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Biologisiin lääkkeisiin ja biosimilaareihin liittyvä osaaminen suomalaisissa avohuollon apteekeissa (2024)Biological medicines are used, for example, in the treatment of diabetes, cancer, and autoimmune diseases. Biological medicines cause a significant part of the costs of prescription drugs in outpatient care. In Finland, automatic substitution of biological medicines will be introduced in 2024–2025 to promote the use of biosimilars and to increase price competition. When substituting biological medicines, pharmacists are required to counsel the customer and ensure proper use of the new administration device. The objective of this study was to study Finnish community pharmacists’ knowledge about biological medicines and biosimilars and the need for further training. Data was collected with an electronic questionnaire and analyzed using frequencies and percentages. Associations between background variables and readiness for automatic substitution were analyzed using crosstabulation and chi-squared test. Differences in drug-specific knowledge were compared using sum variables. Most pharmacists (n=899) answered that they understood at least the basics of what biological medicines and biosimilars are. The important role of biosimilars in reducing society's drug costs seemed to be well understood, but only one in four (25.0%) felt that they were ready for automatic substitution. Master’s degree in pharmacy, graduating as a pharmacist (BSc) between 2010 and 2022, and working in community pharmacy for less than 10 years after graduating as pharmacist (BSc) increased the experience of readiness for automatic substitution. Previous work in the pharmaceutical industry or wholesale trade, in official positions or in research and teaching positions also increased the experience of readiness for automatic substitution, as well as clinical expertise or additional training in the field of pharmacy. Drug-specific knowledge seemed to be best about enoxaparin and insulins. Further training was needed especially on the differences of administration devices and giving injection advice. The strength of this study was a representative sample of pharmaceutical personnel working in Finnish community pharmacies, although low response rate weakens generalizability of the results. The results give an indication of how Finnish community pharmacists assessed their knowledge about biological medicines and biosimilars before the introduction of automatic substitution in Finland. Further research is needed to monitor the development of knowledge about biological medicines and to examine customers’ experience on the quality of medication counselling related to biological medicines at pharmacies.
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(2024)Current therapies for depression have limitations in efficacy and delayed onset of action. Rapid-acting antidepressants like ketamine, an N-methyl-D-aspartate receptor (NMDA-R) antagonist, have gathered attention as an improved treatment option. However, the neurobiological mechanism underlying their antidepressant effect remains uncertain. Integral mechanisms of action seem to be alterations in synaptic plasticity, global cortical excitation, and repair of neuronal dysfunctions prevalent in the pathophysiology of depression. Emerging evidence does suggest that antidepressant drugs act by facilitating brain derived neurotrophic factor (BDNF) mediated tropomyosin receptor kinase B (TrkB) signaling. Interestingly, rapid-acting antidepressants seem to increase TrkB-associated signaling after their acute pharmacological effect has dissipated, and when animals become sedated and show various physiological changes associated with deep sleep (e.g., slow wave EEG activity, SWA). Indeed, recently a close relationship between sedation and molecular signaling implicated in antidepressant effects has been discovered. The aim of this study was to explore the relationship between sedation and molecular signaling associated with antidepressant effect. This was carried out by assessing the localization of TrkB-associated phosphorylation signaling in the adult male mice medial prefrontal cortex (mPFC) using dexmedetomidine, a sedative. Key signaling molecules such as ribosomal protein S6 kinase (p70S6K), ribosomal protein S6 (rpS6), glycogen synthase kinase 3 (GSK3), mitogen activated protein kinases (MAPKs) and immediate early gene c-Fos, were examined through immunohistochemical (IHC) analysis. Two separate experiments were conducted using naïve adult 8-13-week-old (n=8 and n=10) male C57BL/6JRccHs mice. In the experiments mice were injected intraperitoneally with either dexmedetomidine (0,05 mg/kg, Dexdomitor®), or saline followed by a 30-minute recovery period whereafter mice were euthanized. In the first experiment, medial prefrontal cortex samples were collected immediately post decapitation for western blot (WB) analysis. The results showed that dexmedetomidine significantly activated TrkB-associated signaling in brain homogenates, consistent with expectations. In the second experiment, mice were perfused with 4% paraformaldehyde (PFA) before brain collection for IHC analysis. However in this experimental setting, no significant difference in the localization of TrkB-associated signaling induced by dexmedetomidine was observed compared to saline. Although, no significant results for signal localization were observed, the results provide insights into the neurobiological effect of sedation induced TrkB-signaling. Further research factoring in limitations is needed to uncover the involvement of physiological states in antidepressant mechanisms.
