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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.

Lääkkeiden saatavuushäiriöt ovat yleistyneet maailmalla ja Suomessa viimeisten 20 vuoden aikana lisäten lääkealan toimijoiden työmäärää sekä kustannuksia. Saatavuushäiriöt aiheuttavat myös vaikeuksia potilaiden hoidon toteuttamiseen, tietyissä tilanteissa hoito saattaa joutua katkolle tai joudutaan käyttämään vaihtoehtoista lääkitystä, mikä saattaa heikentää potilaan saaman hoidon laatua. Tämän tutkimuksen tavoitteena oli tutkia kirjallisuuden perusteella syitä saatavuushäiriöiden taustalla. Toissijaisena tavoitteena oli löytää mahdollisesti toimintamalleja, mitkä mahdollistaisivat saatavuushäiriöiden määrän vähenemisen tai vaihtoehtoisesti vähentäisivät niiden vaikutuksia potilaiden hoitoon. Tutkimus tehtiin systemoituna kirjallisuuskatsauksena. Tutkimukseen valikoitui mukaan yhteensä kaikkiaan 24 sisäänottokriteerit täyttävää artikkelia. Kirjallisuushaku suoritettiin 20.10.2020 Sopusi ja Pubmed -tietokannoista. Kirjallisuushaku rajattiin koskemaan ajanjaksoa 2000–2020. Tietokantojen lisäksi kirjallisuutta haettiin manuaalisesti löydettyjen artikkeleiden lähdeluetteloista. Kirjallisuushaulla löydettiin yhteensä 2334 artikkelia ja duplikaattien poiston jälkeen jäljelle jäi 1783 artikkelia. Ensin artikkelit käytiin läpi otsikon sekä abstraktin perusteella ja viimeisessä vaiheessa koko tekstin perusteella. PRISMA-listaa käytettiin soveltuvin osin apuna katsauksen laatimisessa. Tähän systemoituun kirjallisuuskatsaukseen mukaan valituista julkaisuista 10 oli alkuperäisiäjulkaisuja artikkeleita ja 14 katsausartikkeleita. Alkuperäisistä tutkimusartikkeleista suurin osa (n=7) oli kvantitatiivisia tutkimuksia ja näistä neljä käsitteli saatavuushäiriöitä Yhdysvalloissa. Kvantitatiiviset tutkimukset olivat kaikki viranomaisten ylläpitämistä rekistereistä tehtyjä tutkimuksia. Laadullisia tutkimuksia alkuperäisissä artikkeleissa oli kolme, nämä olivat toteutettu puolistrukturoituina haastatteluina tai avoimina kyselyinä lääkealan toimijoille Systemoidun kirjallisuuskatsauksen tulosten perusteella saatavuushäiriöiden syyt voivat vaihdella eri markkinoiden välillä. Saatavuushäiriöiden taustalla olevien syiden teemat kuitenkin vaikuttivat tutkimuksen perusteella olevan hyvin samankaltaisia riippumatta markkinoista. Yleisimpinä syinä saatavuushäiriölle olivat tuotantoon liittyvät ongelmat, regulatoriset toimet sekä ekonomiset ratkaisut. Tulosten perusteella ensisijaisena ratkaisuna saatavuushäiriöiden vaikutusten minimointiin olisivat lääkkeiden valmistajien tarpeeksi ajoissa antamat ilmoitukset alkavasta saatavuushäiriöistä.

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.

