overall, patients had positive perceptions about the features of biosimilars but had uncertainties about the use of biosimilars, especially, for the treatment of their own disease and when switching medication. More research is needed on the perceptions among different patient groups, and on the need and optimal form of medication information on biological medicines, biosimilars and their switching.
  • Pernilä, Oona (2022)
    The health and social services reform will enter into force in its entirety from the beginning of 2023. With the reform, the responsibility for organizing social and health care will be transferred from municipalities to the responsibility of 21 wellbeing services counties. At the time of writing this thesis, the changes to the medical legislation brought by the reform have not yet been published. Hospital pharmacies and dispensaries take care of Finland's public pharmaceutical services. The tasks of public pharmaceutical services include pharmaceutical logistics tasks, non-industrial pharmaceutical manufacturing, and the preparing of medicines, as well as pharmaceutical expert tasks and services.The aim of this study is to find out the opinions of current hospital district managers, medical directors, and hospital pharmacists about how future pharmaceutical services should be organized in the upcoming wellbeing service counties. The study was conducted using an electronic structured questionnaire, which was sent in October 2021 by e-mail to the heads of all Finnish hospital districts, medical directors, and hospital pharmacists. The survey also included Åland and the Joint Municipal Authority for Social and Healthcare in Central Uusimaa (Keusote). The questionnaire consisted mainly of Likert-scale questions, but the questionnaire also had open answer fields to which respondents were able to add comments and refine their answers. The questionnaire was evaluated by several experts and piloted by two experts. The questionnaire consisted of seven different sections, which addressed the number and concentration of hospital pharmacies and dispensaries, clinical pharmacy services and medication safety, pharmaceutical purchasing and formulary, automation and information systems, co-operation in wellbeing service counties, and pharmaceutical services in a state of emergency and limited resources. The overall response rate to the survey was 50% (n = 34/68). 79 per cent (n = 19/24) of hospital pharmacists and 35 per cent (n = 15/43) of managers and medical directors responded to the survey. Responses were received from all hospital districts, Åland and Keusote. Based on the responses, it is hoped that the activities of hospital pharmacies will be mainly concentrated in wellbeing service counties so that the services would not move too far. Co-operation in individual pharmaceutical service activities could take place in collaborative areas or nationwide. The current number of hospital pharmacies was thought to be sufficient, but the operation of individual dispensaries could be closed or transferred to the administration and coordination of a hospital pharmacy in the area. It is hoped that clinical pharmacy services will be increased, and medication safety officers are desired for at least all wellbeing service counties. It is hoped that purchasing will be centralized nationwide, especially for expensive and rare pharmaceuticals, but the procurement of pharmaceutical formularies could be done by collaborative area, and the formation of the formularies could be done by wellbeing service county or collaborative area. It is hoped that automation and technology will increase in pharmaceutical services and that information systems will become more integrated. Increasing co-operation both between hospital pharmacies and within wellbeing service counties, for example between community pharmacies, was advocated. In the future, resources should be focused on pharmaceutical services personnel and their training, as well as on automation and technological solutions. It is hoped that the crisis preparedness of the pharmaceutical services will be increased in the future.
  • Harju, Elina (2021)
    Extracellular vesicles (EVs) are nano-sized lipid bilayer-delimited particles, released by cells. They take part in intercellular communication by their molecular composition and are part of both physiological and pathophysiological functions. EVs can be extracted from bodily fluids, and they are particularly abundant in blood. The purpose of this thesis was to evaluate the use of Raman spectroscopy in the characterization of EVs. Raman spectroscopy is an analysis method based on the interaction of light and matter, and the inelastic scattering of light, and it is used to get information on the biochemical composition of a substance. Principal component analysis (PCA) was used to investigate if Raman spectroscopy could differentiate two different platelet-derived EV samples, a red blood cell-derived EV-sample and a red blood cell-derived reference material. Evaluation of the characterization also included a stability study of these samples, where it was examined if any temperature dependent changes occurred that could be detected by Raman spectroscopy. Additionally, the applicability of Raman spectroscopy for lipoprotein contamination detection was evaluated by examining if purification of an EV sample decreased the intensity of carotenoid peaks typical for lipoprotein spectra. Raman spectroscopy was able to differentiate all three EV samples and the red blood cell-derived reference material from each other. The most clear differences were found between red blood cell and platelet-derived samples, due to for example the characteristic haemoglobin peaks of red blood cell-derived samples. Differences were also found between the two platelet EV samples, which were thought to implicate difference in protein compositions. The characterization of red blood cell-derived samples proved to be difficult because haemoglobin contained in the samples covered most of the other signal from the samples. Stability studies implicated that during fridge storage the carotenoid peak intensity of platelet-derived EV samples decreases due to the degradation of carotenoids. In the red blood cell-derived samples, no differences assignable to changes in some specific components of the samples were observed. Contamination studies suggested the intensity of the carotenoid peaks may increase due to purification of the sample. This was counter to the assumption and may suggest the carotenoids of the EV samples are not from lipoprotein contamination, but part of the EV composition. In conclusion, Raman spectroscopy proved to be a promising method for characterization and identification of different EV samples.