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(2023)Obesity has increased in our society for decades and is still increasing. It is a burden for individuals and societies. The healthcare costs, disability, illnesses, and deaths caused by it are unfortunately a big burden on global scale. Binge eating disorder is an eating disorder in which a person uncontrollably devours an excessive amount of food due to a lack of self-control. Binge eating disorder is strongly linked to obesity and it further increases the weight of both normal weight and obese people. Many mechanisms influence the regulation of eating. A long-term research subject and affecting the regulation of eating, serotonergic and serotonin receptors, affect the amount of food eaten and the reward system, and disturbances in serotonin signaling have been linked to obesity. Aim of this study was to exam binge-like eating modelled C57Bl/6J mice and their food consumption, while affecting serotonergic signaling. I studied psychoactive LSD and antipsychotic MDL 100907 effects on serotonergic signaling in a binge-like eating model, using drugs both separately and simultaneously. Mice were induced into a stress-free model of binge-like eating by providing high-energy food once a week for 24 hours. When the binge eating model was runnig, once a week the mice were dosed with a drug or substances and given energy-dense food to binge on. In the study, consumed food and water were measured. The mice were also subjected to locomotor tests to ensure that they were able to eat motorically. Induction of the binge-like eating model was successful and a reduction in binge eating was observed in mice under LSD alone at significant time points. MDL reduced binge-like eating at the first time point. No significant changes were observed in the water intake. The locomotor tests ensured a sufficient amount of movement to enable eating. Even though the drugs individually reduced binge-like eating, it should be noted that the properties of the drugs, and especially the trials of their combined use, which did not show significant results, do not promise significant discoveries in terms of similar research.
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(2023)Prolyl oligopeptidase (PREP) is endopeptidase which cleaves short proline containing peptides. Abnormalities in brain PREP activity has been connected to neurodegenerative diseases. Recently it has been detected that besides its proteolytic activity PREP interacts directly with other proteins which might contribute to generation of neurodegenerative diseases. Further it has been discovered that certain small molecular PREP inhibitors are able to modify these protein-protein interactions (PPIs) and thus have a potential to alleviate the progression of neurodegenerative diseases. This has led to the development of novel second generation PREP ligands which lack the strong inhibitory activity but are potent compounds on modifying the PPIs. Thiazole structure containing PREP modulators has provided most promising class of compounds. It has been detected that these compounds mediate their effects via novel binding site on the enzyme and these effects are not connected to the inhibition of the enzymatic activity. The synthesis of these thiazole containing PREP modulators has proven to be demanding since it have involved a usage of laborious synthesis route and provided low yields. The aim of this research was to examine the synthesis of 2-(2-benzimidazol-1-yl)ethyl)- 4-methyl thiazole containing PREP modulators via previously reported synthesis route. Another aim was to design and develop a synthesis route for 2-(2-(benzimidazol-1- yl)ethyl)-5-bromo-4-methylthiazole, a molecule which serves as valuable intermediate for the lead optimization and generation of second-generation PREP modulators. A synthetic route for 2-(2-(benzimidazol-1-yl)ethyl)-5-bromo-4-methylthiazole was successfully developed. Despite that the total yield of the route remained low. When searching the reasons for the low obtained yield the chemistry behind a thiazole creating cycloaddition reaction and an aromatic halogenation was examined. This led to the discovery of a rare cationic compound which was found to be synthesized from previously undescribed starting materials.
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(2023)The most typical symptoms of dementia include impairment of cognitive brain functions, such as memory and thinking. Most common forms of dementia include Alzheimer's disease, vascular dementia, Lewy body dementia, and frontotemporal dementia, which is caused by degeneration of the frontotemporal lobe. Alzheimer's disease is the most common form of dementia, covering about 75% of all the cases. The pathophysiology of Alzheimer's disease includes beta-amyloid plaques and tau proteins, which accumulate in the brain, and which have been linked to damage to nerve pathways and the appearance of the typical symptoms of the disease. The disorder is progressive, but the exact cause remains unknown. However, old age (>65 years), the APOE-4 gene, lifestyle, and some comorbidities, such as cardiovascular diseases, are considered risk factors. Even though extensive research has been conducted, there is currently no curative treatment for Alzheimer's disease. Sleep disorders can be both a symptom of Alzheimer's disease and a risk factor for the onset of the disorder. Therefore, the mechanisms of sleep and circadian rhythm are connected to the pathophysiology of Alzheimer's disease, for example through the glymphatic system that cleans the brain mainly during deep sleep. Many drugs for Alzheimer's disease have a recommended time of administration. The dosing time can be very important issue in terms of the effectiveness of the drug. According to a recent study, sleep and circadian rhythm have not been considered in most studies on new rapid-acting antidepressants. Therefore, we carried out an analogous systematic literature review for Alzheimer's disease and dementia. The aim of this study was to find out whether sleep and circadian rhythm have been considered in the most cited preclinical and clinical drug research articles for Alzheimer's disease and dementia during the last decade (2010–2020). In addition, it was examined which drug groups the studied compounds belonged to, and what was the sex distribution of the test subjects in the studies. The number of subjects was also determined from clinical studies, and the animal species from preclinical studies. The research articles analysed in the study were collected with a systematic literature review of Scopus database. The study found that most studies did not include any consideration of sleep or circadian rhythm. Most of the investigated compounds were small molecules, followed by supplements and herbs, and rest classified as biological drugs. Most of the clinical trials were relatively small studies with less than a hundred subjects or hundreds of subjects. Among the 100 most cited clinical research articles, there were 14 reanalyses and observational studies that were not included in this analysis of subject numbers. In clinical studies, most of the test subjects were usually female, while preclinical studies used commonly male animals. To conduct more open and reliable science in the future, drug research should pay more attention to the subjects’ sleep patterns, the time of drug administration, and reporting on these issues in the articles, which is usually part of the requirements of scientific journals. This could potentially narrow the translational gap between preclinical and clinical research.
