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  • Takala, Anna (2019)
    Medication safety is a part of patient safety, and means safety related to the use of medicines. Medication safety covers the principles and functions of individuals and organizations working in the healthcare sector to ensure the safety of drug treatment and to protects patient from harm. Medication error is any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient or consumer. Medication errors are the leading cause of preventable harm in health care across the world. Therefore, improving medication safety is important from the point of view of the promotion of patient safety. The aim of this study was to gather information about serious medication errors at national level by utilizing data from Valvira to learn from the cases outside the organizations where they occurred. The data of this study consisted of complaints and regulatory statements resolved by Valvira in 2013–2017, in which drug treatment were identified as a main reason and where inappropriateness was found (n=58). Cases were classified with predetermined classification system, and inductive content analysis was used to identify the causes and contributing factors of medication errors. The theoretical framework of the study was the Human Error Theory by James Reason (1990). According its systems-based approach, this study focused on the processes and circumstances of organizations. Of the included 58 cases, medication errors caused patient’s death in 21 cases (36 %) and severe harm in nine cases (16 %). A majority (n=53; 91%) of the errors were estimated to be either definitely or possibly preventable. Most of the patients were older adults (mean age 74 years). The most commonly related drugs in medication errors were enoxaparin (n=7; 6%) and oxycodone (n=7; 6%). The most common therapeutic group causing medication errors was antithrombotic agents (n=17; 13%). Most errors occurred in hospital settings (n=29; 45%) and in elderly care units. Doctors (n=37; 50%) were most often involved in the errors. Most of the medication errors occurred in the prescribing (n=38; 47%), administrating (n=15; 19%) and monitoring stage (n=14; 17%), drug-related problems being most often connected to the drug selection. In severe and fatal cases, there are often several drug related problems identified at different stages of the patient’s drug treatment process. The data of Valvira provide valuable information about medication errors at national level. Qualitative analysis is important especially for learning purposes as it provides better understanding of the causes and contributing factors of medication errors, as well as the complexity of drug treatment processes. Based on this study, it seems that healthcare organizations involved in severe medication error cases have taken into consideration the importance of process development and focused on identifying latent risks in organizational conditions and processes rather than blaming individuals.
  • Valkonen, Minna (2013)
    The aim of this work was to investigate the feasibility of titanium dioxide (TiO2) photocatalysis for imitation of phase I metabolism of selected anabolic steroids. The role of the solvent composition and the time of UV exposure in the TiO2 photocatalysis were also investigated. TiO2 photocatalysis has been reported to produce mainly the same phase I reaction types formed in drug metabolism in vitro and in vivo. The selected anabolic steroids were testosterone, methyltestosterone, metandienone, nandrolone and stanozolol. Products from TiO2 photocatalysis were compared to products formed in microsomal incubations (HLM). Comparison was made on the basis of same mass, retention time and similarity of the product ion spectra. The samples were analyzed with ultra performance liquid chromatography (UPLC) and quadrupole time-of-flight mass spectrometry (Q-TOF). Electrospray ionization (ESI) in positive ion mode was used for ionization and product ion scan with two different collision energy was used for collision induced dissociation of the steroids and the reaction products. TiO2 photocatalysis is a simple and fast method. For all the steroids studied, the main reactions observed both in TiO2 photocatalysis and microsomal incubations were dehydrogenation, hydroxylation and combination of these two. Several isomers with same mass and retention time were formed. In addition, dihydroxylation and dihydroxylation+dehydrogenation products of stanozolol were observed both in TiO2 photocatalysis, but these were different isomers in different systems. In most cases the product ion spectra of isomers with same retention time were similar but the weak intensity of some peaks caused uncertainty in the interpretation of spectra. TiO2 photocatalysis might be useful in fast screening of possible drug metabolites. However the feasibility of TiO2 photocatalysis needs to be further studied because the differences in stereochemistry in TiO2 photocatalysis and microsomal incubations. If TiO2 photocatalytic reactions can be scaled up, it might be possible to produce standard compounds for example for doping laboratories.
  • Kokkala, Katja (2010)
    The characteristics of macrolides are discussed in general level in the theoretical part of this Master's thesis. The discussion is focused on the properties of two macrolides in molecular level and their tendency to form tautomeric forms highlighting the structural similarities and differences of these macrolides, which will affect both the mechanisms of action and the metabolism. Attention is also paid to biosynthesis and manufacturing process keeping focus on downstream process, especially the impurities, which arise from the macrolide biosynthesis. Also the principles of argentation chromatography are discussed. In the experimental part of Master's thesis a purification method for one macrolide was developed using argentation chromatography. Conventional chromatographic purifications cannot separate the macrolide from its impurities. The purity of the macrolide after argentation chromatography was 98.6%. Also a new crystallization method was developed, which produces anhydrous form of the macrolide instead of traditional monohydrate form. A method for analysing the macrolide using HPLC was developed. The method was validated according to ICH guidelines. The tautomeric forms and the impurities of the macrolide were analysed using LC/MS. One of these impurities was isolated and analysed with NMR thus confirming its identity. An analysed NMR spectrum of this impurity has not been published according to our best knowledge. A previously unknown impurity was identified based on MS analysis and retention time.
