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The obligatory storing of medicines is a vital part of the secure supply of medicines in Finland. Over the past few years, its importance has further increased due to the growing number of medicine shortages. Evaluating the effectiveness of the obligatory storing system is important in order to improve it, but so far research on the matter has been limited. The aim of this study was to investigate how the obligatory storages of pharmaceutical manufacturers and importers are used during medicine shortages in Finland, and to assess the effectiveness of their use in these situations. The material for this study consisted of medicine shortage notifications which had been received by the Finnish, Swedish and Norwegian medicine authorities with a forecasted starting date between January and June 2022. In addition, Finnish exemption permits for lower storage levels from the same time period were investigated. Medicine shortage notifications were grouped based on the obligatory storing status of the medicine. The share of obligatorily stored medicines out of all shortage notifications was the smallest in Finland (10%) when compared to Sweden and Norway. There were no statistically significant differences in any of the countries in the duration of a shortage between obligatorily stored medicines and medicines which are not obligatorily stored. In total, 151 exemption permits had been granted within the time period of the study, 129 (85%) of which did not have a coinciding medicine shortage. This suggests that a patient-affecting shortage had successfully been avoided. The remaining 22 exemption permits were linked to a shortage which started either prior to, or during the validity of the exemption permit. In the Finnish data, 91 notifications concerned obligatorily stored medicines but in 69 (76%) of these cases no exemption permit had been applied for or been granted in relation to the shortage. The results of this study indicate that the obligatory storing of medicines was used to respond to several medicine shortages during the first half of 2022, and in most cases, it seems to have been an effective way to avoid a patient-affecting shortage. However, in some cases the use of an exemption permit was not well-timed, a shortage was experienced despite the releasing of products from the storage, or obligatory storages were not used at all. Based on the results, further research on the practices of obligatory storing and the factors which affect the use of exemption permits is needed to develop the system further and to improve its effectiveness in responding to medicine shortages.

During the past few decades, the explosion of discovery in cancer and immunological research has led to the increased understanding of the interactions between the immune system and tumors. These developments have provided vital information about the immune system’s role in cancer development. It is evidenced that the immunity system is capable to distinguish tumor cells from normal tissue by recognizing tumor antigens that are exclusively expressed on tumor cells or are presented in greater amounts on tumor cells than normal cells. Consequently, the immune cells start to attack tumors for protecting the host. The possibility to use the immune system as a weapon against cancer cells leaded to the promising innovation – cancer immunotherapy – which aims to activate the body’s own immune system and its components to mount antitumor immune responses for eliminating cancer cells. The antitumor efficacy and high safety profile of several immunotherapeutic strategies have already been demonstrated thereby resulting in their integration into clinical practice. However, most patients have not benefited from cancer immunotherapy as a single treatment. In this regard, new innovative methods are clearly needed to overcome the obstacles hindering the clinical success of this field. Therapeutic cancer vaccines are emerging as attractive immunotherapies currently being evaluated in both pre-clinical and clinical studies. The purpose of cancer vaccines is to eradicate tumor cells by eliciting antitumor CD8+ T cell responses against the injected tumor antigens. Due to the ability to specifically kill tumor cells and simultaneously trigger immune responses against tumor antigens via direct oncolysis and by encoding transferred tumor antigens, oncolytic viruses are of significant interest for being used as in situ cancer vaccines. Despite these unique properties, several factors such as tumor immunosuppression and immune tolerance to targeted tumor antigens resembling antigens of normal tissues hamper the use of oncolytic vaccines in clinic. Instead of focusing only on CD8+ T cells, it has been suggested that giving more attention to CD4+ T helper cells, which are required for priming and expansion of CD8+ T cell responses, could be the key to improve the efficacy of cancer vaccines. Researchers have also demonstrated that an ongoing antigen-specific CD4+ T cell response can lead to the bystander activation of surrounding T cells with unrelated antigen specificities. Based on this theory, the hypothesis of this study was to employ the pre-existing immunological CD4+ memory against infectious pathogens in generating bystander CD8+ immunity against solid tumors. In this study, mice transplanted with poorly immunogenic B16-OVA tumors were pre-immunized with the chosen vaccine to induce immunological CD4+ memory against an infectious pathogen. Tumors were then treated with already developed cancer vaccine, which was peptide-coated conditionally replicating adenovirus (PeptiCRAd) complex. PeptiCRAd was constructed by electrostatically coating adenovirus with both pathogen-derived and tumor-derived peptide. The intratumorally injected double-coated PeptiCRAd complex was assumed to activate peptide-specific T cells and thus, result in anti-pathogen CD4+ T cell recall responses and the following bystander activation of antitumor CD8+ T cells, which can then mount an effective immune