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Browsing by master's degree program "Proviisorin koulutusohjelma"

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  • Rissanen, Johanna (2020)
    Lääkevaihto ja sitä täydentävä viitehintajärjestelmä ovat laskeneet lääkekustannuksia Suomessa. Epilepsialääkkeet eivät ole aiemmin kuuluneet lääkevaihdon piiriin, sillä epilepsian hoidossa eri valmisteet eivät välttämättä ole terapeuttisesti tarpeeksi samanarvoisia, ja pienikin muutos hoitotasapainossa voi altistaa epilepsiakohtauksille. Nykyisin epilepsialääkkeitä käytetään kuitenkin usein muihinkin käyttöaiheisiin, kuten psykiatrisiin sairauksiin ja kivun hoitoon. Vuonna 2017 lääkekorvausjärjestelmään tehtiin säästötoimenpiteitä, joiden yhteydessä epilepsialääkkeet sisällytettiin lääkevaihdon piiriin muissa käyttöaiheissa kuin epilepsian hoidossa. Lisäksi otettiin käyttöön poikkeava viitehintaryhmä, joka koski epilepsialääkkeistä pregabaliinia neuropaattisen kivun käyttöaiheessa. Tutkimuksen tavoitteena oli tarkastella epilepsialääkkeiden (pregabaliinin, gabapentiinin, topiramaatin, lamotrigiinin ja valproiinihapon) vaihtamista sekä hintojen kehitystä lääkevaihtoon ja viitehintajärjestelmään sisällyttämisen jälkeen vuoden 2017 alusta vuoden 2019 puoliväliin. Lisäksi tarkasteltiin näiden lääkeaineiden kustannusten, korvausmenojen sekä käyttäjä- ja reseptimäärien kehitystä. Aineistona käytettiin Kansaneläkelaitoksen reseptirekisteriin pohjautuvia tilastoja epilepsialääkkeiden lääkeostoista sekä lääkkeiden hintalautakunnan päätöksiä epilepsialääkkeiden viitehintaryhmistä ja viitehinnoista. Epilepsialääkkeiden vaihtaminen yleistyi tarkastelujakson aikana kaikilla lääkevaihdon piirissä olleilla viidellä lääkeaineella, ja vaihtokieltojen osuus resepteistä laski useimmilla lääkeaineista. Viitehinnat laskivat useimmissa tarkastelluista viitehintaryhmistä, mutta lähes yhtä usein viitehinta ei muuttunut. Viitehinnat laskivat enemmän viitehintaryhmissä, joissa oli useampia vaihtokelpoisia valmisteita. Lääkevaihdon ensimmäisenä vuonna 2017 lääkevaihtoon kuuluvien epilepsialääkkeiden kustannukset ja korvausmenot pääosin laskivat, vaikka lääkkeiden käyttö ei vähentynyt. Lääkevaihdon toisena vuonna kustannukset eivät juuri laskeneet. Pregabaliinin poikkeavan viitehintaryhmän vuoksi vaihtamatta jääneet reseptit aiheuttivat merkittävän osan lääkevaihtoon kuuluvien epilepsialääkkeiden kustannuksista. Pregabaliinille jäi siten todennäköisesti yhä säästöpotentiaalia poikkeavan viitehintaryhmän voimassaolon päätyttyä vuoden 2019 heinäkuussa, mitä on syytä tarkastella jatkotutkimuksissa.
  • Korventausta, Susanna (2022)
    Etätyö yleistyi maaliskuussa 2020 äkillisesti COVID-19 pandemian seurauksena maailman terveysjärjestö WHO:n suosituksesta. Etätyö on ollut ennen koronapandemiaa harvinaista lääketeollisuudessa, joten etätyötä lääketeollisuudessa on tutkittu hyvin vähän. Etätyön on arvioitu jäävän pysyväksi ratkaisuksi, joten on ajankohtaista tutkia etätyön soveltuvuutta ja tehokkuutta lääketeollisuudessa. Etätyöntekijöiden tuottavuus kasvaa yleensä huomattavasti. Työpaikalla koetaan jatkuvasti keskeytyksiä, melua ja muita häiriötekijöitä, joiden lisäksi työmatkat kuormittavat työntekijöitä. Etätyöntekijät säästyvät suurimmalta osalta näistä ongelmista, jolloin suurempi osa heidän työpäivästään kuluu varsinaiseen työntekoon. Valtaosa etätyöntekijöistä tekee etätyötä osan työajastaan. Tutkimuksen tavoitteena oli selvittää kokemuksia etätyöstä, etätyön soveltuvuutta ja etätyön tehokkuuteen vaikuttavia tekijöitä lääketeollisuudessa. Tutkimus on toteutettu Orion Oyj:n Suomen toimipisteissä. Tutkimuksen toteuttamistapa oli kvantitatiivisen ja kvalitatiivisen kyselytutkimuksen yhdistelmä. Yhdistämällä kvantitatiivisia ja kvalitatiivisia kysymyksiä pyrittiin saamaan tarkempia tietoja kuin pelkällä kvantitatiivisella tutkimuksella voitaisiin saada. Kysely oli avoinna 15.11.–26.11.2021. Vastausprosentiksi saatiin 34,9 %. Etätyön merkittävimmiksi hyödyiksi havaittiin työ- ja vapaa-ajan joustavampi yhteensovittaminen ja se, että etätyössä keskittyminen on parempaa. Kommunikaation koetaan onnistuvan hyvin etätyössä, mutta kasvokkain tapahtuvaa kommunikaatiota pidetään myös tärkeänä. Esimerkiksi kehitys- ja ideointipalaverit olisi hyvä järjestää mahdollisuuksien mukaan kasvokkain. Lisäksi hiljaisen tiedon siirtyminen on vähäisempää etätyössä. Etätyö soveltuu hyvin tutkimus- ja tuotekehitystyöhön, eikä sen koeta heikentävän merkittävästi kykyä innovoida. Tulosten perusteella etätyötä haluttaisiin tehdä enemmän kuin 40 % työajasta ja etätyötä pidetään tehokkaana työskentelytapana. Kyselyssä ei selvitetty, minkälaisia etätyömääriä vastaajat ovat tehneet vahvan etätyösuosituksen aikana. Osa vastaajista on saattanut olla muita enemmän lähitöissä, mikä voi vaikuttaa tuloksiin. Saadut tulokset olivat kuitenkin samansuuntaisia kuin aikaisemmissa tutkimuksissa. Suurin osa tähän kyselyyn osallistuneista oli erittäin kokeneita ja työnsä hyvin osaavia työntekijöitä, mikä voi lisätä etätyömyönteisyyttä tuloksissa.