Medication safety is an important target of development in health and social services systems internationally. Medication errors are one of the biggest risk factors in medication safety. Majority of the medication incidents could be avoided by improving the medication treatment process. Patient safety incident reporting systems enable health and social services to collect systematic data from risk factors within the medication treatment process. This study was conducted as a retrospective registry-based study where medication incidents that occurred in health and social care units reported by community pharmacies to the incident reporting system HaiPro from 21st of September 2021 to 31st of October 2022 were analysed. Cases that did not meet the criteria for this study (n=55) were removed from the original data (n=3841). If needed, the nature and type of the reported error were corrected. A descriptive quantitative analysis was conducted for the final data (n=3786) using Microsoft Excel. The number, natures, types, observers, and prescription types of medication errors were investigated from the data. In addition, the most common groups of medicinal substance and high risk medicines were identified. A qualitive content analysis was performed to near miss cases involving high-risk medications (n=446) using the Atlas.ti program. Interventions, measures following the interventions and risks prevented by the measures were identified from the open description in the incident reports. The qualitative analysis was performed as an abductive content analysis. Of the medication errors included in the study (n=3786) 91% were detected by community pharmacies and the majority (68%) of the reported incidents were near misses. Most (96%) of the safety incidents (n=3786) were associated with the patient’s medication treatment and had occurred mostly during the prescribing process (92%). As a result from the prescribing errors, patients were most commonly prescribed wrong dose or strength of the medicine (26%) or the prescription lacked SIC marking (26%). High-risk medications occurred in 16% (n=591) of the incidents (n=3786). Most frequently detected high-risk medications were opioids (35 %). Three quarters (76 %) of safety incidents associated with high-risk medications were near misses (n=446). The majority (92 %) of interventions (n=471) made to prevent safety incidents associated with high-risk medications were made by community pharmacies. The most frequent intervention was community pharmacies contacting the doctor. Based on the HaiPro incident reports made about medication errors in health and social care units reported by community pharmacies, it can be concluded that community pharmacies are a central barrier in primary care medication treatment process. Community pharmacies detect and report medication errors that have occurred in other health and social care units. Safety incidents reported by pharmacies systematically accumulate important information that can be used in the development of medication safety in primary care at a unit, wellbeing services county and national levels.

Vascular endothelial growth factor C (VEGF-C) is the most studied of the growth factors that control the growth of lymphatic vessels (lymphangiogenesis) and belongs to the same VEGF family as VEGF-A, which controls the growth of blood vessels. The growth of blood vessels and lymphatic vessels is centrally related to the pathophysiology of several cancers that form solid tumours and wet macular degeneration. Unlike VEGF-A, VEGF-C is not currently (2023) a target molecule of any approved drugs, but in clinical trials in the indications mentioned above, combining a VEGF C inhibitor with VEGF-A inhibitors has provided better results than VEGF-A inhibitor monotherapy. The study's objective was converting a phage display library containing single-chain antibody variable fragments (scFvs) screened against VEGF-C into full IgG class antibodies. The scFvs had shown a binding affinity towards the human, mouse, or both VEGF-C variants. The DNA sequences of the best binders of the library had previously been cloned into pLK06H plasmids. The scFvs comprise the variable region of the light and heavy chain (VL and VH) but do not contain the constant regions of the antibody (CL and CHx). Using single-chain antibody fragments as drugs is limited because, in most indications, better stability of whole antibodies, lower immunogenicity, and a longer half-life enabling less frequent dosing is desirable. In addition, the Fc part of whole antibodies often mediates the drug effect, such as complement activation, and whole antibodies are also used as research tools. Secondly, the study aimed to investigate how changing the antibody format affects the binding affinity. To produce whole antibodies, original DNA sequences of pVitro-trastuzumab-IgGk1 plasmid encoding VH and VL regions were replaced with new VH and VL sequences from the phage display library. Several recombinant DNA technology methods were utilised, but the most crucial method was the commercially available NEBuilder HiFi DNA Assembly, which enabled the seamless joining of several DNA fragments into a recombinant DNA molecule in a single-tube reaction. The cloning workflow proved uncertain, as only one constructed antibody production plasmid was sufficiently amplified and expressed in bacterial and mammalian cell cultures. Suboptimal overlapping of DNA fragments and insufficient competence of the bacterial strain used in the transformation were probable bottlenecks. Therefore, as such, the method is not suitable for use on a large scale to convert single-chain antibody fragments into whole antibodies. Also, binding tests were not performed. However, the work done and the antibody production plasmid built is a good basis for further optimisation of the method. In the optimisation, attention should be paid, especially to the quality of the DNA primers and the competence of the bacterial cell line. Also, alternative cloning methods, such as restriction enzymes and ligases, could be used instead of the NEBuilder HiFi DNA Assembly.

