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  • Rauvala, Oskari (2023)
    Rodent studies indicate that the effects of pharmacological antidepressant treatments depend on the TrkB (tropomyosin-related kinase B) receptor of the neurotrophic factor BDNF (brain-derived neurotrophic factor). However, the mechanism by which TrkB signaling becomes active remains disputed. Our group proposes that the activation of TrkB signaling is a result of an indirect physiological adaptation to the drug treatment, which is supported by observations made with rapid-acting antidepressants ketamine and nitrous oxide. Previous studies indicate that the immediate effects of the drugs are followed by a sedative state resembling deep sleep, during which TrkB signaling becomes active. The sedative state is accompanied with a drop in core body temperature, and preliminary findings indicate that preventing the drug-induced hypothermia blocks TrkB signaling in the cortex.    The purpose of this study was to investigate the effect of ambient temperature on TrkB signaling in the hippocampus following nitrous oxide administration. Nitrous oxide (65 % ad 100 % O2) was administered to adult male mice for 20 minutes. After the drug treatment the animals were kept in different recovery conditions: room temperature or a heightened ambient temperature of approximately 36 °C for 15 minutes. Following the recovery, the animals were euthanised, and hippocampus samples were collected from the animals. Levels of BDNF and TrkB signaling were analysed with ELISA and western blot, respectively.    Nitrous oxide caused a significant drop in core body temperature, but this was not accompanied with increased BDNF levels or TrkB signaling. Evidence suggests that hippocampal atrophy contributes to depression, but the acute effects of antidepressant treatments on TrkB signaling in this brain area appear to be less pronounced than those seen in the prefrontal cortex. The findings indicate that nitrous oxide has a replicable hypothermic effect, but this is not associated with increased TrkB signaling in the hippocampus.
  • Hakala, Elina (2011)
    The aim of this study was to explore the functions of T-type calcium channels, and their possible role in neuronal stem cells migration. The role of T-type calcium channel in mature brain is known to be in producing electroencephalographic oscillations. This action in turn is the key factor in some neuronal physiological and pathophysiological functions, like non-REM sleep, memory, learning and absence epilepsy. In addition, T-type calcium channels have peripheral actions, but this study concerns on its neuronal functions. This low-voltage activated channels functions in neurogenesis is less known than its role in mature brain. It is known to promote neuronal proliferation and differentiation, but what comes to its possible actions in neuronal migration, is poorly studied. This study shows some evidence of T-type calcium channel taking part in neuronal migration in mice embryonic subventricular zones progenitor cells. Selective T-type antagonists, ethosuximide, nickelchloride and a scorpion peptide toxin kurtoxin, decreased the rate of migration in differentiating progenitor cells. This study consists of a literature review and an experimental part. Another aim of this study is to consider an alternative approach to stem cell therapies based on invasive transplantation of the cells. This other attempt is non-invasive manipulating of endogenous stem cells to proliferate and migrate to the injured or depleted area in the brain, differentiate into a desired phenotype and stop their division after they have completed their mission. Non-invasive altering of the stem cells is awaiting pharmacological solutions to resolve the problems being faced in this effort. There are some non-invasive therapies already being used successfully to cure pathological conditions such as spinal cord injury. These methods could be used as well in stem cell based therapies in the treatment of neurodegenerative diseases and brain injuries. These methods are still in the beginning of their way and lacking the full understanding of the key factors that affect neuronal development. These factors include some important endogenous inducing and inhibiting substances. One of the most important inducing substances is calcium ion regulating a variety of events in neurogenesis. T-type calcium channel, as being widely expressed during early brain development, and decaying by neuronal maturation, might have a pivotal role in conducting progenitor cells.
  • 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.