  • Mäkinen, Heljä (2022)
    Municipal case management is an activity that assesses various functional capacity indicators, utilizing the elderly’s state of health and coping in everyday life. The goal of case management is to refer clients to suitable services, such as home care or a doctor's visit. The problems related to drug treatments are only superficially reviewed. The involvement of a pharmacist in the assessment of case management would provide an opportunity to address the problems of pharmacotherapy and to provide adequate support for the implementation of pharmacotherapy. In this thesis, a remote service of a pharmacist was piloted for new clients over the age of 65 living at home as part of case management. Pharmacist reviewed medications remotely using medication risk management checklist LOTTA. The study examined the suitability of the LOTTA for medication reviews and the problems associated with medications of the elderly participating in case management. In addition, the suitability of pharmacovigilance assessments as a remote service as part of a comprehensive assessment of functional capacity and coping with everyday life was examined. The research material was collected at the case management unit of the city of Turku. The study involved 50 volunteer Finnish-speaking customers over the age of 65, for whom were assessed for a case management at Turku's case management unit. In addition to the assessment of normal case management, two pharmacists with comprehensive medication review qualifications reviewed medications using the medication risk management checklist LOTTA. Subjects were interviewed by telephone. If the pharmacist estimates that the subject will benefit from a multi-professional comprehensive medication review, the physician and pharmacist collaborated to conduct a review using a videophone application. Subjects background information, responses, observations made by pharmacists, and actions taken by physicians were recorded on an electronic form and analyzed. The mean age of the study participants (n = 50) was 82 years (range 67–98). Of these, 36 were women (72%) and 14 were men (28%). Most subjects were multidrug-treated (average medication 10.3, range 3–28). Each subject had at least one drug can be used with consideration for use in the elderly, as defined in the Fimea Drug 75 + database (Class C). 30% of subjects did not have a medication list and 34% reported lack of regular medication monitoring. 96% of the subjects had experienced a symptom on the LOTTA list that repeatedly interferes with their lives. The most common of these were problems such as constipation (54%). Pharmacists proposed changes for medication for 96 % of subjects. The most common proposed change was a change in the time of dosing (46%). Pharmacists estimated that 14 (28%) subjects would benefit from a multi-professional comprehensive medication review. In these cases, pharmacists made an average of 8.1 proposed changes for the physician, and the physician made an average of 6.9 changes for each subject. The most common challenges in coping with medication were symptom, which may be due to adverse drug reactions, a lack of follow-up to medication, and the absence of a treating physician. The results suggest that medication should be reviewed during the case management. The LOTTA list made it possible to identify and address the pharmacological problems of the elderly. The participation of a pharmacist in the assessment of the need for a multi-professional service remotely was possible, but it must be further developed. More research is needed on the benefits of multi-professional case management with a larger sample size.
  • Jalonen, Milla (2020)
    There are significant inter-individual differences in the effects of drugs. These differences can be caused by, for example, other diseases, adherence to treatment, or drug-drug interactions. A drug-drug interaction can lead to an increase in the concentration of the active substance in the circulation (pharmacokinetic interactions) or a change in the effect of the drug without changes in plasma concentration (pharmacodynamic interactions). A drug-drug interaction can change the efficacy of a drug or affect the adverse drug reaction profile. The individual’s genetic background, such as diversity in drug-modifying enzymes (polymorphism), also has an effect on the efficacy and the risk for adverse drug reactions of some drugs. A pharmacogenetic test can be used to study how genetic factors affect drug treatments. The aim of this master's thesis was to examine the possibilities of personalized migraine pharmacotherapy from the perspective of pharmacogenomics and drug-drug interactions. Four online drug-drug interaction databases available in Finland were compared. Inxbase is the most widely used interaction database by physicians in Finland and it is also integrated into Finnish pharmacy systems. Other databases used in this study were the international professional database Micromedex as well as Medscape Drug Interaction Checker and Drugs.com Drug Interactions Checker. The latter two are open-access databases available for healthcare professionals and patients. Interaction searches were conducted in the selected databases between acute and prophylactic drugs used for the treatment of migraine (e.g. bisoprolol-sumatriptan). Fourteen acute and 12 prophylactic drugs were selected for this study based on the Current Care Guidelines in Finland (Käypä hoito), and the data were collected in Excel spreadsheets. The first search was completed in December 2019 and the second search in March 2020. In this study, many potential interactions were found between acute and prophylactic drugs used to treat migraine in Finland. For more than half of the drug pairs studied, a potential interaction was found in at least one of the databases. There were significant differences between the interaction databases regarding which interactions the database contains and how the severity of the interactions was classified. Of the interactions found, only 45% were found in all four databases, and each database contained interactions that were not found in the other databases. Even very serious interactions or drug pairs classified as contraindicated were not found to be consistently presented across all four databases. When selecting drug treatment for a migraine patient, potential drug-drug interactions between acute and prophylactic drugs as well as the patient's genetic background should be considered. Individualizing migraine treatment to achieve the best efficacy and to reduce the risk for adverse drug reactions is important because migraine as a disease causes a heavy burden on individuals, healthcare, and society. Pharmacogenetic tests particularly developed to help choosing migraine treatment are not yet available, but tests are available for few other indications in both public and private healthcare. The use of these tests in clinical practice will increase as physicians’ pharmacogenetic knowledge and scientific evidence on pharmacogenetic tests increase. Utilization of pharmacogenetic data requires that test results are stored in electronic health records so that they are available in the future, when changes are made to drug treatment of individuals. More studies are warranted to better understand the clinical impact of pharmacogenomics and drug-drug interactions in migraine care.