  • Säilä, Pasi (2016)
    Oxysterols and vitamin D related compounds are found to be biologically active in brain. They might be involved in different psychiatric and neurodegenerative diseases. These compounds have traditionally been analysed from tissues using somewhat laborious and time-consuming gas chromatograpy and liquid chromatography mass spectrometric methods. To the side of these methods ambient desorption ionization methods have been developed. The advantage of these methods is rapid and easy operation. Usually minimal or no sample pretreatment is required. In addition these methods can be applied to imaging of for example tissues. The aim of this work was to study if it is possible to detect certain oxysterols and vitamin D related compounds from rat brain tissue samples with desorption atmospheric pressure photoionization (DAPPI). The compounds chosen to this study were cholesterol, vitamin D3, 25-hydroxyvitamin D3, 7-dehydrocholesterol, desmosterol and 7-ketocholesterol. DAPPI is especially suitable for efficient ionization of this kind of neutral and non-polar compounds. Detected MS and MSn spectras of the brain tissue samples were compared to those obtained from standard compounds. As a result we could not detect vitamin D3, 25-hydroxyvitamin D3, 7-dehydrocholesterol, desmosterol from rat brain samples with DAPPI. Excluding vitamin D3 it is possible that those other analytes are present at the spectras of brain samples but there is some other compound with same mass which makes the reliable identification of studied compounds impossible. 7-ketocholesterol and cholesterol were the only compunds we detected from brain tissue sections. 7-ketocholesterol can be formed via auto-oxidation in samples containing excess amount of cholesterol. According to this study it is impossible to say if the detected 7-ketocholesterol is formed endogenously or during sample preparation and analysis.
  • Rimmistö, Riikka (2024)
    Tieteen kehittymisestä huolimatta tehokkaiden syöpähoitojen ongelmana on niiden vakavat systeemiset haittavaikutukset, jotka voivat johtaa jopa hoidon keskeyttämiseen. Haittavaikutusten vähentämiseksi lääkehoitoa on pyritty kohdentamaan paremmin syöpäkudokseen esimerkiksi valoaktivoitavien liposomien avulla, jossa liposomiin pakatun valoherkistimen altistaminen valolle aiheuttaa muutoksia liposomin lipidikaksoiskalvoon siten, että lääkeaine pääsee vapautumaan liposomista kohdennetusti säteilyn alueella. Verteporfiini-valoherkistintä on tutkittu paljon hydrofiilisten lääkeaineiden vapauttamisessa liposomeista, mutta lipofiilisten lääkeaineiden vapauttamiseen liittyviä tutkimuksia on julkaistu hyvin vähän. Tämän maisterintutkielman tarkoituksena oli selvittää, voitaisiinko verteporfiinia hyödyntää lipofiilisen, solunsalpaajana tunnetun paklitakselin vapauttamisessa liposomeista valoakivaation avulla. Hypoteesin mukaan myös sytotoksisia vaikutuksia omaavan verteporfiinin yhdistäminen samaan liposomiin paklitakselin kanssa lisäisi valoaktivoitavien liposomien sytotoksisuutta in vitro. Tutkimuksessa arvioitiin valoaktivoidun verteporfiinin aiheuttamien liposomin lipidikaksoiskalvon muutosten suuruutta hydrofiilisen kalseiinin vapautuskokeen avulla, mitä käytettiin liposomiformulaation optimoinnissa. Lisäksi tutkimuksessa selvitettiin valoaktivaation seurauksena liposomeista vapautuneen paklitakselin määrää sekä arvioitiin valoaktivoitavien paklitakseli-verteporfiiniliposomien sytotoksisuutta A549-keuhkosyöpäsolulinjalla. Tutkimuksessa osoitettiin verteporfiinin valoaktivaation lisäävän muutoksia liposomin ja solujen kalvorakenteissa valoaltistuksen keston pidentyessä. Kuitenkaan paklitakselin lisääminen verteporfiiniliposomeihin ei vaikuttanut lisäävän liposomien sytotoksisuutta A549-soluissa valoaktivaatiota käytettäessä, mutta ei myöskään ilman valoaltistusta. Paklitakselin vapautuskoe ei tutkimuksessa käytetyllä menetelmällä onnistunut, joten syytä sille, miksi sytotoksisuuseroa ei havaittu paklitakseli-verteporfiiniliposomien ja pelkkää verteporfiinia sisältävien liposomien välillä, oli vaikea arvioida. Käytetyillä valoaltisteilla ja liposomiformulaatiolla paklitakselin vapautuminen liposomeista valoaktivaation seurauksena oli kuitenkin todennäköisesti erittäin vähäistä.
  • Nurmi, Riikka (2017)
    Liposomes are spherical nano-sized drug delivery systems which are composed of lipid bilayer. With liposomes drugs can be targeted for example to tumours and targeting can be passive or active. Drug release from liposomes can also be activated by different methods. Light is very promising triggering method, because it enables drug release at specific time and site. This study examined light activated indocyanine green (ICG) liposomes. Drug release from liposomes happens because ICG converts light energy to heat. ICG is clinically approved imaging agent, so ICG liposomes are very promising drug delivery systems even for clinical use. Liposomes were prepared by thin-film hydration method. One aim of the study was to prepare as small ICG-liposomes as possible. The bigger 100 nm liposomes were studied in three different formulations and the purpose was to find differences between those formulations. In formulation A ICG was in PEGs, in formulation B ICG was in lipid bilayer with no PEGs and in formulation C ICG was supposed to be in lipid bilayer although the formulation C included PEGs. In this study, the cell up take of ICG liposomes was studied with pharmacokinetic model and data from in vitro studies was supposed to use in a pharmacokinetic model. In this study, it was possible to prepare 40 nm sized ICG-liposomes. Small liposomes did not release encapsulated calsein as well as bigger 100 nm liposomes. The decreased release from smaller liposomes was probably explained by the results witch pointed out that transition temperature of small liposomes was higher than transition temperature of bigger liposomes. In the future, the lipid composition of the small liposomes need to be reoptimized, that the release would be more effective. This study however proved that small ICG-liposomes can be prepared and the small size lasts even over three months. Three different formulations of 100 nm liposomes were studied and the differences between the properties of the formulations were found. ICG in the lipid bilayer changed properties of the formulation B and the passive release of the calsein and release during the lightning were increased. In formulation C transition temperature was decreased and its storage life was lower than in other formulations. Formulation A was best for the next studies and the phospholipid composition of other formulations need to be optimated that drug release and storage life would be good enough. Intracellular release properties of liposomes were studied with Sytox red probe. Fluorescence of Sytox red increases when it binds with DNA or RNA. With this study, it was proved that liposomes release Sytox red inside the cells and that the lightning time affects to the release. The results weren't useable for pharmacokinetic model, so the model was made based by literature. Pharmacokinetic model can be used in the future studies and different in vitro or in vivo results can be combined with the model.