  • Mäntylä, Juhani (2012)
    Inflammatory bowel diseases are among the fastest growing chronic disease of young people in Europe and they are increasing in Western countries for unknown reasons. Illness often occurs at a young age and the symptoms persist generally throughout life, Crohn's disease and ulcerative colitis are the most common diseases in this category. Inflammatory bowel diseases often cause persistent symptoms and require treatment usually for life, affect the quality of life and the ability to go to work. Conventional treatment usually consists of anti-inflammatory and immunosuppressive drug therapy or surgical intervention. In difficult cases, the biologic drug treatment is used. New biological drug products (TNF-blockers) have improved, in particular in Crohn's disease, a response to treatment. The aim of this study is to provide information about the effectiveness and the costs of the biological treatment in inflammatory bowel diseases. The main results presented are the changes of the quality of life during the observation period measured with the generic and disease-specific HRQoL instruments. The results are also reported on the matter of costs for quality-adjusted life-years gained during the follow-up period. The study consists of FinnIBDQ (inflammatory Bowel Disease Questionnaire) survey (n=2831) and the follow-up survey of the patients who used biologic drug products (n=189). Patients were selected into the follow-up if they reported using the biologic drugs to treat the illness. FinnIBDQ-survey was conducted in 2006/2008 and follow-up questionnaire in 2011. As a generic HRQoL instrument was the 15D-instrument used which is a standardized measure of the health related quality of life. 15D-instrument produces a single index number between 0-1. IBDQ is a disease-specific HRQoL instrument, which consists of 32 questions. The total number of points varies between 32 and 224 from the worst to the best. Patients' medical history, symptoms, medication and health care use were studied in their own partition on the questionnaire. Biological drug therapy group belonged at the baseline (n=148) improved the quality of life (p=0.004) during the follow-up. A disease-specific HRQoL instrument (IBDQ) shows the quality of life has changed in parallel (p=0.003)with the 15D-instrument. Dimensions, where progress was achieved (p<0.05) were the elimination, the usual activities, discomfort and symptoms, as well as vitality and sexual activity. In the research group (n=51), the average cost per patient per QALYs gained during the follow-up period proved to be very high, at over 5 million euro's. During this time, the patient gained an average of 0,01 quality adjusted additional years of life. The evidence of the long-term impact of the biologic drug treatment on the patient's quality of life is still scarce. In most of the research concerned with the benefits of biological treatment, the effectiveness data is derived from the pharmaceutical manufacturers' short-term clinical efficacy studies, or taken from any other quality of life studies.
  • 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.
  • Lahtinen, Ida (2011)
    Celiac disease is life-long autoimmune disorder of the small intestine, which is caused by a reaction to gliadin found in wheat, rye and barley in genetically predisposed individuals. Proline- and glutamine -rich proteins cause villous atrophy and crypt hyperplasia with extensive inflammation in the epithelium and lamina propria. Symptoms of celiac disease vary considerably and elimination of gluten from diet is the only way to treat disease. In small intestine of celiac disease patient transglutaminase 2 (TG2) modifies gluten peptides, which causes T-cell activation and inflammation in the epithelium of mucosa. T-cell activation induces development of celiac disease specific antibodies. These celiac disease specific antibodies recognise TG2 and interfere in vitro and in vivo in angiogenesis. Abnormal angiogenesis is typical in many disorders, such in cancer, in which TG2 has a crucial role in the development and growth of tumor. Overexpression of TG2 has been shown to correlate with accelerated growth of tumor. TG2-specific antibodies are suggested to inhibit differentation of epithelial cell, increase their proliferation, decrease their barrier-function and increase the permeability of blood vessels. The aims of the pilot study were to establish whether celiac disease TG2 antibodies affect in vivo tumorigenesis and tumorangiogenesis as well as to try to clarify the mechanism behind the phenomenon. Tumor xenograft model was used in severe combined immunodeficient (SCID) mice. Human oesophageal carcinoma (OE-19) cancer cells were incubated with celiacs TG2 miniautoantibody (mini 2.8), non-celiac miniautoantibody (mini 6.2) or PBS before cancer cells were injected to mice subcutaneously. During the experiment mice were weighted and tumor size was measured couple of times per week. To estimate the volumes of tumors the following formula was used: π/6 * L* W* H. Experiment lasted for four weeks after which the mice were euthanized, cardiac blood and tissue samples taken and tumours were excised and weighted. Sections were made from tumors and immunohistochemical stainings were done to compare blood vessel areas and to study general tumors'morphology and other parameters. Western blot -analyse were performed to cancer cells. The masses and volumes were clearly smaller in mini 2.8-group compared to control groups and the necrotic area of tumor in mini 2.8 was smallest as percentage compared to control groups. Blood vessel area were smallest in mini 2.8 group. Results suggest that celiac disease anti-TG2-autoantibodies inhibit tumor growth, but the number of animals is insufficient to give an accurate outcome.
