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Rodent studies indicate that the effects of pharmacological antidepressant treatments depend on the TrkB (tropomyosin-related kinase B) receptor of the neurotrophic factor BDNF (brain-derived neurotrophic factor). However, the mechanism by which TrkB signaling becomes active remains disputed. Our group proposes that the activation of TrkB signaling is a result of an indirect physiological adaptation to the drug treatment, which is supported by observations made with rapid-acting antidepressants ketamine and nitrous oxide. Previous studies indicate that the immediate effects of the drugs are followed by a sedative state resembling deep sleep, during which TrkB signaling becomes active. The sedative state is accompanied with a drop in core body temperature, and preliminary findings indicate that preventing the drug-induced hypothermia blocks TrkB signaling in the cortex.    The purpose of this study was to investigate the effect of ambient temperature on TrkB signaling in the hippocampus following nitrous oxide administration. Nitrous oxide (65 % ad 100 % O2) was administered to adult male mice for 20 minutes. After the drug treatment the animals were kept in different recovery conditions: room temperature or a heightened ambient temperature of approximately 36 °C for 15 minutes. Following the recovery, the animals were euthanised, and hippocampus samples were collected from the animals. Levels of BDNF and TrkB signaling were analysed with ELISA and western blot, respectively.    Nitrous oxide caused a significant drop in core body temperature, but this was not accompanied with increased BDNF levels or TrkB signaling. Evidence suggests that hippocampal atrophy contributes to depression, but the acute effects of antidepressant treatments on TrkB signaling in this brain area appear to be less pronounced than those seen in the prefrontal cortex. The findings indicate that nitrous oxide has a replicable hypothermic effect, but this is not associated with increased TrkB signaling in the hippocampus.

Safety of pharmacotherapies is an essential part of patient safety that promotes and supports rational use of medicines. Safety of pharmacotherapies can be divided into two areas; Drug safety and medication safety. Drug safety refers to the safety of a medicine as a product, such as the pharmacological properties and the quality of the manufacturing process. Medication safety ensures the safety of a drug therapy process preventing patients from harm during the course of using medicines. Significant inconsistencies have been identified in the terminology related to drug and medication safety. Challenges to terminology are posed by varying synonyms, ambiguity or overlap of concepts, and misclassification of events in the scientific literature. The primary objective of this study was to scope recent peer-reviewed literature related to the drug safety and medication safety terminology from the period pf 2010-2022. A secondary objective was to examine the relationship between the concepts as presented in the literature, including overlaps and differences between the terms. The study was conducted as a scoping review by using Scopus and Ovid Medline databases. The literature search covered studies from January 2010 to January 2022. The search was conducted by using the following phrases; "("medication safety" OR "drug safety" OR pharmacovigilance) W/5 (definition* OR terminology*)" in Scopus and "("medication safety" OR "drug safety" OR pharmacovigilance) ADJ/6 (definition* OR terminology*)" in Ovid Medline. The references of the included articles were reviewed for any additional material. The relevant material was selected by two researchers. A total of 71 articles were identified from the databases, of which two articles met the predefined inclusion criteria. In addition, one article was included in the study from outside the actual search. Two of the included articles were based on drug safety terminology whereas one article was based on medication safety terminology. The results revealed that there is still a considerable heterogeneity of the terms in the literature. The literature shows several terms and definitions for the same phenomenon and no noticeable consistency in the terms. It would be important to define what a uniform and systematically used terminology would require and to establish a commonly accepted guidelines for its use.

