Browsing by master's degree program "Proviisorin koulutusohjelma"
Now showing items 81-100 of 245
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(2021)Background and objectives: Pharmaceutical services provided by community pharmacies have the potential to improve medication safety and support the implementation of rational pharmacotherapy. The pharmaceutical services are internationally an underused resource to support functioning of social and health care services. The literature review of this Master’s thesis provides an overview of pharmaceutical services, - their funding and remuneration. The primary objective of the empirical study was to create an overview of the development of the pharmaceutical services in Finnish community pharmacies in 2010-2020. The secondary objective was to study differences in the service provision between Finnish provinces. Materials and methods: The study was carried out as a retrospective descriptive survey study annually conducted by the Association of Finnish Pharmacies. Åland was excluded from the provincial review so that individual pharmacies could not be identified. The data was analyzed using Microsoft Excel. The number of pharmacies providing pharmaceutical services annually and the annual number of customers using these services were counted at the national level. At the provincial level, the corresponding data for the prescribing review, medication review, comprehensive medication review and assessment of inhalation technique were analyzed for the years 2017-2020. Results and conclusions: The most common service with the highest number of customers was automated dose dispensing. The second most common service was prescription review. As a whole, the provision of services and the number of customers had increased during the study period in Finnish community pharmacies. Manual dose dispensing was a diminishing service. Differences were found between provinces in the prevalence of services and in the number of customers. It was possible to identify provinces with lower service provision activity, such as Lapland. The service provision prevalence and number of customers varied widely within provinces. The number of customers for a certain service in an individual pharmacy had a large effect on the provincial average, thus, the average number of customers in the provinces does not reflect the provinces' success in implementation of services. Pharmaceutical services, with the exception of the automated dose dispensing, are not well implemented.
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Flavonoids act as positive allosteric modulators of lecithin:cholesterol acyltransferase in silico (2022)Lecithin:cholesterol acyltransferase (LCAT), a key enzyme in maturating high-density lipoprotein (HDL) particles, has been targeted to promote the efficiency of reverse cholesterol transport by small molecular positive allosteric modulators (PAM) of Daiichi Sankyo. For a set of these compounds their Vmax and EC50 values and binding site in the membrane-binding domain (MBD) of LCAT have been determined. Through molecular dynamics (MD) simulations we previously found a metric that qualitatively described which compounds were active, so in this study we aimed to improve it by finding a quantitative metric. This led to the discovery of the Cα distance between CYS50 and ASN65, which correlates with this set’s Vmax values and which can be utilized to predict the Vmax values of novel compounds. Additional simulations were performed to discover whether this metric is changed by a lipid interface present, and to reveal a likely entry pathway PAMs take. As LCAT activation is likely a benign and potentially overlooked effect, we performed a virtual screen of FDA-approved compounds and secondary metabolites associated with LCAT. From secondary metabolites, a key finding was that flavonoids were overwhelmingly associated with LCAT and had a high binding potential to the MBD in docking simulations. The best binding compounds were subjected to MD simulations to discover their Vmax values using the discovered metric. This provided us with a set of compounds, which can be used to validate our in silico model in vitro. Should this model be validated, it can be used in optimising and discovering novel PAMs of LCAT, and it would bring evidence to the benefit of MD in drug discovery processes in general. Furthermore, if our discovered compounds can activate LCAT in vitro, they may be used as precursors for novel PAMs or as therapies by themselves not only for LCAT deficiencies, but perhaps for atherosclerotic cardiovascular diseases as well.
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(2022)Coronary heart disease is a number one killer in westernized countries and the costs from it will continue to grow in the future. It is caused by atherosclerosis, build-up of plaque and chronic inflammation in the arteries of heart, and endogenous lipoproteins have a special role in its development. Among other atheroprotective properties, High density lipoproteins (HDL) have a role in intrinsic mechanism of the reverse cholesterol transport (RCT), of gathering and removing excess cholesterol from peripheral tissues. There have been several HDL raising strategies in the past for the treatment of atherosclerosis, but their success has been modest. Synthetic HDL (sHDL), comprising of various types of phospholipids and proteins or peptides, have been developed to mimic the properties of endogenous HDL. Despite some success in animal studies, failures in clinical studies have turned the focus on the HDL’s interaction with a specific enzyme lecithin:cholesterol acyl transferase (LCAT), responsible for cholesterol esterification, a key step in RCT. ApoA-I, the most abundant protein component of HDL, acts as LCAT cofactor in cholesterol esterification, and many LCAT activating peptides have been developed to mimic the features of apoA-I. The molecular level understanding behind LCAT activation is however still foggy. During enzymatic activation, LCAT goes through conformational changes specific regions, which are generated by interactions with apoA-I or synthetic peptides. These mechanisms have been studied widely with molecular dynamic simulations, in vitro experiments, and imaging. In this study, we investigated 22A (PVLDLFRELLNELLEALKQKLK), apoA-I mimetic peptide known for its as good LCAT activation potency as apoA-I, and four variations of it (21A, 22A-P, 22A-K22Q, and 22A-R7Q), and combined them with phospholipid DPPC to create sHDL nanodiscs by thermal cycling method. We examined the effect of small changes in peptide sequence on LCAT-sHDL binding strength with quartz crystal microbalance with dissipation (QCM-D). The interest was to further test the suitability of thermal cycling method on nanodisc assembly, test the binding strengths against the hypothesis of the role of salt-bridge forming amino acids R7 and K22 in peptide dimerization and its effect on LCAT binding and activation, and to see if QCM could act as a suitable method for the research of sHDL-LCAT interactions. All peptides formed similar sized sHDL particles with diameter of ~10 nm with thermal cycling method. As expected, the LCAT binding tendency of 22A-sHDL was highest, about double compared to four other peptide nanodiscs with almost identical results. The QCM results suggest that binding tendency between LCAT and sHDL is affected by small, one amino acid change in peptide sequence, but it does not necessarily have a big impact on LCAT’s esterification activity, but based on this experiment alone, we cannot make any further conclusions. Electron microscopy revealed exceptional breakdown of 21A-sHDL incubated with LCAT compared to 22A-sHDL. This phenomenon could indicate high lipolytic rate of LCAT but needs further investigation. There were some challenges with the measurement parameters in the beginning, and the variability between parallel measurements with QCM-D was high, which cause a little doubt about the method’s suitability for these kinds of precise measurements. More research for revealing the molecular mechanism behind LCAT activation is needed for the development of more effective treatments.
