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  • Konttinen, Riikka (2017)
    Hepatitis C virus disease is transmitted through blood. Chronic hepatitis C causes liver damages such as liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. It is estimated that there are approximately 20 000 - 30 000 patients infected with hepatitis C virus in Finland. For many years pegylated interferon and ribavirin has been standard of care. However standard of care causes side effects and an adequate treatment response can't be achieved with it. There have been effective direct-acting antivirals available on market which are directed against structural proteins and enzymes of the virus from 2014 onward. These second generation direct-acting antivirals are effective, safe and well tolerated. The only disadvantage is the high price of these medicines which restricts them for severe liver damage patients. More information about cost-effectiveness of second generation direct-acting antivirals is needed to support the decision making. The aim of this master thesis is to describe current care, guidelines, and costs of hepatitis C in Finland. Thesis also describes the principles of economic evaluation and systematic literature review. The purpose of the thesis is to assess cost-effectiveness of second generation direct-acting antivirals versus standard of care in treating of hepatitis C by means of systematic literature review and evaluate the quality of cost-effectiveness analyses. Previously published studies were used to analyze the cost-effectiveness of second generation direct-acting antivirals. In total of 435 references were found through systematic literature search. In addition, two studies were found from the bibliographies of already included studies. Altogether 26 studies were included in the systematic review of which 25 were original studies and one was previously published systematic literature review. The most relevant data of the studies was gathered and analyzed. The quality of the studies was assessed by using three checklists. It is difficult to make conclusions about cost-effectiveness of second generation direct-acting antivirals based on previously published reviews because only one review was found through systematic literature search. The incremental cost-effectiveness ratio (ICER) of second generation direct-acting antivirals varied between dominance and 1 135 655 € /QALY compared to standard of care. When compared to another second generation direct-acting antiviral, ICER of second generation direct-acting antivirals varied between dominance and 65 281 € /QALY. It was also analyzed how stage of liver damage affects the incremental costeffectiveness of second generation direct-acting antivirals. The ICER of second generation direct-acting antivirals was between 299 € - 85 195 € /QALY when treating patients with cirrhosis. When treating non-cirrhotic patients, the ICER of second generation direct-acting antivirals was between 2182 € - 177 679 € /QALY.The connection between funder of the study and the ICER of second generation direct-acting antivirals was also analyzed. The ICER was 1717 € - 86 056 € /QALY in studies funded by pharmaceutical company. The ICER was 299 € - 1 135 655 € /QALY in studies funded by other party. Based on the results of the thesis second generation direct-acting antivirals might be cost-effective compared to current standard of care in treating hepatitis C. The cost-effectiveness ratio of second generation direct-acting antivirals is lower in cirrhotic patients than in non-cirrhotic patients. The incremental cost-effectiveness ratio is lower when pharmaceutical company funds a study. The quality of the cost-effectiveness analyses included in the thesis varied greatly which makes it difficult to draw conclusions and interpretate the results. This study has several strengths. First, literature search was conducted systematically and transparently. Second, quality of the reviewed studies included was assessed by care. Finally, reporting of the results is transparent and repeatable. The study has also some limitations. Selection of the reviewed studies, data extraction and quality assessment of the studies was conducted by one person which may increase the possibility of human error.