response to destroy cancer cells. The efficacy of this treatment was observed in pre-immunized mice by measuring the growth of injected tumors. The experiment was repeated identically with non-immunized naïve mice to see the difference in the results. The immunological background of this treatment approach was investigated by analyzing mouse tissue samples with standard immunological techniques including ELISA, IFN-γ ELISPOT and flow cytometry. This study showed that long-term immunological memory against the pathogen was successfully accomplished and the strongest inhibition of tumor growth in pre-immunized mice was achieved with double-coated PeptiCRAd, whereas the antitumor efficacy was not seen in naïve mice. Additionally, a new ex vivo method to detect pathogen-specific CD4+ T cells from spleen was developed and the stimulation of cell-mediated immunity by this treatment was supported by finding the highest levels of pathogen-specific CD4+ Th1 cells from mice treated with double-coated PeptiCRAd. Some encouraging results concerning the beneficial immune cell composition of tumors and tumor draining lymph nodes were also obtained from other performed experiments. Though further immunological analyses are required for understanding the precise mechanisms of action behind the treatment, the increased immunogenicity and antitumor efficacy of double-coated PeptiCRAd can still be considered as a consequence of the bystander effect, which can possibly be utilized for developing improved strategies to win the fight against cancer.

There is a growing interest towards continuous manufacturing in pharmaceutical industry. When considering solid dosage form manufacturing and continuous wet granulation, twin screw granulation is the most studied technology. In spite of this, process knowledge is not as comprehensive as it is for batch granulation technologies such as high shear granulation. One problem with twin screw granulation seems to be bimodal and broad particle size distribution of granules. Specific causes of bimodal distribution and the ways to possibly gain unimodality either in granulation step or via dry milling are not fully understood. The purpose of this study was to optimize the ConsiGma25 continuous twin screw wet granulation process and study dry milling as a possible way of gaining unimodal particle size distribution in order to optimize particle size for tablet compression purposes. One aim was also to compress tablets from the obtained twin screw granules and evaluate the quality against high shear and direct compressed tablets of same formulation. Central composite circumscribed design was used as a design of experiments for twin screw wet granulation process. Factors (powder feed rate, screw speed, liquid to solid ratio (L/S ratio) and mill screen size) were varied in two levels. In total, 29 experiments were conducted. Tablet compression design was fractional as only 11 experiments from the twin screw granulation design were tableted. High shear granulation was conducted with Diosna P-1/6 using three different L/S ratios. All of these batches were compressed to tablets. Also direct compression was carried out. Formulation used had ibuprofen as active pharmaceutical ingredient, mannitol and MCC as fillers, HPC as binder and croscarmellose sodium as disintegrant. Lubricant, sodium stearyl fumarate, was blended to granules before tablet compression. Torque was measured during granulation in order to evaluate equilibration of the twin screw granulation process. It stabilized quickly and stayed stable after parameter changes and increased as L/S ratio and barrel fill rate increased. Particle size distribution and flowability of granules were analysed and tablets were analysed according to European and United States pharmacopoeias. Also tensile strengths and compactibilities were evaluated. Particle size distributions of unmilled twin screw granules were bimodal and broad. After dry milling, QicPic dynamic image analysis results showed unimodal particle size distributions for all experiments whereas Mastersizer laser diffraction analysis showed more unimodal distributions for experiments milled with smaller mill screen sizes. Mill screen size had the largest effect on particle size and as increased mill screen size increased particle size. Results showed that dry milling was a way to optimize particle size distribution for tablet compression purposes. Also flowability of formulation and process parameters needed to be optimized as granulation parameters had an effect on particle size and manufacturability was enhanced with better flowing formulation compared to previous study. Knowledge of the influence of L/S ratio, screw speed and powder feed rate, on granule size was gained. The effect of these process parameters varied depending whether d10, d50 or d90 was measured and particle size analysis method used. Increased L/S ratio and screw speed increased granule size as increased powder feed rate decreased it. Twin screw tablets showed higher tensile strengths and better compactibility compared to both high shear tablets and direct compressed tablets. Twin screw tablets showed also faster dissolution compared to direct compressed tablets probably due to of lower compression force. Mill screen size had the largest effect on dissolution properties of the twin screw tablets. When larger mill screen size was used, dissolution was slower due to larger particle size. Also increased powder feed rate made dissolution rate slower due to higher fill rate of the barrel. In other tablet properties analysed, no significant differences were seen between different twin screw experiments or between twin screw tablets and direct compressed tablets. All of the twin screw tablets and direct compressed tablets fulfilled the requirements of European and United states pharmacopoeia. As a conclusion, continuous granulation process was successfully optimized and high quality tablets resulted showing especially the effect of dry milling on granule size and shape as well as on tablet properties.

