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(2019)Medicinal products, medical devices and combination products, that include both the medicinal product and medical device part, need to fulfill the regulatory requirements for their efficacy, safety and quality before they can be placed on the market. Documentation requirements, application processes and authoritative processing differ between medicinal product and medical device registration. In European Union, combination products are registered either as medicinal products or medical devices according to their principal mode of action. Registration requirements for medical devices are currently changing since the new medical device regulation 2017/745 (MDR) in the EU came into force in May 2017. Transition period in MDR implementation will last until May 2020. This study is continuation to an earlier study (Nuolimo 2016) where registration process differences between medicinal products and medical devices were investigated. In the earlier study it was concluded that registration process differences seem to favour the registration of the product as CE marked medical device in borderline cases where the product can be registered both as medicinal product and medical device. The aim of this theme interview study was to further clarify registration process differences and particularly underlying factors affecting the selection of the registration status. Furthermore, the study aimed to clarify how the registration process for combination products differs from other registration processes and how the new European medical device regulation 2017/745 influences registration work in practice. In the theme interview study, regulatory affairs professionals with experience from the different product groups were interviewed. In total, eight interviewees participated in the study. Regulatory professionals’ job descriptions varied so much that it was difficult to compare registration processes. Registration process for medical devices was discovered to be lighter than the equivalent for medicinal products. Registration status is chosen product-specifically. Load in registration process for combination products depends on whether the product is registered as a medicinal product or as a medical device. Regarding combination products, borderline cases where it needs to be determined whether the product is registered as a medicinal product or a medical device, can be challenging. Implementation of the new medical device regulation (MDR) was still incomplete when the study was conducted. However, the regulation had already increased workload in medical device and combination product registration and created new business opportunities for contract research organisations.
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(2021)Poor adherence to and non-compliant use of medications are common in long-term patients, and it is estimated that only half of medication use worldwide is appropriate. Poor adherence to medication undermines public health, reduces the cost-benefit of resources invested in medication care, and burdens health care. Various interventions have sought to improve adherence to drug treatment, but they have not brought about the desired change in medication adherence. The aim of this master's thesis was to develop a method and pilot it to investigate the reasons for the non-compliant use of medications in the context of the medication reconciliation process. The aim of this new method was to find out the reason for non-compliant use of a medicine in a patient-centered way, and the possibility for the pharmacist to motivate the patient to use the medicine according to the instructions. In addition, it was examined whether the method can measure prevalence of non-compliant use of medicines differs according to the ATC classification of medicines and whether the total number of medicines contributes to the non-compliant use of medicines. The pilot study was carried out as part of a standard pharmacist's medication reconciliation process at Vantaa primary health care. The data required for the study were collected on the electronic HUSeCRF platform. Patients were collected to the extent that we were able to verify the functionality of the method and to plan the reporting of the results of the actual study with larger research data. The data were collected during the year of 2021. The theoretical framework of the study was the Medication-Related Burden model and the iceberg model of non-compliant use of medicines. The research material was analyzed using descriptive statistical analysis in IBM SPSS 27. The analysis of the data was done in terms of the functionality and development of the new method. A total of 8 patients participated in the pilot study (women 63% n = 5). Patients had an average of 16 medications per patient (range 8-22), and the last time their medications were reconciliated was on average 1 year ago. Non-compliant use of medicines was observed in 88% of patients (n = 7). In total, there were non-compliant use of medicines in the data for 21 drugs. The most common medicines which were used non-compliant were for the treatment of cardiovascular diseases. The total number of medicines and the number of non-compliant use correlated with each other (Pearson correlation coefficient 0.472), but the result was not statistically significant (p = 0.238). The most common reason for non-compliant use was a drug-induced side effect. After a motivational discussion which was involved in the medication reconciliation process with pharmacists, in 14 % of non-compliantly used medicines, patients decided to start taking the medication as directed. The pharmacist was able to motivate the patient to use the medicine as directed when the reason for non-compliant use of medicine was unclear instructions. In this study, a method was developed and validated to determine the reasons for non-compliant use of medicines. During medication reconciliation process, the pharmacist was able to find out the reasons for non-compliant use of medicines. Pharmacists may motivate the patient to use the drug as directed, however, most patients did not want to change the use of the medicine as directed. As the total number of medications increase, the probability of non-compliant use of medicines may increase.