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(2023)For pediatric patients, it is often necessary to resort to off-label use of available commercial products. This may require manual modification of the preparations, which may result in reduced dose accuracy. In the past, there have been discussions about the potential of 3D printing technologies for on-demand manufacturing of medicines in hospitals. Printing technologies can be used to tailor medicines to the individual needs of patients. This could be a possible solution to the lack of commercial products for pediatric patients, for example. Semi-solid extrusion is a printing technique that could potentially be used in the future in hospitals. This study aims to design the simplest possible excipient composition for a printing material for semi-solid extruded preparations for pediatric patients. The finished products will be examined to determine the type of products achieved with this printing method and excipient composition. In addition, the suitability of semi-solid extrusion in a hospital environment will be observed and evaluated. Printing was performed with a pneumatic bioprinter. The desired formulations could not be prepared with a printing material containing only a gel former (poloxamer 407) and a solvent (water). Therefore, a filler (microcrystalline cellulose) was added to the printing material to improve the mechanical strength of the preparations. The model drug used in the study was warfarin sodium and the target strengths of the preparations were 0.1 mg, 0.5 mg and 1.0 mg. The preparations were dried at room temperature for 22-23 hours. The tablets produced in the study were small (diameter less than 7 mm, height less than 2 mm) grid-structured preparations. The method was successful in producing tablets of uniform mass. For all strengths, the tablets passed the European Pharmacopoeia test for uniformity of content of single-dose preparations. Only the 0.5 mg strengths passed the test of uniformity of dosage units. The excipient composition should still be optimized to improve the mechanical strength of the products. The overall preparation time of the formulations should be reduced, for example by shortening the drying time, to make semi-solid extrusion suitable for extemporaneus preparations in hospitals.
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(2023)Biologiset lääkkeet ovat keskeinen osa syöpäsairauksien hoitoa. Ne ovat usein perinteisiä pienimolekyylisiä lääkkeitä kalliimpia, ja niiden aiheuttamia kustannuksia potilaalle ja yhteiskunnalle voidaan hillitä edullisempien biosimilaarien eli vertailukelpoisten biologisten lääkkeiden käytöllä. Tutkimuksen tavoitteena oli tutkia kyselyaineiston perusteella syöpäpotilaiden näkemyksiä lääkärin toteuttamasta biologisten lääkkeiden lääkevaihdosta ja niihin vaikuttavia tekijöitä avoterveydenhuollossa. Lisäksi tutkittiin, miten yleisesti syöpäpotilaat tunnistavat biologisen lääkkeen ja biosimilaarin käsitteet, ja potilaiden syöpälääkitystään koskevia lääketiedon lähteitä. Tutkimuksen osana toteutettiin järjestelmälliseen kirjallisuushakuun perustuva katsaus syöpäpotilaiden näkemyksistä biologisista lääkkeistä ja/tai biosimilaareista ja niiden lääkevaihdosta. Tutkimus perustui Yliopiston Apteekin ja Helsingin yliopiston yhteistyössä Suomen Syöpäpotilaat ry:n kanssa toteuttamaan tutkimuskyselyyn syöpäpotilaille tammikuussa 2021. Tutkimuskutsu lähetettiin Yliopiston Apteekin kanta-asiakkaille tutkimusuutiskirjeenä ja Suomen Syöpäpotilaat ry tiedotti tutkimuksesta sähköisessä viestinnässään. Tutkimuksen kohderyhmänä olivat aikuiset, joilla oli lääkärin toteama syöpäsairaus ja jotka olivat käyttäneet syöpäsairautensa hoitoon lääkärin määräämä lääkehoitoa kyselyä edeltävän 12 kuukauden aikana. Tutkimusaineisto koostui 294 kohderyhmän potilaasta. Ensisijaisella tulosmuuttujalla (summamuuttuja) tutkittiin syöpäpotilaiden näkemyksiä lääkärin toteuttamasta biologisten lääkkeiden lääkevaihdosta. Vastaajilla oli keskimäärin myönteinen näkemys lääkärin toteuttamasta biologisten lääkkeiden lääkevaihdosta, mutta lääkevaihdon toteuttamiseen liittyi potilaiden kokemaa epävarmuutta (summamuuttuja: Cronbachin alfa 0,808; keskiarvo 3,29/5,00, 95 % lv 3,20–3,38). Myönteinen näkemys oli yhteydessä potilaiden myönteisiin näkemyksiin biosimilaarien ja geneeristen lääkkeiden ominaisuuksista, kuten tehosta, haittavaikutuksista ja käytettävyydestä sekä vastaajan korkeampaan koulutustasoon ja vähäisempiin huoliin yleisesti omasta lääkehoidostaan. Enemmistö (72 %) vastaajista tunnisti biologisen lääkkeen käsitteen, biosimilaari-käsite tunnistettiin heikommin (19 %). Vastaajien käytetyimmät lääketiedon lähteet syöpälääkityksestään olivat terveydenhuollon ammattilaiset (48–88 %) ja pakkausseloste (80 %). Syöpäpotilaiden näkemyksiin biologisten lääkkeiden lääkärin toteuttamasta lääkevaihdosta vaikuttivat useat tekijät, kuten näkemykset biosimilaarien ja geneeristen lääkkeiden ominaisuuksista. Vaikka useat syöpäpotilaat suhtautuivat keskimäärin myönteisesti lääkärin toteuttamaan biologisten lääkkeiden lääkevaihtoon, siihen liittyi usein epävarmuutta. Tulevaisuudessa tulisi tutkia tarkemmin syöpäpotilaiden tietämystä biologisista lääkkeistä ja biosimilaareista. Lisäksi tulisi tutkia millaista lääkeinformaatiota potilaat tarvitsevat päätöksenteon tueksi biologisten lääkkeiden lääkevaihdossa.