Orexin receptors have gained more attention due to increased knowledge of their physiological significance. The successful development of orexin receptor antagonists treating insomnia has enlarged the scope of research leading to an interest in developing small molecule agonists that have drug-like properties and induce activation in the orexinergic system. Transforming this idea into reality has remained an unaccomplished challenge. In this work, molecular mechanism of activation in orexin receptor type 2 is studied by conducting molecular dynamics simulations after capturing coordinates of active and inactive state crystal structures. The crystal structure coordinates define the starting pose for the protein and the ligand in the simulations. Preliminary steps prior to simulation include building the surrounding system and model building in which homology modeling is employed to reconstruct missing loops. A 100-nanosecond simulation is executed for both models. Active and inactive state models display stable binding event characteristics when examining the coordinate changes of every atom during the simulation. No major conformational changes are observed. The most congruent feature relative to the literature is the difference in the interactive role of residue Q3x32 between the simulations. The agonist forms two consistent hydrogen bonds with the upward-shifted Q3x32 while an inactive downward-facing version is observed in the antagonist model. Some residues present unexpected features omitting comparative functions of literature, which along with general inconsistency of protein-ligand contacts undermine the reliability of models heavily. The simulations conducted need to be extended to produce a hypothesis for the activation mechanism because of the defects around simulation protocols and the low quantity of simulation runs.

Osastofarmasian ja kliinisen farmasian palvelut Suomen sairaala-apteekeissa ja lääkekeskuksissa ovat jo 2000-luvun alusta lähtien kehittyneet suuntaan, johon Maailman terveysjärjestön (WHO) lääkitysturvallisuusohjelma Medication Without Harm ohjaa. Suomen viranomaiset ovat viime vuosina linjanneet farmasistien roolista moniammatillisessa lääkehoidon toteutuksessa useissa ohjeistuksissa. Vuosina 2017–2022 kotimaisessa ja kansainvälisessä tutkimuksessa osastofarmasian ja kliinisen farmasian hyötyjä sekä niiden yhteyttä lääkitysturvallisuuteen on tutkittu aktiivisesti. Osastofarmasian ja kliinisen farmasian palveluiden tilanteen ja niiden avulla saavutettujen hyötyjen ensimmäinen kansallinen kyselytutkimus sairaala-apteekeille ja lääkekeskuksille tehtiin Suomessa vuonna 2011, ja se toistettiin samalla menetelmällä vuonna 2016. Tämän tutkimuksen tavoitteena oli tehdä vastaava valtakunnallinen seuranta-tutkimus osastofarmasian ja kliinisen farmasian palvelujen tilanteesta Suomessa vuonna 2022. Tämä