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(2020)The ability to regulate release of noradrenaline, dopamine and GABA is one of the most important roles of the nicotinic receptors. The release of neurotransmitters following stimulation of nicotinic receptors is addressed in the thesis, with focus on dopamine and noradrenaline. Release of neurotransmitters, mediated through nicotinic receptors, has been researched using various methods, including brain slices, microdialysis and synaptosomes. Research using synaptosomes have provided valuable information regarding nicotinic receptors and their ability to regulate neurotransmitter release. Research using receptor specific antagonists have provided information regarding the stoichiometry of nicotinic receptor in different regions of the brain. The primary focus in the thesis, was the characterization of [3H]dopamine release following stimulation of nicotinic receptors with varenicline and acetylcholine, using synaptosomes from mouse striatum. Using a-conotoxin-MII, the [3H]dopamine release was divided into a-conotoxin- MII-resistant and -sensitive release. [3H]Dopamine release was mediated through a6b2*- and a4b2*-receptors from striatal synaptosomes. The involvement of other receptors could not be ruled out, but based on these results and results from previous studies, the involvement of other nicotinic receptors is supposedly low.
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(2023)Introduction: European legislation on orphan medicinal products, Regulation (EC) No. 141/2000 of the European Parliament and of the Council, entered into force in April 2000. Although the prevalence of rare diseases is low according to legislation (less than 5/10,000), 18–30 million people in the European Union (EU) are affected by rare diseases. The introduction of orphan medicine legislation has increased the number of orphan medicines developed but the fairness of the legislation has also raised concern and criticism. The literature review of this Master ́s thesis provides an overview of rare diseases, orphan medicines and EU orphan medicine legislation. The aim of the empirical study was to investigate the evolution of orphan medicine selection during European legislation on orphan medicinal products in 2000–2022. In more detail, aims were to describe the evolution of orphan medicine selection, the approved indications for orphan medicines and the number of orphan medicines approved for children. Methods: The research material was orphan medicines that received a marketing authorisation during the EU orphan drug legislation. This material was collected from the European Commission's Community Register of orphan medicinal products and the European Commission's Community Register of not active orphan medicinal products. Qualitative document analysis was used as the research method, where information on orphan medicines were quantified. Results and conclusions: In the 10-year review of orphan medicine development, the number of new orphan medicine products approved for the market doubled, being 63 products between 2001 and 2010 and 127 products between 2011 and 2020. In the latter 10-year period of the review, the focus of approved indications for orphan medicines shifted slightly from orphan medicines developed for the treatment of cancers (36%) to orphan medicines developed for the treatment of inborn errors of metabolism or immune disorders (43%). In the 10-year reviews, the relative share of orphan medicines approved for children decreased from 55 percent in 2001– 2010 to 40 percent in 2011–2020. Based on the results of the study, the fairness and targeting of the benefits of the orphan medicine legislation should be further investigated. Orphan medicine legislation should encourage the development of medicines for rare diseases for which there is no treatment at all, and for the population most affected, in other words children.
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(2021)Continuous monitoring of the safety profile of medicinal products is essential also after marketing authorisation approval to ensure the patient safety. Spontaneous reporting of adverse drug reactions is one of the most important methods to collect post-approval safety data of medicinal products. The advantages of spontaneous reporting system include reaching large population throughout a long period of time for many medicinal products, however, it also has some limitations. One commonly recognized problem of the system in many countries is under-reporting of adverse drug reactions. The national reporting scheme in different countries slightly vary, even between Nordic countries. The main aim of this study was to find out what improvements should be done to the current reporting scheme in Finland so that it would better encourage healthcare professionals to report in relevant situations, which respond to the purpose of the spontaneous reporting system. Physicians (n=20), pharmacists (B.Sc.) (n=78), pharmacists (M.Sc.) (n=21) and nurses (n=13) responded to the anonymous open voluntary online questionnaire. Close-ended questions were analyzed and results summarized in graphs and tables. Statistical analysis was done using chi-squared test. Content analysis was performed for open-ended questions by utilizing both, inductive and deductive approach. In the study, we found some differences in healthcare professionals’ opinions what kind of adverse drug reactions should be reported. Some of the healthcare professionals were also aware that they had not reported all suspected adverse drug reactions that came into their knowledge and several reasons were recognized for this. Seriousness of the reaction was considered the most motivating factor for healthcare professionals to report about suspected adverse drug reactions. The results of this study suggest that in healthcare professionals’ opinion, the most important factors that should be considered to improve reporting in Finland are training for healthcare professionals and simplifying the reporting as much as possible. Some differences were noticed between the occupational groups regarding preferences in the reporting route and especially physicians seemed to prefer formation of the report from the information system as a reporting method more than open web-based reporting form. Mobile application for reporting was not preferred that much among Finnish healthcare professionals. The results of this study support the hypothesis that under-reporting of suspected adverse drug reactions is also present in Finland. The reporting instructions should be clarified, training availability should be considered and reporting should be simplified as much as possible to improve the reporting.