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(2023)Adequate vaccine coverage and vaccine refusal have been prominently featured in the media during the COVID-19 pandemic. The decision-makers have considered adequate vaccine coverage important for maintaining the capacity of healthcare. The purpose of this study is to produce population-based research data about the factors affecting the willingness to take the COVID-19 vaccine. With the help of that information, it is possible to identify the factors that influence individual’s decision-making about whether to take the COVID-19 vaccine. The data of the study is the first Kansalaispulssi-data of the year 2022. Kansalaispulssi is a survey, made by the assignment of the State Council, which is used to research Finnish citizen’s views of the current topics. The research design is cross-sectional. The analysis of the study is done by crosstabulation using the Chi-square test. Age and financial situation of the person were related to the willingness to take the COVID-19 vaccine and the person's view of the role of the vaccine in preventing severe corona disease and getting rid of the COVID-19 pandemic. Age also influenced the person's view of the importance of the vaccine in preventing the COVID-19 disease. Gender, province, or educational level had no effect on a person's vaccine views in this study. Based on the research, Finnish citizens are very pro-vaccine. They also understand well the role of the vaccine in preventing a serious illness caused by the disease.
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(2023)Ramansironta on sähkömagneettisen säteilyn ilmiö, jonka avulla voidaan havaita molekyylivärähdyksiä niistä sironneen valon avulla. Kun sähkömagneettinen säteily kohtaa molekyylin se voi häiritä elektronipilveä ytimen ympärillä ja prosessin lopputuloksena energiaa vapautuu sironneen säteilyn muodossa. Tätä kutsutaan epäelastiseksi sironnaksi. Mikäli sironnassa ei tapahdu fotonin energiassa muutosta kyseessä on elastinen siroaminen. Mikäli näytteeseen menevän ja sironneen fotonin välillä havaitaan energian muutos, käytetään ilmiöstä nimeä epäelastinen Raman sironta. Energian muutosta voidaan mitata, ja saatu spektri antaa tietoa kohdemolekyylistä. Tämän työn tarkoituksena oli tutkia eri Raman-spektroskopiatekniikoiden, lähinnä spontaani-Raman spektroskopian sekä koherentti anti-Stokes Ramanspektroskopian ja mikroskopian soveltuvuutta lääkemolekyylien havaitsemiseen sekä nanopartikkeleiden karakterisoinnissa ja nanopartikkeleiden ja solujen välisten interaktioiden tutkimisessa. Tekniikan vahvuuksiin kuuluu käytön suhteellinen helppous ja CARS-mikroskopian nopeus sekä korkea erotuskyky, mahdollisuus havainnoida solunäytteitä, ja epätodennäköisyys vaurioittaa tutkittavaa kohdetta. Haasteisiin lukeutuu fluoresenssin taipumus häiritä signaalia, spontaani-Raman mikroskopian heikompi erottelukyky, analyysin hitaus sekä tarve valikoida molekyyli, jonka rakenne antaisi vahvan Raman-signaalin. Tutkimuksen alatavoitteina oli sopivan lääkemolekyylin valitseminen nanopartikkeliformulaatioon, nanopartikkeleiden formulointi, niiden karakterisointi Raman-spektroskopiatekniikoilla, ja lopulta tutkia Raman spektroskopian soveltuvuutta nanopartikkeleiden ja lääkeaineen sekä solujen interaktioiden tutkimisessa ja lääkeaineen havaitsemisessa solujen sisältä. Tutkimuksessa uutta on se, että ensimmäistä kertaa polymeerinanopartikkeleiden ja niihin ladattujen lääkeaineiden soluunkulkeutumisen tutkiminen pelkällä Raman-spektroskopialla ilman esim. fluoresoivia merkkiaineita. Tutkimuksen tavoitteen pääasiallisesti täyttyivät. Valitsimme kohdemolekyyliksi klorotaloniilin, fungisidin joka on edullinen ja antaa selvästi tunnistettavan Raman-signaalin. Klorotaloniilille suoritettiin normaalit sytotoksisuuskokeet sekä vapaana lääkeaineena että formuloituina nanopartikkeleina. Nanopartikkelien formulointi onnistui ja molemmat Raman-spektroskopiatekniikat näyttivät selvästi sekä lääkemolekyylin että polymeerin kemikaalispesifiset Raman signaalit. Lääkemolekyylin havaitsemin solujen sisältä onnistui. Polymeerimolekyylit eivät missään vaiheessa kulkeutuneet solujen sisälle. Tämä oli ehkä yllättävää koska käytimme makrofageja, mutta toisaalta myös johdonmukainen muiden tutkimusten kanssa. Raman-tekniikat osoittautuivat hyviksi tutkimusmenetelmiksi, ja erityisesti CARS-mikroskoopin suuri erotuskyky osoittautui hyödylliseksi soluunkulkeutumisen kuvantamisessa.