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(2021)Background. Parallel importing of pharmaceuticals has potential to generate significant savings but results of previous theoretical and empirical studies on the consequences of parallel importing and its ability to generate competition have been contradictory. Little research on the effects of parallel importing has been conducted in Finland. In April 2017, the reference price system in Finland was extended to also cover substitution groups determined on the basis of parallel imports. The aim of the reform was to increase competition between direct and parallel imports and thus to generate savings in reimbursement costs. However, the impact of the reform has not yet been significantly studied. Aim. The aim of this study was to examine the effects of parallel importing and the expansion of the reference price system on the price development of direct and parallel imported medicines and reference prices. The purpose was to investigate in general the price development of products and reference prices in the period following the expansion of reference price system, to examine the importance of how long a reference group was involved in the system on price development, to examine the impact of the extension of the reference price system and the market entry of a competing parallel import in particular on prices of direct imported products and to examine the importance of the number of parallel imports competing with the direct imported product on price development. Methods. Reference price decisions and lists of prices of reimbursable medicinal products were used as research material. The data was found on the website of the Pharmaceuticals Pricing Board. Quarterly price data on the prices of products belonging to the reference price groups determined on the basis of parallel imports was extracted from the data. Price data was examined from January 2016 to October 2019. Price development was monitored as percentage changes on a quarterly and annual basis. The effect of extension of the reference price system and the entry of a competing parallel import was examined using a sort of before-after set-up by comparing the price development of products before the change to the price development of products after the change. Regression analysis was used to assess the statistical significance of the variables explaining price development of products. Results and conclusions. During the period, the prices of direct and parallel imports and the reference prices decreased in most of the reference price groups. Price increases amongst the groups were very rare. Based on price development and regression analyzes, both the expansion of the reference price system and the market entry of a competing parallel import significantly reduced the prices of direct imports. However, the time that the reference group was involved in the reference price system or the number of parallel imports competing with the direct import did not have a significant impact on the price development of direct and parallel imports. It can be stated that parallel imports are likely to generate significant savings in Finland and the expansion of the reference price system has contributed to the ability of parallel imports to generate savings. However, further research on the real savings generated by parallel imports is still needed.
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(2022)Lääkkeiden saatavuushäiriöt ovat yleistyneet Suomessa ja muualla maailmassa aiheuttaen lisätyötä ja -kustannuksia lääkealan toimijoille. Saatavuushäiriöt voivat aiheuttaa katkoksia lääkehoitoon tai saatetaan joutua turvautumaan muihin hoitovaihtoehtoihin, mikä voi johtaa potilasturvallisuuden vaarantumiseen. Tämän tutkimuksen tavoitteena oli antaa yleiskuva saatavuushäiriöistä ja saatavuushäiriövalmisteiden ominaispiirteistä Suomessa keväällä 2020. Tutkittaviin ominaispiirteisiin kuuluivat mm. lääkkeen terapiaryhmä, myyntiluvan haltija, häiriön kesto, valmisteen hintaluokka, kuuluminen velvoitevarastoitavien valmisteiden tai Maailman terveysjärjestö WHO:n välttämättömien lääkkeiden luetteloon ja myyntiluvan myöntövuoteen perustuva lääkkeen elinkaarivaihe. Saatavuushäiriövalmisteiden (n=879) tiedot kerättiin myyntiluvan haltijoiden Lääkealan turvallisuus- ja kehittämiskeskus Fimealle kahden kuukauden aikana (14.2.