Multiple Sclerosis (MS) is an incurable autoimmune demyelinating disease affecting the central nervous system (CNS). Although the detailed pathogenesis remains unclear, recent research has highlighted the involvement of B cells. For decades, however, MS research was based on T cell-focused animal models of autoimmune encephalomyelitis (EAE), which do not reflect the involvement of B cells in the pathogenesis. Therefore, B cell-dependent EAE models are hypothesized to allow a better understanding of MS immunohistopathology and may therefore lead to the development of efficient treatments. In our spontaneous relapsing-remitting (RR) EAE model, B cells are recruited from the endogenous repertoire by transgenic myelin oligodendrocyte glycoprotein (MOG) -reactive T cells, causing the development of EAE in 3–4-month-old mice. Interestingly, MOG-specific antibodies are present long before actual onset of clinical disease and can be detected already in 5-week-old RR mice and disease development in RR mice is dependent both on the presence of (presumably MOG-specific) B cells as well as on stimuli provided by intestinal microbiota. Firstly, we evaluated the broader usability of induced germinal center cell (iGB) culture as a model for B cell repertoire studies. Then, by using iGB culture, we studied whether MOG-specific B cells are present in secondary lymphoid organs of younger than 4-week-old and germ-free RR mice. Finally, this study aimed to investigate whether the repertoire of MOG-specific B cells undergoes significant qualitative changes from young healthy mice to older acutely sick RR mice, and whether at the time of disease onset the recruited MOG-specific B cells expand and mature in the cervical nodes (cLN) or in the CNS. To do so, following the hosting-lab’s previous single-cell RNA sequencing (scRNA-seq) of B cells derived from cLN of 5-week-old RR mice, we performed the scRNA-seq of B cells from CNS, spleen, and cLN of acutely sick RR EAE mice. We demonstrated that iGB culture is an unsuitable tool to expand pre-activated B cells, and hence, in our hands it was inappropriate for repertoire studies. However, iGB culture proved to be useful for screening different organs for MOG-specific B lymphocytes, and we found that anti-MOG antibodies were firstly detected in 3-4-week-old RR mice, and MOG-specific B cells were present also in germ-free RR mice. Our scRNA-seq results revealed many highly expanded MOG-specific B cell clonotypes in acutely sick RR mice. Moreover, the B cell repertoire of sick RR mice was more diverse, including IgG1, IgM, IgG2b, IgG2c, and IgG3 isotypes, compared to healthy 5-week-old RR mice that had only IgG1 or IgM isotypes. Two-thirds of the expanded clonotypes were primarily detected in the CNS in sick RR mice, indicating that clonotypes develop further and continue isotype switching within the CNS. We also detected more somatic mutation in the variable region of expanded clones of sick RR mice compared to 5-week-old RR mice. The results of this study clearly show an antigen-driven evolution of the MOG-specific B cell repertoire from healthy young to acutely sick RR mice, which seems to occur mainly in CNS itself. In contrast, cLN are the major initial priming site of MOG-specific B cells in healthy RR mice, even under germ-free conditions. This suggests that commensal microbiota is not required for initial recruitment of MOG-specific B cells, but for the development of EAE. To further validate our encouraging scRNA-Seq results, it is necessary, in future experiments, to confirm the MOG-specificity of expanded clonotypes.

Medication related risks have been identified as one of the main threats to patient safety, both internationally and nationally. In Finland, implementation of pharmacotherapy in health services system is guided by the Safe pharmacotherapy -guideline. The guideline instructs work units to implement a pharmacotherapy plan, which is a statu-tory quality management document to describe the unit’s pharmacotherapy process and related responsibilities and obligations. However, there is currently limited research data available on pharmacotherapy plans and their impact on medication safety. The aim of this study was to explore the use of pharmacotherapy plans as a tool for promoting medication safety in the Finnish health services system with an emphasis on systems-based risk management. The research was con-ducted as an electronic survey in November-December 2021. The target group of the survey was health care professionals licensed as nurses and pharmacists who are working in wards or clinics or otherwise participate in drawing up or updating of pharmacotherapy plans. The study analyzed 901 responses. Most respondents (90 %) worked as licensed nurses and 10 % as pharmacists. The majority of the respondents’ units (91,5 %, n=824) had a pharmacotherapy plan. Medication safety practices were comprehensively described in pharmacotherapy plans and no significant differences observed between work environments. The multi-professional development processes of pharmacotherapy plans were not complete, only 11,6 % of the units the writing was done in multi-professional collaboration. Medication safety practices were best implemented in university hospitals (m. 3,87, sd. 0,57), with the difference being statistically significant for primary healthcare wards (m. 3,51, sd. 0,63, p<0,001) and social care housing services units (m. 3,63, sd, 0,68, p=0,018). The comprehensiveness of the content in pharmacotherapy plans and the implementation of medication safety practices were correlated (r=0,60, p<0,001). Pharmacotherapy plan is an important tool for systems-based medication safety promotion in the Finnish health services system. There is need for improvement in the multi-professional collaboration when developing the plans and in training the healthcare staff of practices described in the unit’s pharmacotherapy plans. In the future, special emphasis should be placed on the medication safety and development of primary healthcare wards and social care units.