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(2023)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.
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(2023)Orexins (hypocretins) are two neuropeptides, orexin-A (OX-A) and orexin-B (OX-B), produced by a neuron subpopulation in the mammalian hypothalamus. They are natural substrates of two G-protein-coupled receptors (GPCRs), orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R), respectively. Orexin receptors are expressed widely in the central nervous system. Orexin peptides and receptors were originally discovered in 1998 and have been extensively researched ever since. Maintaining a steady state of wakefulness has been identified as one main physiological function of orexinergic signalling, and loss of orexinergic neurons in the hypothalamus has been linked to narcolepsy. Over the past decade orexin receptor antagonists have been developed for treatment of insomnia – suvorexant as the first one, approved for clinical use in 2014. Orexin receptor agonists remain under development for treatment of narcolepsy as one potential therapeutical indication, with no clinical applications yet approved. Orexin receptor activation by small-molecule agonists has proven a challenge not yet conclusively resolved. The aim of this study was to validate a novel scaffold for orexin receptor agonists from compounds identified as orexin receptor agonists in previous studies. Total of ten compounds were designed for synthesis, three of which were successfully synthesized. These three compounds exhibited very low orexinergic activity (0.06–1.36% and 2.33–5.19% response of full activation for OX1R and OX2R, respectively). After activity testing retrospective modelling of the receptor binding of the synthesized and designed compounds was implemented computationally by structure-based molecular docking to the recently discovered (2021) crystal structure of OX2R in complex with bound small-molecule agonist 3′-(N-(3-(2-(2-(2H-1,2,3-triazol-2-yl)benzamido)ethyl)phenyl)sulfamoyl)-4′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-3-carboxamide. Some of the key interactions known as crucial for receptor activation, such as hydrogen bonds with glutamine Q1343.32, were found possible for some of the synthesized and designed compounds. This may in part explain the orexinergic activity, however very low, measured for the synthesized compounds. Low activity of the synthesized compounds may be a result of low binding since their binding was not tested in this study. Interactions between the synthesized compounds and OX2R predicted by molecular modelling are consistent with the low measured activity of the compounds, and alternative, more optimal chemical scaffolds for orexin receptor activation could be searched in future studies.
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(2023)Immune checkpoint inhibitor (ICI) therapy aims to enhance the endogenous immune response against tumour cells, and it has become a potent treatment option for various types of cancers. Despite the promise of ICIs, most patients do not respond to the treatment. The primary limitation of ICI therapy is the immunosuppressive tumour microenvironment (TME), which is characterised by the lack of tumour- infiltrating cytotoxic T cells (CTLs) and the presence of immunosuppressive cells, such as tumour- associated macrophages (TAMs). A promising immunotherapeutic strategy that can promote antitumor immunity is oncolytic virus (OV) therapy. OVs can selectively replicate in and kill cancer cells, leading to the release of immunostimulatory molecules. These molecules can induce local inflammation and prime and recruit CTLs to the tumour site. In addition, OVs can also be used as a delivery platform for immunostimulatory transgenes that can further enhance the activation of anti-tumour immune response and help to overcome the immunosuppressive TME. Another strategy used to support anti-tumour immune responses and overcome immunosuppressive TME is epigenetic therapy. Epigenetic therapy can reprogram both cancer and immune cells towards a less immunosuppressive phenotype, thus helping to overcome the limitation of immune checkpoint therapy. The aim of this study was to generate a novel oncolytic adenovirus armed with epigenetic modifying transgene (EpiCRAd) to overcome the immunosuppressive TME and enhance the anti-tumour immune response. We tested its efficacy and immunogenicity in vitro and in vivo using a murine triple-negative breast cancer model. We demonstrated that EpiCRAd was able to modulate the epigenome of cancer cells without affecting viruses’ infectivity. Upon examining the potential effect of EpiCRAd on cancer cells, we observed that epigenetic regulation did not notably influence the expression of MHC class I and PD- L1 proteins, both of which play a role in the immune evasion mechanism of tumour cells. In addition, the in vivo experiments show that EpiCRAd controls tumour growth the best, especially together with an immune checkpoint inhibitor, suggesting that the virus was able to create an immune microenvironment more favourable for anti-tumour response. Interestingly, the TAM infiltration in the TME seems to reduce after treatment with EpiCRAd. Overall, the combination of epigenetic therapy with oncolytic virotherapy has shown promising results in converting immunotherapy-resistant tumours into immunotherapy-responsive tumours. Our findings provide valuable insights into the effect of EpiCRAd on cancer and immune cells. This study encourages exploring the use of epigenetic cancer remodelling and oncolytic viruses for cancer immunotherapy.