–15.4.2020) toimittamista tai voimassa olevista saatavuushäiriöilmoituksista. Aineistoa täydennettiin hinta- ja korvattavuustiedoilla Kansaneläkelaitoksen lääketietokannasta sekä tiedoilla muista markkinoilla olevista pakkauskoista, vahvuuksista ja vaihtokelpoisista lääkevalmisteista. Aineistosta tehtiin kuvaileva tilastollinen analyysi käyttäen perustunnuslukuja ja -jakaumia. Analyysissä keskityttiin pääasiassa avohoidossa käytettäviin reseptivalmisteisiin (n=654). Ihmislääkkeiden saatavuushäiriöt (n=829) koskivat etenkin sairausvakuutuksesta korvattavia reseptivalmisteita (65 % kaikista saatavuushäiriöistä), ja ne keskittyivät suurten potilasryhmien käyttämiin lääkkeisiin, kuten sydän- ja verisuonisairauksien lääkkeisiin (31 %) ja hermostoon vaikuttaviin lääkeaineisiin (28 %). Avohoidon reseptivalmisteiden häiriöistä yli puolet (53 %) kohdistui rinnakkaisvalmisteisiin. Häiriövalmisteet kuuluivat elinkaarivaiheeltaan vanhempiin ja hintaluokaltaan edullisempiin valmisteisiin. Viidennes valmisteista (19 %) kuului velvoitevarastoitavien tai WHO:n välttämättömien lääkkeiden luetteloon. Rinnakkaisvalmiste löytyi 73 prosentille häiriövalmisteista. Vain kolme prosenttia myyntiluvan haltijoista oli tehnyt ilmoituksen saatavuushäiriöstä Fimealle vaadittua kahta kuukautta ennen myynnin keskeytymistä saatavuushäiriön vuoksi. Tulosten perusteella saatavuushäiriöt Suomessa koskevat samankaltaisia lääkevalmisteita kuin muuallakin maailmassa. Tämän osoitti myös tutkielman kirjallisuusosassa toteutettu kansainvälistä empiiristä saatavuushäiriötutkimusta koskenut systemaattinen kirjallisuushaku. Valtaosaan saatavuushäiriöistä on mahdollista reagoida apteekissa toimittamalla rinnakkaisvalmiste, kun taas osa vaatii yhteydenottoa lääkkeen määränneeseen lääkäriin. Saatavuushäiriötiedon linkittämistä sähköiseen reseptijärjestelmään ja lääkevaihdon laajentamista farmasian ammattilaisille voisi harkita toiminnan kehittämiseksi saatavuushäiriötilanteissa. Covid-19-pandemia on lisännyt kansainvälisiä toimia häiriötilanteiden hoitamiseksi. Tätä varten kehitetään yhteisiä toimintatapoja muun muassa Euroopan unionissa, jossa tavoitteena on luoda kaikki jäsenmaat kattava saatavuushäiriöportaali.
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(2021)Good availability of medicines means that authorised medicines are placed on the market and not in a short supply. Drug shortages have increasingly become a common problem that has compromised the continuous availability of medicines. Drug shortages are caused by many complex factors, such as capacity constraints, manufacturing difficulties, business decisions, availability of raw materials, and sudden increase in demand. Drug shortages can cause adverse effects, medication errors, allergies, and delays in necessary treatments. There have been studies that have explained the reasons behind medicines shortages. However, more information is needed especially from the perspective of markets in Finland. The aim of this study was to reinforce and deepen the knowledge concerning the availability of medicines in Finland. The aim was to identify the group of medicines that are more exposed in short supply than others and define the root causes of medicine shortages. In addition, the aim was to form an overview of the availability of medicines in Finland. The study was based on a Finnish medicine agency's registry. Data were collected retrospectively from materials that contained shortage notifications from marketing authorisation holders and mandatory reserve supplies permissions for exemption to maintain lower stock levels. The study was dated between the years 2017 and 2020. More detailed data from the medicine shortage was only available from the year 2020 because of changes in procedures. The study also contained data from the register for all marketed and non-marketed medicinal products with marketing authorisation. The data classified with ATC-codes, because it is used internationally and thus makes the study to comparative to other studies. Data were analysed with cross-tabulation and frequency distributions. The study addressed that drug shortages were reported of medicines that are commonly used in Finland, such as nervous and cardiovascular system drugs. These medicines covered almost half of the annual shortage notifications. The number of drug shortage notifications has increased annually by approximately 40 percent. Correspondingly mandatory reserve supplies permission for an exemption to maintain lower stock levels were reported most on nervous system drugs and anti-infectives for systemic use. The number of annual permissions remained quite constant. The amount of the permissions increased 14 percent between the years 2017 and 2018 and a further 6 percent to the year 2019. However, the amount of permissions increased 26 percent in the year 2020. There is clearly recognized the effect of the COVID-19 pandemic when considered the rate of shortage notifications and mandatory reserve supplies permissions. The main reasons for the shortages were capacity constraints (32%) and increased demand (21%). Most of the drugs in short supply were drugs with national (33%) or decentralised (30%) marketing authorisation procedures. Broadly were able to state that the availability of medicines was at an acceptable level. 62 percent of all medicinal products with marketing authorisation were placed on the market. In addition, only 29 percent of older drugs with marketing authorisation accept during the years 1996 to 2003 were withdrawn from the market. In future, more large-scale studies are needed based on this study to improve the system that maintains the continuous and high-quality medicine distribution. Most important is to create a better tracking system and co-operation between national and international officials.