There are certain characteristics in children’s medication process, such as weight or body surface area-based drug dosing and off-label use of medications, that expose children to medication errors. Small children especially are prone to physical injuries resulting from medication errors. High-alert medications bear a heightened risk of causing significant, even life-threatening harm to a patient when used in error. The aim of this study was to promote children's medication safety by identifying medication errors and contributing factors to errors associated with the use of high-alert medications in pediatric medication process in a hospital environment. The data of this retrospective register study consisted of voluntary medication error reports (HaiPro) made in the pediatric and adolescent units at Helsinki university hospital (HUS). ISMP's (Institute for Safe Medication Practices) list of high-alert medications in acute care settings was used to limit the data. The data was analyzed by using both quantitative and qualitative methods. The aim of the quantitative analysis was to report the frequencies (n) and proportions (%) of high-alert medications and routes of administration and the aim of the qualitative analysis was to identify the types of medication errors and contributing factors in the data. ISMP’s high-alert medications accounted for approximately one-fifth (19.7%) of all medication error reports made in pediatric and adolescent units in 2018–2020. Twelve medications and intravenous route covered approximately 65.0% of all high-alert medications and routes of administration mentioned in the data. Medication errors were mostly identified in medication administration stage (43.3%) and administration errors were often preceded by prescribing errors. Dosing errors (20.5%) and documenting errors (16.8%) were the most common medication error types in the data. Errors associated with dosing and infusion rate were most often involved in severe medication errors. The most frequently identified contributing factors in the data were associated with the work situation and conditions, documenting and information transfer or medications. More detailed risk analysis considering high-alert medications and the intravenous medication process and targeting preventive barriers to identified risk areas are recommended in pediatric and adolescent units in the future. Barriers should be planned to cover the entire medication process. Among different types of medication errors, multiple dosing errors and errors during the programming of infusion rate require special attention in the future.

Drug-induced liver injury (DILI) is a relatively rare hepatic condition that can be classified as predictable and unpredictable. However, DILI is a primary reason for drug withdrawals, post-marketing warnings, and restrictions of use. DILI is a problem for the drug users but also for the pharmaceutical industry and regulatory bodies. From the perspective of patients' and clinicians', DILI is the major cause of acute liver injury. At present, a major problem predicting DILI in drug discovery is a poor understanding of its mechanisms as well as the complexity of DILI pathogenicity. The main mechanism behind DILI are alterations in bile acid homeostasis, oxidative stress, and mitochondrial dysfunction. More than 50 % of drugs causing DILI are causing mitochondrial impairment. If the normal function of mitochondria is disturbed, the energy production of the cell decreases, and cell function decline leading eventually to the cell death. In this study prediction of mitochondrial toxicity was studied using cryopreserved primary hepatocytes of humans and rats. The aim of the study was to clarify if there are interspecies differences in the prediction of toxicity but also investigate possible differences in the mechanisms behind hepatotoxicity by using three well-known compounds toxic to mitochondria. To determine these differences, total cellular ATP was measured after 2- and 24- hour exposure time to gain information on overall viability and possible adaptive responses. Mitochondrial energy pathways were studied as a real-time monitoring acute exposure of test compounds. Morphology, location, and possible adaptive response of mitochondria were studied using a fluorescent probe and antibody staining combined with high content imaging (HCI). Overall, primary rat hepatocytes were more sensitive to the test compounds than human hepatocytes. Also, there were differences between human hepatocyte batches that may reflect the metabolic differences between hepatocyte donors. Immunolabeling did not bring any additional values compared to the fluorescent probe staining in the study of morphology of mitochondria. Additionally, it was noticed that treatment with paraformaldehyde significantly changed the hepatocyte mitochondria morphology. Overall, more effort is needed to develop image analysis of mitochondria morphology. Finally, studying mitochondrial morphology has proven to be difficult, and this study did not unfortunately reveal any information about the adaptive responses of mitochondria for drug-induced liver injury.