  • Niemelä, Aliisa (2023)
    Annually thousands of Finnish children are placed in foster care as a measure of child welfare. Institutional foster care is provided by child welfare institutions. Social and health care professionals, such as bachelors in social services, youth workers, practical nurses, and registered nurses working in these institutions are responsible for carrying out the children’s medication treatment. Depending on completed basic and additional training and work experience, the personnel have varying competencies in medication treatment. The aim of this study was to provide research-based information on the challenges and development needs related to the safe and rational medication treatment of children in foster care living in child welfare institutions. This was studied from the point of view of institution personnel and social workers responsible for placement decisions. Furthermore, the study investigated the medication use process of children in institutional foster care and, how the child’s health and medication treatment related needs are considered in the placement process and in selecting the foster care place. The study was conducted as a qualitative study using focus group discussions (FGDs) carried out to child welfare social workers (n=1) and child welfare institution personnel (n=10) during November and December 2022. Semi-structured focus group discussions (n=3) were conducted over the video conferencing software Microsoft Teams®. The participants (n=11) were recruited through child welfare services of Central Uusimaa Wellbeing County. Qualitative content analysis was used to analyze the data. According to the focus groups, medication treatment is common among children living in child welfare institutions. In the daily life of child welfare institutions, there were challenges and development needs related to medication treatment and medication use process. The main challenges and development needs were the lack of up-to-date information regarding the children’s health status and medication, challenges in organizing acute medication treatment, the personnel’s up-to-date drug administration permissions and varying competencies in medication treatment. In addition, fragmented overall responsibility of the medication treatments and poor access to healthcare presented challenges for organizing and carrying out medication treatment for the children. Medication use process during foster care appeared to be fragmented and it was seen to be susceptible to errors. According to this study, the possibilities for taking children’s health status and medical needs into account at the point of placement were scarce. These needs often did not guide placement decisions. Considering the medication use process and medication safety, it is essential that child welfare institutions have access to up-to-date health and medication information of the children. To achieve the best interests of the children, organizing acute medical treatment should be facilitated and the overall responsibility health care and medication therapy clarified. In addition, seamless access to the necessary healthcare must be ensured for children in foster care. Considering medication safety, it is important to ensure that the personnel of child welfare institutions have up-to-date competencies in medication treatment that meet the needs of the children.
  • Hämäläinen, Sanni (2019)
    Kasvavan antibioottiresistenssin vuoksi terveydenhuollossa tarvitaan uusia antibiootteja ja antibioottien apuaineita. Tästä syystä tässä työssä tutkittiin Combretaceae- ja Annonaceae-heimoihin kuuluvien tansanialaisten lääkekasvien antibakteerisia vaikutuksia. Kansanlääketieteessä näitä kasveja on perinteisesti käytetty mm. bakteerien aiheuttamien sairauksien ja oireiden hoitoon, mikä antaa viitteitä siitä, että ne sisältävät antibakteerisia yhdisteitä. Tutkimuksen tarkoituksena oli pyrkiä löytämään raakauutteita ja neste-nesteuutolla saatuja fraktioita, joilla on mahdollisimman hyvät estovaikutukset bakteerien kasvuun. Lisäksi oli tarkoitus selvittää Annonaceae-heimon lajien sisältämiä yhdisteitä, mikä voi osaltaan auttaa löytämään uusia antibiootteja. Antibakteerisia tutkimuksia tehtiin Combretaceae- ja Annonaceae-heimoihin kuuluvien Combretum-, Terminalia-, Friesodielsia- ja Hexalobus-sukujen lajien uutteille ja fraktioille käyttäen agardiffuusio- ja mikrodiluutiomenetelmiä. Yhteensä 45 eri uutteen ja fraktion estovaikutuksia tutkittiin ruokamyrkytyksiä aiheuttavien Bacillus cereus - ja Salmonella enterica -bakteerien kasvuun. Lisäksi tutkittiin Annonaceae-heimoon kuuluvien Friesodielsia obovata - ja Hexalobus monopetalus -lajien uutteiden ja fraktioiden sisältämiä yhdisteitä käyttäen HPLC-DAD - ja UHPLC/Q-TOF-MS -menetelmiä. Tutkimustulosten perusteella useilla Combretaceae- ja Annonaceae -heimoihin kuuluvilla lajeilla on antibakteerisia vaikutuksia grampositiivista B. cereus -bakteeria vastaan, mutta ei niinkään gramnegatiivista S. enterica -bakteeria vastaan. Aiemmissakin tutkimuksissa on usein, ei kuitenkaan aina, saatu parempia estovaikutuksia grampositiivisten kuin gramnegatiivisten bakteerien kasvuun. Tässä tutkimuksessa parhaimmat tulokset (MIC = 156 µg/ml) saatiin mikrodiluutiomenetelmällä B. cereus -bakteerin kasvun estoon Combretum fragrans -lajin lehtien kuumalla Soxhlet-metanoliuutteella ja Friesodielsia obovata -lajin lehtien metanoliuutteen veteen liukenemattomalla fraktiolla. Tarvitaan kuitenkin vielä paljon lisätutkimuksia, varsinkin H. monopetalus - ja F. obovata -lajien kohdalla, jotta voidaan selvittää, voidaanko tutkituista kasviuutteista ja niiden fraktioista eristää mahdollisia uusia antibiootteja tai antibioottien apuaineita ihmisten ja eläinten infektioiden lääkintään. Annonaceae-heimon lajeista löydettiin samantapaisia yhdisteitä kuin on löydetty aiemmissa tutkimuksissa, mutta 6,8-dimetyyli-monohydroksi-pinosembriiniä karakterisoitiin ensimmäistä kertaa F. obovata -lajista. F. obovata -lajin lehdistä tunnistettiin ensimmäistä kertaa (-)-krotepoksidi ja krotepoksidin johdannaisia. Lisäksi H. monopetalus -lajin juuresta karakterisoitiin ensimmäistä kertaa 3-(2',3'-dihydroksi-3'-metyylibutyyli)-5-(3''-metyylikrotonyyli)indolia, 3-(1,3-dihydroksi-3-metyylibut-2-yyli)-6-(2-hydroksi-3-metyyli-3-butenyyli)indolia sekä heksalobiini C:tä ja D:tä.
