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(2012)Review of the literature: The purpose of the review is to go through what is known about mechanisms of actions of different neurotrophic factors (GDNF, neurturin, CDNF and MANF) and how they are transported within the brain. Neurotrophic factors are endogenous and secreted proteins which have a pivotal role in the development and maintenance of neurons. They support the survival of neurons and they can help them to recover from different injuries. Due to these functions neurotrophic factors might be beneficial for the treatment of neurodegenerative disorders like Parkinson's disease. There are a great deal of studies that clearly show the neuroprotective and neurorestrorative function of GDNF and neurturin on dopaminergic neurons. They are also studied in clinical studies with Parkinson's patients but the results have been partly contradictory. The signalling route of GDNF and neurturin via RET tyrosinekinasereceptor is fairly well known but the other mechanisms of action of these factors needs to be studied further. CDNF and MANF constitute a novel, evolutionarily conserved family of neurotrophic factors. They are shown to have neuroprotective and neurorestrorative actions on dopaminergic neurons both in vitro and in vivo in a rodent model of Parkinson's disease. The mechanisms of action of CDNF and MANF are not quite clear at the moment. There are two different domains in their structure both of which are likely to carry different functions. The N-terminal domains of these proteins are close to saposins, lipid and membrane binding proteins, some of which are shown to have neurotrophic and anti-apoptotic effects. The C-terminal domain of MANF, in turn, is structurally close to the SAP-domain of Ku70-protein which binds Bax in the cytoplasm and thus inhibits apoptosis mediated by Bax. CDNF and MANF might protect neurons both via intracellular mechanisms and extracellularly acting like a secreted neurotrophic factor. CDNF and GDNF are transported retrogradially from striatum to substantia nigra. MANF, unlike the others, is transported from striatum to the frontal cortex. MANF and CDNF are shown to have better diffusion properties in the brain parenchyma than GDNF. Experimental part: We studied, by means of microdialysis, the effects of CDNF, MANF and GDNF on the dopaminergic neurotransmission of naive rats within the striatum. Neurotrophic factors (10 µg) and PBS as a negative control were injected into the left striatum in stereotaxic surgery. After this rats recovered one week before the first mircodialysis. The second mircodialysis was performed three weeks after the surgery. The samples were collected from the left striatum of freely moving rats. During the microdialysis neurotransmission was stimulated by replacing the perfusion solution with hypertonic potassium solution and with amphetamine solution. The concentration of dopamine, DOPAC, HVA and 5-HIAA was measured from the dialysate samples. In vivo TH-activity experiment was carried out for three rats in each group. NSD1015 was injected i.p.after which rats were decapitated and their striatums were dissected. The concentration of L-DOPA, dopamine and metabolites on the treated and untreated hemisphere were analyzed from the tissue samples. The amount of L-DOPA in the striatum after NSD1015-treatment indicates how active TH-enzyme is. There were no significant differences in the concentrations of dopamine and metabolites during the baseline. MANF and CDNF increased the release of dopamine from the nerve terminals compared to GDNF and PBS one week after the surgery. Three weeks after the surgery there was still significant increase in the release of dopamine in MANF group compared to GDNF group. Also the dopamine-DOPAC-turnover was increased significantly in MANF group compared to GDNF and PBS groups one week after the surgery. DOPAC/HVA -ratio was significantly smaller in GDNF group than in other groups one week after the surgery. These findings suggest that MANF potentiates dopaminergic neurotransmission most drasticly. The effects of MANF seem to last longer time than the effects of other neurotrophic factors. CDNF seems to increase the release of dopamine from the nerve terminals as well. The potentiation of dopaminergic neurotransmission could be due to increased biosynthesis of dopamine or due to the potentiation of the function of nerve terminals. In the results of the TH-activity experiment there was a trend according to which L-DOPA is synthesized less after the neurotrophic factor treatment that after the PBS treatment. This suggests that neurotrophic factors might decrease the activity of TH-enzyme.