tutkimus toteutettiin samalla e-lomakepohjalla kuin aikaisemmat tutkimukset, muokaten kysymyksiä ajantasaisemmaksi. Kysely lähetettiin sairaala-apteekkeihin, julkisiin ja yksityisiin lääkekeskuksiin sekä joukolle vastaanottajia kuntayhtymissä, hyvinvointialueilla ja yrityksissä, joissa mahdollisesti tuotettiin osastofarmasian ja kliinisen farmasian palveluita. Kyselyn vastausprosentti (62 %) sekä osa tuloksista raportoitiin edeltävään tutkimukseen vertailemisen vuoksi vain sairaala-apteekkien ja itsenäisten julkisten lääkekeskusten osalta (n=29). Muut vastaajat (n=16) analysoitiin omana ryhmänään, mutta uusien kysymysten osalta raportoitiin yleisimmin kaikkien vastaajien (n=45) vastaukset yhdessä. Osastofarmasian ja kliinisen farmasian palveluita tuotti 82 % (n=37/45) kaikista vastaajista. Palveluiden avulla saavutettuja hyötyjä oli tutkinut 24 % (n=9/37) kaikista vastaajista, jotka tuottivat palveluja. Kyselyn tulosten perusteella osastofarmasian ja kliinisen farmasian henkilökunta oli vastaajaorganisaatioissa kasvanut vuosina 2017–2022, ja palveluita tarjottiin yhä laajemmin erilaisissa hoitoympäristöissä. Erityisesti palvelut olivat yleistyneet potilaita vastaanottavissa yksiköissä, kuten ensiavussa ja päivystyksessä, terveyskeskusten vastaanotoilla sekä poliklinikoilla, joissa työ painottuu lääkityksen ajantasaistamiseen. Työtehtävät olivat monipuolisia, ja kliinisten asiantuntijatehtävien osuus oli edelleen kasvanut. Järjestelmälähtöinen lääkitysturvallisuuden edistäminen sekä lääkehoitoprosessin kokonaisvaltainen kehittäminen näkyivät tehtävien jakaumassa. Eniten olivat yleistyneet eri tasoiset lääkityksen arvioinnit sekä lääkitysturvallisuusauditoinnit, kun vuonna 2016 eniten oli yleistynyt lääkitystiedon ajan-tasaistaminen. Tässä kyselyssä farmasian ammattilaisten osallistuminen potilaan kotiutusvaiheeseen oli vähentynyt. Lisäksi osastofarmaseuttien logististen tehtävien selvää vähenemistä ei vielä nähty huolimatta automaation, älylääkekaappien ja osastolääketyöntekijöiden yleistymisestä. Palveluiden avulla saavutetuista hyödyistä lääkehoidon arviointien lisääntymistä oli tutkittu eniten, ja lääkehoidon arviointiin liittyvät koulutukset olivat myös eniten suoritettuja täydennyskoulutuksia. Kliinisen farmasian palveluiden kohdentamista niistä eniten hyötyville potilaille tulisi edelleen kehittää, ja täydennyskoulutukseen käytettävää aikaa tulisi organisaatioissa lisätä. Osastofarmasian ja kliinisen farmasian palvelut ovat laajentuneet kotimaisten ja kansainvälisten suositusten mukaisesti ja keskittyvät yhä enemmän lääkitysturvallisuuden edistämiseen. Palvelut painottuvat tällä hetkellä erityisesti potilaita vastaanottaviin yksiköihin. Jatkossa kliinisen farmasian palveluita tulee kohdentaa enemmän myös potilaan kotiutusvaiheeseen, koska kansainvälisten tutkimusten mukaan se voisi olla erityisen kustannusvaikuttavaa.