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(2024)New drugs against malaria are required, as millions of people are still affected yearly by this deadly disease. The development of drug resistance to current antimalarials is an ongoing process. Membrane-bound pyrophosphatases (mPPases) are potential new drug targets against malaria and other protozoan diseases. mPPases play a crucial role in the survival of the malaria parasite, they couple the energy released from the hydrolysis of pyrophosphate into the transport of protons or ions against an electrochemical gradient. The aim of this study was to identify potential mPPase inhibitors through a docking-based virtual screen of the Tres Cantos Antimalarial Compound Set, which consists of over 13500 malaria-active compounds. The virtual screen against a Thermotoga maritima mPPase protein structure identified a 2,4-diamino-1,6-dihydrotriazine among the top-ranking scaffolds. Four compounds found among the docking results containing this scaffold were synthesised: three with a halophenyl substituent, and one with a hydroxyl substituent. The compounds in their hydrochloride salt forms were synthesised using a three-component method for the synthesis of 2,4-diamino-1,6-dihydrotriazines. The compounds were also freed from the hydrochloride salts into their corresponding molecular forms. The structural characterisation of the compounds, especially the molecular forms, presented challenges. The docking results were also searched to identify compounds containing previously identified mPPase-active substructures. From the docking results, several other interesting compounds were identified in addition to the synthesised compounds. The knowledge and results obtained from this study can be used as openings for potential future docking and synthesis projects in the development of mPPase inhibitors. The activity of the compounds synthesised in the project remains to be evaluated in subsequent investigations.
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(2024)Barcode-assisted medication administration can be used to prevent medication errors in pediatric hospital settings, as the medicine and the patient can be safely identified during the drug preparation and administration. The use of barcode-assisted medication administration has been examined in a few qualitative studies. In addition to the benefits, many challenges related to the implementation of this new workflow have been identified. The aim of this study was to identify facilitators and barriers related to the use of barcode-assisted medication administration in a children's hospital. The topic has not been studied in Finland before. A qualitative focus group study was carried out at HUS Helsinki University Hospital in the Department of Children and Adolescents. Ward pharmacists (n=14) were selected for the focus groups (n=3) by purposive sampling to identify persons using barcode-assisted medication administration on their daily work. Two researchers conducted the inductive content analysis independently, after which a consensus was formed first with these researchers and later with the entire research group. COREQ checklist was used to support detailed reporting and to consider the factors that might affect to the reliability of the study in each phase of the study. Four main themes were identified from the data; the barriers, the risk behavior caused by the barriers, the facilitators and the development ideas. The barriers included challenges related to negative attitudes of the end-users, barcodes on drug packages and labels, use of the electronic health record system, workstations and equipment, as well as orientation, competence and management. The barriers caused risk behavior that was related either to the system or to the end-user. On the other hand, the facilitators were associated with the positive experience of the end-user, the increase in expertise and multi-professional cooperation, the functions of the electronic health record system that supported the preparation and administration of the medicines, as well as the benefits of the barcode-assisted medication administration workflow. The development ideas aimed to remove the barriers and the risk behavior related to the use of barcode-assisted medication administration. The users found that the use of barcode-assisted medication administration increased patient and medication safety, although there were still many challenges associated with the new workflow. Barcode-assisted medication administration can be used to reduce medication errors and protect patients from adverse events. The results of this study can be used to develop the usability of barcode technology and their implementation.