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(2024)Syöpäsairaudet tai niiden hoito aiheuttavat potilaille usein huomattavaa fyysistä ja psyykkistä taakkaa. Merkittävien fysiologisten muutosten lisäksi hoidot johtavat usein voimakkaaseen ahdistuneisuuteen, psyykkisiin liitännäissairauksiin ja heikentyneeseen yleiseen elämänlaatuun. Näiden oireiden kasaantuessa ne heikentävät merkittävästi potilaiden elämänlaatua, arjen toimintakyvyn ja henkisen jaksamisen madaltuessa. Syöpäpotilaiden monet subjektiiviset oireet jäävät kuitenkin usein alihoidetuiksi tai hoitavalta taholta tunnistamattomiksi. Hoitoihin tai sairauteen liittyvien oireiden piiloon jääminen saattaa johtaa madaltuneeseen hoitoon sitoutumiseen, korkeampiin kuolleisuuslukuihin ja on terveydenhuollon tuottajan näkökulmasta tehotonta. Rutiininomainen ja spesifisti kohdennettu oireiden seuranta on tärkeää niiden oikea-aikaista ja tehokasta esilletuontia varten ja se on yhdistetty parantuneeseen hoitovasteeseen syöpäpotilailla. Kliinisten tulosten seurannan tueksi hoidon onnistumista voidaan seurata validoiduilla potilaslähtöisillä mittareilla (vointimittarit, PROM ja potilaskokemusmittarit PREM). Niillä voidaan saada oikein käytettynä riippumatonta ja reaaliaikaista tietoa potilaiden kokemasta terveydentilasta. Potilaskeskeisen (arvoperustaisen) terveydenhuollon kehitystyön edistyessä tutkimustieto hoidon vaikuttavuuden mittaamisesta potilaiden itse raportoimien tulosten avulla perinteisten kliinisten mittareiden lisäksi tulee korostumaan. Syöpähoitoja tarvitsevien määrän kasvu ja uusien, kalliiden pienmolekyylisten, biologisten, ja geeniterapiahoitojen markkinoille tuleminen, tuottavat taloudellisen paineen kestäville ja arkikäytössä vaikuttaville ratkaisumalleille hoidon toteutuksen tutkimukselle. Modernien viestintäjärjestelmien käyttö potilaiden raportoimien tulosten esilletuonnissa ja tallentamisessa voi tarjota mahdollisuuden parantaa vaikuttavuuden mittaamisen toteutusta kliinisessä arjessa. Tutkielman yhteistyöorganisaatio Istekki oy pyrkii kehittämään terveysteknologisia ratkaisuja julkisen terveydenhuollon käyttöön. Kartoittavan katsauksen periaatteiden mukaisesti, tutkimalla järjestelmällisesti olemassa olevaa kirjallisuutta selvitettiin, minkälaisia mittareita erilaisissa syöpähoitoja tarjoavissa ympäristöissä on käytetty. Katsauksen aineisto koostui 20 vertaisarvioidusta alkuperäistutkimuksesta, jotka keskittyivät potilaslähtöisten mittareiden käyttöön onkologisessa ympäristössä. Näistä saatiin tarkasteluun 28 erilaista validoitua potilaslähtöistä mittaria. Digitaalisten alustojen käyttö mittareiden käyttöympäristönä korostui kaikissa tutkimuksissa. Oikein käytettynä potilaslähtöiset mittarit edistivät potilaiden ja hoitohenkilökunnan välistä kommunikaatiota, potilastyytyväisyyttä ja mahdollistivat hoidon vaikutusten reaaliaikaisen seurannan potilasnäkökulmasta. Kuitenkin tekniset, kulttuuriset ja organisatoriset esteet, kuten koulutuksen puute, resurssien niukkuus ja tiedon puute (asenteet), ovat haasteita, jotka hidastavat mittareiden käyttöönottoa kliiniseen arkeen. Vointimittareiden tehokas hyödyntäminen edellyttää kattavaa koulutusta, selkeitä käyttöönotto- ja reagointistrategioita, sekä hyvin saatavissa olevaa teknistä tukea niin potilaille, kuin henkilökunnallekin.