Multi-drug tolerance is a phenomenon, in which microorganisms normally susceptible to an antimicrobial agent are able to withstand a treatment via phenotypic alteration. The tolerance is conveyed by a microbial subpopulation that is in a non-replicative and metabolically inactive state also known as persistence. Through this kind of dormancy, the subpopulation may survive an otherwise appropriate course of antimicrobials, since the majority of the drugs target cellular division or metabolism. Upon the reduction of the surrounding antimicrobial concentration the multi-drug tolerant cells - persisters - become resuscitated thus allowing repopulation. As opposed to the more widely acknowledged challenge of antimicrobial resistance, the offspring of the specialist survivor cells are genetically identical to the susceptible majority. Persisters are especially abundant in biofilms, a microbial lifestyle characterized by aggregated microcolonies that are covered in a self-produced slimy matrix known as extracellular polymeric substance (EPS). Partly owning to this protective matrix, biofilms are inherently somewhat tolerant to antimicrobial chemotherapy. Moreover, microbes confined in a biofilm are additionally protected against the components of the host immune system. Conversely, it is assumed that persisters in planktonic, i.e. freely floating state, are easily cleared out by white blood cells. Combined, the immune evasive properties of biofilms and the remarkable multi-drug tolerance of persisters give rise to recalcitrant infections that are immensely difficult to eradicate. The described phenomenon constitutes crucially to the major healthcare challenge of chronic, treatment-resistant infections. Tuberculosis, cystic fibrosis lung disorder, bacterial endocarditis and infections related to indwelling medical devices are only a few examples of such problems. Despite the need for antimicrobials with anti-persister efficacy, no such therapeutics is available and very few are being investigated - one important factor being the lack of relevant drug discovery platforms. Therefore, the aim of this study was to develop an anti-persister assay and to carry out a pilot screening of natural product derived bioactive compounds. Based on the notion that persisters are enriched in bacterial cultures that have reached the stationary phase of growth, a persister model was designed using Staphylococcus aureus ATCC 25923 as the test strain. The bacteria were grown in liquid cultures until they reached the stationary phase and subsequent experimentation was carried out to confirm the tolerant state. After the stationary phase persister model was validated, a small pilot screening of natural products was undertaken in the hope of finding novel anti-persister activity. Mitomycin C, a cytotoxic drug with an existing anti-cancer indication was assigned as the positive control compound because of its previously established anti-persister activity. Since it is common for all of the persister-related diseases that the target microorganisms reside within a protective biofilm, an additional assay based on biofilm regrowth was designed to characterize the hit compounds on a more clinically relevant platform. The persister model culture was shown to be tolerant to conventional antibiotics. The re-induction of metabolic activity by diluting into fresh medium recovered the antimicrobial susceptibility expectedly. A total of 4 compounds were identified as anti-persister hits in the pilot screening campaign. Chromomycin A3, dehydroabietic acid, mithramycin A and oleanolic acid were all able to reduce the viable bacterial count in the stationary phase persister model more than 2 logarithmic units at 100 µM. Mithramycin A was the most potent, reducing the viability over 6 log units. The model compound mitomycin C reduced the viable counts 5.49 (± 0.96) logarithmic units. Out of the 4 hits, dehydroabietic acid was selected for the biofilm relapse assay because of its favourable biocompatibility properties. It reduced regrowth for the treated biofilms by 4 logarithmic.

The medication process in palliative care is prone to medication errors and their significant consequences.The complex nature of palliative care medication includes frequent use of parenteral drugs and drug mixtures. Many of the medications used parenterally are considered high-alert medications which carry a significant risk of harm if used in error. By investing in medication safety initiatives, quality of palliative care can be improved, and costs reduced. The aim of this study was to identify the most common compositions of parenteral morphine and oxycodone mixtures administered in patient units providing special level (level B) palliative and hospice care in Helsinki. Identifying the most common compositions enables further researchon standardizing mixtures and centralizing compounding to improve medication safety. This study was conducted as a retrospective medical record review. The data was extracted from the electronic client and patient record system Apotti and consisted of medication administration records of 120 patients receiving special level B palliative and hospice care in Helsinki At-home Hospital and two patient wards in Suursuo Hospital. The data was analyzed with descriptive statistics using Microsoft Excel program. Patient characteristics, including age and ICD-10 diagnosis groups were analyzed. The most common drug combinations used in the mixtures and the combinations with the most variation were identified. Four drug combinations with the most unique compositions were selected for further analysis in which drug concentrations and daily drug doses were analyzed based on continuous infusion rates. 182 drug mixtures including morphine and 147 including oxycodone were identified. A diluent (NaCl 0.9%) was used in 225 mixtures and most often (178/225) the mixtures were diluted into volume of 20 ml. The most frequently used drug combination was comprised of morphine, midazolam, and haloperidol (26.4%), followed by the combination of oxycodone, midazolam, and haloperidol (21.8%). These combinations were also among the four combinations with the most unique compositions with the combination of oxycodone and midazolam and the combination of morphine, midazolam, haloperidol and glycopyrronium. In the four drug combinations with the most unique compositions, the variation was often relatively minor, and the largest variations were observed in opioid components: especially morphine was used in a wide variety of concentrations (2.00–17.91 mg/ml) and daily doses (15–260 mg). Most of the mixtures selected for further review (89/96) were compounded to provide a continuous infusion over a period of four days. In the studied units, mixtures with comparable compositions and features were frequently utilized, suggesting that standardization may be a feasible way to improve medication safety and quality of care in palliative care. As most of the mixtures were administered via PCA, standardization could be particularly advantageous. While it may be possible to standardize and centrally compound mixtures used in this study, more research is needed in several aspects, including physiochemical properties of the mixtures, meeting the clinical requirements in the units, and understanding the underlying factors behind medicine prescribing.