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(2015)In hospital care many medicines should be usually prepared before they are administered to patients. In Finland Finnish Medicines Agency (Fimea) gives regulatory requirements and instructions for preparation of medicines in hospital pharmacies and action in hospital pharmacies is strictly controlled regularly by Fimea. According to Fimea's instructions hospital pharmacies should also ensure that medicines are prepared properly before they are administered to the patients in hospital wards. Preparing of medicines in hospital wards should be done in accordance with instructions given from the hospital pharmacy. Medicines should be prepared by using aseptic technique in order to protect patient safety. Aim of this study was to develop an assessment tool which can be used to assess the quality of ward- prepared medicines. The assessment tool should be suitable for self-assessment and external audit. Aim of the assessment tool is to ensure the safety of preparation of medicines in the wards and at the end improve patient safety. For the assessment tool ISMP Guidelines for safe preparation of sterile compounds were translated to Finnish. The assessment tool was then developed from the translated ISMP-guideline and other literature. The assessment tool was validated by using two-rounded Delphi-method. Delphi-method is a consensus method in which selected experts evaluate the data. At the first Delphi-round suitability and feasibility of the tool were evaluated and new items were created based on the consensus of experts. At the second round the feasibility of the tool items, which were developed by the first round, were evaluated once again. A total of 19 experts were participated to the Delphi-rounds. After the Delphi-rounds the developed assessment tool contained 64 items for safe preparing of medicines in hospital wards. The developed assessment tool reviews the entire process of preparing medicines and it can be used to identify which items are not followed in preparing of medicines before administering to patients in hospital wards. The developed assessment tool for safe preparation of medicines in hospital wards can be used widely in Finnish hospitals in order to ensure the quality of preparing medicines and detect the deficiencies and errors in preparation processes. By detecting deficiencies and errors in preparing medicines, they can be corrected and processes can be modified appropriate. In this way patient safety can be improved.
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(2014)The aim of this thesis was to investigate the potential of label-free CARS microscopy as a new method for chemically-specific imaging of live cells and particle-cell interactions in a drug delivery context. Cells used to mimic the intestinal epithelium, Caco-2 cells and HT-29 cells and nano-/ microcrystal particle interactions with macrophages were studied. More information about drug absorption from intestinal and particle cell interactions are needed, since many novel drugs lack properties needed for good bioavailability. It would be beneficial if these events could be visualized without labels. CARS microscopy was found to be well suited to imaging live Caco-2 and HT-29 cells that were grown on PTFE Transwell inserts. CARS microscopy revealed lipid droplets inside these cells. The size of lipid droplets increased in Caco-2 cells a lot during a three week period so that at the end a large part of the inner part of the cell was filled with lipid droplets. It was also observed that Caco-2 cells and HT-29 cells can grow on top of each other on Transwell inserts and not just as a monolayer. These two facts could cause variations in drug absorption studies based on Caco-2 cell monolayers. CARS microscopy was able to detect nanocrystals as small as about 500 nm with label-free, molecular-specific CARS microscope inside RAW 264.7 macrophages after incubation of 120 min. This observation was important, since nanocrystal drug formulations are gaining interest in the field of pharmacy. Nanocrystals can be used in parenteral drug formulations as well as in oral dosage forms. In suspensions, nanocrystals can be used to cause long lasting drug release. Nanocrystals can be also used to enhance poor bioavailability of drugs. Whether these nanocrystals are used in parenteral formulations or in oral drug formulations it is evident that imaging techniques are needed to image interactions between these nanocrystals and cells. CARS microscopy could be one of those techniques, since it is suitable for live cell imaging and it can be used to image nanocrystals that are not labeled. The results in this thesis suggest that CARS microscopy could be used as fast imaging technique for nanocrystal particle cell interactions. Overall, CARS microscopy is a relatively new imaging method that shows much promise as a label-free chemically specific imaging technique for imaging cells and cell-particle interactions in a drug delivery context. As the technique becomes more widely available and undergoes some technical developments, it will become much more widespread imaging method in the future.