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(2010)Histamine is an important neurotransmitter in peripheral as well as in central nervous system. Histaminergic neurons modulate various functions such as sleep-wake cycle, energy metabolism, memory and pain. In addition the brain histaminergic system has been shown to play a role in reinforcement, addiction and addiction related behaviors. After finding the H3 receptor in 1980s it was realised how essential the neuronal histamine is in modulating several central nervous system (CNS) disorders. H3 receptor modulates the synthesis and release of histamine. Furthermore it modulates the release of various other neurotransmitters, such as serotonin, noradrenalin, dopamine, glutamate, γ-aminobutyric acid (GABA) and acethylcoline. The H3 receptor is predominantly expressed in the brain and therefore it is an attractive target for various CNS indications. For more than a decade H3 receptor has gained the interest of many pharmaceutical companies. Several H3 receptor ligands, mainly antagonists or inverse agonists, have been assessed in preclinical as well as in clinical studies. So far there are not enough clinical data on the safety and efficacy of H3 receptor ligands, but there is a strong possibility that H3 receptor antagonists will be used in the treatment of various important disorders, including narcolepsy, schizophrenia and cognitive disorders. Earlier in our research group it was shown that H3 receptor ligands play a major role in ethanol related behaviors. These observations were confirmed in the practical part of this Master's thesis. H3 receptor modulates ethanol stimulation as well as ethanol reinforcement. Both H3 receptor antagonists, ciproxifan and JNJ-10181457 were able to inhibit ethanol-evoked conditioned place preference (CPP). This means they were able to inhibit ethanol reward and reinforcement. Ciproxifan also increased ethanol stimulation. Immepip on the other hand did not alter ethanol-evoked CPP, but it totally inhibited the stimulation of locomotor activity by ethanol. The dopaminergic system regulates both reward and motor functions. The postsynaptic H3 receptors have been shown to be able to heteromerize with both dopamine D1- and D2- receptors in striatum. The formed heteromers modulate dopaminergic neurotransmission in vitro, which may lead to alterations in behavior in vivo. It is therefore possible that the responses we have seen on a behavioral level in this Master's thesis project are due to interactions between histaminergic and dopaminergic systems in striatal areas. The H3 receptor is an interesting target in the drug development of various CNS disorders. The responses seen in this Master's thesis project also indicate that the blockade of H3 receptor inhibit ethanol reward and reinforcement. In conclusion, these findings indicate that H3 receptor antagonists could possibly have therapeutic potential in treating ethanol addiction.
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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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(2014)In Finland the elderly residents of long-term care facilities are often prescribed a lot of medications, especially psychotropic drugs. It also happens that a patient or a resident has to be physically or chemically restrained. Chemical restraining can be defined in many ways, for example as using a drug - usually an antipsychotic - to restrict the freedom or movement of a patient and to control his or her behavior. In nursing homes the staff is in a key position when it comes to deciding on the use of chemical restraining or PRN medication. A legislation to guarantee the self-determination of a patient and to define how physical restraining can be used is now being prepared in Finland. Only a few studies on chemical restraining from a nurses' point of view have been made so far. Thus, the aim of this study is to provide more information on the level of knowledge, the attitudes and perceptions of nurses regarding chemical restraining and the effect of those on deciding whether to use chemical restraints or not. Three focus groups with nurses were conducted in Hyvinkää nursing homes (n=13). The groups were recruited both by e-mail and directly from the wards. The focus group discussions were digitally audiotaped and transcribed verbatim. The content of the transcripts was then analyzed using a constant comparative method. According to the study most of the antipsychotics used in long-term care were used daily. However, it is not uncommon for the nurses to be unsure about their knowledge on the use of medicines. It is thus important to help the nursing staff to increase their knowledge and skills in pharmacology. The nurses also wished to get extra training for treating people with dementia. The concept of chemical restraining is quite ambiguous, and the use of chemical restraints is a complex ethical issue because the reasons for and effects of administering it vary depending on the situation. The study shows that the chemical restraining is most often considered justified when it is used to ensure the safety of a patient, relieve anxiety or to keep the working conditions of the staff tolerable. Also a shortage of manpower and a request by the family can influence the decision on using chemical restraints. The lack of proper common guidelines causes confusion and wide variation in the use of chemical restraints. Many interviewees were hoping for more open discussion and cooperation on using chemical restraining. The nurses also mentioned many alternatives to rely on instead of using chemical restraints, such as soothing, comforting and creating a safe feeling for the patients, daily routines and stimulus. One of the key factors for taking to these instead of chemical restraints are the manpower resources in the facilities. Educating the staff can also help them to find more options for chemical restraining and make staff members recognize new or remember forgotten routines for caring for the patients without using psychotropic drugs.