  • Li, Mingchen (2021)
    Parkinson’s disease (PD) is a progressive chronic neurodegenerative disorder, which results in the selective loss of dopaminergic neurons in the substantia nigra (SN). The loss of these neurons results in the dysfunction of the nigrostriatal pathway bringing forth the characteristic motor symptoms seen in PD: postural instability, rigidity, slowness of movement and resting tremors. Non-motor symptoms, such as cognitive deficits, depression and impaired olfaction, typically emerge before motor symptoms. Currently available treatments only provide symptomatic relief with diminishing returns over time and no improvements on the overall outcome of the disease. Neurotrophic factors (NTF) have been of particular interest as a possible curative treatment for PD due to their potential for neuroprotection and neurorestoration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an NTF that has shown promising results in numerous in vitro and in vivo studies of PD. However, therapy with MANF and other NTFs involves surgical intervention for local administration, as NTFs cannot cross the blood-brain barrier (BBB). Therefore, the therapeutic potential of a systemically administered NTF would be tremendous, as it would lead to a significantly more favorable risk-benefit ratio for the patient. The aim of the current investigation is to evaluate the efficacy of a next generation variant of MANF in the 6-hydroxydopamine toxin-induced unilateral lesion rat model of PD. Prior in vivo results suggested that subcutaneously injected MANF variant is able to penetrate the BBB. Amphetamine-induced rotational behavior (AMPH-ROTO) was used to evaluate the severity of the unilateral lesions during the experiment every other week until the end of the experiment at week eight. Animals were divided into treatment groups during week two based on their AMPH-ROTO results. Animals received MANF variant either subcutaneously through an implanted osmotic minipump at two different dosages or as a single dose divided into three separate intrastriatal injections. Tyrosine hydroxylase (TH) immunohistochemical staining was performed on brain sections collected from the striatum and SN for data analysis. In addition to AMPH-ROTO results, the efficacy of treatment was determined via the optical density of TH-positive striatal fibers and the number of TH-positive cells in the SN. Statistically significant differences (defined by p < 0.05 and a non-zero mean difference at a 95 % confidence interval) were observed only in the number of TH-positive cells in the SN favoring intrastriatal MANF variant treatment over both intrastriatal MANF and the vehicle treatment. The main concern regarding the validity of the results was related to the heterogeneous lesion sizes in different treatment groups possibly resulting in unsuccessful randomization due to excessive baseline differences. The inadvertent negative effects of this was further exacerbated by low a priori statistical power, which in the end had likely caused inflated effect sizes. Thus, assessment of the definitions of the used statistical parameters and the limitations of the experimental design suggest that presently, the efficacy of the MANF variant could not be evaluated reliably, in spite of the statistically significant result.
  • Muurman, Tuulikki (2021)
    Background: Poor health literacy (HL) is associated to increased hospitalization and decreased seeking for screenings. Shared decision making can increase patient knowledge, decrease anxiety over the care process, improve health outcomes and reduce health care costs. Little is known about factors influencing health literacy and participation in treatment decision making in different population groups. Objectives: To investigate factors predicting HL and participation in the treatment decision making. Methods: A cross-sectional population online survey conducted in Finland in 2019 by Finnish Medicines Agency. Both health literacy and participation in the decision making were assessed by three statements that sum variables were created with score 1-5 (Cronbach’s alpha value 0.584 and 0.810). Age, gender, education, household income and most common chronic diseases were chosen as possible predicting factors. Two-variable Pearson’s chi-squared test was first used to find significant factors followed by logistic regression analysis to take into account several variables. Results: Of all the respondents (n=2104) 76.5% had good HL and 73.4% had willingness to participate in the treatment decision making. In the two-variable test older age (p<0.001), lower education (p<0.001), lower household income (p=0.001), higher number of chronic diseases (p=0.003), having cardiovascular diseases (p=0.003), diabetes (p=0.029) and cancer (p=0.001) predicted poorer health literacy. Male gender (p=0.001), not having chronic diseases (p=0.001), not having a musculoskeletal disorder (p=0.050) or mental health disorders (p<0.001) predicted poorer participation in the treatment decision making. In the logistic regression analysis older age and having cancer predicted poorer health literacy. Male gender and not having mental health disorders predicted less willingness to participate in the decision making. Conclusions: Older age and cancer predicts poorer health literacy and male gender poorer willingness to participate in the decision making. Further research should focus on investigating more in detail the contributing factors to these findings, and how health literacy in elderly and men’s involvement to the decision making could be improved.
  • Ritamäki, Kaisu (2019)
    Pharmaceutical companies are required to comply with fair market guidelines and regulations. However, definition of fair market value (FMV) in clinical trial is not unambiguous. In literature are some suggestions how to determine the phenomenon of FMV in clinical trial. Understanding the FMV and how it should be applied into practice when conducting clinical research is challenging. This study provides more focused information on FMV in clinical trials and its determination. FMV should be determined for research-related activities in clinical drug research. FMV of research related activities can be consistent if similar sites are performing similarly conducted studies for similar sponsors. Therapeutic area and geographical location of the trial site can also influence for the FMV. This study was performed in co-operation with Roche. The aim of the study was create a consistent and transparent method to assist in the determination of FMV in medical drug research in relation to the payments paid by the sponsor to the sites. Clinical trial agreements (CTA) and associated agreements were analysed to investigate FMV of research-related activities by study site, study type, therapeutic area and geographical area. Average price and price range of each research-related activity from previous CTAs and associated agreements of Roche Finland was calculated. Based on available data from literature and study results research-related activities and factors affecting to the FMV of clinical trials were discussed to create comprehensive understanding of FMV in clinical drug research. Based on this study average price of the specific research-related activities can be different by therapy area, site, study type and geographical area. All these factors are relevant when assessing FMV of specific research-related activity. Studied therapy area and site seems to have the most important impact when evaluating FMV. For some research-related activities such as national coordinator investigator (NCI) fee price ranges could be very big whereas in other research-related activities such as pharmacy fees prices could be quite similar. Some research-related activities were very study specific which affected evaluation of those activities. CTAs and associated agreements are valid documents to gather information assessing FMV of research-related activities in medical drug research. Average price and price range of the research related activity can be used when assessing FMV in medical drug research. However, price of the specific research-related activity need to be evaluated considering the studied therapy area, site, study type and geographical area.