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(2016)Healthcare professionals in patient care, including practical nurses, need medicines in-formation in their work. One strategic goal in national Medicines Information Strategy in Finland is to make sure, that healthcare professionals use reliable information sources and services. One part of the national medicines information network in Finland is work-ing group on medicines information for healthcare professionals. It's central aim is to advance availability of reliable medicines information in different environments in social- and healthcare. Objective of this study was to explore medicines information sources and needs among practical nurses. This study concentrated on practical nurses who work in atypical areas of medical care (for example at school and day care), homecare and social care and were members of The Finnish Union of Practical Nurses. Survey was made in co-operation by working group on medicines information for healthcare professionals and The Finnish Union of Practical Nurses. The survey was carried out in December 2013 - January 2014 by e-mail. The random sample consisted of 1 000 practical nurses. The material was analyzed using direct distributions, cross tabulation, Kruskal-Wallis -test and Mann-Whitney U-test. Open ended questions were analyzed by qualitative methods. The response rate was 67 (n = 666). The most commonly utilized medicines information among practical nurses were package leaflets (PL) and medical database Terveysportti. Those sources were also the most preferred ones. Practical nurses reported they would like to have additional medicines information about drug-drug interactions (86 %) and adverse effects (63 %). Information was also needed about generic drugs. The majority of practical nurses in this study were satisfied with current medicines information sources. Additional information about pharmacological treatment was needed by respondents, 14 % daily and 31 % weekly. 82 % of respondents would benefit from pharmacy's services in their work. 64 % of practical nurses had always or usually and 28 % had never mobile device for information seeking. 73 % of practical nurses took part in education concerning pharmacological care less than once in one to two years. Package leaflets and Terveysportti were the most commonly utilized and preferred medicines information sources. There is still need for detailed information about practical nurses' medicines information sources in various working environments.
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(2022)The package leaflet (PL) is a technical document sheet included in medicine packages to provide guidance on safety and rational use of medicines for the user. The EU is increasingly encouraging the adoption of digital product information, which in time should be seen as the basic medicine information. The outdated package leaflet has for a long time been criticized by both patients and pharmaceutical operators. As a result, it is important to map the perspectives of various pharmaceutical operators on the electronic package leaflet. The aim of the study was to gain broader knowledge and deeper understanding of what opportunities and challenges the electronic package leaflet entails from the perspective of different pharmaceutical operators, and whether there are differences between opinions of the pharmaceutical operators. The study also sought to find out how the electronic package leaflet compared with the printed current leaflet from an environmental perspective. The study was conducted as a questionnaire e-survey, whose target groups were companies in the pharmaceutical industry, The Finnish Medical Agency (Fimea) and hospital pharmacies / departmental pharmacists. The material was collected over a three-week period in April 2022. The data was analysed both quantitatively and qualitatively. Based on the results of the study, it emerged that 55 experts, broadly across the pharmaceutical field, took part in the study. According to the pharmaceutical operators, the main opportunities of the electronic package leaflet were its ease of use and environmental friendliness. Patient safety, which is always a focal point when discussing medicines, would also increase as the users would have access to the most up-to-date medicine information (75 %, n = 41). In addition, the QR code on the medicine packages could be utilized when introducing ePL. The challenges, however, mainly concerned the user's lack of internet connectivity and incompetence in the use of e-services. Although pharmaceutical operators are of different opinion on the electronic package leaflet, it is highlighted that the majority of respondents (69 %, n = 38) believe that ePL would be an improvement and a more environmentally friendly alternative than the current printed leaflet. The study shown that there are differences in the perspectives on ePL between different pharmaceutical operators. The varying opinions on the electronic package leaflet depends on the respondent's position in the pharmaceutical sector. Despite the disagreement, the majority believe that ePL would be a positive development and a prerequisite for achieving the challenges of the future.
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(2013)Laminins are a family of heterotrimeric glycoproteins found mainly in basement membranes. They interact with numerous other extracellular matrix components and cell surface receptors, including integrins and α-dystroglycan. Laminins play roles in myriad of functions including tissue morphogenesis, organogenesis, maintenance of tissue integrity and compartmentalization. In central nervous system laminins are involved in every major developmental stage from neural tube closure to synaptogenesis. Laminin expression in central nervous system decreases after maturation but has been found inducible by injury after trauma or disease. Since laminins are known to promote neurite outgrowth and neuronal survival, this has been proposed as a regenerative response to injury. Although the effects of endogenous laminin are clearly inadequate for repair, laminin based compounds could be powerful therapeutic agents. In previous in vivo studies KDI-tripeptide, a neurite outgrowth promoting fragment from γ1-laminin, has proved effective neuroprotective and regeneration promoting compound. Encouraged by these results I set out to test whether KDI would rescue midbrain dopaminergic neurons in unilateral 6-hydroxydopamine-induced rat model of Parkinson's disease. KDI (1-30µg) was injected to the striatum six hours prior to 6-hydroxydopamine. The severity of the lesion was then evaluated by measuring D-amphetamine induced rotation 2, 4 and 6 weeks postlesion and by assessing the number of neurons in substantia nigra pars compacta and optical density of striatum after tyrosine hydroxylase immunostaining at week seven. The only effective KDI dose studied was 3 µg. Compared to control it decreased Damphetamine induced rotational behaviour significantly at week four. KDI, however, failed to save tyrosine hydroxylase positive dopaminergic neurons in substantia nigra pars compacta or their axons in striatum. KDI might be usable in treating Parkinson's disease but it's mode of action doesn't appear to rely on protecting dopaminergic neurons or promoting the branching of their axons. KDI is known to inhibit ionotropic glutamate receptors and could therefore improve motor function by opposing striatal denervation induced overactivity of glutamatergic subthalamic nucleus neurons.