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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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(2012)Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) have two unique properties: the self-renewal capacity and the broad developmental potential. They both have their advantages and disadvantages, but the current perception is that hESCs and hiPSCs complement rather than replace each other. New scientific problems and ethical challenges will arise because stem cell research is developing rapidly. The potential of hiPSC and hESC technologies in drug discovery is tremendous. The human pluripotent stem cell (hPSC)-derived cells have a potential to replace a part of the current preclinical toxicity and efficacy screening tests and to prevent misrouted drug development and use for lead optimization at phases before clinical trials. The hPSC-based disease models can also narrow the gap between traditional animal models and clinical trials. One major challenge is the differentiation process of hPSCs into cells of the relevant tissue. The recent study of our laboratory shows that the liver cell-deried acellular matrix (ACM) promotes the hepatic commitment of hESCs. To create chemically defined, xeno-free and feeder-free culture matrices for the differentiation of the hESCs into hepatocyte-like cells (HLCs), the ECM components of the ACM were characterized. The results suggest that the ACM contains fibronectin, laminins. After the characterization, the object was to identify which of the ECM proteins are essential and effective in the differentiation. A three-step differentiation protocol with differenent ECM protein solutions was used to produce HLCs. The hESCs were first induced into definitive endoderm (DE) cells. The DE cells were committed to the bipotential hepatic progenitors positive for HNF4α and AFP. Finally the progenitors were differentiated into HLCs. The mRNA expression of albumin, CK8, CK18, AAT, and BCRP was increased in HLCs. All the derived HLCs were albumin positive. The hESCderived HLCs showed hepatic morphology, cytoplasmic vacuole characteristics, and functional albumin secretion. The chemically defined matrices showed a supportive role in the differentiation of the hESCs into HLCs. This study establishes an efficient, chemically defined, xeno-free system to produce HLCs as a cell source for pharmaceutical and developmental studies.
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(2011)Angiogenesis, the formation of new blood vessels from preexisting vascular network, is an essential process during tumor development. Growing tumors secrete different growth factors that induce angiogenesis, of which vascular endothelial growth factor (VEGF) is predominant. Angiogenesis inhibitors act either by blocking the extracellular bindning of growth factor to its receptor by monoclonal antibodies or by blocking the intracellular signalling pathway by small-molecule agents. The small-molecule agent sunitinib is a multitargeted tyrosine kinase inhibitor that has antiangiogenic and antitumor activities due to the selective inhibition of several tyrosine kinase receptors. Sunitinib is approved for treatment of gastrointestinal stromal tumors, renal cell carcinoma and pancreatic neuroendocrine tumors. Known side effects are hypertension, cardiotoxicity and renal damage. These toxic effects are due to sunitinibs "off-target" toxicity, which occurs when a tyrosine kinase inhibitor causes adverse effects via inhibiton of a kinase not intended to be a target of the drug. For example inhibition by sunitinib of AMPK, a kinase that plays key roles in maintaining metabolic homeostasis in the heart, accounts in part for the toxicity seen in cardiomyocytes exposed to sunitinib. By achieving a better understandning of what causes the side effects it could be possible to develop treatments that reduce off-target effects. Caloric restriction is one nonpharmacological approach that has been shown to have beneficial effects on the heart partly by activating sirtuins. Sirtuins regulate a diverse array of cellular functions, including metabolism, gene transcription, cell division and cellular stress response. The aim for this study was to investigate whether caloric restriction improves sunitinib-induced cardiovascular toxicity and renal damage in rats, and to study activated cellular pathways. In this study 40 spontaneously hypertensive rats (SHR) and 10 normotensive Wistar-Kyoto (WKY) rats were used. They were divided into groups depending on treatment; I WKY control, II SHR control, III SHR + caloric restriction 70 %, IV SHR + sunitinib 3 mg/kg and V SHR sunitinib 3 mg/kg + caloric restriction 70 %. The follow-up period was eigth weeks. Blood pressure was messured weekly, metabolic cages were used week 4 and week 8 for urine samples, echocardiography was performed the last week and vascular response was studied at the end. The proteins Sirt1 and AMPK in heart were investigated by Western blot and the amount of the marker of macrofage ED1 in kidney by immunohistochemistry. Based on this study it was observed that the dose 3 mg/kg sunitinib was well tolerated in rats because it did not cause more extensive hypertension, worse hypertrophy or renal damage compared to untreated SHR groups. This study also showed that short-term caloric restriction has beneficial cardiovascular effects.