  • Vuorela, Maiju (2014)
    The aim of this Master's Thesis was to assess experiences of access to medications and follow up services. The aspects studied were: access to medications from the public's perspective, also in relation to availability of follow-up services and support for self-management in long-term medications, and difficulty to buy necessary medicines due to economic reasons. The respondents were also asked to identify needs for developing new customer-oriented services for follow up of treatments. The data were collected during December 2013 and January 2014 by an email survey to those registered in the loyal customer program of University Pharmacy. The data were analyzed by using the statistical programme SPSS. Responses to open-ended questions were analyzed (a preliminary analysis). Respondents' age, gender, area of residency and financial situation were used as background variables. 606 responses were received (84% women, 16% men). The mean age of the respondents was 53.5 years and 91% had at least one disease or symptom diagnosed by a doctor. Almost all (93%) used some medicine or vitamin product. Eleven percent of the respondents reported that they had not been able to purchase a medicine they needed due to poor personal financial situation. A majority (85%) of the respondents perceived their health status as good. The average number of visits at the doctor during a one year period was 5.5. About 22 % of the respondents reported that they were not able to get an appointment when they needed it. About half of the respondents had regular health controls by a doctor. The respondents indicated a wish that getting the appointment regularly should be easier and that there should be time to have a holistic discussion on one's care. About half had a personal doctor and 42% had a medication card. The most common ways to self-monitor one's care were by observing general health status, measuring blood pressure and weight. Almost two-thirds (63%) discussed the monitoring results with their doctor. Many respondents reported in the open comments that they did not have instructions for self-monitoring and there was no healthcare provider to share the results with. The respondents wanted have more information concerning the reasons to use medicines, and the benefits of a long-term medicine use. They also wanted to know more about adverse effects and interactions, as well as about non-pharmacological treatment options. The prescriptions were most commonly renewed at the doctor's office (47%).The respondents also expressed a wish to have more options to contact their healthcare providers, e.g., though electronic services (online doctor, email counselling). There are limitations in the Finnish health care system from the medication management's perspective. Aspects needing improvement include access to regular controls and follow-up services, having more options to contact healthcare providers, also through electronic services, having better access to information on diseases and medication, and finally, improve caring for people's health concerns in a holistic way.
  • Nenonen, Satu (2017)
    Ankylosing spondylitis is an inflammatory rheumatoid disease, that is typically diagnosed in young adults. The symptoms include inflammatory back pain, rigidity in the lumbar and thoracic spines, and peripheral inflammations. The incidence of ankylosing spondylitis among northern European population ranges from 0.2 to 0.5%. The mortality rate of people with ankylosing spondylitis is about 50% higher than in the average population. First-line treatment for ankylosing spondylitis includes physiotherapy and NSAIDs. TNF inhibitors are used for patients whose symptoms cannot be controlled with first-line treatment. In Finland, there are five TNF inhibitors indicated for ankylosing spondylitis on the market: infliximab, etanercept, adalimumab, golimumab, and sertolizumab pegol. In 2015, the average medication cost for a patient entitled to reimbursement for TNF inhibitors in Finland was over 12 000 €. The cost-effectiveness of TNF inhibitors in the treatment of ankylosing spondylitis compared to conventional care has been extensively studied, but there is less data on the differences between TNF inhibitors. In this thesis, previously published literature on the cost-effectiveness of TNF inhibitors in the treatment of ankylosing spondylitis was reviewed, and a patient-specific simulation model based on data from the National Register for Biologic Treatment in Finland was conducted. The aim of the simulation was to compare the cost-effectiveness of TNF inhibitors (infliximab, etanercept, adalimumab and golimumab) in the treatment of ankylosing spondylitis as the patient's first biological treatment compared to other TNF inhibitors. The simulation was conducted on a lifetime time horizon and incorporated direct health care and medication costs in 2015 euros. As conclusions of the model, all other TNF inhibitors were found dominant over etanercept. The greatest effectiveness was achieved with golimumab, while the costs were lowest with infliximab. The incremental cost-effectiveness ratio of golimumab compared to infliximab was 63 840 €/QALY. In sensitivity analyzes, the model was found to be very sensitive to TNF inhitors' prices. In addition, sensitivity was also observed for the discount rate and time horizon used.