Operations of pharmaceutical supply chain and medication management practices will be evaluated as part of the ongoing social and health services reform in Finland. One of the goals is to develop digital medication management tools and services to meet the needs of both healthcare professionals and medicine users. The aim of this study was to examine population's willingness to use on new digital services by community pharmacies to promote rational pharmacotherapy and to support cooperation between those involved in the medication use process. The material for this study consisted of the national population survey conducted in 2020 for the VN TEAS report “Activation of price competition for pharmaceutical products and the population's expectations for pharmacy operations” (online survey for 18–79-year-old adults, n = 1650). The survey respondents represented well the target population expect those with higher educational level were over-represented. The current study focused on questions related to digital medication management services provided by community pharmacies, which were divided into the following 4 topics to form sum variables: 1) purchasing and dispensing process of medicines (4 items), 2) customer`s communication with pharmacy and health care personnel (2 items), 3) pharmacy and healthcare personnel`s communication with the customer (4 items) and 4) support services for medication self-management (12 items). The associations of the background variables to the sum variables were calculated using cross-tabulation and the Chi-Square test. Frequencies and percentages were used to present. The majority (85–90%) of the respondents were in favor of the possibility of sending messages electronically between the customer, the community pharmacy and other healthcare personnel by using a shared communication channel, such as My Kanta to update medication information online. Multimorbidity, medication use, and higher medication costs increased the respondent’s positive attitude towards the electronic communication channel. Three-quarters (76%) of respondents were willing to use electronic medicine purchasing and dispensing services. Younger respondents (18–34 years) were more interested in these services than older ones. The electronic medication self-management support services had more discrete opinions among respondents. More than half of the respondents indicated their strong willingness to use at least one of the medication self-management support online services listed in the survey instrument. Those aged 18–34 years (69%), those with higher education (62%), those living in the Province of Southern Finland (60%) and those living in the Helsinki Metropolitan Area (67%) were more positive than others. Of the respondents who opted for pharmacy's remote online services, 55% were willing to seek advice for reconciling their medication list. According to the survey, Finnish adults are willing to use new electronic services by community pharmacies. In particular, they were willing to use a shared electronic communication channel between the customer, the pharmacy and other healthcare personnel, such as MyKanta to update information related to their medication. The willingness to have support self-care support for medication self-management primarily from the pharmacy's online services was lower than the willingness to use online purchasing and dispensing services. Of the remote medication self-management services medication reconciliation had the highest demand. Future research should focus on enhancing use of electronic medication self-management services provided by community pharmacies. Further research should also be targeted to understand medicine user needs for support as it may vary between patient groups, requiring segmentation of services.