  • Hallila, Susanna (2013)
    There is a strong need for new in vitro methods in early drug development that predict in vivo conditions more reliably. One of the prerequisites for successful drug therapy is sufficient permeability. A drug needs to be transported through a cell membrane before it can have a pharmacological effect. Therefore, the drug-cell interactions are studied in the early stage of the drug development process. The literature review of this work covers the traditional in vitro and in silico methods of predicting the permeability of drugs across the intestinal membrane. The widely applied methods are reviewed briefly and the predictability of the methods is evaluated. Moreover, the surface plasmon resonance (SPR) technique is introduced. The principle of SPR and its applications for predicting intestinal permeability using lipid membranes resembling the intestinal membrane and for studying drug-cell interactions are discussed. The advantage of the SPR technique is that it is an optical method which allows real-time monitoring under a constant flow without labeling agents. The aim of the experimental part of this work was to evaluate the suitability of the SPR technique for cell-based studies to monitor drug-cell interactions in native cellular environments. Previously, the SPR technique has been almost merely used in routine biomolecular interaction analysis. Recently, the SPR technique has also been applied to cellbased assays but in those studies the reason for the SPR signal responses is generally poorly discussed. The objective of the experimental study was to evaluate and optimize different cell culturing approaches for living cell sensing for SPR, i.e. cells immobilized on the roof of the PDMS molded flow channel in the SPR instrument and cells immobilized directly on the SPR sensor surface. ARPE-19 cells were immobilized on the PDMS substrates but the challenge of imaging cell monolayers on PDMS molded SPR flow channels suggested that immobilizing the cells directly on the SPR sensor surface would be a more straightforward procedure. Hence, ARPE-19 and MDCKII cell culturing protocols were optimized for successful immobilization of confluent cell monolayers directly on the SPR sensor surface. However, ARPE-19 cells showed poor resistance against shear stress in the flow channel; whereas MDCKII cells showed much better resistance against shear stress in the flow channel. Therefore, only MDCKII cells immobilized on the SPR sensor surfaces were used for drug-cell interaction studies. After three days of culture MDCKII cells were exposed to test compounds in separate SPR measurements. The used test compounds were propranolol, D-mannitol, D-glucose and HSPC:Chol liposomes. During the SPR measurements, the changes in the SPR peak minimum angular position and SPR peak minimum intensity were recorded in real-time, and these were further used for analysis after the measurements. The results showed that clear differences in both SPR signals between propranolol and D-mannitol were observed when the cells were exposed to the test compounds. Propranolol diffuses effectively by the transcellular pathway into cells whereas D-mannitol uses the paracellular pathway. This indicates that the introduced SPR approach may be a potential in vitro method in order to provide real-time information on the permeability of drugs and possibly on cell uptake mechanisms of nanoparticles for a better mechanistic understanding of drug-cell interactions on a cellular level.
  • Lehtola, Minna (2018)
    Tramadol products for cats are not commercially available. Problems may occur when dividing a tablet registered for humans due to uneven distribution of active ingredient within a tablet and bitter taste of tramadol. Minitablets have multiple benefits, including small size, better uniformity of content, coatability and fast administration, in comparison to a divided conventional tablet. The purpose of this study was to develop minitablets which are possible to coat with a taste masking coating. Physical and chemical properties of tramadol hydrochloride, such as water solubility, temperature behavior and hygroscopicity were studied. Additionally, compatibility of tramadol hydrochloride with excipients was studied by a 3-month stability exam. The pre-tests of granulation were carried out by using lactose or ascorbic acid as an active ingredient to model tramadol hydrochloride. The granulation was performed with high shear granulator and tableting with a rotary tablet press. The only variable factor between the granulation batches was the amount of granulation fluid. The impact of the amount of granulation fluid to the tableting properties was examined by determining particle size distribution, Carr index and Hausner ratio. Uniformity of mass, uniformity of content, hardness, disintegration time and dissolution were examined. The study revealed that tramadol hydrochloride did not have incompatibilities with the examined excipients. Tramadol hydrochloride was not hygroscopic even though it was found out to be freely soluble in water. Tablets with adequate hardness were successfully compressed of both granulated masses and the direct compression mass. However, the direct compression mass had more undesirable properties regarding the processes. Most batches fulfilled the requirements set for uniformity of mass and uniformity of content. Although the purpose of this study was to develop a tablet for veterinary medicine, the results in this study may be utilized in developing a formulation for pediatric medicine.
  • Hannula, Juha (2015)
    Ambient mass spectrometry includes methods where ions are produced outside of the mass spectrometry in atmospheric pressure direct from the surface of the sample without sample preparation. The first and most popular ambient ionization methods are DESI, desorption electrospray ionization and DART, direct analysis in real time. DAPPI, desorption atmospheric pressure photoionization is an ionization method where samples are desorbed with hot vapor from surface and then ionized by photoionization. The aim of this study was to develop desorption atmospheric pressure photoionization method in transmission geometry. In transmission geometry hot vapor for microchip is directed through metal or polymer meshes to mass spectrometer inlet. Liquid samples can be analyzed either by soaking the mesh to liquid sample or apply a sample droplet to the mesh. Hot vapor desorbs analytes from the mesh and analytes are ionized in a gas phase by photoionization using VUV lamp. In this method optimal positioning of the mesh and the microchip was determined. Additionally optimal microchip heating power, dopant flow rate, nebulizer gas flow rate, capillary voltage and drying gas parameters were determined. Optimized method was applied for analyzing standard samples, vitamin juice samples and milk samples. According the analysis with authentic samples, transmission mode DAPPI can be applied for analyzing liquid samples without sample preparation. According the analysis with standard samples, transmission mode DAPPI can be applied for extraction of hydrophobic analytes from water samples. Comparing to conventional DAPPI, in transmission mode DAPPI spectra, intensities of the background ions are lower resulting higher signal-to-noise ratios with transmission mode DAPPI.