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(2024)Finland is one of the first countries in the world to introduce automatic substitution of biological medicines in community pharmacies. The automatic substitution for biological medicines will be introduced in stages in years 2024–2026. The successful and safe transition requires guidelines for implementing new operating practices and dispensing practices, including possible continuing education to community pharmacists to ensure their sufficient competence e.g. in advising patient how to use their administration devices. Therefore, the change process requires competence development and management. The purpose of competence management is to create, maintain and develop an organization. Competence management is part of strategic personnel management, which ensures that the organization has the core competence and other necessary competence to implement its mission. The aim of this master's thesis was to study the competence management while preparing for the automatic substitution of biologics in community pharmacies in Finland. The research focused on the competence management practices and competence development needs within the framework of 1) personnel management and competence development and 2) automatic substitution of biologics. The research was carried out as a qualitative focus group discussions (FGDs) (n = 6, altogether of 23 participants) in January 2023. Voluntary participant participated in the group discussions from community pharmacies of different sizes and from different parts of Finland. Of the participants there were pharmacy owners with M.Sc. (Pharm) degree (n = 5/23, 22 %), pharmacists with M.Sc. (Pharm) degree (n = 10/23, 43 %) and pharmacists with B.Sc. (Pharm) degree (n = 8/23, 35 %). Qualitative content analysis was carried out inductively, i.e. data oriented. In addition to the themes emerging from the research material, the main themes of the discussion body partially guided the analysis. SRQR checklist was used to support detailed reporting to evaluate the reliability of the study. The data analysis identified 1) factors related to the current practices and needs of competence management and needs for competence development, 2) methods applicable for competence development of pharmaceutical personnel, and 3) functions related to the delivery of the biological medicine, such as medication counselling, support for the patient's self-care and a possible substitution of biologics, as well as the functions and tools that support these. The results of this study indicated that competence management practices vary between community pharmacies, and the competence management actions were not always systematically planned. Community pharmacies did not yet have operating models or practices for implementing automatic substitution of biologics, although they perceived that automatic substitution practices for inhalable medicinal products could perform as a model for the substitution of biologics. Despite some perceived uncertainties concerning implementation of automatic substitution of biologics, community pharmacists and pharmacy owners had mainly positive attitude towards the coming changes.
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(2024)Light-sensitive liposomes have gained attention for their ability to deliver cargo to tissues, offering spatiotemporal control over drug release. Red-light wavelengths have been utilized as an external trigger in light-sensitive reactive oxygen species (ROS)-mediated drug delivery, due to their favorable properties, such as the low light absorption by tissue chromophores. The ROS-sensitive drug delivery systems use photosensitizers (PS), which upon light exposure generate ROS in the presence of molecular oxygen. Palladium(II)phthalocyanine (Pd(II)PC), a new second-generation photosensitizer, can upon light irradiation generate relatively high singlet oxygen concentrations, enabling the efficient oxidation of the unsaturated lipids. The oxidation of the lipids leads to the disruption of the liposome bilayer and eventually, the release of the encapsulated cargo. To gain deeper insight on the phthalocyanine-labeled liposomes in drug delivery, a red light-triggered cationic liposome formulation encapsulating Pd(II)PC was formulated. The characteristics of the liposomes, the release mechanisms, and the release quantities of calcein (623 Da) and fluorescent-conjugated dextrans (4 000-70 000 Da) were studied following red-light exposer with 630 nm, 450 mW/cm2 laser while utilizing varying Pd(II)PC-loading quantities. Following oxygen removal and temperature-induced release studies, the mechanism of release of the liposomes was principally observed to be light-triggered reactive oxygen species-mediated. In the light-induced release studies an effective release of the calcein, and a relatively effective release of the Rhodamine B dextrans (10 kDa, 70 kDa) were observed from the liposomes via the Pd(II)PC-generated and reactive oxygen species-mediated oxidation of the unsaturated lipids. The release of the biomacromolecules from the liposomes was observed to require longer irradiation times than that of calcein. The longer irradiation times likely lead to deeper oxidation of the unsaturated phospholipids, resulting in a comprehensive eruption of the liposome bilayer. The comprehensive eruption of the liposome bilayer eventually enables the sufficient release of biomacromolecules from the liposomes.