The use of different methods of extended reality (xR) as a support in teaching has been under research for a long time. Although the use of various xR-technologies in other fields of healthcare, such as medical and nursing education, is already common, their use in pharmacy education is not yet well established. There is evidence that xR-technology has a positive impact for example on students’ motivation and learning outcomes. On the other hand, there are limiting factors that inhibit the technology becoming widespread, such as costs as well as a lack of knowledge about the technology usability. The aim of the study was to investigate usability and advantages of the augmented reality (AR) in a laboratory course as an educational supportive tool by using AR-glasses. The aim was also to investigate the learning outcomes of the students who participated in the study in three different phases: before carrying out the laboratory work (pre), immediately after the laboratory work (post) and in the course exam (delayed). Furthermore, the motivation of the students to use new technology in their studies was studied. The research was done in a collaboration with the Centre for University Teaching and Learning (HYPE) and with Sciar Company Oy. The researchers of HYPE were responsible for the pedagogical point of view, whilst the experts from the Faculty of Pharmacy were responsible for the study measurements of laboratory work related content knowledge. The research was implemented in two laboratory courses in Bachelor of Science level pharmacy studies: Medicinal product II and Pharmaceutical biology and asepsis in the fall of 2020. The students (n=18) prepared eye drops by using AR-glasses in the Medicinal product II -course and reference group (n=14) without AR-glasses. In the course of Pharmaceutical biology and asepsis, students (n=7) used AR-glasses to study the microbiological purity of the eye drops by utilizing membrane filtration method in cleanroom and reference group (n=9) without AR-glasses. ln addition, a serial dilution method was performed on a 96-well plate using an AR mobile application. The effect on learning outcomes was evaluated by using six open-ended questions measuring the understanding of content knowledge underlying the laboratory work, that were answered by the students at three different stages of the study (pre, post, delayed). To measure the usability of the AR equipment, a five-point Likert scale questionnaire studied the experimental groups students’ opinions on whether the AR mobile application could provide sufficient guidance and feedback while performing the laboratory work. In an open question, the students had the possibility to comment on the overall user experience of the AR mobile application. There were no statistically significant differences in learning outcomes between the AR-group and the reference group in both laboratory courses. The results showed indicative differences in short-term and long-term learning, with the AR-group achieving better learning outcomes in the short-term and the reference group in the long-term. In the course of Pharmaceutical biology and asepsis, the learning outcomes were the opposite. Students’ were found to be receptivity to the new technology that together with motivation supports positively the learning process. The use of AR-hardware increased certainty and reduced nervousness about the use of AR technology. As a conclusion, the study could not demonstrate the benefit of AR-technology in student learning outcomes. The study was limited by the small sample size. However, further studies are encouraged due to students’ positive attitudes and motivation towards AR technology. Regarding further studies, it is important to take into consideration the different backgrounds and learning methods of students. Thereby, the effects of xR-technologies on learning outcomes can be assessed as objectively as possible.

The problems caused by hypromellose in sterile filtration of ophthalmic products in the pharmaceutical industry were investigated. The research project was performed at NextPharma Oy's ophthalmics manufacturing facility in Tampere during the autumn of 2020. Hypromellose is an excipient commonly used in ophthalmic products as a viscosity enhancer to prolong the contact time of the preparation on the eye surface. In the ophthalmics compounding process, hypromellose is first dispersed by slowly sprinkling it into a hot solution and thoroughly mixing, after which the solution is cooled to room temperature. During cooling, the hypromellose dissolves and gels, increasing the viscosity of the solution. Incomplete dispersion or dissolution of hypromellose during the manufacturing process can slow down the filtration rate or even clog the filter completely due to undissolved hypromellose polymer material. Hypromellose is an industrially produced cellulose derivative that often contains some amounts of unreacted cellulose and other sparingly soluble polymer particles as impurities, which can also cause problems in filtration processes. Sterile filtration is a commonly used sterilization method for ophthalmic products, in which the prepared bulk solution is filtered through a 0.1 to 0.2 µm pore size filter membrane into a sterile receiving vessel. Due to the very small pore size, sterile filters are easily clogged if the solution contains poorly dissolved material. The purpose of this work was to collect additional information on the possible causes of clogging caused by hypromellose and to determine whether the filterability of a solution containing hypromellose can be improved by optimizing the manufacturing process parameters. The design of experiments was prepared, creating a two-level full-factorial test matrix