  • Tenhola, Ella (2023)
    Medicine shortages have been an increasing problem in the pharmaceutical industry for several years. While the causes of these shortages have been widely researched, they have been found to be diverse and the root causes are difficult to identify. The pharmaceutical care system has been formed over a long period of time, which has led to a growing problem of shortages for various reasons. This study aims to investigate he views of different pharmaceutical sectors on what reforms to the mandatory reserve supply law could help to prevent and shorten the medicine shortages. The study was conducted through a thematic interview. Abductive analysis and thematic analysis were selected as the method of analysis. The study found that mandatory reserve supply is successful in acting as a buffer against short-term shortages, but that a comprehensive reform of the law would be necessary. According to the study, the reform of the law is linked to a wide range of issues. More flexible processes in regulatory aspects, the profitability of the Finnish market, and hospital procurements are closely related to the mandatory reserve supply law. The reform of the mandatory supply list could bring flexibility to exemptions to maintain lower stock levels by renewing the list of medicines and categorizing them into different groups. The act on public contracts law and the mandatory supply reserve law should be better coordinated to avoid wastage and thus ensure Finland's adequate competitiveness However, it should be noted that ensuring Finland's competitiveness and reducing shortages is not solely the responsibility of the mandatory reserve supply law. It also requires extensive international cooperation and it is also believed that bringing production back to Europe and even to Finland is crucial to shorten medicines shortages.
  • Ylitalo, Merja (2016)
    Ethanol intake and the use of several drugs of abuse lead to the activation of the endogenous opioid system which has an important role in reward and reinforcement. Ethanol can affect also many other neurotransmitter systems, for example the dopaminergic, GABAergic and glutamatergic systems. The ability of opioid antagonists to decrease ethanol intake refers to the important role of the opioidergic system in mediating the reinforcement from ethanol. Important brain areas in the mesolimbic reward system are the ventral tegmental area, nucleus accumbens and ventral pallidum. The ventral pallidum is regarded as the endpoint of the mesolimbic reward system and as the cross point of the motivational circuit and reward circuit. The role of the ventral pallidum and its GABAergic and opioidergic systems in ethanol reinforcement has been proven in many studies. This review goes through the brain areas involved in the reward circuit and ethanol's effects on the neurotransmitter systems connected to the reward system. This review concentrates especially on the opioidergic system and on the role of the ventral pallidum in ethanol reinforcement. The aim of this study was to research the role µ-opioid receptors in the ventral pallidum on ethanol intake using an ethanol-preferring AA (Alko, Alcohol) rat line. The hypothesis of the study was that local inhibition of the ventral pallidum with an excess of µ-opioid receptors effects ethanol intake. We infused µ-opioid receptor gene overexpressing viral vectors (AAV-MOR), control vectors or vehicle into the ventral pallidum of rats. Ethanol drinking of the rats was examined in the limited access paradigm. After the ethanol drinking study rats received injections of an opioid receptor antagonist, naltrexone (0.1 mg/kg and 0.3 mg/kg, s.c) and an opioid receptor agonist, morphine (3 mg/kg, repeatedly, s.c) before the ethanol drinking session to see what effect the drugs have on ethanol drinking. The biological activity of the viral vectors was confirmed with immunohistochemical staining and qPCR. In the ethanol drinking study there were no statistically significant differences between the groups. Naltrexone 0.1 mg/kg dose decreased statistically significantly ethanol drinking only in AAV-MOR group and caused statistically significant difference in ethanol drinking between the AAV-MOR and control vector groups when proportionate to the control. These results suggest that possibly part of to that naltrexone's ethanol intake decreasing effects are mediated via the ventral pallidum. Morphine did not cause statistically significant differences in ethanol drinking between the groups. The results of this study do not exclude the role of the ventral pallidum in controlling ethanol drinking.