  • Räsänen, Pirjo (2011)
    A notable amount of the R&D resources of the proprietary drug firms seems to be directed towards the improvement of existing drugs. Hypothetically, this may lead to interesting formulation development strategies. The purpose of the study was to find out, whether any trends in pharmaceutical product development could be detected from data on granted marketing authorisations. Also the lifecycle management approaches the major pharmaceutical companies use to protect their blockbuster products from generic competition and to ensure their market share were in the interest of this study. The emphasis of the study was on oral solid dosage forms. A combination of qualitative and quantitative methods was employed to obtain a wide view on the subject of the study. Qualitative interviews with the Finnish regulatory authorities were used to collect background information for the quantitative part, which consisted of the marketing authorisation databases covering all MA procedures in Finland, the centralised procedure in the EU, and world's ten major pharmaceutical companies in the US. Based on the study results, there was a remarkable rise in the proportion of generic products of all MAAs authorised in Finland and through the centralised procedure within the European Union during 2000-2010. This change may be at least partly amounted to the legislative changes creating incentives for the use and the manufacture of generic drug products, such as the generic substitution and the reference pricing systems. The US data showed the inclination of the big pharma towards lifecycle management: the majority of the new MAs granted to the world's ten major pharmaceutical companies in 2005-2010 were for this purpose. The ratio of lifecycle management to new molecular entities was almost 4:1. Solid oral dosage form is undeniably the most popular method of drug administration, which was confirmed by the expert interviews and the marketing authorisation data as well. The role of oral solids was even more pronounced within the generic MAs. When innovation was measured by the proportion of non-conventional dosage forms, the US data on solid oral dosage forms indicated strong innovation compared to the Finnish or EU data. This may reflect the innovative product portfolio of the major pharmaceutical companies. The proportion of non-conventional oral solid dosage forms was remarkably smaller in generic than in reference products across all regions. In lifecycle management, the most commonly used strategies were new formulation, new strength or new combination of an existing product. Within the solid oral dosage forms, two-thirds of the new LCM formulations were modified-release preparations. Lifecycle management is an essential part of the major pharmaceutical companies' business strategy, the importance of which was illustrated by the case study of Coreg tablets.
  • Annala, Iina (2021)
    Subanesthetic-dose ketamine, an N-methyl-D-aspartate receptor (NMDAR) blocker, exerts rapid antidepressant effects that sustain long after its elimination from the body. The precise mechanism remains unknown, but regulation of TrkB (tropomyosin receptor kinase B), ERK (extracellular-regulated kinase 1 and 2), GSK3β (glycogen synthase kinase 3β) and mTOR (mammalian target of rapamycin) signaling within the prefrontal cortex (PFC) have been deemed important for its antidepressant-like effects in rodents. In addition, activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is thought to be an important step in its mechanism. Nitrous oxide (N2O), another NMDAR antagonist and a putative rapid-acting antidepressant, regulates the same molecular pathways as ketamine in the rodent PFC. The fast pharmacokinetics of N2O have been exploited to show that markers of neuronal excitation, including phosphorylation of ERK, are upregulated in the PFC during its acute pharmacological effects (NMDAR blockade), while regulation of TrkB, GSK3β and P70S6K emerges only upon N2O withdrawal. In the first part of this study, we investigated the N2O-induced biochemical changes associated with neuronal excitation and BDNF-TrkB signaling in the PFC and further, the requirement for AMPAR activation in inducing them. We focused on the effects seen after the acute pharmacological effects of N2O. N2O (65% for 20 min) was administered to adult male C57BL/6 mice with or without pretreatment with AMPAR antagonist (NBQX, 10 mg/kg) and PFC samples were collected 15 minutes after stopping N2O delivery. Within this time N2O is expected to be completely eliminated. The brain samples were analyzed using western