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(2023)Medical devices play a crucial role in healthcare, yet their importance is underscored by the potential for adverse events that can lead to serious consequences for patients and users. As a result, manufacturers of medical devices are required to actively monitor the safety and performance of their devices after placing them on the market. In response to incidents involving medical devices and their safety, the European Union Medical Device Regulation (MDR) came into force in May 2021, bringing more emphasis to the post-market surveillance (PMS) of medical devices. In this study, the current state of the post-market surveillance system of medical device manufacturers in Finland was investigated by conducting an online questionnaire in 2023. A total of 30 medical device companies participated in the questionnaire for a return rate of 17%. The dataset included manufacturers of different sizes, producing medical devices of all risk classes. To identify differences in the use of post-market surveillance data sources between different types of companies, the two-sided non-parametric Kruskal-Wallis-Test was used. The rest of the data was analysed using descriptive analysis. The post-market surveillance data sources with the highest reported intensity of use included customer complaints and feedback, production monitoring, and regulatory intelligence monitoring, while Post Market Clinical Follow-up and health services research were used significantly less. Significant differences between manufacturers of different device risk classes were identified for three data sources; manufacturers of higher risk class devices were found to utilize these data sources to a higher extent than manufacturers of low-risk devices. The manufacturers of medical devices seem to utilise reactive post-market surveillance data consistently to a high extent. On the other hand, the results suggest that proactive post-market surveillance methods remain underutilised despite the introduction of the MDR. Medical device manufacturers also use post-market surveillance data sources to different extents, in particular with respect to the medical device risk class. Overall, the results indicate that the MDR is bringing more emphasis on post-market surveillance, which in turn has increased the workload of medical device manufacturers.
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(2023)Metastatic prostate cancer is often fatal disease stage. Mechanism causing prostate cancer remains unknown, but possible mechanism relies on hormones. Testosterone may activate spontaneous cell division of oncogenes. Prostate cancer cells require androgen cell stimulation of AR to grow in early stages of prostate cancer, approximately 80-90% of prostate cancer cases are androgen dependent. 3bHSD1, encoded by HSD3B1, catalyzes the conversion of dehydroepiandrosterone to androstenedione and further to T and DHT. SNP (1245A to C) in HSD3B1 changes asparagine to threonine in position 367 resulting the enzyme accumulation and increased function. With androgen deprivation therapy castrate levels of testosterone are often achieved and it induces positive response in most PCa patients, but the polymorphism of 1245C is related with lower survival rate and higher probability for PCa to develop into CRPC. The aim of this study was to find out the effect of SNP in 3bHSD1 to androgen levels in patients treated with ADT. 32 patients were first genotyped based on SNP in the HSD3B1 gene (rs1047303) with 96.9 % success rate. 21 patients represented genotype AA, 9 AC and 1 patient CC. Other mutation in rs6203 was also detected. Genotyping was done by isolating DNA from blood samples and preparing it further for Sanger sequencing. Steroid analysis was performed by using LC/MS, using liquid-liquid extraction as sample preparation method. Altogether 21 steroids were analyzed from serum samples. Samples were taken every 3 months, during 33 months period for longest. The concentrations of T and DHT were reduced in AA genotype group after ADT as was expected to happen in all of the groups. In fact, the only significant changes were seen in AA genotype with for example the concentrations of previously mentioned T, DHEA and also A4. The changes in measured androgen levels cannot be generalized to concern especially the CC genotype, as there was only one patient homozygote with the mutation. Even though these results gave promising data of possible androgen synthesis pathways, a similar study must be rerun with larger patient data to be sure of the characteristics of different genotypes. Also, the effect of SNP in rs6203 remains still unknown.
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(2023)This qualitative study was carried out as a semi-structured interview study, which was supplemented with quantitative information from centralized cytotoxic preparation units in Finland hospital pharmacies and with information about interviewees. Quantitative information was collected using questionnaires. The proportion of centralized cytotoxic preparation units that responded to the background information questionnaire was 95% (19/20) of all centralized cytotoxic preparation units in mainland Finland. In the autumn of 2022, hospital pharmacy employees (n=23) participating in the reconstitution of cancer drugs were interviewed. On average, the interviewees had 14 years of work experience in the reconstitution of anticancer medicines. They represented 75% (15/20) of the centralized cytotoxic preparation units in mainland Finland, covering centralized cytotoxic preparation units of different sizes and locations in different parts of Finland. In 2021, 88% of the anticancer medicines in all centralized cytotoxic preparation units in Finland were reconstituted at the workplaces of interviewed. According to the interviews, the reconstitution of anticancer medicinal products involves the possibility of an error in several stages of the process. An error can occur when prescribing the medicine, transferring prescription information, when selecting the raw materials, reconstituting of the cancer medicine and during transport. The interviewees identified 24 risks associated with these stages, that could lead to patient safety incidents. Safeguards have been built to avert errors or promote the detection of the errors. Based on the research data, the safeguards were classified into six categories: the development of the technology, guiding work through guidelines, strengthening competence, standardizing practices, controlled working environment and learning from deviations. In Finland, it has not previously been studied or classified with which functions and principles the centralized cytotoxic preparation units have built safeguards to prevent patient safety incidents. This study shows that reconstitution of cancer medicines is a risky process. To improve the quality of reconstituted cancer medicines and patient safety, both the system- and person-focused safeguards have been built into the risk points of the processes of the centralized cytotoxic preparation units, but their utilization varied between centralized cytotoxic preparation units. Based on comprehensive data, the research result can be generalized to centralized cytotoxic preparation units in Finland hospital pharmacies.