Parkinson's disease is characterized primarily as a bradykinetic disorder with severe nigral cell loss. In addition to motor symptoms, up to 85 % of patients with Parkinson's disease experience pain and in about 60 % of cases pain is related to Parkinson's disease. Most of it is classified as musculoskeletal pain. Bradykinesia and muscle cramps lead to pain by causing malpositions of joints and trunk. Up to 40 % of parkinson patients experience pain caused by dystonia. Neuritic or radicular pain is also related to Parkinson's disease. Less than 10 % of patients have primary central pain. Pain threshold and nociceptive flexon reflex threshold are lower among patients with Parkinson's disease than in healthy subjects. Common comorbidities, namely restless legs syndrome and depression can also exacerbate pain. The pathology of pain in patients is not well understood. It is known that basal ganglia take part in pain perception and modulation. Lesions in basal ganglia can interfere pain perception and cause the exacerbation of pain. The modulation of pain in central nervous system is altered and descending inhibitory tracts are thought to work insufficiently. Levodopa alleviates the pain in about 60 % of patients with Parkinson's disease suffering from pain. Levodopa normalizes dopamine function at least partly in basal ganglia and that way alleviates the pain caused by dysfunction of dopamine tracts. Levodopa relieves motor symptoms and so alleviates the secondary pain caused by muscle cramps and stiffness. Levodopa raises the pain thresholds of patients to normal level. Levodopa may have also a direct analgesic effect via dopamine D2 receptor activation. The mutations of the gene that codes catechol-O-methyltransferase (COMT) change its activity and are related to pain perception. Low COMT activity is related to several functional differences including increased sensitivity to pain and increased response to opioids. Also COMT inhibitors sensitize mice and rats to pain. The mechanism underlying the sensitization is not well understood. We examined the effects of COMT gene disruption and COMT inhibition in acute pain models. In the first part of our study, we examined the effect of COMT inhibitor OR-486 in COMT deficient mice. We tried to clarify wether sensitization to pain is caused by COMT inhibition or some other mechanism. We also tested the effects of endogenous opioids (swim stress) and exogenous opioid (morphine) in COMT deficient mice. In the second part, we tested the effects of an atypical COMT inhibitor CGP 28014 in acute pain models. CGP 28014 does not inhibit COMT in vitro but it inhibits the Omethylation of catecholamines in vivo. The main finding of our study was the sensitization to pain caused by CGP 28014. The result gives support to hypothesis claiming that sensitization to pain is caused by O-methylation of catecholamines. The results of our study are also in line with the theory that low COMT activity is related to pain sensitization and increased response to opioids.

Obesity is considered one of the major public health challenges. One way to control obesity is to regulate appetite. Because brain is the primary regulative unit responsible for food intake, the research in this field has now been allocated especially to the central nervous system. The aim of this thesis was to clarify the role of cholinergic projections from pedunculopontine tegmentum (PPT) to lateral hypothalamus (LH) in food intake. In this study, DREADD-technology (designed receptors exclusively activated by designer drugs) based on chemogenetics was utilized with a gene manipulated mouse strain. For the experimental part of this work the mice were divided in three separate groups: one transducted with an activating DREADD-receptor (hM3Dq), one transducted with an inhibiting DREADD-receptor (hM4Di) and one transducted only with a fluorescent protein called m-Cherry. The last group was also defined as a control group of this study. In addition, the gene which coded m-Cherry fluorescent protein was transducted together with hM3Dq- and hM4Di-receptor genes for the first two groups to be able to examine the receptor expression later. At the baseline level, no differences were observed in food intake between the three study groups. The food intake did not differ between the groups while clozapine-N-oxide (CNO), a selective DREADD-receptor ligand, was administered straight into the LH area (0,03 µg/injection) with or without fasting of the animals. While administrating CNO to the mice intraperitoneally (1 mg/kg), the hM3Dq-group mice were observed to consume more food compared to the hM4Di-group or the control group. This difference was detected while food consumption was examined cumulatively during total four measuring hours. When the animals were fasted before the intraperitoneal administration test, however no differences were found between the study groups regarding food intake. As a conclusion of this study, cholinergic projections from pedunculopontine tegmentum (PPT) to lateral hypothalamus (LH) were not regulating food intake in mice. However, the cholinergic cells in PPT and some of their axons might be involved in the regulation of food intake while the food consumption is studied continuously and long-term. More studies are required to better define the role of the cholinergic projections from pedunculopontine tegmentum (PPT) to lateral hypothalamus (LH) in food intake.