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(2023)Nonadherence has been a challenge in health care since ancient times, and it is still a major source of poor therapeutic outcomes today. Various theories and theoretical models have been applied to explain adherence. So far no single theory or theoretical model has proved comprehensive, and the effects of various interventions applied have been limited. Theorizing of adherence is still incomplete. The aim of this study was to review the theoretical background of adherence so far, and to find the commonalities in theories and theoretical models, but also to discover possible trends in them. Study material comprised 20 theories and theoretical models. Material was found in reference books and documents with an aspect of adherence. Inclusion criteria involved adult outpatients with chronic diseases, excluding any special groups such as pregnant women. Emphasis was on the relevance of the theory, but comprehensive time span as well as various theory views were also considered. A chronological order was created. A qualitative content analysis was conducted, where phrases describing essential theory contents were categorised into distinctive classes. The incidence of classes and the possible trends of the incidence were analysed. Five classes emerged as commonalities in majority of the theories: Patient factors; sociocultural factors; motivation; phrases that referred to a behavioral view; and cognitive processes. Factors that diminished towards this day were the pivotality of cognitive processes in theory, and the subjective view of the health threat. Several factors were found to increase towards present-day theories and models: phrases that described the individual’s agency, such as self-efficacy or empowerment, concrete expressions of the individual’s abilities, skills and actual opportunity to the desired behavior, phrases that consisted of behavior being a function of its context or environment, and phrases where multifaceted intervention or tailoring the intervention according to the change process phase were considered. The commonalities found in the material reflect its emphasis on psychological behavior theories. The changes reflect the shift in how the patient’s agency is viewed in a patient care relationship. Newer theories also amplify the importance of viewing health behavior change as a series of phases. To achieve patient-centered care, these aspects create an increasing demand to health care professionals’ proficiency in how they encounter their patients. Moreover, there is an important signal for future intervention development in the form of a shift into multifaceted interventions and a system approach. Furthermore, a trend exists from using more general and abstract theories to a more concrete and applied approach. In the future, it is probably more fruitful to pursue knowledge-based and validated models and guidelines that are applicable to practice instead of aiming at developing a comprehensive universal theoretical approach.
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(2020)Medication-related errors have been identified as the single most important risk factor for patient safety across the world. According to previous research, medication errors are common in nursing homes. However, the existing data on medication errors in Finnish nursing homes is scarce, although the challenges and defects in nursing home care services, including drug treatments, are well known. Furthermore, nursing home residents are typically characterized by old age, multimorbidity and polypharmacy. Therefore, they are particularly vulnerable to potential adverse events caused by medication errors. The aim of this study was to investigate the rates and causes of medication errors reported in nursing homes and evaluate their impact on medication safety. Additionally, the proportions of potentially inappropriate medication (PIMs) and high-risk medication involved in the medication errors were determined. The data of the study consisted of 251 medication errors reports that were submitted to the safety incident report system (HaiPro) in nursing homes located in Central Uusimaa healthcare and social welfare joint municipal authority (Keusote) in 2019. Quantitative analysis of the data provided an overview of the medication errors that had occurred in nursing homes and the medicines most commonly involved in them. Content analysis and simplified root cause analysis enabled to study more in-depth the contributing factors of medication errors and potential risks associated with the medication process in nursing homes, as well as the possibilities of preventing similar errors in the future. James Reason's human error theory and in particular its system perspective was applied as a theoretical framework in this study. Medication errors were reported regularly in nursing homes during the follow-up period of the study. The most frequent medication error type was administration error. The majority of these errors were medication omissions, followed by the wrong time of administration and administration to the wrong patient. The most common drug classes causing medication errors were antithrombotics, opioids, antidementia drugs, diuretics, antipsychotics, antidiabetics, and antidepressants. Nearly a quarter of the reported medicines were high-risk medications, most commonly opioids, antithrombotics, or antidiabetic drugs. PIMs accounted for approximately 13% of all medications in the data. Errors were most often caused by unsafe medication practices, communication problems, and deficiencies in the work environment such as excessive workload or time pressure. A significant part of the medication errors were related to transdermal medication patches. The study also showed that the quality of medication error reporting in nursing homes is in part insufficient and should be improved so that the reports can be better used for learning purposes. The results of the study provide valuable additional information on medication errors in Finnish nursing homes and their contributing factors. The information can be used to improve medication safety practices in nursing homes. Safe and uninterrupted medication use process is a goal that should be pursued not only in health care but also in social welfare services such as nursing homes.
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(2024)In Finland, an increasing number of older adults who need around-the-clock assistance in their daily activities are taken care of in an intensive service housing unit, i.e., in a nursing home. The care organized in a nursing home also includes the resident's medical treatment and care. Medication safety and medication management processes have been widely studied in healthcare units, but there is a lack of similar research data from social care units. The topic is current because problems have arisen within the medication management process of the nursing homes, to which system-oriented solutions are needed. To develop risk management, additional information is needed on the risk points occurring in the medication management process of nursing homes. The study aimed to produce information on what kind of medication errors can be detected in the practical implementation of medication in a nursing home and in which stages of the medication management process they occur. The study was based on participatory observation data collected in a nursing home. The data was analyzed using quantitative and qualitative content analysis methods. The study’s theoretical framework was James Reason's human error theory and the Swiss cheese model. It was found that medication errors were common in the observed nursing home, as almost every fourth observed situation contained at least one medication error. Medication errors were detected at almost every stage of the medication management process. Storage errors (28 %) and medication administration errors (19 %) were detected more often than other types of errors. Detected storage errors were mostly related to not locking the medicine storage facilities or leaving medicines without monitoring. The most frequent administration error was medication omission. After storage and administration errors, the most commonly detected medication error types were error in cleaning or tidiness (7 %), ordering error (7 %) and error in medication administration checks (6 %). Other types of medication errors represented less than 5 % of the data. Almost a quarter of the errors were found to have happened to the resident, causing a medication safety incident. Actual adverse events could not be identified based on the data. About a fifth of the errors were near misses. Although about half of the errors did not happen directly to the residents, they were identified as medication, client, and patient safety risks. Pharmaceutical information was found to function as a good barrier in the medication management process, as some of the possible adverse events were prevented with the help of medical advice given to nurses. The medication management process of nursing homes could be developed by considering unit-specific risk factors and utilizing pharmaceutical expertise in the implementation of medical treatment. Through observation, it would also be possible to identify contributing factors of medication errors, enabling risk management activities to be targeted at the risk points of the medication management process. The study results offer valuable information about medication errors in nursing homes, which can be used in developing the medication management process.