  • Jäntti, Heli-Noora (2019)
    Farmasian ammattilaiset ovat lääkealan asiantuntijoita, joilta vaaditaan uudenlaista osaamista muun muassa teknologiakehityksen myötä. Nykypäivän asiantuntijuus edellyttää alakohtaisen eli sisällöllisen osaamisen lisäksi geneerisiä eli yleisiä taitoja ja ammatti-identiteetin muodostumista. Geneerisillä taidoilla tarkoitetaan yleishyödyllisiä taitoja, kuten ongelmanratkaisu- ja kommunikointitaitoja. Ammatti-identiteetillä tarkoitetaan käsitystä omasta työminästä, jonka avulla omaa roolia ja työnkuvaa järkeistetään. Näiden elementtien muodostamaa osaamisen kokonaisuutta kutsutaan kompetenssiksi. Asiantuntijoilta vaadittavan osaamisen muutos on ohjannut yliopistoja vastaamaan paremmin työelämän tarpeisiin. Helsingin yliopistossa toteutettiin Iso Pyörä -koulutusuudistus, jossa koulutusohjelmia uudistettiin komeptenssilähtöisesti. Kaikkiin koulutusohjelmiin ja opintojaksoihin lisättiin osaamistavoitteet, jotka opiskelijoiden tulisi saavuttaa valmistumiseensa mennessä. Osaamistavoitteiden täyttymistä edistää esimerkiksi portfoliotyöskentely, minkä avulla opiskelijat pääsevät hyödyntämään ja kehittämään reflektiotaitojaan. Opiskelijat voivat tuoda opetuksen kehittämiseen aivan uudenlaista näkökulmaa avatessaan käsityksiään esimerkiksi hyvistä opetusmenetelmistä, mitkä ovat auttaneet heitä saavuttamaan laaditut osaamistavoitteet. Toisaalta opiskelijoiden näkökulmasta saadaan tietoa, mikä osaaminen voidaan kokea puutteelliseksi, jolloin opetuksen kehittäminen on mahdollista. Tutkimuksen tavoitteena oli selvittää opiskelijoiden käsityksiä omasta osaamisestaan ja ammatti-identiteetistään sekä millä tasoilla opiskelijat reflektoivat osaamistaan. Tutkimuksessa analysoitiin vuoden 2017 kolmannen vuosikurssin kandiportfolion loppureflektioesseet käyttäen aineistolähtöistä sisällönanalyysimenetelmää. Esseissä opiskelijat reflektoivat osaamistaan suhteessa farmaseutin tutkinnolle asetettuihin osaamistavoitteisiin ja pohtivat omaa ammatti-identiteettiään. Tulosten mukaan opiskelijat saavuttivat monipuolista osaamista lääkkeiden ja lääkehoitojen näkökulmasta sekä kehittivät geneerisiä taitojaan. Puutteellisesti hallittiin useimmiten kielitaito sekä yrityksen ja yhteiskunnan taloudelliset periaatteet. Opiskelijoiden mukaan farmaseutin ammatti-identiteettiä määrittelevät erityisesti lääkeosaaminen ja terveydenhuolto sekä ammatin arvostaminen. Opiskelijoiden pohtimat valmiudet mukailivat osaamistavoitteita. Opiskelijat osasivat arvioida omaa osaamistaan ja nostaa esille vahvuuksiaan ja heikkouksiaan. Opetussuunnitelmaan on onnistuttu sisällyttämään geneeristen taitojen opetus, sillä opiskelijat kokivat saavuttaneensa näitä taitoja pääasiassa hyvin. Opetusta tulisi kehittää kielitaidon ja liiketalouden kohdalla, sillä nämä koettiin usein puutteellisesti hallituksi. Ammatti-identiteettikäsitykset mukailivat kirjallisuutta, sillä muissa tutkimuksissa on saatu samankaltaisia tuloksia.
  • Valve, Kiia (2021)
    Background and objectives: Pharmaceutical services provided by community pharmacies have the potential to improve medication safety and support the implementation of rational pharmacotherapy. The pharmaceutical services are internationally an underused resource to support functioning of social and health care services. The literature review of this Master’s thesis provides an overview of pharmaceutical services, - their funding and remuneration. The primary objective of the empirical study was to create an overview of the development of the pharmaceutical services in Finnish community pharmacies in 2010-2020. The secondary objective was to study differences in the service provision between Finnish provinces. Materials and methods: The study was carried out as a retrospective descriptive survey study annually conducted by the Association of Finnish Pharmacies. Åland was excluded from the provincial review so that individual pharmacies could not be identified. The data was analyzed using Microsoft Excel. The number of pharmacies providing pharmaceutical services annually and the annual number of customers using these services were counted at the national level. At the provincial level, the corresponding data for the prescribing review, medication review, comprehensive medication review and assessment of inhalation technique were analyzed for the years 2017-2020. Results and conclusions: The most common service with the highest number of customers was automated dose dispensing. The second most common service was prescription review. As a whole, the provision of services and the number of customers had increased during the study period in Finnish community pharmacies. Manual dose dispensing was a diminishing service. Differences were found between provinces in the prevalence of services and in the number of customers. It was possible to identify provinces with lower service provision activity, such as Lapland. The service provision prevalence and number of customers varied widely within provinces. The number of customers for a certain service in an individual pharmacy had a large effect on the provincial average, thus, the average number of customers in the provinces does not reflect the provinces' success in implementation of services. Pharmaceutical services, with the exception of the automated dose dispensing, are not well implemented.