Solids most commonly come in two broad forms: crystalline or amorphous. Crystalline solids have a regular, organized long-range structure of atoms and crystals, and are characterized by having a distinct shape, specific volume, and melting point. They can also have multiple polymorphs. On the other hand, amorphous solids do not usually have a regular long-range atomic and crystal structure and their molecules are more easily separated, which makes them more soluble in their surroundings compared to crystalline solids. However, despite this, short-range order can also occur. To improve the solubility of crystalline solids, co-amorphous systems can be created by mixing together two or more chemically different compounds in a way that they don't form a regular crystalline structure, but rather an irregular, amorphous one. Co-amorphous systems can be analyzed qualitatively or quantitatively. Qualitative analysis is often the main focus when studying amorphous matter, as it can be difficult to accurately quantify these materials using techniques based on crystal structures. Additionally, many amorphous systems are made up of complex mixtures of polymers with different chemical and physical properties. This study aimed to determine the most effective method for obtaining quantitative information about the co-amorphization of indomethacin and tryptophan. Three analytical techniques were used for this purpose: differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and Raman spectroscopy. The co-amorphous system was created by mixing together α-indomethacin and tryptophan, γ-indomethacin and tryptophan, and amorphous indomethacin and tryptophan. This study showed that DSC, XRPD, and Raman spectroscopy are effective in providing quantitative information about crystallinity and crystal size. These techniques were able to accurately detect and characterize discrete residual crystals, and were able to measure and quantify the amount of these substances. Even though these methods may not be able to detect nanoscale structures with precision, they still provided valuable information about the crystalline and amorphous nature of the samples studied. Additionally, the fact that similar quantitative results were obtained using different analysis methods further supports the reliability of these techniques. Of all the techniques discussed, Raman spectroscopy was able to identify even small residual crystals, resulting in the highest calculated crystallinity percentage.

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.

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.

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.

Children´s medication treatment has many special features that predispose to medication errors, such as dosing of medications according to weight or age and the off-label use of medications. In the medical treatment of children high-alert medicinal substances are used and the incorrect use of which can cause harm to the patient. The aim of this study was to identify medication errors in pediatric patients of parenteral nutrition products (PN) and concentrated electrolytes, which belong to high-alert medicinal substances in different stages of medication management and use process and also to identify the contributing factors behind the errors in order to promote medication safety. The data for the retrospective registry study were made up of HaiPro accident reports (n=528) related to PN, lipids, concentrated electrolytes, solutions affecting electrolyte balance and dialysis fluids made in the period 2018-2020 at the Children`s and Adolescent`s hospital in Helsinki from which the reports related to high-alert medications were identified (n=317). ISMP´s (Institute for Safe Medication Practices) and JCI´s (Joint Comission International) lists of high-alert medications was used to limit the data. The final research material was further limited to reports (n=254) in which the medicinal substance appeared more than ten times in the entire material. The data were analyzed quantitatively to describe the frequencies (n) and percentages (%) of PN and concentrated electrolytes, and qualitativevely to identify the stages of the medication management and use process, types of medication errors and contributing factors. High-alert medications accounted for more than half (n=317/528, 60,0 %) of the entire material of this study. Medication errors (n=378) were identified most during the administration and preparation phase of the medication. In the administration phase, 56,8 % (n=117/206) of errors were identified with PN and the most common error was disturbances in the infusion tubing, wrong infusion rate or wrong dose. With concentrated electrolytes, errors in the administration phase were identified in 50,0 % (n=86/172) of all errors and the most common error was wrong product the patient received, wrong infusion rate and medicine not being administered. In the medication preparation phase, errors were identified in 20,9% (n=43/206) of PN and 30,2% (n=52/172) of concentrated electrolytes. The most common error in the preparation phase was incorrect preparation of medicine with both groups of medicinal substances. Factors related to workload and resources and human factors related to the employee, were most identified as contributing factors (n=753) in both medication groups. Targeting preventive protections, especially in the administration and preparation phases of the medicine is desirable both with PN and concentrated electrolytes. It is also important to plan safeguards comprehensively for the entire mediacation management and use process taking into account the key contributing factors that predispose to medication errors.