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(2022)Indomethacin is in a BCS-classification class two drug, meaning it has poor solubility but good permeability. Because of this solubility is a limiting factor for it reaching bloodcirculation. Amorphous form has better solubility than crystalline form. Most common problems with amorphous form are poor stability and process technical problems. In this study Indomethacin was combined with two different kind of polymers that were prepared by hot-melt extrusion. By hot-melt extrusion we can get more stable product than pure amorphous drug. These polymers were polyvinylpyrrolidone (PVPK179 and polyvinylpyrrolidonevinylacetate (PVPVA). They were prepared with Indomethacin 1:1 mass ratio. The aim was to study these extrudates and their stability, cumulative release and especially permeability. By using differential scanning calorimetry, X-ray diffraction and polarized light microscopy it was possible to analyze whether the drug was amorphous or crystalline. In the study it was found that by using hot-melt extrusion it was possible to make amorphous combinations of Indomethacin and polymers. Their permeability was between crystalline and amorphous form. PVPK17-Indomethacin combination had better permeability than PVPVA-Indomethacin combination. On the other hand PVPVA-Indomethacin had better cumulative release than PVPK17-Indomethacin combination
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(2020)Diacylglycerol (DAG) is a lipid second messenger, which activates classical and novel protein kinase C (PKC) isozymes at the plasma membrane. Abnormalities in PKC signaling have been linked to several diseases, and defective PKC function connects to multiple pathophysiological components of Alzheimer’s disease. However, aimlessly activating all PKC isozymes with synthetic ligands can be problematic, since the activation of certain isozymes can also promote unwanted processes. There are indications that DAGs with varying degrees of acyl chain saturation may have different and specific PKC activating abilities. Thus, understanding how the structural differences in DAGs relate to their behavior at the lipid bilayer may be beneficial for the development of new, isozyme-specific ligands of PKC. The aim of this master’s thesis was to compare the orientation, positioning and dynamics of two unsaturated DAG molecular species, 1,2-dioleoyl-sn-glycerol (DOG) and 1-stearoyl-2-docosahexaenoyl-sn-glycerol (SDG) in glycerophospholipid bilayers using conventional molecular dynamics (MD) simulations and umbrella sampling. The glycerophospholipid bilayers were composed of either 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE) or 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphatidylethanolamine (SDPE), representing the glycerophospholipid environment in the inner leaflet of the plasma membranes in peripheral tissues and in brain tissue, respectively. Both DAG molecular species displayed very dynamic behavior in all systems, with wide distributions of glycerol moiety tilt angles and acyl chain conformations. Multiple occurrences of transbilayer movement (flip-flop) of DAGs was observed during the MD simulations in all systems. In POPE bilayers, SDG was observed to position closer to the aqueous interface compared to DOG, with larger values of solvent accessible surface area (SASA) of the glycerol moiety and the sn-3 hydroxyl group. In SDPE bilayers, no significant difference in this regard was observed between the DAG molecular species. Although potential of mean force (PMF) profiles did not reveal any major differences in the energetically favoured position of the hydroxyl group between the DAG molecular species, the calculations exposed that the dynamics of DOG are affected more by the surrounding lipid environment compared to SDG. Based on these results, it is probable that while the solvent accessibility and overall position of DAGs is affected by the length and degree of saturation of their acyl chains, there are also other mechanisms and processes causing the differing levels of PKC activation yielded by different DAG molecular species.