Inappropriate polypharmacy refers to a situation where more than appropriate amount of medicines are used by a patient. Aged people with multiple morbidities and medications use a lot of health care services and are thus especially vulnerable to iatrogenesis, the health hazards resulting from the acts of a health care system. As a part of normal ageing, geriatric syndromes (e.g. falls, delirium and urinary incontinence) are clinical conditions and symptoms crossing several organ systems and they cannot be connected to a certain individual disease. Geriatric syndromes complicate recognition of adverse drug reactions on aged. This increases the risk of prescribing cascade, where medicines are prescribed to treat adverse drug reactions caused by another medicine. In this master´s thesis the root causes for inappropriate polypharmacy and drug-related problems (DRP) with home-dwelling aged were researched retrospectively from the viewpoint of risk management. Research method was based on root cause analysis (RCA) that was simplified suitable for this research. Research material was based on an intervention research conducted in 2015– 2017 on home-dwelling aged receiving regular home care from the City of Lohja, Finland. In the intervention research, a coordinated community-based medication management model for home-dwelling aged in primary care was developed to identify homedwelling aged with clinically significant drug-related problems. As research material, there were five (n=5) patient cases used who received comprehensive medication review (CMR) in the intervention research to solve their drug-related problems. The research material composed of individual patient interviews conducted at patients’ homes as a part of their CMR visits. Also, the nurses (n=3) of home care and physicians (n=2) from local health centres having participated in the treatment of the home-dwelling aged in question, were interviewed individually. Markings made in the patient records were utilized as well as research material. The interviews of the nurses and physicians were recorded, transcribed and analysed with inductive content analysis considering principles of root cause analysis. According to the nurses and physicians, central clinically significant medication-related problems with home-dwelling aged are various prescribing care parties, multiple medications, the increased use of over-the-counter (OTC) medicines and natural products, the uncertainty of health care professionals of the medication of a home-dwelling aged as well as the occurrence and medication of pain and sleeping disorders with aged. Other essential problems related to the health care system are various attending physicians, obscurely recorded medication data in patient record system, the use of benzodiazepines and other psychopharmaceuticals and ignored renal function in medicine dose adjustment. Problems related to home-dwelling aged are attachment for medicines, resistance to change and desire to take care of their own medication. In addition, memory disorders and vertigo were mentioned as problems related to the medication of aged. Seven root causes for inappropriate polypharmacy and drug-related problems were observed: lack of health care resources, segmented treatment between various health care parties, varying skills and knowledge of health care professionals, ambiguous division of responsibilities between health care professionals, challenges in communication between different care parties, the heterogeneity of patient record systems and problems related to their use as well as the knowledge, opinions and personal situation of a home-dwelling aged. Based on the research, the medication of home-dwelling aged should be improved by striving for centralizing care in one physician either on private or public health care. Among home care nursing personnel there is a need for additional training on medications and pharmacists should participate in regular medication reviews for home-dwelling aged. Patient record systems and data transmission between them should be improved and medication data should be recorded more precisely. Cooperation and communication between home care and health centre should be developed and the division of responsibilities should be clarified. Participation of the home-dwelling aged and their relatives in the care should be promoted. Furthermore, geriatric expertise should be utilized better in the care of the home-dwelling aged.