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(2023)Biologisten lääkkeiden käyttö on merkittävästi lisääntynyt 2000-luvulla, mikä on hoidollisten hyötyjen ohella lisännyt lääkekustannuksia. Vaihtokelpoisten ja halvempien biosimilaarien käyttöä on edistetty koulutuksella, lääkemääräyskäytäntöjen ohjauksella ja lainsäädännöllä. Vuosina 2024–2025 useat avoterveydenhuollossa käytettävät biologiset lääkkeet tulevat apteekissa tapahtuvan lääkevaihdon (apteekkivaihdon) piiriin. Potilaiden näkemykset biologisista lääkkeistä ovat tärkeä tutkimusaihe hoitotulosten, lääkevaihdon, rationaalisen lääkehoidon edistämisen ja lääkepolitiikan kehittämisen näkökulmista. Tutkimuksen tavoitteena oli tutkia potilaiden näkemyksiä biologisten lääkkeiden hinnoista, kustannuksista ja niiden merkityksestä. Tavoitteiden mukaiset tutkimuskysymykset liittyivät: 1) potilaiden preferenssiin lääkkeiden hoidollisesta arvosta lääkkeen hintaan verrattuna (ensisijainen tutkimuskysymys) ja yhteiskunnan lääkesäästöistä, 2) lääkkeiden hinnan merkitykseen lääkevaihdossa (potilaiden taloudellisten taustatekijöiden vaikutus ja euro-määräinen hyväksymis/maksuhalukkuus lääkevaihdossa) ja 3) potilaan oman lääkehoidon kustannettavuuteen. Tutkimus perustui Yliopiston Apteekin (YA) ja Helsingin yliopiston (HY) tammikuussa 2021 toteuttaman kyselytutkimuksen aineistoon. Kyselyyn vastasivat YA:n kanta-asiakkaat sekä Reumaliiton ja IBD- ja muut suolistosairaudet ry:n viestinnän kautta tavoitetut henkilöt. Kysely oli kohdistettu reuma-, IBD- (tulehduksellinen suolistosairaus) ja ihopsoriasispotilaille, jotka käyttivät alkuperäistä biologista lääkettä (BA), biosimilaaria (BS) tai perinteisiä pienimolekyylisiä lääkeitä (PL). Vastaajia oli yhteensä 1338 (BA-käyttäjiä 226, BS-käyttäjiä 71 ja PL-käyttäjiä 1041). Tulosmuuttujina käytettiin yksittäisiä kysymyksiä ja summamuuttujia. Lääkekäyttäjäryhmän ja muiden taustamuuttujien yhteyttä tulosmuuttujiin tutkittiin kaksi- ja monimuuttuja-analyyseillä. Suurin osa (83 %) potilaista oli sitä mieltä, että lääkkeen hinta ei saisi vaikuttaa lääkkeen valintaan biologista lääkettä määrättäessä, ja 62 %:n mielestä biosimilaarien käyttö auttaisi säästämään terveydenhuollon lääkekustannuksissa ja mahdollistaisi suuremman potilasmäärän hoidon biologisilla lääkkeillä. Potilaan taloudelliset taustatekijät eivät olleet monimuuttuja-analyysin perusteella yhteydessä näkemyksiin biologisten lääkkeiden lääkevaihdosta tai kiinnostukseen lääkevaihdosta. Jos biologisen lääkkeen hypoteettinen omavastuuhinta potilaalle olisi 600 euroa vuodessa, 14 % alkuperäisvalmisteen käyttäjistä olisi valmis vaihtamaan biosimilaariin, jos sen kustannus olisi hänelle 30 % nykyistä pienempi. Biosimilaarien käyttäjistä 38 % olisi valmis maksamaan lisää saadakseen alkuperäisvalmisteen. Biologisten lääkkeiden käyttäjillä (BA 36 % ja BS 44 %) oli ollut enemmän taloudellisia ongelmia lääkkeiden ostossa kuin perinteisten lääkkeiden käyttäjillä (25 %) (p <0,001). Potilaat suhtautuivat yleisesti myönteisesti biosimilaarien käyttöön lääkekustannusten hillitsemiseksi, mutta pitivät hoidollisia perusteita hintaa tärkeämpänä. Potilaan taloudelliset tekijät eivät olleet yhteydessä näkemyksiin lääkevaihdosta tai vaihtohalukkuuteen. Merkittävä osa potilaista on kiinnostunut vaihdosta edullisempaan biosimilaariin. Tulokset korostavat biologisiin lääkkeisiin ja lääkevaihtoon liittyvän lääkeinformaation merkitystä.