  • Tamminen, Tuulia (2012)
    Parkinson's disease is a progressive degenerative brain disease that causes degeneration of dopaminergic neurons in the substantia nigra. Characteristic motor symptoms in Parkinson's disease are caused by dopamine deficiency in striatum. Tyrosine hydroxylase (TH) is the enzyme that catalyzes the rate-limiting step in the dopamine biosynthesis. Because of this TH has a significant role in the function of the dopaminergic system. TH activity is regulated by several mechanisms. The most important regulatory mechanism is phosphorylation of TH protein by spesific protein kinases. Alterations in the function of TH have been associated with Parkinson's disease. The most prominent findings are decreased TH protein and TH mRNA content in the nigrostriatal dopaminergic neurons. A possible pathogenic role of TH in Parkinson's disease has also been suggested. In addition TH might be a potential therapeutic protein for gene therapy. One possible approach is viral vector-mediated gene transfer of TH gene directly into the brain. Simultaneous gene transfer of TH gene and neurotrophic factor gene could both enhance dopamine synthesis and prevent remaining dopaminergic neurons from dying. None of the current treatments of Parkinson's disease can halt or retard dopaminergic neuron degeneration. Novel treatments are being developed and amongst other strategies neurotrophic factors have proven promising candidates for the treatment of Parkinson's disease. Member of CDNF/MANF family of neurotrophic factors, cerebral dopamine neurotrophic factor (CDNF), is currently being studied. Previous studies have demonstrated the neuroprotective and neurorestorative effects of CDNF but more research is needed for optimal administration technique and dose. The aim of this work was to study the neuroprotective effect of AAV vector-mediated delivery of CDNF (AAV-CDNF) in a rat model of Parkinson's disease. Rats' brains were unilaterally lesioned with intrastriatal injection of 6-OHDA two weeks after viral vector injections and amphetamine-induced rotational behavior was monitored for ten weeks. The CDNF protein expression after intrastriatal AAV vector-mediated gene transfer was analyzed with immunohistochemical staining of brain sections. We confirmed that CDNF protein is expressed in rat brain after intrastriatal injection of AAV-CDNF. AAV-CDNF treatment also reduced the amphetamineinduced ipsilateral rotations nearly as much as AAV-GDNF treatment. AAV-CDNF treatment also had an effect on the amount of remaining TH-immunoreactive cells in the substantia nigra pars compacta and the optical density of striatal TH-immunoreactive fibers but these results did not reach statistical significance. The immunohistochemical measures did not correlate completely with the behavioral data and further studies are needed to confirm the results obtained here. The results of this research support the conclusion that AAV-CDNF treatment has a neuroprotective effect on nigrostriatal dopaminergic neurons.
  • Kontti, Arttu (2014)
    Parkinson's disease causes changes in the basal ganglia GABAergic neurotransmission in addition to the well-known dopaminergic changes. These GABAergic modulations may cause somed of the symptoms not responding well to the standard dopaminergic medication. Neurotrophic factors are a group of endogenous proteins showing promise as a future treatment for Parkinson's disease. They are known to have neuroprotective and neurorestorative effects on the dopaminergic cells. Their effects to the GABAergic cells are still mostly unknown. Intrastriatal injection of GDNF to rats caused significantly slower weight gain compared to CDNF, MANF one week after stereotaxic operation (p=0,002 for CDNF vs. GDNF and p<0,001 for MANF vs. GDNF). Difference to the vehicle (phosphate buffered saline) used as a negative control was not statistically significant (p=0,055). Three weeks after the operation the differences between the treatment groups were no longer statistically significant. Because of problems with the separation in analysis, microdialysis samples remain still to be analysed. To help the analysis of GABA in the future we determined the analytical parameters of the analytical apparatus. We also defined differences in probe permeability between 1 mm and 2 mm probes and between old and new batches. GABA analysis was performed with a HPLC-fluorometric detection of o-phtaldialdehyde-derived GABA. Detection limit for old apparatus was 7,2 nM and for new apparatus 6,2 nM in a sample of 15 µl (0,11 pmol and 93 fmol respectively). Quantification limits defined were 22 nM and 19 nM (0,33 pmol and 0,28 pmol) for the old and the new apparatus, respectively. Upper limit of quantification was estimated to be 246 nM (3,7 pmol). Probes had significant differences in permeability between 1 mm and 2 mm probes, as well as between batches. The variance of permeability of 1 mm probes was estimated to be approximately twofold compared to the 2 mm probes. Furthermore the permeability of 1 mm probes varied between batches significantly. An average of permeability of the old batch was 34 % lower than that of a new batch (p<0,001).