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(2024)MDMA is an illegal stimulant known for its empathy-enhancing effects. Its positive effects are mainly based on increasing the concentrations of monoamines such as serotonin (5-HT), dopamine (DA) and norepinephrine (NE). In addition to its positive effects, MDMA can cause adverse effects such as hyperthermia and neurotoxicity. Especially with long-term use, MDMA can cause serotonergic and dopaminergic neurotoxicity. In addition, there are also indications of MDMA-induced neurotoxicity in systems where gamma-aminobutyric acid (GABA) functions as the main neurotransmitter. Glutamate decarboxylase (GAD) 67 is an enzyme that synthesizes GABA from glutamate and is a specific marker for GABAergic cells. The amygdala is a nucleus in the brain that regulates anxiety and fear response. In addition to GABAergic interneurons, there are also glutamatergic cells in the basolateral nucleus (BLA) of the amygdala, however in the central nucleus (CeA) there are only GABAergic cells. Disturbances in the GABAergic system can predispose to psychiatric diseases such as anxiety. The aim of thisstudy was to investigate the effects of MDMA (20 mg/kg) on the number of GAD67-positive cells in two nuclei of the mouse amygdala, BLA and CeA. In addition, this study aimed to examine the importance of the dose (4 or 16 injections) for neurotoxicity and the duration of the effects (2, 7 or 30 days). Adolescent wild type mice were divided into 12 groups according to the treatment (MDMA or saline), dose and timepoint. After euthanasia, the brain sections at the level of the amygdala were collected and stained with an immunohistochemical method and imaged using a confocal microscope. This study showed that MDMA reduced the number of GAD67-positive cells in the BLA when mice were given a total of 4 injections. This effect lasted up to 30 days. In contrast, MDMA did not reduce the number of GAD67-positive cells in the BLA in mice that were given 16 injections. Also, MDMA did not decrease the number of GAD67-positive cells in the CeA, regardless of dose. Statistical significance could have been improved, for example, by using more mice or analysing more sections from each individual animal. It is important to continue studying the effects of MDMA to better treat and prevent its adverse effects. In addition, increased understanding would urge users to exercise caution when using MDMA.
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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)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)African medicinal plants have been used to treat symptoms of infection successfully for thousands of years. However, no antimicrobial drugs have been developed from these plants. As antibiotic resistance is increasing rapidly, these traditional African herbal medicines can be an important solution in the fight against antibiotic resistance due to their antimicrobial properties. In this research, various extracts o the leaves of Combretum adenogonium (Combretaceae) and the fruits of Piper cubeba (Piperaceae) and Xylopia aethiopica (Annonaceae) were tested for their growth inhibitory effects against Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli. Extracts were made with methanol, water, hexane, and chloroform. In addition, water and ethyl acetate extracts were separated from an 80 % methanol extract using solvent partition. All the studied plants are used for the treatment of infections and wounds in African traditional medicine. Water was used as extraction solvent since it is commonly used in African folk medicine. Both single solvent technique and sequential extraction were used. The antibacterial effects were screened using agar diffusion and microdilution methods. The interaction between an extract and an antibiotic was measured with a checkerboard method. Time-kill experiments were performed using microdilution and plate count methods. In this study, the chloroform extract of C. adenogonium leaves gave the best inhibitory effect of all studied plants against B. cereus (MIC 78.125 µg/ml). In general, B. cereus was the most susceptible of the selected bacteria against extracts and E. coli was the one with most resistance. Time-kill test showed that the antibacterial efficacy was fairly stable throughout the 24-hour period considered with few exceptions. According to checkerboard results, C. adenogonium chloroform extract and tetracycline appeared to inhibit each other's antibacterial activity against B. cereus. However, only one extract was studied in this study, and it is possible that C. adenogonium contains compounds that would have a potentiating effect on antimicrobials. In general, C. adenogonium extracts were effective against B. cereus. The extracts of P. Cubeba were particularly effective against S. aureus. X aethiopica extracts were equally effective for both B. cereus and S. aureus. Methanol extract X. aethiopica is the only extract studied that gave more than 90% inhibition against P. aeruginosa. Therefore, it could be concluded that X. aethiopica has the broadest activity range of the examined plants.