without replicates and with three centre points. Four different process parameters were used (mixing time, mixing speed, dispersion temperature, and cooling temperature). Minimum and maximum levels for the parameters were obtained in the initial tests, after which the test solutions were prepared and filtered in a randomized order according to the test matrix. The aim of the screening was to find out which parameters were affecting the filterability and what would be their optimal combination that would maximize the filtration rate and the yield of filtration. Finally, the optimized parameters were used to test different batches of hypromellose, comparing the results to previous filtration tests. Additionally, an alternative hypromellose dispersion method was tested to minimize the amount of insoluble material remained during the dispersion and cooling steps. Of the parameters tested, mixing speed was the least significant, while cooling temperature had the most effect on the filtration results. The solutions with lower cooling temperature had better filtration results, which may be due to reduced aggregation of hypromellose due to increased hydration of the polymer chains. The temperature behaviour of hypromellose solutions could be an interesting subject for further investigation. Longer mixing times and higher dispersion temperatures produced slightly better filtration results on average, but the differences were not statistically significant. Most challenging in the study was controlling the temperature and mixing of the solutions, and the retention of insoluble hypromellose material at the walls of the compounding vessel. The alternative dispersion method gave promising preliminary results, but the method still requires further testing. It would be important to also find the root cause of the filter clogging mechanism e.g., by further analysing the clogged filter membrane. The study provided additional useful information of the behaviour of hypromellose solutions in solution preparations and during sterile filtration, which has been helpful in solving production problems.

Municipal case management is an activity that assesses various functional capacity indicators, utilizing the elderly’s state of health and coping in everyday life. The goal of case management is to refer clients to suitable services, such as home care or a doctor's visit. The problems related to drug treatments are only superficially reviewed. The involvement of a pharmacist in the assessment of case management would provide an opportunity to address the problems of pharmacotherapy and to provide adequate support for the implementation of pharmacotherapy. In this thesis, a remote service of a pharmacist was piloted for new clients over the age of 65 living at home as part of case management. Pharmacist reviewed medications remotely using medication risk management checklist LOTTA. The study examined the suitability of the LOTTA for medication reviews and the problems associated with medications of the elderly participating in case management. In addition, the suitability of pharmacovigilance assessments as a remote service as part of a comprehensive assessment of functional capacity and coping with everyday life was examined. The research material was collected at the case management unit of the city of Turku. The study involved 50 volunteer Finnish-speaking customers over the age of 65, for whom were assessed for a case management at Turku's case management unit. In addition to the assessment of normal case management, two pharmacists with comprehensive medication review qualifications reviewed medications using the medication risk management checklist LOTTA. Subjects were interviewed by telephone. If the pharmacist estimates that the subject will benefit from a multi-professional comprehensive medication review, the physician and pharmacist collaborated to conduct a review using a videophone application. Subjects background information, responses, observations made by pharmacists, and actions taken by physicians were recorded on an electronic form and analyzed. The mean age of the study participants (n = 50) was 82 years (range 67–98). Of these, 36 were women (72%) and 14 were men (28%). Most subjects were multidrug-treated (average medication 10.3, range 3–28). Each subject had at least one drug can be used with consideration for use in the elderly, as defined in the Fimea Drug 75 + database (Class C). 30% of subjects did not have a medication list and 34% reported lack of regular medication monitoring. 96% of the subjects had experienced a symptom on the LOTTA list that repeatedly interferes with their lives. The most common of these were problems such as constipation (54%). Pharmacists proposed changes for medication for 96 % of subjects. The most common proposed change was a change in the time of dosing (46%). Pharmacists estimated that 14 (28%) subjects would benefit from a multi-professional comprehensive medication review. In these cases, pharmacists made an average of 8.1 proposed changes for the physician, and the physician made an average of 6.9 changes for each subject. The most common challenges in coping with medication were symptom, which may be due to adverse drug reactions, a lack of follow-up to medication, and the absence of a treating physician. The results suggest that medication should be reviewed during the case management. The LOTTA list made it possible to identify and address the pharmacological problems of the elderly. The participation of a pharmacist in the assessment of the need for a multi-professional service remotely was possible, but it must be further developed. More research is needed on the benefits of multi-professional case management with a larger sample size.