  • Heinonen, Pia (2021)
    Oxygen has been used as a medicine since the 18th century and is widely used as prescription and over-the-counter (OTC) medicine. Especially with global COVID-19 pandemic, which started in 2020, the demand for medicinal oxygen has increased significantly and the quality of medicinal oxygen has become increasingly important. Only few studies have been published on the critical process and quality parameters of gases and their impact on product quality. Because oxygen is classified as a medical product, it must be manufactured in accordance with good manufacturing practices regulations (GMP). One part of EU and other GMP guidelines is mandatory annual product quality review (PQR) which must assess the critical quality and process parameters as well as their trends. The aim of the study was to define the critical process and quality parameters for the medicinal oxygen filling process and to analyze the process control, stability, and capability for annual PQR using process data. Process stability and the state of control of processes were assessed using statistical quality and process management tools, such as the Shewhart control diagram and process capability index. Studied process parameters included vacuum level and pressure measured by the filling equipment. Evaluated quality parameters included analysis pressure, O2 and H2O contents. The results of the study showed that the process is not stable and there was a lot of variation between the parameters. Most variation was detected between different cylinder volumes and filling and analysis ramps in all parameters and between different weekdays in H2O content. However, all parameters remained within the specification limits and the Cpk values of all critical parameters were good. By analyzing the data, many variables that can affect the parameters and add variation to the process data can be identified. Based on the results, the necessary measures to improve and optimize the process and quality was identified. In order to stabilize processes and improve performance, the demonstrable variation in process data should be reduced, for example by harmonizing operating methods. According to the study, it was also possible to assess the revalidations required for the process.
  • Krannila, Elina (2012)
    In pharmaceutical industry GMP compliance and quality of operations can be ensured with quality management system (QMS). QMS is an operational system, which consist of multiple different elements depending on the size of the company and nature and complexity of its operations. For the QMS to be functional, documented and defined operations need to be managed and monitored systematically. Conducting internal audits has been considered necessary with regard to QMS, though it has not always been perceived as adding value or seen as an opportunity to utilise more fully. Internal audits are mainly utilized to control compliance to requirements. However, there are possibilities to utilise it more in improving and developing operations, preparation to external audits, quality risk assessment, finding out the best practices, basis for decision making, learning experience as well as the assessment of functionality and effectiveness of the QMS. The aim of this study was to examine the utilisation of internal audits in Orion (Espoo) and find solutions to improve the utilisation of internal audits with QMS. The focus was on how internal audits can monitor and guide QMS and what is required from internal audits for monitoring and guidance of QMS. These aims were approached qualitatively by conducting semi-standardized open-ended interviews. Interviewees (n=9) were selected from both auditor and auditee side and they had their background in quality assurance or production. Data compiled from these interviews was analysed mainly by qualitative methods, using also some quantitative analysis. Monitoring of the QMS can be looked at as the starting point to guide QMS. Valuable information can be gathered with internal audits with regard to QMS. By utilising this information, internal audit process and QMS can be improved and the quality of operations can be ensured. Based on this work internal audits can be utilised to monitor and have the potential to guide QMS under certain conditions. Internal audit topics need to be systematically selected, QMS needs to be monitored and guided based on the internal audit findings, flow and distribution of information needs to be efficient and flexible, and internal audits should be better utilised and managed. Further research is needed on the development and deployment of tools to aid better utilisation of internal audits in the control of QMS. Also ways to measure the effects of internal auditing should be further investigated.