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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)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)Poorly water soluble active pharmaceutical ingredients cause problems for the drug development. Solid state modification offers one approach to overcome the issue. In this study, co-amorphous systems and co-crystals were prepared with indomethacin at molar ratio of 1:1 using nicotinamide as a co-former. Co-amorphous systems were prepared by two different preparation methods: melting the physical mixture and then quench cooling it with liquid nitrogen and dry milling with a ball mill. Co-crystals were prepared by liquid-assisted ball milling. After that, the properties, dissolution, and physical stability of the formed formulations were investigated and compared. The characterisation methods were differential scanning calorimetry, X-ray powder diffraction, Fourier-transform infrared spectroscopy, polarised light microscope and scanning electron microscope. In addition, the solubility and physical stability of the formulations were investigated. Co-amorphous systems were successfully prepared by quench cooling the melt and co-crystals by liquid-assisted ball milling. Dry milling did not induce the formation of co-amorphous systems. In the intrinsic dissolution test, both the co-amorphous system and co-crystal enhanced the dissolution of crystalline indomethacin. When examining the dissolution rate with the paddle apparatus, it was observed that the co-crystal had the highest dissolution rate among both powder and tablet samples. The co-amorphous powder sample floated on the surface of dissolution medium which impeded the dissolution of indomethacin. However, co-amorphous tablet sample showed a higher dissolution rate than crystalline indomethacin. Stability testing (25 °C, 18 %RH) showed that the co-amorphous system recrystallised into a co-crystal after two weeks of storage, while the co-crystal was found to stay stable the whole study period.
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(2023)The long-term use of antidepressants has increased significantly worldwide in recent decades. Deprescribing and the expertise related to it is an important part of the individual drug treatment optimization, the management of long-term diseases, the avoidance of adverse drug effects and the improvement of treatment outcomes. The aim of this thesis was to examine the information found in the statutory Summary of Product Characteristics (SmPC) and other key information sources for healthcare professionals about antidepressant deprescribing. A qualitative content analysis was conducted on SmPC (n=15) of the antidepressants (escitalopram, mirtazapine, sertraline, citalopram, venlafaxine) selected for the study, three national depression treatment guidelines (Suomalainen Lääkäriseura Duodecim: Depressio Käypä hoito -suositus, American Psychological Association APA: Practice Guideline for the Treatment of Patients with Major Depressive Disorder, United States and National Institute for Health and Care Excellence NICE: Depression in Adults: Treatment and Management, United Kingdom) and one decision supporting deprescribing tool (MedStopper). The content, quantity, and quality of information about antidepressant deprescribing varied between the information sources included in the study. However, the information found in the SmPC and the MedStopper -tool was mostly in line with the information found in the clinical practice guidelines included in the study. Most general information about antidepressant deprescribing or measures that can be used to guide deprescribing was found in the clinical practice guidelines. In all examined sources, antidepressants were recommended to be discontinued in a controlled manner by gradually reducing the dose. However, the recommended duration of the dose reduction varied in different information sources. A detailed dose reduction program was not found in most of the information sources. A detailed dose reduction program was found in only one clinical practice guideline (NICE) and the MedStopper -tool. The continuation of antidepressant treatment after remission and the timing of stopping the medication was discussed in only two clinical practice guidelines (APA and Käypä hoito). However, instructions for action if severe or intolerable discontinuation symptoms appears were found in almost all information sources. Only the clinical practice guidelines mentioned the recurrence of depression as a possible harm when stopping the medication and instructed how to act in the event of a possible relapse. Benefits related to antidepressant discontinuation was not mentioned in any of the examined information sources and only one clinical practice guideline (NICE) discussed barriers related to stopping antidepressants. The information found in individual information sources was insufficient and provided little support for healthcare professionals to guide deprescribing. Current key sources of information for healthcare professionals provide limited information and relatively imprecise guidance on antidepressant deprescribing and how to support the antidepressant discontinuation process. Better randomized clinical trials are needed to develop clearer and more extensive evidence-based guidelines for healthcare professionals on antidepressant deprescribing and to prevent unnecessary long-term antidepressant treatment and patient exposure to possible adverse drug effects.