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(2023)Chlamydia pneumoniae is an intracellular Gram-negative bacterium, that can cause respiratory infections. Infections are typically mild or asymptomatic, but it can also lead to more severe infections, for example, pneumonia. Severe infections might need antibiotic treatment. When the bacteria are exposed to stressful conditions, they can change to a chronic, persistent form. Amoxicillin and penicillin are known to transform bacterium into persistent forms. Antibiotics are not effective for persistent infection very often. Amoxicillin is the recommended treatment for pneumonia in Finland and worldwide, which is problematic from the perspective of C. pneumoniae. That is why there is a need for effective treatment for persistent C. pneumoniae infection. Probiotics and their by-products short chain fatty acids (SCFAs) are known to have beneficial effects on human health. Based on the current knowledge, SCFAs and other probiotic by-products are known to inhibit pathogen bacterial growth. Thus, SCFAs could have a potential effect on the treatment of C. pneumoniae infection. The aim of this work is to study the impact of SCFAs, acetate, propionate, and butyrate on C. pneumoniae infection and its antibiotic susceptibility. To study the impact of acetate, propionate and butyrate on C. pneumoniae infection and its antibiotic susceptibility, three different infection models were used: productive C. pneumoniae infection model with A549 cells, amoxicillin-induced persistent infection model with A549 cells, and persistent infection model with THP1 cells. Bacterial growth was followed with immunofluorescence and the number of the bacterial genome was studied with quantitative polymerase chain reaction (qPCR). The studied SCFAs did not have a significant impact on productive C. pneumoniae infection. With amoxicillin- induced persistent infection, the results were varying. For example, sodium acetate, and propionate showed some increase in bacterial growth on the first infection, but with sodium butyrate, there were not any impact. The only SCFA that decreased the bacterial growth in the persistent infection model with THP1 cells was sodium butyrate (200 μM). The same treatment also decreased the number of bacterial genomes with qPCR in the same infection model. In addition, the same condition increased the antibiotic susceptibility of persistent C. pneumoniae to azithromycin in THP1 cells. In conclusion, the studied SCFAs seemed to have more impact on C. pneumoniae infection with human immune cells compared to human lung epithelial cells. Based on this study, sodium butyrate could have positive impacts against persistent C. pneumoniae infection. Nevertheless, further studies of the impact of sodium butyrate on persistent C. pneumoniae infection are needed.
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(2023)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.
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(2023)Alpha-beta-hydrolase domain containing proteins (ABHD) are involved in lipid metabolism and its regulation in human and animal cells. Approximately 50 of these proteins have been identified and their physiological and pathophysiological functions are still further investigated. ABHD2, ABHD3, ABHD4, ABHD5, ABHD6, ABHD12 and ABHD16 are involved in the metabolism of glycerin esters and phospholipids, in particular lipid mediator 2-arachidonoylglycerol (2-AG) and its metabolites have a significant effect on neuroinflammation via the endocannabinoid system. ABHD12 and ABHD16A were at the center of focus in this thesis as enzymes regulating phosphatidylserine and pro-inflammatory lysophosphatidylserine. In this study, toxicity of five (5) abietane terpene derivatives was tested using mouse E15/16 prenatal cortical neurons, cultured in 96-well plates. There were totally 8 plates cultured in three different batches, 60 cell containing wells per each plate. Wells from each plate were divided into treatment groups of 17, three concentrations of every five compound, control and VEH groups. Those concentrations were 0,1 µM, 1 µM and 10 µM, and for the last two plates 1 µM, 10 µM and 100 µM. Treatment was also separated into three batches like the cell culturing. After treatment, number of living cortical neurons in each treatment groups were counted. For that, cells were treated with immunofluorescent NeuN and DAPI antigens and the fluorescence was imagined with automated microscope. CellProfiler was used to recognize and count the number of living cortical neurons. Immunofluorescent MAP2 antigens were also used but because the shape of MAP2-fluorescing cells, CellProfiler could not recognize them. Intensity of MAP2-fluorescence were measured from those imaged, so the work would not be wasted. One-way ordinary variance analyze ANOVA was carried out for the data to figure out if there were statistically significant results. For compound TAC174, there were several significant results with different concentrations but unfortunately, some results showed signs of toxicity and others improved cell-growth. Some significant results were also found with compounds TAC121, TAC147 and TAD40 showing sings of toxicity, but reliability of those results was questioned. Only one compound, TAC150 was not showing clear toxicity towards mouse cortical neurons, at least with lower concentrations. For conclusion, there were no clear or significant results if these compounds are toxic for cortical neurons. TAC150 showed the least sings of toxicity, therefore it could possibly be considered for further studies in medical field.
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(2023)Physiologically based pharmacokinetic modelling (PBPK) can be used to predict pharmacokinetic behaviour of new drug molecules in human. PBPK model represents the body anatomically and physiologically with compartments connected to each other and combines those to drug specific parameters. PBPK modelling can be used to predict the absorption, disposition, and time-concentration profiles of drug molecules. The purpose of the study was to build a PBPK model for new drug molecule under research (compound A) and predict pharmacokinetics in human, to support the selection of dosing interval, formulation, and sampling time points for the first clinical trial. In this work it is described the building of the model in the ”bottom-up”-approach using in vitro parameters in GastroPlusTM-software. The modelling was done also for preclinical species (mouse, rat, dog) comparing the simulations to the observed in vivo data, which gave the confidence to the methods used in the modelling also for human. The model was first built for systemic kinetics and thereafter it was used for predicting pharmacokinetics after oral dosing. Parameters of systemic kinetics were compared also to the predictions from allometric scaling. Based on the preclinical species the most predictive method for the volume of distribution of compound A was the method by Lukacova, which predicted the volume of distribution to be moderate in human (1.7 l/kg). From the in vitro-to-in vivo -extrapolation methods the most predictive method to predict the clearance was the method by Poulin, which predicted low clearance in human (8.1-14.3 l/h). Empirical scaling factors based on the preclinical data were not needed, as the models predicted well the observed in vivo data. Allometric methods predicted the systemic kinetic parameters to be in the similar range. Advanced compartmental absorption transit -model (ACAT) integrated to GastroPlusTM-software predicted the absorption after oral dosing well in the preclinical species (predicted/observed ratio 0.8-1.3 for systemic exposure) despite the low solubility of the compound A. The model predicted the absorption in human to be sensitive to particle size and absorption rate to be clearly affected by the particle size. The feeding status was also predicted to affect on the absorption with larger particle sizes. The gut metabolism was not predicted to limit the oral exposure notably, whereas moderate bioavailability was predicted to be achievable. Compound A could be given in a capsule if the target particle size distribution could be achieved. The built PBPK-model can be used in the future to predict the first clinical doses by comparing the predicted plasma concentrations to in vitro pharmacodynamic parameters and to the plasma concentrations needed for efficacy in the pharmacodynamic models. The model can also be used to predict the drug-drug interactions.