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(2016)Breast cancer is the most common cancer among women, about 25 % of all cancers in women. 15 - 20 % of them are HER2 positive. HER2 is a transmembrane protein receptor with tyrosine kinase activity. When the overexpressed receptor is activated it turns on a cascade which results to activation of genes coding for for the growth of the cancer cells. Drugs against HER2 protein have significantly improved the survival of patients with HER2 positive breast cancer. In this systematic review the epidemiology, diagnostics and the principles of treatment is reviewed with focus on the treatment of HER2 positive breast cancer and anti-HER2 medications. Endpoints of clinical trials and handling the data are also reviewed. The aim of this study is to collect data of lapatinib, pertuzumab and trastuzumab emtansine in randomized clinical trials studying progression free survival, overall survival and adverse effects of patients with metastatic HER2 positive breast cancer. As a result of the literature search 22 whole text articles were found. There were 14 of randomized clinical trials, 2 of previous systematic reviews and 6 of meta-analysis. The facts and results of the selected studies were collected in tables. The quality of the studies was evaluated with CONSORT and PRISMA guidance. Lapaninib is used mainly for treatment of patients with resistanse to trastuzumab. Lapatinib improves the progression free survival and overall survival but the effect has not been as goog as expected. Lapatinib is better than chemotherapy but worse than trastuzumab in the treatment of metastatic HER2 positive breast cancer. Combinaition therapy is better than none of these alone. Lapatinib is a small molecule tyrosine kinase inhibitor. Pertuzumab and trastuzumab emtansine are monoclonal antibodies targeting HER2 receptor. In trastuzumab emtansine there is also a cytotoxic drug which is delivered into the cancer cell. Pertuzumab is effective in the treatment of metastatic HER2 positive breast cancer and it improves the survival also after treatment with trastuzumab. Pertuzumab is now approved also as neoadjuvant. Promising results has been published with trastuzmab emtansine in the treatment of heavily medicated patients with progressive disease. Adverse effects were abundant but usually manageable and reversible. The quality of the studies was mainly good. Some limitations were noticed, especially in reporting methods. Cancer therapy with targeted medication improves the effect of the treatment and decrease systemic adverse effects. It seems that the use of lapatinib is going to be mostly complementary when more promising pertuzumab and trastuzumab emtansine turned up to be more effective in the treatment of metastatic HER2 positive breast cancer. In the future there should be more clinical experience with the use of lapatinib, pertuzumab and trastuzumab emtansine. That would guarantee a cancer patient the most effective treatment, hopefully at the early stage of cancer.
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(2013)There aren't always available suitable authorized drug products for different age and different weight pediatric patients. Hospital pharmacies have to prepare suitable doses and dosage form for these very young patients extemporaneously. In Finland oral powders are usually used in pediatric medication. In previous studies it has been found that part of drug dose sticks to paper of oral powder and the patient doesn't get the entire intended dose. It is suggested that hard capsules may be better dosage form than oral powders, because capsules have smaller area than oral powders, where the powder can stick. The aim of this study was to examine, whether warfarin- and spironolactone capsules prepared by hospital pharmacy meet European Pharmacopeia standards of uniformity of content. Capsules were compounded from commercial tablets and capsulated by Feton-capsulating device. In this study capsules manufactured with automatic capsule filling device attached to analytical balance, oral powders and capsules prepared from pure drug substance were also compared to capsules compounded from tablets. The three month stability of compounded capsules was also examined. In hospital pharmacy many different strengths are compounded from same drug substance, ordered by physician. Ordered strengths can be nearly identical, but whether the small differences in concentration can possibly be prepared in hospital pharmacy is unknown. From both drug substances two strengths with small difference in concentration were prepared and it was studied if statistically significant difference exists. The drug concentrations of preparations were measured by high performance chromatography (HPLC). Aqualab-water activity meter was used to study water activity of samples during the stability testing. Content uniformities of all capsule batches complied with test specified in the European Pharmacopeia.The drug concentrations of capsules were significantly lower than target concentrations. With these drug substances no difference, between the drug concentration of oral powder and capsules, was found. According to this study oral powders can be replaced by capsules. Warfarin and spironolactone capsules remain at least three months, when storaged in room temperature. Warfarin capsules can be prepared accuracy of 0,1 mg and spironolactone capsules accuracy of 0,5 mg.