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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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(2011)The background of this study is increase in the ageing population and in medication use. Aged-related changes in pharmacodynamics and pharmacokinetics may change medication response in elderly patients and lead to adverse reactions. For elderly people the risk of being hospitalized due to adverse drug reactions is four times higher than for younger people. Many of these problems could be prevented by avoiding the use of certain drugs in the elderly. Several criteria have been developed to assess medication appropriateness in the elderly. The aim of this study was to develop a new Finnish Medication Risk Assessment (MRA) tool to be used by trained nurses to assess the presence of risks related to use of medicines in outpatients aged 65 years and older. A preliminary tool was developed through a comprehensive literature review of tools to indicate appropriateness and risks of elderly medications, and through expert opinions. The tool was then validated by using three-round Delphi-method. Delphi-method is a qualitative consensus method which is based on group judgement of a subject matter. The first and the second Delphi-rounds measured the tool's suitability and the third Delphi-round measured the importance of the items of the tool in estimating risks related to the use of medications of elderly patients. In this study, 33 expert geriatric panelists were approached of whom 11 physicians, three pharmacists MSc (Pharm.) and four nurses agreed to participate. The results from the Delphi-rounds were evaluated both quantitatively and qualitatively. Through the three-round Delphi-method was developed a MRA -tool that contains 19 items. According to the panelists the items of the tool are either important or moderately important. This indicates that the tool is valid to estimating medication risks in use of medications in this population. Further studies are needed to test the tool among nurses and patients. The MRA -tool was primary developed for estimating risks in medication use, but it could also be used for educational purposes. In the future, it is possible to implement safer and more appropriate pharmaceutical treatment for elderly patients by using this Medication Risk Assessment -tool.
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(2013)Polypharmacy and age-related changes in pharmacodynamics and pharmacocinetics may lead to drug-related problems in elderly patients. Accurate medication reconciliation and medication review on admission may help to control drug-related problems and optimize drug therapy in elderly patients. Several models have been developed to reconciliate and review medications at this point of care. A Finnish model can be developed on the basis of the se models. The aim of this study was to develop a tool for medication reconciliation and medication review on admission for ward pharmacists’ use in the Lahti city hospital. The tool was developed with an action research method in cooperation with the multiprofessional study group. A preliminary tool was developed through doctors’ (n = 2), nurses’ (n = 3) and ward pharmacists’ (n = 2) interviews, a literature review and the expertise of the multiprofessional study group. The preliminary tool was piloted twice in the Lahti city hospital. After the first pilot a view changes were made to the too l by the experiences of the ward pharmacists. Doctors (n = 3) who worked at the study ward during the first pilot were interviewed to find out their views on the medication reconciliation and medication review process so that their views could be taken into consideration in the development of the final version of the tool. After second pilot ward Pharmacists (n = 2), researchers (n = 2) and an expert of geriatrics from the study group took part in a group conversation. Through the group conversation and doctors’ interviews was developed the final version of the tool. The developed tool contains sections for patient’s background information, patient interview, medication reconciliation, drug-related problems, proposed medication changes and doctor’s decisions on the proposed changes. Also instructions of the medication reconciliation and medication review process were developed for ward pharmacists. The developed tool will be used in an intervention study in the Lahti city hospital. In the future a new version of the tool could also be developed to be used in other hospitals in Finland to reconciliate and review medications at the time of hospital admission.