  • Suo-Yrjö, Ville (2010)
    Nearly all drugs that are abused release dopamine in the nucleus accumbens, the end point structure of mesolimbic dopamine pathway. This why effect of those drugs is closely attached to dopaminergic system. It seems that function of mesolimbic dopamine pathway is necessary for rewarding effects of drugs as cocaine and amphetamine. However rewarding effects of ethanol seems to mediate routes despite of mesolimbic dopamine pathway. This conclusion is a result of several studies that have showed that destruction of synapses of in nucleus accumbens have no effect on ethanol drinking of rats. So it might be that the possible place were effects of ethanol mediate beside of straight stimulation of nucleus accumbens, are GABA- and opioidergic medium spiny neurons that project from nucleus accumbens to ventral pallidum and also from ventral pallidum back to nucleus accumbens. Ventral pallidum is the structure of brain that is thought to be the last common pathway of brain reward circuitry. Ventral pallidum is also found to mediate reinforcement of pleasure of natural rewarders and also drugs that are abused. Meaning of this study was to find how opioidreceptors in ventral pallidum control the drinking of ethanol. The method of study was observe how opioidergic drugs (µ-, δ-, κ-agonist and -antagonist) that are microinjected in brain of AA-rats mediate voluntary ethanol drinking of these animals. Hypothesis of this study was that activation of opioidreceptors in ventral pallidum leads to lower consumption of ethanol and inactivation of these receptors leads to higher consumption of ethanol. Study was performed in National institute for health and welfare, Department of Alcohol, Drugs an Addiction, in research group of Kalervo Kiianmaa. There were used ethanol prefering AA-rats which were microinjected in ventral pallidum with opioidergic drugs. Study involved 72 male rats form generation F99. There were six groups and each had 12 rats. Before the actual trial rats were taught to drink 10 % ethanol/water-solution voluntary. Surgery and placement of canulaes were done with stereotactic device. Bilateral guide canulaes were placed above the ventral pallidum. Each drug was given in three different size doses and also ringer's solution was given as a control. Volume on injections were in each drug and with the ringer's solution 0,3 µl and rate of injection was 0,3 µl/min. Total trial involved four experiment days (three with the drugs and one with the ringer's solution). Injections were given in mixed order. Immediately after injection rats were moved in their homecages and they were given drinking bottle which was filled with ethanol. The consumption of ethanol was observed in time of 10, 20, 30, 50, 70 and 90 minutes. After all experiment's were done rats were decapitated and the places of injections were checked from brain slices that were stained with thionine. Results were analyzed with repeated measures ANOVA and if difference between groups were found the post hoc test were done with Dunnett's test. If the statistical difference were found with repeated measures ANOVA the result were analyzed also in exact time point with ANOVA and Dunnett's test. The only significant result was found with µ-opioidreceptoragonist (DAMGO). It lowered the ethanol consumption significantly. The drop in ethanol consumption was dose dependent and was seen with two highest doses of DAMGO. Clearest difference was seen at the first 50 minutes after rats had started drinking ethanol. The second highest dose of µ-opioidreceptorantagonist (CTOP) had a little tendency to elevate ethanol consumption and was near to be a significant (p=0.08). There were found no effects with other drugs. The main conclusion of this study was that activation of µ-opioidreceptors in the ventral pallidum lowers consumption of ethanol in AA-rats. Inhibition the µ-opioidreceptors had a mild effect of elevating ethanol consumption but this could not be taken as reliable and more studies are needed to be done. δ- and κ-opioidreceptor activation or inhibition had no effect in ethanol consumption in these rats. Conclusions made by these results give support to the theory of role of ventral pallidum as a part of brain reward circuitry. When these results are compared to studies were GABAergic drugs are injected in ventral pallidum and ethanol consumption is observed and also with the knowledge of how these drugs affect the cell's membrane potential, there can be made conclusion that inhibition the activity of ventral pallidum has effects that block pleasure mechanisms that interface with ethanol.
  • Juuti, Hanne (2010)
    The blood-brain barrier protects brain from xenobiotics that are in blood. Different in vivo and in vitro methods have been developed for studying blood brain barrier and those can be found in the literature. There are only few computational models pharmacokinetics of compounds in the brain. In this study permeability factors, which were measured in vitro or in vivo, were collected from literature. Additionally two different pharmacokinetic computer models of blood-brain barrier were described. One of which is called microdialysis model and the other efflux model. Microdialysis model is a very simple two compartmental model, the compartments being the blood and the brain. Five substances were simulated according to the values measured in vivo in rat. The model did not correlate well with the in vivo results, because of the simplicity of the model as the model missed the compartment of brain tissue and the kinetics of transporters. Efflux model has three compartments, blood, blood brain barrier endothelial cells and brain. The model was used to study the impact of the of efflux transporter at the luminal barrier of endothelial cells and passive permeability to the steady-state concentration of a compound in the brain extracellular fluid with theoretical simulations. The relation between free drug concentrations in blood and brain extracellular fluid (Kp,uu) was studied. The impact of Michaelis-Menten kinetics of efflux transporter to the concentration of compound was shown in the results. The efflux model is suitable for theoretical simulations. It is possible to add new active transporters. With theoretical simulations the results from in vitro and in vivo studies can be combined and the different factors can be studied in one simulation.