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(2018)Marketing authorized pharmaceutical preparations that are aimed at adult use cause problems both in administration and when dosing. Over and underdosing are the most common medication errors in pediatric population. Only a fraction of medicinal products are clinically tested and evaluated for pediatric use. Children should have the right for the best achievable health, medical care and rehabilitation. The aim of this study was to determine problematic pharmaceutical preparations, formulations or excipients experienced by healthcare professionals. The another aim of this study was to comprise (?) the view of healthcare professionals about 3D-printed medicinal products by using the collected data. By using the data, the problems, challenges, targets for development and other suggestions regarding pediatric medication were identified. New 3D printed medicines suitable for children can be developed by using the observations of this study. The study was carried out as semi-structured interview. Frameworks of the themes were structured by using the subjects of a recently made semi-structured questionnaire. The semi-structured interview was carried out as a group-interview, where the participants were presented open questions according to the themes structured before. According to the study results, the prejudices of the interviewees towards the new technology were mainly positive. The adjustability of the printed medicine by the means of the patient was most highlighted property in the interviews. Accoring to the experiences of the interviewees’, the most suitable pharmaceutical preparations used are liquid preparations such as oral liquids or suspensions. When using solid oral formulations, the age of the patient was not seen as significant. The most common reason for compounding the preparation was the wrong size of the product or dose. The varying availability of pharmaceutical preparations was seen as delaying factor at the start of the medical treatment. In the interview the pharmacists recognized the most common excipients causing adverse events. The different roles of the occupational groups were identified according to their work duties.
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(2016)Parkinson's disease is a progressive neurodegenerative disease where dopaminergic neurons die in the substantia nigra pars compacta. Dopamine depletion induces typical parkinsonian motor symptoms which are treated by the golden standard medication levodopa and compounds enhancing the effect of levodopa. However in 4-6 years after the initiation of the chronic levodopa therapy abnormal involuntary movements (AIMs, also called levodopa-induced dyskinesia, LID) often develop and can notably worsen the quality of life. The most effective treatment for LID is deep brain stimulation (DBS), but as an invasive method its use is rare and not suitable for all patients. To date the only effective therapy for LID with marketing authorisation is amantadine. The disadvantage of amantadine is loss of efficacy which might appear less than a year after the initiation of medication. The pathophysiology of LID is a diverse phenomenon and includes dysfunctions in several different neurotransmitter systems both in the basal ganglia and in surrounding brain areas. The role of nicotinic acetylcholine receptors (nAChRs) in the pathophysiology of LID has been studied recently. Both nicotine and several nicotine-like agents have been shown to alleviate LID in preclinical studies and nicotine itself has been tested in a clinical phase II study as a potential LID medication. Of various different nAChR subtypes, the α7 receptor seems to be a potential option for future therapy of LID. It has been shown that α7 nAChR knock out mice display an increase in LID suggesting that this nicotinic receptor subtype has an inhibitory impact on the development of LID. Other studies have confirmed this view by showing that a selective α7 nAChR agonist (ABT-107) alleviates LID in primates and is neuroprotective for dopaminergic neurons in rats. Based on these observations, the aim of this study was to examine the effect of a novel α7 nAChR agonist (AZD0328) on LID in a 6-OHDA mouse model of Parkinson's disease. C57BL/6J female mice (n=17) were injected unilaterally 6-OHDA solution (3 µg) into the right medial forebrain bundle (MFB). Degeneration of dopaminergic neurons was detected two weeks after the 6-OHDA injection by measuring the motor performance in rotating rod with accelerated speed and with amphetamine-induced rotametry (2.5 mg/kg, i.p.). In the beginning of the chronic treatment, levodopa (4.5 mg/kg, s.c.) was administered twice daily for four days and then continued once daily (from Mon to Sun) to the end of the experiments. Levodopa treatment had been ongoing for 10 days before the first testing of drug effects. The pretreatment (AZD0328 0.06, 0.19, 1.9 mg/kg or 0.9 % saline, s.c.) was given 30 minutes before levodopa. The study was conducted using a within subject design so that each mouse received all four treatments on four test days during three weeks. Mice were videorecorded for 1 minute 20, 40, 60, 80 and 100 minutes after the levodopa injection was given. After the last recording day mice were killed under anesthesia via perfusion fixation and brains were collected for immunohistochemical staining to measure the extent of degeneration of dopaminergic neurons. 54 % of mice who survived from surgery (13/17) were dyskinetic (n=7). AZD0328 alleviated axial dyskinesia statistically significantly 40 minutes after levodopa injection but the statistical analysis did not reveal which of the doses was the most effective. The pretreatment with AZD0328 did not affect orolingual or forepaw dyskinesia. A potential mechanism of AZD0328 in alleviating LID might be the desensitization of α7 nAChRs which would happen only at very low doses. This means that LID are only attenuated when receptors are temporarily activated and then immediately gradually inactivated. The doses used in this study might have only activated the α7 nAChRs which might explain why no clear alleviation of LID was observed. On the other hand, the acute treatment may also be insufficient to develop desensitization. Additional studies are needed to investigate the effects of chronic administration of AZD0328 on LID in mice.