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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)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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(2023)Tausta: Lääkehoitoon liittyvät haittatapahtumat aiheuttavat merkittävää inhimillistä kärsimystä ja taloudellista taakkaa yhteiskunnalle. Lääkitykseen liittyviä haittatapahtumia voidaan ehkäistä tunnistamalla ja puuttumalla lääkitysriskejä aiheuttaviin tekijöihin. Tavoitteet: Tutkimuksen tavoitteena oli tutkia lääkitysriskien hallintakeinoja lääkkeen toimittamisen yhteydessä suomalaisissa avohuollon apteekeissa. Tavoitteena oli selvittää, miten apteekeissa tunnistetaan ja puututaan asiakkaan lääkehoitoon liittyviin ongelmiin ja millaista lääkitysriskien hallintaan liittyvää osaamista ja lisäkoulutustarvetta apteekeissa työskentelevillä farmaseuteilla ja proviisoreilla on. Aineisto ja menetelmät: Tutkimus oli valtakunnallinen poikkileikkaustutkimus, jonka aineisto kerättiin syksyllä 2022 sähköisellä kyselyllä. Alkuperäinen kyselylomake luotiin vuonna 2015 kirjallisuuden ja järjestelmälähtöisen riskien hallinnan teorian pohjalta ja päivitettiin tätä tutkimusta varten. Tulokset: Kyselyyn vastasi 192 apteekkia (n=610). Apteekeissa tunnistettiin ja puututtiin lääkehoito-ongelmiin, mutta toimintatavat olivat harvoin systemaattisia. Yleisin puuttumistapa oli keskustelu asiakkaan kanssa ja kehotus ottaa yhteyttä lääkäriin, näin toimi 78 % apteekeista tilanteessa, joissa asiakkaan lääkitys ei toiminut toivotulla tavalla. Suurimmalla osalla apteekeista ei ollut muun terveydenhuollon kanssa yhteisesti sovittuja toimintatapoja lääkehoito-ongelmien ratkaisemiseksi. Myös apteekin sisäiset toimintaohjeet olivat puutteellisia Johtopäätökset: Apteekkien ja muun terveydenhuollon välinen nopea viestintäkanava ja yhteisesti sovitut toimintatavat voisivat parantaa apteekkien mahdollisuuksia puuttua lääkehoito-ongelmiin. Apteekkien rooli lääkitysriskien hallinnassa tulee määritellä tarkemmin. Apteekkien ja muun terveydenhuollon välisessä yhteistyössä on paljon hyödyntämätöntä potentiaalia.
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(2023)The lack of up-to-date medication information in healthcare electronic information systems, the transfer of medication information with the patient, and the overall management of medication are key challenges in health care. The number of cancer patients in Finland will increase in the future due to the aging of the population, early detection of cancer, improvement in cancer prognosis and the development of cancer treatments. The development creates a need for operating models that improve medication safety. Medication safety of cancer patients can be improved with clinical pharmacy services, such as medication reconciliation and medication review. The aim of this study was to investigate the accuracy of the medication charts and identify the drug related problems and risks related to home medications among patients with newly diagnosed cancer in the Oncologic Outpatient Clinic of Turku University Central Hospital. This was a retrospective register-based study carried out as an operational development project to obtain information about the current operational model of pharmacist-led medication reconciliation and to further develop it. The theoretical starting point for the study was the theory of human error, according to which factors endangering patient safety can be prevented by using system-based safety defences. In the study, almost every (93 %, 69/74) patient's medication information differed from the hospital's information. A total of 392 discrepancies related to medication information and an average of 5,3 discrepancies per patient were observed in the data (range 0-15 discrepancies). High alert medications accounted for 14 % (n=53/392) of all discrepancies. It took an average of 19 minutes per patient to confirm a medication reconciliation (range 5-48 minutes). During medication reconciliation the pharmacist recorded observations for the doctor in 15 (20 %, n=15/74) patients. In the retrospectively performed medication review, a total of 183 possible drug related problems or risks related to patients’ home medications were observed in 31 (84 %, n=31/37) patients. Pharmacist-led medication reconciliation proved to be a fast and effective way to find out the patient's overall medication. In the future, the operating model should be developed to detect drug related problems, and risks related to patients’ home medications. In situations of limited resources, the clinical pharmacy services should be targeted to patients with the highest risk to drug related problems.
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