  • Harju, Elina (2021)
    Extracellular vesicles (EVs) are nano-sized lipid bilayer-delimited particles, released by cells. They take part in intercellular communication by their molecular composition and are part of both physiological and pathophysiological functions. EVs can be extracted from bodily fluids, and they are particularly abundant in blood. The purpose of this thesis was to evaluate the use of Raman spectroscopy in the characterization of EVs. Raman spectroscopy is an analysis method based on the interaction of light and matter, and the inelastic scattering of light, and it is used to get information on the biochemical composition of a substance. Principal component analysis (PCA) was used to investigate if Raman spectroscopy could differentiate two different platelet-derived EV samples, a red blood cell-derived EV-sample and a red blood cell-derived reference material. Evaluation of the characterization also included a stability study of these samples, where it was examined if any temperature dependent changes occurred that could be detected by Raman spectroscopy. Additionally, the applicability of Raman spectroscopy for lipoprotein contamination detection was evaluated by examining if purification of an EV sample decreased the intensity of carotenoid peaks typical for lipoprotein spectra. Raman spectroscopy was able to differentiate all three EV samples and the red blood cell-derived reference material from each other. The most clear differences were found between red blood cell and platelet-derived samples, due to for example the characteristic haemoglobin peaks of red blood cell-derived samples. Differences were also found between the two platelet EV samples, which were thought to implicate difference in protein compositions. The characterization of red blood cell-derived samples proved to be difficult because haemoglobin contained in the samples covered most of the other signal from the samples. Stability studies implicated that during fridge storage the carotenoid peak intensity of platelet-derived EV samples decreases due to the degradation of carotenoids. In the red blood cell-derived samples, no differences assignable to changes in some specific components of the samples were observed. Contamination studies suggested the intensity of the carotenoid peaks may increase due to purification of the sample. This was counter to the assumption and may suggest the carotenoids of the EV samples are not from lipoprotein contamination, but part of the EV composition. In conclusion, Raman spectroscopy proved to be a promising method for characterization and identification of different EV samples.
  • Paavilainen, Nea (2024)
    The eye is well-protected by several anatomical and physiological barriers which also pose significant challenges for ocular drug delivery. Even though ocular pharmacokinetics and the permeability of eye’s important anatomical barriers, such as the cornea and the blood-ocular barriers, have been thoroughly investigated, the significance of active transport in the eye is not completely understood. It is known that several drug transporters are also expressed in ocular tissues, but scientific information on this area is still dispersed and incomplete. The aim of the literature review in this master’s thesis was to compile the current knowledge on the expression and activity of OATP transporters (SLCO; organic anion transporting polypeptides) in cornea and in the blood-ocular barriers. Main principles of ocular pharmacokinetics and common methods for studying transporters are also discussed. The experimental part in this thesis is focused on retinal pigment epithelium (RPE) which is a substructure of the blood-retinal barrier. The transporters of the RPE were studied with three different RPE model systems: human RPE cell line (ARPE-19), fetal primary RPE cells (hfRPE; human fetal retinal pigment epithelium) and ocular tissues of the rabbit. In detail, transporter expression was studied with proteomics from the plasma membrane of isolated rabbit RPE and transporter activity by cellular uptake assays (ARPE-19, hfRPE) in vitro and permeability experiments with rabbit RPE-choroid-sclera ex vivo. As with the literature part, the experimental work was mainly focused on the human and rabbit OATP/Oatp transporters. In this thesis, ten important drug transporters were detected from the rabbit RPE. No significant OATP/Oatp activity was observed either in vitro or ex vivo experiments so these transporters seem not to have a great role in the disposition of their substrates in the studied RPE models. However, signs of other active transport were evident especially in the ARPE-19 cell line, in which significant accumulation of the tested substrate, 4’,5’-dibromofluorescein (DBF), was noted in the presence of several inhibitors. The phenomenon was suspected to result from efflux inhibition, but the responsible transporters could not be unequivocally detected. In conclusion, the findings of this thesis highlight the importance of conducting further research on the transporters of the RPE and choosing a suitable RPE model case-by-case for each study. With the compounds used in this thesis, ARPE-19 and hfRPE cells showed marked differences in efflux activity while the small size and fragile structure of the posterior ocular tissues of the rabbit caused notable difficulties in performing the transporter studies.
  • Randén, Sari (2024)
    Jätevedenpuhdistamon käsittelymenetelmät eivät poista kokonaan lääkeaineita jätevedestä. Lääkeainejäämiä jää käsiteltyyn jäteveteen ja siksi niitä löytyy pintavedestä. Vielä ei ole täysin selvää, miten altistuminen lääkeainejäämille vaikuttaa ihmisten terveyteen ja ympäristön hyvinvointiin. Tämän pro gradu -tutkielman tavoitteena oli ensin tunnistaa vesiympäristölle haitallisimmat lääkeaineet ja sen jälkeen selvittää, mitkä olivat haitallisimpien lääkeaineiden käyttömäärät HUSin hoitoyksiköissä vuonna 2021. Tutkimuksen tuloksia on tarkoitus hyödyntää jatkossa HUSissa, kun arvioidaan mahdollisia toimenpiteitä ympäristöriskien vähentämiseksi. Tässä tutkimuksessa ympäristöriskiä mahdollisesti aiheuttavien aineiden arviointi koski lääkeaineita, joita käytettiin ihmisten hoitoon vuonna 2021 Suomessa. Tutkimukseen otettiin mukaan ne lääkeaineet, joista oli saatavilla riittävästi dataa riskiosamäärän laskemiseksi (kun ei otettu huomioon lääkeaineen poistumaa jätevedenpuhdistamolla). Tutkimuksen ulkopuolelle rajattiin lääkeaineiden yhdistelmävalmisteet, eläinlääkkeet, vitamiinit, elektrolyytit, aminohapot, peptidit, proteiinit, hiilihydraatit, lipidit, kasvirohdosvalmisteet ja rokotteet. Riskiosamäärä laskettiin 521 lääkeaineelle. Lääkeaineiden, joiden riskiosamäärä oli suurempi kuin 1, katsottiin aiheuttavan riskiä vesiympäristössä: mitä suurempi oli aineelle laskettu riskiosamäärä, sitä suurempi oli ympäristöriski. 