  • Keskimäki, Sanne (2023)
    Plasmidit ovat geneettisiä elementtejä, joita voidaan käyttää esimerkiksi geeninsiirtovektoreina. Transposonit ovat DNA-fragmentteja, joilla on kyky siirtyä genomissa paikasta toiseen. Tutkimuksessa käytettävä transposoni on piggyBac, joka on eristetty tupsumetalliyökkösen (Trichoplusia ni) soluista. Transpositiossa piggyBac tunnistaa ITR-osat (käännetty terminaalinen toistojakso) siirtäen osien välissä olevan DNA:n. Tutkimuksen tavoitteena oli tuottaa kaksi erilaista plasmidia. pAc5.1-piggyBac-plasmidiin sisällytettiin piggyBac ja pMT-In-EGFP-PB-ITR-plasmidiin ITR-osat sekä niiden väliin hygromysiiniresistenssigeeni sekä EGFP-geeni. BTI-Tn-5B1-4-solujen DNA:sta eristettiin piggyBac sekä ITR-osat ja ne siirrettiin plasmidiin pTOPO-piggyBac-R. Tästä plasmidista irrotettiin erilleen piggyBac ja ITR-osat, joista välivaiheiden kautta rakennettiin lopulliset plasmidit. Plasmidit rakennettiin pitkälti pilkkomalla DNA-fragmentteja restriktioentsyymeillä ja yhdistämällä niitä ligaatiolla. Plasmideja tuotettiin suurempia määriä siirtämällä niitä transformaation avulla E.Coli-soluihin lämpöshokkimenetelmällä ja eristämällä tämän jälkeen saadut plasmidit. Tuotettujen plasmidien onnistuminen varmistettiin pilkkomalla ne restriktioentsyymeillä ja tutkimalla DNA-fragmenttien kokoa agaroosigeelielektroforeesilla. Plasmidinäytteet myös sekvensoitiin osittain. Banaanikärpäsen (Drosophila melanogaster) S2-solut transfektoitiin kehitetyillä plasmideilla ja solukonsentraatioita sekä elinkelpoisuutta mitattiin 8 päivän ajan transfektion jälkeen. Tavoitteena oli hyödyntää EGFP-geeniä fluoresenssimittauksiin. Solunäytteisiin lisättiin kokeen aikana hygromysiini, jotta voitiin selvittää, olivatko viljellyt solut saavuttaneet hygromysiiniresistenssin. Tutkimuksen tuloksena plasmidit saatiin kehitettyä, mutta solukokeiden tulokset jäivät epäselviksi. Solunäytteissä ilmeni kasvatuksen aikana kontaminaatioita. Lisäksi EGFP-osia ei voitu luotettavasti mitata käytössä olleella laitteella. Transfektio tulee siis toistaa transposonisysteemin toiminnan tutkimiseksi. Lisäkokeilla voidaan selvittää tarkemmin kehitetyn transposonisysteemin mahdollisuuksia sekä toiminnan yksityiskohtia.
  • Tilli, Irene (2017)
    Melanoma is the most severe case of skin cancer and there is no curative treatment if it has progressed. Despite the recent advances in drug therapy tens of thousands of patients die of melanoma annually. There is still need for new antimelanoma drugs for which marine compounds are a potential source. Halogens are common elements in drug molecules as they enhance their molecular properties. So far most of the halogenated drugs contain fluorine and/or chlorine but the role of bromine and iodine is probably growing in the future due to halogen bonding. Bromotyrosines are originally isolated from Verongiida-order sponges but whether they are truly of bacterial origin is under controversy. All bromotyrosine compounds consist of brominated tyrosine and/or tyramine residues or their derivatives. Purpurealidin I is one of the newest bromotyrosine derivatives extracted from Pseudoceratina purpurea and it has shown activity against melanoma. In this study eight new purpurealidin I derivatives were synthesized following a successful route previously designed. All synthesized derivatives contained the original N-oxime structure which's stereochemistry was determined to be E by X-ray crystallography. Cytotoxicity against A375 melanoma cells was determined for seven compounds synthesized here and for 15 compounds synthesized previously. All seven compounds and one previously synthesized purpurealidin I analog were active with CC50 values between 4,7 and 22,1 µM. The previously synthesized bromotyrosine derivative intermediates and aerophobin-1 analogs were not active. The selectivity of the active compounds was calculated by determining their CC50 value against Hs27 fibroblast cells. None of the compounds showed remarkable selectivity the most selective 2-pyridin containing derivative having four times better selectivity against melanoma. The tyrosine part and N-oxime seem to be important parts to preserve while the tyramine part can be modified more freely and maintain the activity. Still more derivatives need to be synthesized and tested to confirm these observations. More data is also needed considering the selectivity of the compounds.