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(2021)Current treatments for major depressive disorder have notable limitations including the delay achieving the therapeutic effect. Ketamine has been shown to alleviate the symptoms of depression rapidly and promising findings have also been found when using nitrous oxide. However, the mechanisms behind rapid antidepressant effect are not fully discovered. It seems that rapid-acting treatments alter brain energy metabolism, enhance synaptic plasticity, and repair neuronal dysfunction connected to depression. Particularly, the activation of brain derived neurotrophic factor (BDNF) mediated tropomyosin receptor kinase B (TrkB) signaling has been connected to rapid antidepressant effect. Fasting is also known to induce BDNF production and it is thought to activate BDNF-TrkB signaling. In addition, both of these treatments alter the brain energy metabolism. The objective of this study was to find out how fasting and nitrous oxide alone and in combination affect the rapid antidepressant effect and synaptic plasticity related BDNF-TrkB signaling in mice. Another aim of the research was to determine whether the body temperature changes after these treatments as a marker of metabolic rate. The analyzed brain samples of the mice were collected 15 minutes after cessation of nitrous oxide administration. As a result, it was found that the fasting protocol used in this study did not activate the studied BDNF-TrkB signaling. However, after nitrous oxide administration, the studied signaling and markers related to synaptic plasticity were partly activated. The results from the combination of nitrous oxide and fasting were similar compared to nitrous oxide administration only. It is therefore conceivable, that the effects were caused exclusively by nitrous oxide. Furthermore, a fascinating finding related to energy metabolism was that nitrous oxide reduced the body temperature of the mice significantly 15 minutes after cessation of the gas administration. Overall, these results are promising and consistent with previous research indicating that nitrous oxide administration could be related to induced synaptic plasticity and therefore have antidepressant associated effects. Nitrous oxide could be used to understand the mechanisms behind rapid antidepressant effect and it could be a potential option to treat depression in the future. Based on these results, it seems that energy metabolism could be related to rapid antidepressant effect. It also supports the observations that all different rapid-acting treatments alter the brain energy metabolism.
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(2024)Falls are common in older people, some of which result in serious injuries. Falls are a burden on the health care system and preventing them could reduce the burden. Risk factors for falls include impaired vision, certain chronic diseases, female gender, old age, alcohol consumption, foot problems and environmental factors. Certain medications also increase the risk of falls. Drugs affecting the central nervous system and drugs affecting the cardiovascular system are the main drugs that increase the risk of falls, known as fall-risk-increasing drugs (FRIDs). The aim of the thesis was to analyze the medication lists of patients who had fallen or were at risk of falling and who were living at home and were transported by the emergency services to the HUS emergency unit in Jorvi. The aim of the study was to investigate whether the medication lists of patients (n=216) included fall-risk-increasing drugs, potentially inappropriate medication, adverse risks associated with the risk of falling and drug-drug interactions. The study also compared three groups of patients with different fall statuses. Group 1 consisted of patients who had fallen and patients at risk of falling (n=79). Group 2 consisted of patients at risk of falling who had not fallen (n=85). Group 3 included patients who had fallen but were not at risk of falling (n=52). Microsoft Excel and IBM SPSS Statistics were used to analyze the data. In the data 52.3% of patients were on polypharmacy. Patients in group 3 had fewer regular medications than patients in group 1 (p=0.001) and group 2 (p=0.010). Almost half (46.3%) of the patients in the data set had at least one FRID medication in regular use. Group 1 patients had the highest number of FRIDs in use and Group 3 patients the lowest. The most frequently used FRID was furosemide (n=54). According to the Med75+ database, about a quarter of patients (27.3%) and almost half (48.6%) of patients according to the Beers criteria were regularly using potentially inappropriate medication (PIM) in older people. Level D adverse events associated with risk of falls were present in 28.2% (n=62) of patients in the whole dataset when considering regular medication use. Multiple patients were taking risperidone, amitriptyline and tramadol, which belong to FRIDs and PIMs medicine and are associated with D-level adverse risks. In the whole dataset, only a few patients (n=12) were found to have a category D interaction with regular medications. Class C interactions were found in 38.9% of patients. The falls risk assessment performed by emergency medical services was reasonably good at predicting medical risk factors associated with falls. Particular attention should be paid to patients at risk of falling who have not fallen yet. The reduction of medication factors that increase the risk of falls could potentially prevent falls in the future. Once patients at risk of falls have been identified, pharmacists could be used in the emergency department to identify and possibly unwind medication factors that increase the risk of falls in the older people, in collaboration with physicians. The knowledge of pharmacists could also be utilized to review medication risks associated with falls in community pharmacies.
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(2024)Current therapies for depression have limitations in efficacy and delayed onset of action. Rapid-acting antidepressants like ketamine, an N-methyl-D-aspartate receptor (NMDA-R) antagonist, have gathered attention as an improved treatment option. However, the neurobiological mechanism underlying their antidepressant effect remains uncertain. Integral mechanisms of action seem to be alterations in synaptic plasticity, global cortical excitation, and repair of neuronal dysfunctions prevalent in the pathophysiology of depression. Emerging evidence does suggest that antidepressant drugs act by facilitating brain derived neurotrophic factor (BDNF) mediated tropomyosin receptor kinase B (TrkB) signaling. Interestingly, rapid-acting antidepressants seem to increase TrkB-associated signaling after their acute pharmacological effect has dissipated, and when animals become sedated and show various physiological changes associated with deep sleep (e.g., slow wave EEG activity, SWA). Indeed, recently a close relationship between sedation and molecular signaling implicated in antidepressant effects has been discovered. The aim of this study was to explore the relationship between sedation and molecular signaling associated with antidepressant effect. This was carried out by assessing the localization of TrkB-associated phosphorylation signaling in the adult male mice medial prefrontal cortex (mPFC) using dexmedetomidine, a sedative. Key signaling molecules such as ribosomal protein S6 kinase (p70S6K), ribosomal protein S6 (rpS6), glycogen synthase kinase 3 (GSK3), mitogen activated protein kinases (MAPKs) and immediate early gene c-Fos, were examined through immunohistochemical (IHC) analysis. Two separate experiments were conducted using naïve adult 8-13-week-old (n=8 and n=10) male C57BL/6JRccHs mice. In the experiments mice were injected intraperitoneally with either dexmedetomidine (0,05 mg/kg, Dexdomitor®), or saline followed by a 30-minute recovery period whereafter mice were euthanized. In the first experiment, medial prefrontal cortex samples were collected immediately post decapitation for western blot (WB) analysis. The results showed that dexmedetomidine significantly activated TrkB-associated signaling in brain homogenates, consistent with expectations. In the second experiment, mice were perfused with 4% paraformaldehyde (PFA) before brain collection for IHC analysis. However in this experimental setting, no significant difference in the localization of TrkB-associated signaling induced by dexmedetomidine was observed compared to saline. Although, no significant results for signal localization were observed, the results provide insights into the neurobiological effect of sedation induced TrkB-signaling. Further research factoring in limitations is needed to uncover the involvement of physiological states in antidepressant mechanisms.