521 lääkeaineesta 39 lääkeaineen riskiosamäärä ylitti raja-arvon 1. Lääkeaineet, joiden riskiosamäärä oli yli 10, olivat ibuprofeeni, dabigatraanieteksilaatti, sulfasalatsiini, estradioli, lerkanidipiini, sertraliini, abirateroni, amoksisilliini, rifaksimiini ja vankomysiini. Näiden kymmenen vesiympäristölle haitallisimmin lääkeaineen kulutus vuonna 2021 HUSissa laskettiin hoitoyksiköittäin, jotta saatiin selville, missä hoitoyksiköissä käytettiin näitä lääkeaineita eniten. Kulutuksen laskennassa ei otettu huomioon hoitoyksiköiden jo olemassa olleita lääkevarastoja, jotka oli hankittu ennen vuotta 2021, eikä lääkehävikkiä (lääkejätettä). Tämän tutkimuksen perusteella puuttuva data oli merkittävin tulosten luotettavuuteen vaikuttava tekijä, koska ne lääkeaineet, joista ei ollut riittävästi dataa käytettävissä, jouduttiin rajaamaan tutkimuksen ulkopuolelle. Siten vesiympäristölle haitallisimpien lääkeaineiden luettelosta saattaa puuttua sinne kuuluvia lääkeaineita. Dataa olisi tarvittu etenkin lääkeaineiden poistumasta jätevedenpuhdistamolla sekä tutkimuksesta poisjääneiden lääkeaineiden kulutuksesta, teoreettisista vuorokausiannoksista ja ennustetuista vaikutuksettomista pitoisuuksista. Koska kaikkia haitallisimpia lääkeaineita ei ole vielä selvitetty, lisää tutkimusta ja työkaluja tarvitaan ongelman ratkaisemiseksi
  • Niemissalo, Sanna (2022)
    The aim of this master’s thesis was to investigate whether drug-induced inhibition of cytochrome P450 enzymes (CYP), especially time-dependent inhibition (TDI), could be the reason for bioaccumulation of the pharmaceuticals present in the aquatic environment in fish and whether the in vitro method could identify pharmaceuticals causing an environmental risk, which should primarily be investigated more closely. The half-maximal inhibitory concentrations (IC50) of seven antimicrobial drugs detected in the environment (erythromycin, clarithromycin, ketoconazole, clotrimazole, miconazole, ciprofloxacin, and sulfamethoxazole) and three known human time-dependent inhibitors (furafylline, diltiazem and verapamil) chosen for the validation of the method, were determined by EROD (7-ethoxy-resorufin-O-deethylase) and BFCOD (7-benzyloxy-4-trifluoromethyl-coumarin-O-debenzyloxylase) activities. The IC50 shift method and commercially available rainbow trout (Oncorhynchus mykiss) liver microsomes were used in determinations. The known human time-dependent inhibitors chosen for the validation of the method, furafylline (EROD) and diltiazem (BFCOD) proved to be possible time-dependent inhibitors also in rainbow trout in vitro, but this was not observed for verapamil (BFCOD). All antimicrobial drugs, except ciprofloxacin, inhibited more selectively BFCOD-reaction, as in human. In the case of sulfamethoxazole, inhibition was not observed at the concentrations used (0–500 µmol/L). Both enzyme activities (EROD and BFCOD) were inhibited in rainbow trout by ketoconazole, clotrimazole and miconazole. Among antimicrobial drugs acting as time-dependent inhibitors in human, erythromycin inhibited BFCOD activity in a time-dependent manner also in rainbow trout, but this was not observed for clarithromycin. Strongest inhibitors for CYP enzymes of rainbow trout in vitro were ketoconazole (EROD, IC50=4,19 µM and BFCOD, IC50=2,31 µM) and clotrimazole (EROD, IC50=33,78 µM and BFCOD, IC50=1,55 µM). The IC50 values of diltiazem, erythromycin, clarithromycin, ciprofloxacin, and verapamil were of the same order of magnitude as in human. The IC50 values of furafylline, ketoconazole, clotrimazole and miconazole were several times higher in rainbow trout than in human. Based on the results of this study, the IC50-shift method is also valid for fish, but there are differences in the inhibition potencies between human and fish, and the inhibition potency of human CYP enzymes cannot therefore directly predict enzyme inhibition of fish or the mechanism of inhibition. The In vitro measured IC50 values of rainbow trout were several orders of magnitude higher than the average concentrations of the pharmaceutical residues measured in the environment. Exposure to pharmaceutical mixtures is long-term, so interactions and bioaccumulation may still be possible due to inhibition of CYP enzymes. Developing a valid in vitro method for environmental risk assessment would be important, as animal experiments are ethically challenging.
  • Laakkonen, Laura (2024)
    Barcode-assisted medication administration can be used to prevent medication errors in pediatric hospital settings, as the medicine and the patient can be safely identified during the drug preparation and administration. The use of barcode-assisted medication administration has been examined in a few qualitative studies. In addition to the benefits, many challenges related to the implementation of this new workflow have been identified. The aim of this study was to identify facilitators and barriers related to the use of barcode-assisted medication administration in a children's hospital. The topic has not been studied in Finland before. A qualitative focus group study was carried out at HUS Helsinki University Hospital in the Department of Children and Adolescents. Ward pharmacists (n=14) were selected for the focus groups (n=3) by purposive sampling to identify persons using barcode-assisted medication administration on their daily work. Two researchers conducted the inductive content analysis independently, after which a consensus was formed first with these researchers and later with the entire research group. COREQ checklist was used to support detailed reporting and to consider the factors that might affect to the reliability of the study in each phase of the study. Four main themes were identified from the data; the barriers, the risk behavior caused by the barriers, the facilitators and the development ideas. The barriers included challenges related to negative attitudes of the end-users, barcodes on drug packages and labels, use of the electronic health record system, workstations and equipment, as well as orientation, competence and management. The barriers caused risk behavior that was related either to the system or to the end-user. On the other hand, the facilitators were associated with the positive experience of the end-user, the increase in expertise and multi-professional cooperation, the functions of the electronic health record system that supported the preparation and administration of the medicines, as well as the benefits of the barcode-assisted medication administration workflow. The development ideas aimed to remove the barriers and the risk behavior related to the use of barcode-assisted medication administration. The users found that the use of barcode-assisted medication administration increased patient and medication safety, although there were still many challenges associated with the new workflow. Barcode-assisted medication administration can be used to reduce medication errors and protect patients from adverse events. The results of this study can be used to develop the usability of barcode technology and their implementation.