  • Niemelä, Akseli (2022)
    Lecithin:cholesterol acyltransferase (LCAT), a key enzyme in maturating high-density lipoprotein (HDL) particles, has been targeted to promote the efficiency of reverse cholesterol transport by small molecular positive allosteric modulators (PAM) of Daiichi Sankyo. For a set of these compounds their Vmax and EC50 values and binding site in the membrane-binding domain (MBD) of LCAT have been determined. Through molecular dynamics (MD) simulations we previously found a metric that qualitatively described which compounds were active, so in this study we aimed to improve it by finding a quantitative metric. This led to the discovery of the Cα distance between CYS50 and ASN65, which correlates with this set’s Vmax values and which can be utilized to predict the Vmax values of novel compounds. Additional simulations were performed to discover whether this metric is changed by a lipid interface present, and to reveal a likely entry pathway PAMs take. As LCAT activation is likely a benign and potentially overlooked effect, we performed a virtual screen of FDA-approved compounds and secondary metabolites associated with LCAT. From secondary metabolites, a key finding was that flavonoids were overwhelmingly associated with LCAT and had a high binding potential to the MBD in docking simulations. The best binding compounds were subjected to MD simulations to discover their Vmax values using the discovered metric. This provided us with a set of compounds, which can be used to validate our in silico model in vitro. Should this model be validated, it can be used in optimising and discovering novel PAMs of LCAT, and it would bring evidence to the benefit of MD in drug discovery processes in general. Furthermore, if our discovered compounds can activate LCAT in vitro, they may be used as precursors for novel PAMs or as therapies by themselves not only for LCAT deficiencies, but perhaps for atherosclerotic cardiovascular diseases as well.
  • Natri, Ossi (2022)
    Coronary heart disease is a number one killer in westernized countries and the costs from it will continue to grow in the future. It is caused by atherosclerosis, build-up of plaque and chronic inflammation in the arteries of heart, and endogenous lipoproteins have a special role in its development. Among other atheroprotective properties, High density lipoproteins (HDL) have a role in intrinsic mechanism of the reverse cholesterol transport (RCT), of gathering and removing excess cholesterol from peripheral tissues. There have been several HDL raising strategies in the past for the treatment of atherosclerosis, but their success has been modest. Synthetic HDL (sHDL), comprising of various types of phospholipids and proteins or peptides, have been developed to mimic the properties of endogenous HDL. Despite some success in animal studies, failures in clinical studies have turned the focus on the HDL’s interaction with a specific enzyme lecithin:cholesterol acyl transferase (LCAT), responsible for cholesterol esterification, a key step in RCT. ApoA-I, the most abundant protein component of HDL, acts as LCAT cofactor in cholesterol esterification, and many LCAT activating peptides have been developed to mimic the features of apoA-I. The molecular level understanding behind LCAT activation is however still foggy. During enzymatic activation, LCAT goes through conformational changes specific regions, which are generated by interactions with apoA-I or synthetic peptides. These mechanisms have been studied widely with molecular dynamic simulations, in vitro experiments, and imaging. In this study, we investigated 22A (PVLDLFRELLNELLEALKQKLK), apoA-I mimetic peptide known for its as good LCAT activation potency as apoA-I, and four variations of it (21A, 22A-P, 22A-K22Q, and 22A-R7Q), and combined them with phospholipid DPPC to create sHDL nanodiscs by thermal cycling method. We examined the effect of small changes in peptide sequence on LCAT-sHDL binding strength with quartz crystal microbalance with dissipation (QCM-D). The interest was to further test the suitability of thermal cycling method on nanodisc assembly, test the binding strengths against the hypothesis of the role of salt-bridge forming amino acids R7 and K22 in peptide dimerization and its effect on LCAT binding and activation, and to see if QCM could act as a suitable method for the research of sHDL-LCAT interactions. All peptides formed similar sized sHDL particles with diameter of ~10 nm with thermal cycling method. As expected, the LCAT binding tendency of 22A-sHDL was highest, about double compared to four other peptide nanodiscs with almost identical results. The QCM results suggest that binding tendency between LCAT and sHDL is affected by small, one amino acid change in peptide sequence, but it does not necessarily have a big impact on LCAT’s esterification activity, but based on this experiment alone, we cannot make any further conclusions. Electron microscopy revealed exceptional breakdown of 21A-sHDL incubated with LCAT compared to 22A-sHDL. This phenomenon could indicate high lipolytic rate of LCAT but needs further investigation. There were some challenges with the measurement parameters in the beginning, and the variability between parallel measurements with QCM-D was high, which cause a little doubt about the method’s suitability for these kinds of precise measurements. More research for revealing the molecular mechanism behind LCAT activation is needed for the development of more effective treatments.
  • Hedström, Anna (2020)
    The ability to regulate release of noradrenaline, dopamine and GABA is one of the most important roles of the nicotinic receptors. The release of neurotransmitters following stimulation of nicotinic receptors is addressed in the thesis, with focus on dopamine and noradrenaline. Release of neurotransmitters, mediated through nicotinic receptors, has been researched using various methods, including brain slices, microdialysis and synaptosomes. Research using synaptosomes have provided valuable information regarding nicotinic receptors and their ability to regulate neurotransmitter release. Research using receptor specific antagonists have provided information regarding the stoichiometry of nicotinic receptor in different regions of the brain. The primary focus in the thesis, was the characterization of [3H]dopamine release following stimulation of nicotinic receptors with varenicline and acetylcholine, using synaptosomes from mouse striatum. Using a-conotoxin-MII, the [3H]dopamine release was divided into a-conotoxin- MII-resistant and -sensitive release. [3H]Dopamine release was mediated through a6b2*- and a4b2*-receptors from striatal synaptosomes. The involvement of other receptors could not be ruled out, but based on these results and results from previous studies, the involvement of other nicotinic receptors is supposedly low.