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(2023)P-glycoprotein (ABCB1, MDR1) is an efflux transporter expressed widely through the body, but mainly focused on tissues that have protective or excretive function, such as liver and blood-brain-barrier. Many clinically used drugs from variety of therapeutic groups are substrates of P-glycoprotein, and changes in the function of P-glycoprotein may have impact on the drugs pharmacokinetics and -dynamics. The impact of genetic polymorphism on P-glycoprotein activity have been investigated for several years, but due to contradictory results no consensus has been made. The aim of this Master’s thesis was to investigate the effect of five different P-glycoprotein single nucleotide polymorphisms (SNPs) on transport activity. The study was performed by Spodoptera frugiperda (Sf9) membrane vesicles expressing P-glycoprotein variants. Baculovirus-derived expression system was used to introduce the ABCB1 gene to the cells. Vesicle assay was performed with N-methylquinidine (NMQ), and ATP-dependent transport of P-glycoprotein variants was compared to the reference gene. Amino acid change Cys717Tyr led to no transport activity compared to reference gene, and Arg669Cys associated with higher transport activity of NMQ. Arg588Cys, Ser795Cys and Ile836Val indicated no effect on the transport activity. Other aim for this Master’s thesis was to create a new in-house protocol to study P-glycoprotein polymorphism in vitro. Substrate accumulation assay for Rhodamine-123 in Sf9 cells analysed with flow cytometry was established, as flow cytometry is widely used method in other laboratories to study P-glycoprotein polymorphism. The baseline for flow cytometry assay was created successfully by optimizing substrate concentration and incubation time. According to the results, SNPs can impair P-glycoprotein function. New method to study P-glycoprotein function was created, and this method can be used to further study the effects of genetic polymorphism of P-glycoprotein and to compare the result between studies. The results gained from these in vitro studies can be utilized to understand in vivo pharmacogenetic findings.
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(2019)Organic Anion Transporting Polypeptide 2B1 (OATP2B1) is an influx transporter expressed widely throughout the body in tissues such as intestine, liver, brain, placenta and skeletal muscle. Since many clinically used drugs are transported by OATP2B1, changes in the function of the transporter due to genetic polymorphism could lead to altered pharmacokinetics or -dynamics of OATP2B1 substrate drugs. The aim of this Master’s thesis was to create and optimize a cellular uptake assay to study the function of OATP2B1. Furthermore, the aim was to study the effects of six naturally occurring nonsynonymous single nucleotide variants on OATP2B1 transport function in vitro. With site-directed mutagenesis, single nucleotide changes were introduced into the gene coding for OATP2B1. OATP2B1 variants were expressed in human derived HEK293 cell line using baculovirus expression system. A cellular uptake assay with estrone-3-sulfate and a fluorescent probe 4’, 5’-dibromofluorescein (DBF) as substrates was set up and optimized. With the assay, OATP2B1-mediated uptake of variants was compared to the transport activity of OATP2B1 wild type. Amino acid changes Ser486Phe and Cys520Ser impaired OATP2B1 transport function severely. In addition, variant Thr318Ile transported DBF and estrone-3-sulfate less efficiently compared to OATP2B1 wild type, but Arg312Gln, Thr392Ile and Ser532Arg transport function was not affected. A method to study OATP2B1 function was created successfully. According to the results, single amino acid changes in OATP2B1 can impair OATP2B1 function. The results and method can be utilized to understand findings from pharmacogenetic studies in vivo, and to predict consequences of especially rare variants, which can be difficult to detect in small sample populations in clinical studies. However, further studies on the expression level and cellular localization of OATP2B1 variants are needed to fully characterize the impact of the variants studied.