  • Zwiers, Harry (2021)
    Membraanipyrofosfataasit eli mPPaasit katalysoivat pyrofosfaatin hydrolyysiä kahdeksi ortofosfaattimolekyyliksi vapauttaen samalla energiaa. mPPaasit ovat merkittävässä roolissa useiden patogeenisten alkueläinloisten mahdollisuudessa selvitä ulkoisesta osmoottisesta stressistä ja pH:n vaihteluista, joiden lisäksi mPPaasit vaikuttavat niiden kasvuun ja virulenssiin. mPPaaseja ei toistaiseksi ole löydetty ihmisistä eikä eläimistä, jonka vuoksi ne ovat mielenkiintoisia lääkevaikutuksen kohteita. Tässä työssä syntetisoitiin 9 uutta yhdistettä, joita ei ole aiemmin raportoitu kirjallisuudessa. Johtomolekyyleinä käytettiin aiemmassa tutkimuksessa löydettyjä isoksatsolijohdannaisa, jotka inhiboivat T. maritiman mPPaasia IC50-arvoilla 6‒7 μM (Johansson ym. 2020). Uusiin yhdisteisiin liitettiin formyyliryhmiä useaan eri kohtaan, joiden avulla toivotaan saavan lisää tietoa niiden sitoutumisesta mPPaasiin ja niiden rakenne-aktiivisuussuhteista. Uudet yhdisteet tullaan testaamaan aktiivisuuden varalta in vitro T. maritiman mPPaasissa ja tarvittaessa myös P. falciparumissa. Formyyliryhmät liitettiin isoksatsolirenkaiden 3-, 4- ja 5-asemiin erilaisten substituenttien välityksellä. Isoksatsolirenkaan 3-aseman karboksylaattiryhmään esteröitiin kolme eri bromiformyylifenolia formyyliryhmän paikkaa vaihdellen. Isoksatsolirenkaan 4-asema halogenoitiin mikroaaltoavusteisesti, jonka jälkeen liitettiin formyyliryhmiä sisältäviä heterosyklisiä booriyhdisteitä Suzuki-reaktioilla. Myös isoksatsolirenkaan 5-asemaan sitoutuneeseen fenyylirenkaaseen liitettiin formyyliryhmän sisältävän yhdisteen Suzuki-reaktiolla. Uusien yhdisteiden aktiivisuuskokeiden tulokset julkaistaan myöhemmin. Yhdisteiden rakenne-aktiivisuussuhteisiin tai tehokkuuksiin ei ole tässä työssä vielä mahdollista ottaa kantaa.
  • Saharinen, Janne (2020)
    Prolyloligopeptidase (PREP) and alphasynuclein are linked to various neurological and psychiatric conditions of which the most relevant considering this study is parkinsonism. PREP cleaves small peptides after a proline residue. It has also protein-protein ineractions with alphatubulin, GAP-43 and alphasynuclein. PREP inhibitors have been shown to have an effect to elimination of alphasyuclein via autophagy. Thiazole is a heteroaromatic compound with two heteroatoms (sulphur and nitrogen). Thiazole can be found as a structural component among various active pharmaceutical ingredients with wide array of indications. Synthetic route for thiazole was published in 1887 and a considerable amount of literature regarding the use of thiazole in medicinal and synthetic chemistry has been published. The aim of the study was to extend the the scope of research done in the research group on small-molecular thiazole-based PREP inhibitors. The goal was to develop a synthetic route to access a series of molecules and gain information of the possible biological activities of the produced compounds by determining their IC50-values in vitro, effect on dimerization of alphasynuclein and removal of alphasynuclein via autophagy in a cell culture. Optimization of the synthetic route and search of alternative reactions were among the aims to some extent. During the course of study yields of some steps of the synthesis were improved and some new molecules had biological activity.
  • Ikonen, Jasmina (2016)
    In tablet compression the objective is to obtain a durable tablet. The main deformation mechanism of substance affects how good tablet is obtained. The pharmaceutical powders is often divided into two categories with respect to their principal deformation mechanism: plastic and fragmented. Good tablet formulation requires its components to deform with both of these mechanisms. It is possible to examine in many ways, whether material is plastic or fragmented. These include force-time graphs and indentation methods, as well as different compression equations such Heckel equation. Examination and identification of the deformation mechanisms is important in order to design a formulation which provides the most durable tablet. The aim of experimental work in this study was to test the new compression device and method, and to compare the results of the device shown in the earlier literature results. Comparison with previous research, new in this study was compression rate and without a motor acting compaction system. In this study, there was two compression method developed, dynamic and static. Data from a dynamic method were analysed by time-travel - and force-displacement -curves. Results were parameterized, and on the basis of these parameters the behaviour of various materials was evaluated and compared to the earlier literature. Relaxation study was also performed in this research. The results of these measurements were analysed with the parameterized function fit, after which the results were compared with earlier results presented in the literature. The results of this work in dynamic measurements are cosistent with the research results received earlier. In terms of almost all parameters investigated, substances were divided into two groups in the same way as in the previous literature on the basis of the main deformation mechanism. The results obtained in static measurements, however, were quite inconsistent with previous research. Based on the results it can be stated that the method makes it possible to get consistent results with the literature. However, the method still requires development, and possible error sources and the choice of analytical method should pay special attention.