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(2023)In pharmaceutical sciences the pharmaceutical supply chain is often examined from a quality perspective. As the world is becoming more uncertain due to pandemics and conflicts the societal and political situation where the supply chain operates should be considered. Understanding the big picture helps to consider the cause and effect that lead to medicinal shortages. Effects of these shortages can be seen on every level of the supply chain from the manufacturer to the patient, which is why actors on the supply chain can benefit from understanding the background factors. The aim of the master’s thesis was to examine, whether pharmaceutical field actors could affect realisation of geopolitical risks by preparation and examination that the pharmacotherapy would not be interrupted. Second aim was to bring forward political and societal aspects to pharmaceutical availability which are often side-lined by quality aspects in pharmaceutical context. The study was conducted as a qualitative semi-structured interview between October 2022 and February 2023. Participants (n=11) were recruited via e-mail using representative sampling. Due to recruitment problems, convenience sampling was also used. Questions presented to the interviewees were depending on the group (n=3) they were assigned. Term ”geopolitics” was associated mainly with political and economic factors. Main geopolitical risks for Finland were seen to be small market size and distant location. For Europe, the risks were centralisation of manufacturing (and dependence) to Asia due to economic factors and long disruption-prone supply chain. Transport of pharmaceuticals from Asia to Europe was with sea and air cargo. Inside Europe, transport to Finland was with mainly with lorries utilising ferries. Rail transport was mentioned to be used only on one interview. The transport routes were seen to be staying the same in the future both for Asia-Europe and Europe-Finland. Even though risk management is an important part of functioning of every company, the change in the type of risks requires a new mindset in the pharmaceutical field both from the individual actors as well as international organisations. From risk of strikes and natural disasters we have moved to trade wars, pandemic restrictions, and the strategic acting of industries critical to society. At the same time, the ability/willingness of societies to pay for pharmaceuticals is decreasing, which leads to the manufacturers to find new ways to ensure business.
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(2023)Migreeni on toistuvia päänsärkykohtauksia aiheuttava neurologinen sairaus, jonka esiintyvyys on hyvin laajaa – Suomessa migreeniä sairastaa lähes joka kymmenes väestöstä. Migreenin puhkeamisella on tutkimusten mukaan vahva yhteys genetiikkaan, ja migreenin hoidossa käytettyjen lääkevalmisteiden metabolia on oleellisesti sidoksissa geeneihin. Farmakogenetiikka tutkii tieteenalana, miten perintötekijät vaikuttavat lääkeaineiden aineenvaihduntaan ja niistä syntyvään lääkevasteeseen. Tässä tutkimuksessa tarkasteltiin migreenin estolääkkeenä käytetyn trisyklisen masennuslääkkeen, amitriptyliinin, metaboliassa esiintyviä mahdollisia geneettisiä eroja itä- ja länsisuomalaisten välillä. Tutkimus toteutettiin tarkastelemalla yli 10 000 Terveystalon Biopankin biopankkinäytettä, joista määritettiin kolmen CYP-entsyymin (CYP2C9, CYP2C19, CYP2D6) fenotyyppien esiintyvyys itä- ja länsisuomalaisissa. Tutkimustulosten mukaan eroavaisuudet fenotyyppien esiintyvyydessä itä- ja länsisuomalaisten välillä olivat maltillisia. Amitriptyliinin metaboliassa erityisen oleellisen CYP2C19 geenin osalta sekä normaalia hitaampi että hidas metabolia olivat yleisempiä idässä kuin lännessä. Hitaan metabolian riskinä on tavallista suuremmat plasmapitoisuudet ja siten lisääntyneet lääkevalmisteen haittavaikutusriskit. Näin ollen amitriptyliiniä tulisi hitailla metaboloijilla käyttää harkiten, aloittaa vaihtoehtoinen lääkitys tai pienentää aloitusannosta puoleen tavanomaisesta. Oikean annostuksen löytämisessä tulisi hyödyntää laboratorion pitoisuusmäärityskokeita. Lisäksi farmakogeneettisillä testeillä voitaisiin havaita mahdollinen geenien tarkempi polymorfia, ja siten varmistaa sekä turvallinen että tehokas yksilöllinen lääkehoito.
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