  • Salminen, Veera (2021)
    Continuous monitoring of the safety profile of medicinal products is essential also after marketing authorisation approval to ensure the patient safety. Spontaneous reporting of adverse drug reactions is one of the most important methods to collect post-approval safety data of medicinal products. The advantages of spontaneous reporting system include reaching large population throughout a long period of time for many medicinal products, however, it also has some limitations. One commonly recognized problem of the system in many countries is under-reporting of adverse drug reactions. The national reporting scheme in different countries slightly vary, even between Nordic countries. The main aim of this study was to find out what improvements should be done to the current reporting scheme in Finland so that it would better encourage healthcare professionals to report in relevant situations, which respond to the purpose of the spontaneous reporting system. Physicians (n=20), pharmacists (B.Sc.) (n=78), pharmacists (M.Sc.) (n=21) and nurses (n=13) responded to the anonymous open voluntary online questionnaire. Close-ended questions were analyzed and results summarized in graphs and tables. Statistical analysis was done using chi-squared test. Content analysis was performed for open-ended questions by utilizing both, inductive and deductive approach. In the study, we found some differences in healthcare professionals’ opinions what kind of adverse drug reactions should be reported. Some of the healthcare professionals were also aware that they had not reported all suspected adverse drug reactions that came into their knowledge and several reasons were recognized for this. Seriousness of the reaction was considered the most motivating factor for healthcare professionals to report about suspected adverse drug reactions. The results of this study suggest that in healthcare professionals’ opinion, the most important factors that should be considered to improve reporting in Finland are training for healthcare professionals and simplifying the reporting as much as possible. Some differences were noticed between the occupational groups regarding preferences in the reporting route and especially physicians seemed to prefer formation of the report from the information system as a reporting method more than open web-based reporting form. Mobile application for reporting was not preferred that much among Finnish healthcare professionals. The results of this study support the hypothesis that under-reporting of suspected adverse drug reactions is also present in Finland. The reporting instructions should be clarified, training availability should be considered and reporting should be simplified as much as possible to improve the reporting.
  • Porru, Anna (2020)
    Medication-related errors have been identified as the single most important risk factor for patient safety across the world. According to previous research, medication errors are common in nursing homes. However, the existing data on medication errors in Finnish nursing homes is scarce, although the challenges and defects in nursing home care services, including drug treatments, are well known. Furthermore, nursing home residents are typically characterized by old age, multimorbidity and polypharmacy. Therefore, they are particularly vulnerable to potential adverse events caused by medication errors. The aim of this study was to investigate the rates and causes of medication errors reported in nursing homes and evaluate their impact on medication safety. Additionally, the proportions of potentially inappropriate medication (PIMs) and high-risk medication involved in the medication errors were determined. The data of the study consisted of 251 medication errors reports that were submitted to the safety incident report system (HaiPro) in nursing homes located in Central Uusimaa healthcare and social welfare joint municipal authority (Keusote) in 2019. Quantitative analysis of the data provided an overview of the medication errors that had occurred in nursing homes and the medicines most commonly involved in them. Content analysis and simplified root cause analysis enabled to study more in-depth the contributing factors of medication errors and potential risks associated with the medication process in nursing homes, as well as the possibilities of preventing similar errors in the future. James Reason's human error theory and in particular its system perspective was applied as a theoretical framework in this study. Medication errors were reported regularly in nursing homes during the follow-up period of the study. The most frequent medication error type was administration error. The majority of these errors were medication omissions, followed by the wrong time of administration and administration to the wrong patient. The most common drug classes causing medication errors were antithrombotics, opioids, antidementia drugs, diuretics, antipsychotics, antidiabetics, and antidepressants. Nearly a quarter of the reported medicines were high-risk medications, most commonly opioids, antithrombotics, or antidiabetic drugs. PIMs accounted for approximately 13% of all medications in the data. Errors were most often caused by unsafe medication practices, communication problems, and deficiencies in the work environment such as excessive workload or time pressure. A significant part of the medication errors were related to transdermal medication patches. The study also showed that the quality of medication error reporting in nursing homes is in part insufficient and should be improved so that the reports can be better used for learning purposes. The results of the study provide valuable additional information on medication errors in Finnish nursing homes and their contributing factors. The information can be used to improve medication safety practices in nursing homes. Safe and uninterrupted medication use process is a goal that should be pursued not only in health care but also in social welfare services such as nursing homes.