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(2024)Indomethacin is a poorly soluble but highly permeable drug, and its biological availability can be improved by enhancing its solubility. In this study, co-crystals and co-amorphous systems of indomethacin and nicotinamide were prepared in a 1:1 molar ratio, which have previously been shown to enhance the solubility of indomethacin. It has also been observed that the co-amorphous indomethacin-nicotinamide system crystallizes into a co-crystal during storage. This study aimed to further investigate the properties, solubility, and stability of these compounds, and tablet formulations were also prepared from the co-crystal and co-amorphous systems. Powdered co-crystals and co-amorphous systems, as well as tablets prepared from them, were stored at 25°C with 60% relative humidity and at 40°C with 75% relative humidity, and their solubilities were studied for 12 weeks. The stability of the samples was also examined using Fourier infrared spectroscopy and differential scanning calorimetry over the same period, and changes in the physical properties of the tablets were monitored throughout the study period. Additionally, the effect of HPMC on the prevention of indomethacin recrystallization was investigated. Both the co-amorphous and co-crystalline forms were found to enhance the solubility of indomethacin in both powder and tablet formulations in this study. The co-crystal was stable, with no changes observed in its crystal structure or solubility over the 12-week study period. However, handling the co-amorphous material turned out to be difficult due to its low glass transition temperature of 19.68°C, causing the powder to soften at room temperature. During storage, it was shown to crystallize into a co-crystal, but its solubility properties were weaker to those of the actual co-crystal. None of the solubility tests showed evidence of indomethacin recrystallization, so the potential effect of HPMC on this phenomenon could not be determined in the study. Warmer and more humid conditions were found to increase the tensile strength of the tablets, resulting in slower dissolution.
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(2020)Background: Inhaled therapy is the most widely used treatment for asthma and chronic obstructive pulmonary disease (COPD). Inhaled medicinal product has several advantages, including high local drug concentration in the lungs and reduced systemic adverse effects. However, the challenge with inhaled therapy is that many asthma and COPD patients do not know how to use their inhaler properly. Suboptimal inhaler use can lead to poor clinical control. The Association of Finnish Pharmacies has developed inhalation technique assessment service (ITAS) to detect and correct patients’ inhalation technique and to give information regarding the inhaler and inhaled therapy, such as drug storage and oral care. Objective: The aim of the study is to investigate whether asthma and COPD patients’ ability to prepare the Respimat inhaler and the patients’ ability to properly inhale the drug improve after receiving ITAS. The second objective is to find out what patients and pharmacists think about the service and which customer groups benefit the most from the service. Methods: The study design is an uncontrolled pre-post intervention. 33 pharmacies participated in the study. All patients who were buying a prescribed Respimat inhaler, were offered to participate in the study. Patients’ inhalation technique was assessed before (baseline) and immediately after ITAS (follow up 1). In addition, the inhalation technique was assessed the next time the patient came to pharmacy to buy Respimat inhaler (follow-up 2). Questionnaires were used to assess patients’ and pharmacists’ perceptions of ITAS. Results: 228 baseline and follow-up ITAS were performed. The results of follow-up 2 will be published later in a separate article. 14 % of the patients performed all the steps (both inhaler preparation before first inhalation and inhalation process itself) correctly at baseline. After ITAS the number increased to 77 %. At baseline 30 % of the patients had an optimal inhalation technique (all inhalation steps correct) and after ITAS the number increased to 85 %. 70 % of the patients had an acceptable technique (all critical steps correct) before and 93 % after ITAS. Both patients and pharmacists felt that the service was beneficial to the patients when thinking the proper inhaler preparation and proper inhalation technique. Overall patients’ and pharmacists’ satisfaction were high towards ITAS. Our study indicates that patients benefit from ITAS regardless of patient’s age or how long the patient have been using the Respimat inhaler. Conclusions: A pharmacist-led inhalation technique assessment service significantly improves asthma and COPD patients’ inhalation technique with Respimat inhaler. ITAS should be performed regularly as part of the delivery of the inhaled drug to the patient. Further research is needed on the effectiveness of ITAS with other inhalers.
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(2022)Drug-induced liver injury (DILI) is a relatively rare hepatic condition that can be classified as predictable and unpredictable. However, DILI is a primary reason for drug withdrawals, post-marketing warnings, and restrictions of use. DILI is a problem for the drug users but also for the pharmaceutical industry and regulatory bodies. From the perspective of patients' and clinicians', DILI is the major cause of acute liver injury. At present, a major problem predicting DILI in drug discovery is a poor understanding of its mechanisms as well as the complexity of DILI pathogenicity. The main mechanism behind DILI are alterations in bile acid homeostasis, oxidative stress, and mitochondrial dysfunction. More than 50 % of drugs causing DILI are causing mitochondrial impairment. If the normal function of mitochondria is disturbed, the energy production of the cell decreases, and cell function decline leading eventually to the cell death. In this study prediction of mitochondrial toxicity was studied using cryopreserved primary hepatocytes of humans and rats. The aim of the study was to clarify if there are interspecies differences in the prediction of toxicity but also investigate possible differences in the mechanisms behind hepatotoxicity by using three well-known compounds toxic to mitochondria. To determine these differences, total cellular ATP was measured after 2- and 24- hour exposure time to gain information on overall viability and possible adaptive responses. Mitochondrial energy pathways were studied as a real-time monitoring acute exposure of test compounds. Morphology, location, and possible adaptive response of mitochondria were studied using a fluorescent probe and antibody staining combined with high content imaging (HCI). Overall, primary rat hepatocytes were more sensitive to the test compounds than human hepatocytes. Also, there were differences between human hepatocyte batches that may reflect the metabolic differences between hepatocyte donors. Immunolabeling did not bring any additional values compared to the fluorescent probe staining in the study of morphology of mitochondria. Additionally, it was noticed that treatment with paraformaldehyde significantly changed the hepatocyte mitochondria morphology. Overall, more effort is needed to develop image analysis of mitochondria morphology. Finally, studying mitochondrial morphology has proven to be difficult, and this study did not unfortunately reveal any information about the adaptive responses of mitochondria for drug-induced liver injury.
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