  • Fant, Alexandra (2020)
    Many pharmacies sell medicines through digital online pharmacy services but studies have shown that only a small fraction of the population are aware of and are using these. There is a need to investigate online pharmacy services and the obstacles they are facing. What should be considered are e.g. the legislation online pharmacies operate under, how the health competency of the population is taken into account in the design of the services, the skills and attitudes of the professionals toward digitalization and distance communication as well as practical circumstances. The aim of this study is to examine the online pharmacy operators' perceptions of the services they provide and how they are organized in Finland and Sweden. How the national regulations that exist regarding online pharmacies, and especially regarding medicine counseling at online pharmacies, are implemented in practice are also examined. The study was targeted to all pharmacy actors in Finland (72) and Sweden (11) who offer online pharmacy services and have reported this to the authorities. Of these, 20 (28 %) responded in Finland and 4 (36 %) in Sweden. The study was designed as a survey consisting of closed/structured- and open-ended questions. The survey questions were developed from previous literature on the subject and a background analysis of the online pharmacies' web pages to ensure the baseline and the relevance of the questions. The survey was available to respondents in digital format and the link was distributed through e-mail in Winter 2020. Data from the closed-ended questions were compiled and analyzed using Microsoft Office Excel, while data from the open-ended questions were analyzed through qualitative content analysis. In Finland, only a small fraction of the total turnover of pharmacies comes from the online pharmacy business. Many believe in an increased importance of online pharmacies when younger age groups begin to use pharmacy services more frequently and technology enables more versatile solutions. In both countries, the main age group using online pharmacies were 36-45 years. The goods that were purchased were mainly cosmetics, skincare and non-prescription drugs. In Sweden, customers suffering of long-term illness were also reported to be a large customer group. As distance communication methods, telephone and e-mail were mostly offered, but in Sweden also chat. About half of the staff had received special communication training for distance communication. Many respondents stated being unaware of the fraction of customers asking for medication counseling and whether this counseling is appreciated. In most cases, the operators stated that the legislation on online pharmacy services was adequate. There are differences in the possibilities of operating online pharmacies in different markets. In Finland, the online pharmacy business's share of pharmacies' total sales is very limited. In Finland there is hope that online pharmacies will become more important to younger customer groups in the future and that the technology is developed to enable more versatile services. Operators in Finland believe that the services should be more beneficial to customers in the future. In both countries an increase in the sale of prescription medication is expected. Online pharmacies have great opportunities to offer customers versatile means of communication for medication counseling, but there is still a need to investigate employees' skills in distance communication. The counseling situation at online pharmacies should be evaluated to ensure equivalency with the one at physical pharmacies.
  • Äijö, Nelli (2019)
    As the population becomes older and the amount of multimorbid patients increases, also health care spending increases. New care models are needed where patients’ needs are taken into consideration by providing preventive and patient-centred care. In Finland and internationally, new ways to treat elderly, chronically ill patients have been developed. One of the new models is the health and care plan model. This longitudinal, randomised, controlled trial studied the health and care plan model’s impact on healthcare costs, patients’ physical functioning and patients’ quality of life. The aim of the study was to study the cost-effectiveness of the health and care plan model compared to standard care practice. The goal of this study was to study if rational pharmacotherapy and self-management support can prevent the decline in physical functioning, the decline in quality of life and the increase in health service use and costs among elderly population. This study was conducted between 2014-2018 as a multi-disciplinary cooperation between Tornio health station, University of Helsinki Faculty of Pharmacy and Alatornio pharmacy. The patients in this study were over 75-year old, multimorbid, community dwelling, polypharmacy patients. The patients in the intervention group received an interview based clinical medication review and were formed a medication plan. Furthermore, the patients in the intervention group were planned a health and care plan that was combined with the medication plan into a comprehensive self-management plan in a multi-disciplinary meeting. A case manager was appointed for the patients in the intervention group and the case manager could be contacted by the patients in the intervention group at any point of the study if there arose a non-acute concern with the patient’s health. The patients in the control group were conducted a prescription review based on the information available in the electronic health records system and continued receiving the standard care practice. Cost and effectiveness data were gathered from the patients over the period of two years. The effectiveness data were gathered at Tornio health station where the intervention and control group’s quality of life was measured with the SF-36 generic quality of life measure and physical functioning was measured with Short Physical Performance Battery (SPPB). The quality of life data gathered with SF-36 were transformed into one preference based single index score SF-6D to calculate the quality of life and quality adjusted life years (QALY). Data about the use of health services were extracted from the electronic health records system and transformed into costs by using the national reference costs. At the beginning of the study, the intervention and control group were statistically significantly similar. During the two-year follow-up, no statistically or clinically significant differences were observed between the intervention and control group in their quality of life, in their physical functioning or in the costs of used health services. However, in the intervention group, the cost of used health services was on average 2 406 euros smaller than those of the control group’s during the two-year follow-up. The health and care plan model was cost-effective compared to standard care practice. The incremental cost-effectiveness ratio was -64 504 € per one QALY. Based on this study, it is recommended to support the self-management and physical functioning of the elderly with an intervention like health and care plan model to decrease the health care spending. The results of this study can be applied to Finnish healthcare system to decrease the health care spending of multimorbid, community dwelling and polypharmacy elderly patients. The use of real-world evidence increases the reliability of this study.