  • Heinonen, Suvi (2020)
    Diacylglycerol (DAG) is a lipid second messenger, which activates classical and novel protein kinase C (PKC) isozymes at the plasma membrane. Abnormalities in PKC signaling have been linked to several diseases, and defective PKC function connects to multiple pathophysiological components of Alzheimer’s disease. However, aimlessly activating all PKC isozymes with synthetic ligands can be problematic, since the activation of certain isozymes can also promote unwanted processes. There are indications that DAGs with varying degrees of acyl chain saturation may have different and specific PKC activating abilities. Thus, understanding how the structural differences in DAGs relate to their behavior at the lipid bilayer may be beneficial for the development of new, isozyme-specific ligands of PKC. The aim of this master’s thesis was to compare the orientation, positioning and dynamics of two unsaturated DAG molecular species, 1,2-dioleoyl-sn-glycerol (DOG) and 1-stearoyl-2-docosahexaenoyl-sn-glycerol (SDG) in glycerophospholipid bilayers using conventional molecular dynamics (MD) simulations and umbrella sampling. The glycerophospholipid bilayers were composed of either 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE) or 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphatidylethanolamine (SDPE), representing the glycerophospholipid environment in the inner leaflet of the plasma membranes in peripheral tissues and in brain tissue, respectively. Both DAG molecular species displayed very dynamic behavior in all systems, with wide distributions of glycerol moiety tilt angles and acyl chain conformations. Multiple occurrences of transbilayer movement (flip-flop) of DAGs was observed during the MD simulations in all systems. In POPE bilayers, SDG was observed to position closer to the aqueous interface compared to DOG, with larger values of solvent accessible surface area (SASA) of the glycerol moiety and the sn-3 hydroxyl group. In SDPE bilayers, no significant difference in this regard was observed between the DAG molecular species. Although potential of mean force (PMF) profiles did not reveal any major differences in the energetically favoured position of the hydroxyl group between the DAG molecular species, the calculations exposed that the dynamics of DOG are affected more by the surrounding lipid environment compared to SDG. Based on these results, it is probable that while the solvent accessibility and overall position of DAGs is affected by the length and degree of saturation of their acyl chains, there are also other mechanisms and processes causing the differing levels of PKC activation yielded by different DAG molecular species.
  • Järvinen, Janina (2021)
    Current treatments for major depressive disorder have notable limitations including the delay achieving the therapeutic effect. Ketamine has been shown to alleviate the symptoms of depression rapidly and promising findings have also been found when using nitrous oxide. However, the mechanisms behind rapid antidepressant effect are not fully discovered. It seems that rapid-acting treatments alter brain energy metabolism, enhance synaptic plasticity, and repair neuronal dysfunction connected to depression. Particularly, the activation of brain derived neurotrophic factor (BDNF) mediated tropomyosin receptor kinase B (TrkB) signaling has been connected to rapid antidepressant effect. Fasting is also known to induce BDNF production and it is thought to activate BDNF-TrkB signaling. In addition, both of these treatments alter the brain energy metabolism. The objective of this study was to find out how fasting and nitrous oxide alone and in combination affect the rapid antidepressant effect and synaptic plasticity related BDNF-TrkB signaling in mice. Another aim of the research was to determine whether the body temperature changes after these treatments as a marker of metabolic rate. The analyzed brain samples of the mice were collected 15 minutes after cessation of nitrous oxide administration. As a result, it was found that the fasting protocol used in this study did not activate the studied BDNF-TrkB signaling. However, after nitrous oxide administration, the studied signaling and markers related to synaptic plasticity were partly activated. The results from the combination of nitrous oxide and fasting were similar compared to nitrous oxide administration only. It is therefore conceivable, that the effects were caused exclusively by nitrous oxide. Furthermore, a fascinating finding related to energy metabolism was that nitrous oxide reduced the body temperature of the mice significantly 15 minutes after cessation of the gas administration. Overall, these results are promising and consistent with previous research indicating that nitrous oxide administration could be related to induced synaptic plasticity and therefore have antidepressant associated effects. Nitrous oxide could be used to understand the mechanisms behind rapid antidepressant effect and it could be a potential option to treat depression in the future. Based on these results, it seems that energy metabolism could be related to rapid antidepressant effect. It also supports the observations that all different rapid-acting treatments alter the brain energy metabolism.
  • Tikkanen, Alli (2019)
    Organic Anion Transporting Polypeptide 2B1 (OATP2B1) is an influx transporter expressed widely throughout the body in tissues such as intestine, liver, brain, placenta and skeletal muscle. Since many clinically used drugs are transported by OATP2B1, changes in the function of the transporter due to genetic polymorphism could lead to altered pharmacokinetics or -dynamics of OATP2B1 substrate drugs. The aim of this Master’s thesis was to create and optimize a cellular uptake assay to study the function of OATP2B1. Furthermore, the aim was to study the effects of six naturally occurring nonsynonymous single nucleotide variants on OATP2B1 transport function in vitro. With site-directed mutagenesis, single nucleotide changes were introduced into the gene coding for OATP2B1. OATP2B1 variants were expressed in human derived HEK293 cell line using baculovirus expression system. A cellular uptake assay with estrone-3-sulfate and a fluorescent probe 4’, 5’-dibromofluorescein (DBF) as substrates was set up and optimized. With the assay, OATP2B1-mediated uptake of variants was compared to the transport activity of OATP2B1 wild type. Amino acid changes Ser486Phe and Cys520Ser impaired OATP2B1 transport function severely. In addition, variant Thr318Ile transported DBF and estrone-3-sulfate less efficiently compared to OATP2B1 wild type, but Arg312Gln, Thr392Ile and Ser532Arg transport function was not affected. A method to study OATP2B1 function was created successfully. According to the results, single amino acid changes in OATP2B1 can impair OATP2B1 function. The results and method can be utilized to understand findings from pharmacogenetic studies in vivo, and to predict consequences of especially rare variants, which can be difficult to detect in small sample populations in clinical studies. However, further studies on the expression level and cellular localization of OATP2B1 variants are needed to fully characterize the impact of the variants studied.