blot, enzyme-linked immunosorbent assay and quantitative reverse transcription PCR. We observed that N2O increased levels of phosphorylated TrkB, GSK3β and P70S6K, and these effects were not attenuated by NBQX pretreatment. At the same time, we observed a decrease in the levels of phosphorylated ERK, which was attenuated in mice that received NBQX prior to N2O. Tissue levels of BDNF protein or messenger RNA (exon IV) were not different between control and experimental groups. These results indicate that the mechanism of N2O is associated with TrkB and ERK signaling that are regulated independently of each other. It appears that AMPAR activation is not required for TrkB signaling, although it might play a role in ERK signaling. Further, N2O-induced TrkB phosphorylation in the PFC is not associated with changes in total levels of BDNF. In the second part of the study, we aimed to search for new ketamine-like NMDAR blockers with antidepressant potential. Ketamine was used as a query compound for in silico substructure search to find commercial ketamine analogs. The retrieved ketamine analogs were filtered by their computed ADMET properties and then further screened virtually by docking them to the pore region of NMDAR complex (protein data bank code: 4TLM), around the predicted binding site of ketamine. Finally, we sought to study if selected ketamine analogs could elicit ketamine-like effects on TrkB and ERK signaling in mouse primary cortical neurons. However, we did not proceed to test the analogs since ketamine (positive control) did not show any effects on TrkB or ERK phosphorylation in our culture. Overall, this study advances the understanding of the mechanism of N2O, possibly giving new insight of the antidepressant mechanisms of NMDAR-blocking agents more generally. Additionally, we found promising ketamine analogs that await experimental testing.
  • Halinen, Sara (2023)
    Current pharmacological treatments for major depressive disorder leave many patients unresponsive to treatment or treatment response is delayed by weeks. More effective treatments with quicker effect onset are therefore needed. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonists has demonstrated sustained rapid antidepressant activity after single dose. Precise mechanisms behind this effect are unknown, however some crucial contributors to ketamine-induced behavioural effects in rodents include phosphorylation of Tropomyosin receptor kinase B (TrkB), ribosomal protein s6 kinase (p70s6k), glycogen synthase kinase 3 (GSK3), mitogen activated protein kinases (MAPKs), and activation of α-amino-3-hydroxy-5- methyl-4- isoxazolepropionic acid receptors (AMPAR). Similar TrkB related signaling cascades are also activated with another NMDA receptor antagonist and a putative rapid-acting antidepressant, nitrous oxide (N2O). During acute effects of N2O, cortical excitation increases MAPK phosphorylation and upregulates expression of activity dependent immediate early genes (IEG; c-Fos and Bdnf IV). Phosphorylation of TrkB, GSK3 and p70s6k appearing only after N2O has been eliminated suggest that TrkB signaling is induced as an adaptive response to treatment. The first objective of this study was to corroborate previous results from our group to validate our gas administration set up and protein analysis protocol. To analyze N2O-induced phosphorylation of proteins implicated in ketamine’s behavioral effects in mice, we treated C57BL/6J male mice with either room air (control) or 65% nitrous oxide for 20 minutes. After gas exposure and 15-minute washout period, medial prefrontal cortex samples were dissected to be analyzed with western blotting. In this study nitrous oxide exposure did not induce increased TrkB signaling in nitrous oxide withdrawal. Another aim of this study was to investigate the involvement of AMPARs in inducing cortical excitation with N2O. Pretreatment of AMPAR antagonist (10 mg/kg, NBQX) or saline was given to C57BL/6J male mice 10 minutes prior to 1 hour exposure to 50 % O2 or 50 % N2O, a N2O dose previously shown to induce IEG expression. One hour after gas exposure mice were euthanized and mPFCs were dissected and analyzed with reverse transcriptase quantitative PCR (RT-qPCR). No regulation in IEG expression was induced with nitrous oxide, NBQX pretreatment or combination compared to control. Additional studies factoring in limitations of this study are needed to uncover the involvement of AMPAR in inducing cortical excitation and antidepressant-like behavioral effects of N2O in preclinical models of depression.
  • 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.