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(2012)The medicines information and counseling given by health care professionals are essential in supporting patients' medication therapy. Given that medication therapies are often associated with medicine-related problems among the elderly, proper knowledge on medicines and their use is especially important for this particular patient group. Benzodiazepines and related drugs are of special concern in the elderly. Despite the current care guidelines, they are commonly used by the elderly, often also regularly and long-term basis. Benzodiazepines and related drugs are associated with multiple potential adverse drug reactions that their elderly users should be aware of. This study aimed at assessing the knowledge on medications, and needs and sources of medicines information on benzodiazepines and related drugs in the elderly. Especially, medicines information related to benefits and adverse drug reactions was studied. Additionally, data on use and subjective experiences of benzodiazepines or related drugs in the elderly were explored. Structured interviews were conducted among patients aged 65 years and using benzodiazepines or related drugs (n = 38) in acute wards (n = 2) of Pori City Hospital in 2004. Elderly patients reported that the package leaflet was the main source of medicines information on benefits and adverse drug reactions relating to medicines they used. The physician was reported as a second source after the package leaflet. More than 50 percent of the elderly (n = 20) had not received information about the benefits or adverse drug reactions of benzodiazepines from their health care providers or relatives. The information received had merely focused on benefits of drug than adverse drug reactions. Most commonly the elderly (61 %, n = 23) knew, that the use of benzodiazepines can cause drug dependence. Least commonly, they were aware that benzodiazepines can cause muscular weakness, depression and falling over. Eight elderly were not aware of any asked adverse drug reactions and nearly two thirds of the patients (63 %, n = 24) knew less than four adverse drug reactions out of eleven. The results indicate that elderly patients are not well aware of the effects of benzodiazepines and related drugs they use. Additionally, they may more often receive information from the package leaflet than health care professionals. Physicians and other health care professionals should pay more attention to counseling elderly patients especially about the benefits and adverse drug reactions of benzodiazepines and related drugs.
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(2019)Streptococcus pneumoniae is a bacterium that causes invasive pneumococcal disease (IPD) such as bacteraemia and meningitis, and pneumonia. The prevalence of pneumococcal diseases is high in infants and in ≥65-year-olds. Also, the incidence of pneumococcal disease is higher in medical risk groups compared to the base population. Pneumococcal diseases can be prevented by vaccinations and since 2010 pneumococcal vaccine PCV10 has been in the national vaccination programme for infants in Finland. The aim for this study is to evaluate the cost-effectiveness of pneumococcal vaccinations in national vaccination programme for the 65-year-olds in medical risk groups (diabetes, chronic coronary artery disease, asthma and COPD). Secondary aim is to examine uncertainty factors that are related to economic evaluations of pneumococcal vaccinations in the elderly. Cost-utility analysis was used as the economic evaluation method. It is a method where health gains are measured by quality-adjusted life years (QALYs). Static multicohort model was chosen for the modelling. Some of the used parameters were acquired from the literature and most of the epidemiology and cost parameters were acquired from research reports and articles published by National Institute for Health and Welfare. Analyses were made for both pneumococcal vaccines that are registered for adults (PCV13 and PPV23) and in 2 different scenarios: Finland’s present situation where PCV10 is in the vaccination programme for infants (scenario A), and hypothetical situation where PCV13 would be in the vaccination programme for infants (scenario B). Based on the analysis, when PCV10 was in the vaccination programme for infants (scenario A), vaccinating 65-year-olds in medical risk groups was cost saving intervention in the health care perspective for both vaccines in chronic coronary artery disease and asthma and COPD risk groups. In diabetes risk group the costs per QALY’s gained were 2 100 € in scenario A. When PCV13 was in the vaccination programme for infants (scenario B), costs per QALY’s gained for PCV13 vaccinations were: diabetes 52 400 €, chronic coronary artery disease 35 900 € and asthma and COPD 22 000 €. The uncertainty of results was tested with deterministic and probabilistic sensitive analysis. In scenario B the results were sensitive for the waning of the PCV13 produced immune protection, the price of the vaccine, the proportion of pneumonia caused by S. pneumoniae, the changes in the pneumococcal disease incidences and the effect that pneumonia has for the health related quality of life. The cost-effectiveness of vaccinating 65-year-olds with pneumococcal vaccines was different depending on the risk group and on which pneumococcal vaccine is in the vaccination programme for infants. In addition, there are several uncertainty factors that have an impact on the results of economic evaluation of pneumococcal vaccinations.
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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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