  • Rossi, Vilma (2020)
    Background: Inhaled therapy is the most widely used treatment for asthma and chronic obstructive pulmonary disease (COPD). Inhaled medicinal product has several advantages, including high local drug concentration in the lungs and reduced systemic adverse effects. However, the challenge with inhaled therapy is that many asthma and COPD patients do not know how to use their inhaler properly. Suboptimal inhaler use can lead to poor clinical control. The Association of Finnish Pharmacies has developed inhalation technique assessment service (ITAS) to detect and correct patients’ inhalation technique and to give information regarding the inhaler and inhaled therapy, such as drug storage and oral care. Objective: The aim of the study is to investigate whether asthma and COPD patients’ ability to prepare the Respimat inhaler and the patients’ ability to properly inhale the drug improve after receiving ITAS. The second objective is to find out what patients and pharmacists think about the service and which customer groups benefit the most from the service. Methods: The study design is an uncontrolled pre-post intervention. 33 pharmacies participated in the study. All patients who were buying a prescribed Respimat inhaler, were offered to participate in the study. Patients’ inhalation technique was assessed before (baseline) and immediately after ITAS (follow up 1). In addition, the inhalation technique was assessed the next time the patient came to pharmacy to buy Respimat inhaler (follow-up 2). Questionnaires were used to assess patients’ and pharmacists’ perceptions of ITAS. Results: 228 baseline and follow-up ITAS were performed. The results of follow-up 2 will be published later in a separate article. 14 % of the patients performed all the steps (both inhaler preparation before first inhalation and inhalation process itself) correctly at baseline. After ITAS the number increased to 77 %. At baseline 30 % of the patients had an optimal inhalation technique (all inhalation steps correct) and after ITAS the number increased to 85 %. 70 % of the patients had an acceptable technique (all critical steps correct) before and 93 % after ITAS. Both patients and pharmacists felt that the service was beneficial to the patients when thinking the proper inhaler preparation and proper inhalation technique. Overall patients’ and pharmacists’ satisfaction were high towards ITAS. Our study indicates that patients benefit from ITAS regardless of patient’s age or how long the patient have been using the Respimat inhaler. Conclusions: A pharmacist-led inhalation technique assessment service significantly improves asthma and COPD patients’ inhalation technique with Respimat inhaler. ITAS should be performed regularly as part of the delivery of the inhaled drug to the patient. Further research is needed on the effectiveness of ITAS with other inhalers.
  • Lindstedt, Hanna (2022)
    Drug-induced liver injury (DILI) is a relatively rare hepatic condition that can be classified as predictable and unpredictable. However, DILI is a primary reason for drug withdrawals, post-marketing warnings, and restrictions of use. DILI is a problem for the drug users but also for the pharmaceutical industry and regulatory bodies. From the perspective of patients' and clinicians', DILI is the major cause of acute liver injury. At present, a major problem predicting DILI in drug discovery is a poor understanding of its mechanisms as well as the complexity of DILI pathogenicity. The main mechanism behind DILI are alterations in bile acid homeostasis, oxidative stress, and mitochondrial dysfunction. More than 50 % of drugs causing DILI are causing mitochondrial impairment. If the normal function of mitochondria is disturbed, the energy production of the cell decreases, and cell function decline leading eventually to the cell death. In this study prediction of mitochondrial toxicity was studied using cryopreserved primary hepatocytes of humans and rats. The aim of the study was to clarify if there are interspecies differences in the prediction of toxicity but also investigate possible differences in the mechanisms behind hepatotoxicity by using three well-known compounds toxic to mitochondria. To determine these differences, total cellular ATP was measured after 2- and 24- hour exposure time to gain information on overall viability and possible adaptive responses. Mitochondrial energy pathways were studied as a real-time monitoring acute exposure of test compounds. Morphology, location, and possible adaptive response of mitochondria were studied using a fluorescent probe and antibody staining combined with high content imaging (HCI). Overall, primary rat hepatocytes were more sensitive to the test compounds than human hepatocytes. Also, there were differences between human hepatocyte batches that may reflect the metabolic differences between hepatocyte donors. Immunolabeling did not bring any additional values compared to the fluorescent probe staining in the study of morphology of mitochondria. Additionally, it was noticed that treatment with paraformaldehyde significantly changed the hepatocyte mitochondria morphology. Overall, more effort is needed to develop image analysis of mitochondria morphology. Finally, studying mitochondrial morphology has proven to be difficult, and this study did not unfortunately reveal any information about the adaptive responses of mitochondria for drug-induced liver injury.
  • Böhling, Linda (2021)
    Tablet is the most common pharmaceutical dosage form due to ease of administration, chemical and physical stability, and relatively low manufacturing cost. Direct compression is the preferred method for tablet production. Direct compression formulations typically contain a considerable amount of excipients. Therefore, excipients can have a significant effect on the tableting properties of formulations. More research is needed for better comprehension of the compression behaviour of different materials. The objective of this work was to investigate tableting properties of different excipients and their binary mixtures with two different laboratory scale tableting devices; the Gamlen® D1000 Powder Compaction Analyzer and the FlexiTab®. The excipients used were microcrystalline cellulose (MCC), lactose, mannitol, starch, and dicalcium phosphate (DCP). Different compression pressures were used to survey the compression behaviour of the excipients at a wide pressure range. In addition, potential effects of compression speed, dwell time, and lubrication method were considered. The excipients and their binary mixtures were characterised based on compressibility (solid fraction vs. compression pressure) and tabletability (tensile strength vs. compression pressure). The results obtained with the devices were compared to enhance process understanding. Based on the compressibility curves, it appeared that plastic deformation was the main compression mechanism of MCC and starch and fragmentation the main compression mechanism of lactose, mannitol, and DCP. The tabletability of MCC was excellent, and also the tabletability of mannitol was good. The tabletability of DCP was intermediate, whereas lactose and starch had inferior tabletabilities. In general, the tabletabilities and compressibilities of the binary mixtures were more or less what was expected based on the results of the individual materials. The results obtained with the different speed parameters and lubrication methods were mainly in line with the perceptions of the compression mechanisms of different materials. In overall, the results obtained in the Gamlen and FlexiTab experiments were quite similar. However, tensile strengths appeared generally slightly lower in the FlexiTab experiments. Probable explanations are the higher compression speed of the FlexiTab and differences in hardness measurements. This study indicated that the FlexiTab and Gamlen devices have different benefits. The Gamlen device is clearly very suitable for investigating tableting properties during formulation development, but the FlexiTab device has the advantages of higher compression speed and automatic powder feeding mechanism. Tabletability results were slightly better with the Gamlen, but more experiments are needed for solving the reasons (e.g. compression speed and hardness measurements). More information of the compression behaviour of different materials could be obtained by analyzing punch displacement data and by using different compression equations.