  • Valle, Jenni (2018)
    Gut inflammation and permeability is speculated to play a major role in the pathophysiology of several human diseases. Signs of a low-grade gut inflammation in patients with type 1 diabetes (T1D) have been found. Focus of this study was to understand the role of gut inflammation and increased gut permeability in the development of diabetic complications, especially nephropathy. Approximately, one-third of Finnish patients with T1D develop kidney disease during their lifetime. Inflammatory mechanisms may have an essential role in the pathophysiology of the disease. Lipopolysaccharide, LPS, is found in the outer membrane of gram-negative bacteria. LPS activates innate immune system and triggers the activation of inflammatory cytokines, neutrophils and macrophages as well as many pathophysiological processes in vivo, for instance fever and endotoxic shock. Aim of this study was to establish a zebrafish gut inflammation model using fluorophore conjugated endotoxin, LPS. We hypothesized that delivery of LPS in addition to EDTA in the gut of zebrafish triggers inflammation and increased gut permeability which may lead to leakage of LPS to blood stream and potentially kidney injury. This novel zebrafish inflammation model could possibly be used for studying the pathophysiological mechanisms of gut inflammation and possible kidney injury as well as for screening new anti-inflammatory drugs. In addition, this animal model can be used for studying intestinal alkaline phosphatase (IAP) in reducing gut permeability and LPS-mediated kidney damage. IAP is an enzyme produced in small-intestinal epithelium. IAP can detoxify several bacterial endotoxins including LPS and thus protect against the induction of intestinal inflammation. LPS and EDTA were delivered in the gut of 6 days old zebrafish larvae using microgavage injection. Fluorescence microscopy imaging of live zebrafish enabled following the same individual at different timepoints after injections. Paraffin sectioning of the small larvae was promising for investigating the morphology and permeability of the gut as well as possible immunostaining for detection of IAP. L-phenylalanine was used for inhibition of IAP enzyme. Using the novel method of microinjection to gut on zebrafish larvae the timing and amount of delivered materials to gut can be controlled well. The anatomy and function of the gut in zebrafish is very similar to small intestine of mammals and the highly developed vertebrate immune system makes zebrafish an interesting model organism for studying gut inflammation and permeability. In addition, inflammatory processes can be visualized in live, intact transparent zebrafish larvae. However, the technique has a lot of challenges including small size of the fish and possible tissue damage of the fish while performing injection. More experiments need to be carried out to establish the model for drug screening. Also, along with microscopy images, a more precise way for quantification the gut permeability is needed. Based on the images it’s not yet possible to conclude whether LPS increased gut permeability or if IAP inhibition with L-phenylalanine worked in zebrafish larvae. Using adult zebrafish in the future will give more information about the chronic gut inflammation and development of possible kidney injury.
  • Yli-Rantala, Anni (2014)
    Zebrafish (Danio rerio) is a vertebrate model organism. It is suited for many phases of drug development process like toxicological studies. The major advantage of using zebrafish is the possibility to conduct high-throughput screens on a whole vertebrate animal. However, there is not as much knowledge about zebrafish as there is about other model organisms. Therefore there might be differences between zebrafish and humans that affect the use of zebrafish as a model in the drug development process. The purpose of this thesis was to characterize the structure of the zebrafish oxytocin system and assess the role of oxytocin on zebrafish behaviour. In humans defects in the oxytocin system have been linked to many psychiatric disorders like autism. If the mammalian and zebrafish oxytocin systems resembled each other functionally and structurally, it would enable the use of zebrafish as a model when studying the role of oxytocin in pathophysiology of diseases and also in oxytocin system related drug development. The structure and development of zebrafish oxytocin system was studied by staining adult zebrafish brain cryosections and larval brains with antibodies made against mammalian oxytocin. The specificity of the antibodies to recognize zebrafish oxytocin was determined by absorption and cross-reactivity controls. The role of oxytocin on zebrafish locomotion was studied by inhibiting the splicing of oxytocin messenger RNA with morpholino oligonucleotides (MOs). The MOs were used to address the relevance of the model in pharmacology, since the zebrafish oxytocin receptors have not been expressed and pharmacologically characterized. In zebrafish oxytocin was produced in the cells of the preoptic nucleus. There were thick oxytocin fibers towards the pituitary and also thinner fibers into areas in the telencephalon, diencephalon, mesencephalon and rhombencephalon. One of the MOs was able to inhibit the production of oxytocin with a dose that did not cause morphological abnormalities. The MO reduced the locomotor activity of the fish, but the specificity of the MO has to be determined. The structure of the zebrafish oxytocin system resembles mammalian oxytocin system in terms of the location of oxytocin cells and fiber projections. Therefore zebrafish seems a suitable model organism for oxytocin research. However, the structure of the zebrafish oxytocin receptor system and the effect of oxytocin on other behavioural aspects have to be determined in order to further evaluate the applicability of zebrafish for oxytocin research.