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(2011)Heart failure is a complex and severe syndrome caused by different kinds of cardiovascular diseases. Pathophysiology of heart failure involves, for example, activation of sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS), insufficiently contracting left ventricle, cardiac remodeling, myocyte mishandling of Ca2+ and myocyte loss owing to apoptosis. Despite advances in the management of patients with heart failure, the mortality of patients with heart failure remains high. The use of classic inotropic agents is hampered by poor prognosis due to increase in [Ca2+]i, induction of arrhytmias and increase in the myocardial oxygen consumption. Levosimendan is an inotropic agent that has positive inotropic and anti-stunning effects mediated by the calcium sensitization of the contractile proteins and vasodilatory, anti-ischemic and cardioprotective effects mediated by opening of sarcolemmal and mitochondrial KATP channels. Levosimendan also inhibits cardiac PDE3 predominately at higher concentrations. Levosimendan is currently used only as 24-hour infusion to improve symptoms of acute decompensated heart failure. However, other promising indications have also been discovered. For example, chronic use of oral levosimendan improves survival and protects cardiovascular system in vivo. In the present study, the effects of oral levosimendan, valsartan and their combination use on survival, blood pressure and cardiac remodeling were examined in Dahl/Rapp rats on a high salt diet (8 %). Levosimendan improved the survival in Dahl/Rapp rats on a high-salt diet, although not statistically significantly when compared to control group. The drug combination prevented completely salt-induced cardiovascular mortality. The combination therapy also produced a blood pressure-dependent protection against hypertension-induced hypertrophy measured by heart weight-to-body weight ratio (HW/BW) and echocardiographic parameters. Interestingly, the combination use of levosimendan and valsartan had an additive antihypertensive effect in Dahl/Rapp rats. Levosimendan slightly improved systolic function. However, echocardiography revealed increased IVRT in Dahl/Rapp control rats when compared to control group on low salt diet (0,2 %) indicating impaired diastolic relaxation in Dahl/Rapp rats. In the present study, levosimendan, alone and in combination with valsartan, also corrected hypertension-induced diastolic dysfunction.
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(2022)Mild traumatic brain injury (mTBI) is an insult to the brain caused by an external force. Typically contact sport players and military soldiers are prone to mTBI. TBI events trigger pathological processes in the brain and may cause long-term and progressive damages. Increased formation and accumulation of misfolded toxic protein aggregates in the brain leading to neuronal death has been observed after mTBI. In particular, repetitive mTBIs are a risk factor for the development of many neurodegenerative diseases, such as chronic traumatic encephalopathy, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. As there is no curative treatment to neurodegenerative diseases, research regarding neurodegenerative processes is highly important. Prolyl oligopeptidase (PREP) negatively regulates functions of protein phosphatase 2A (PP2A). It has been shown that PP2A activity is decreased in the brain of those with neurodegenerative diseases and TBI patients, which is thought to be a contributing factor to the development of pathologies of neurodegenerative diseases. The primary objective of this study was to study behavioural changes after repeated mild TBI in PREP knockout mice. The aim was to model mild repeated brain injuries that are common, for instance, in contact sports and that are not accompanied by skull fractures or brain swelling. The intension was to clarify the involvement of the PREP enzyme in behavioural changes induced by repeated mTBI’s and to elucidate long-term pathological changes in the brain. The injury was induced as a closed-head injury with an electromagnetic impactor with one hit every 24 hours and altogether 5 times. A locomotor activity test was performed before the induction of brain injury and was repeated 3 times after mTBI induction. Barnes maze test was used to assess memory and learning functions. In this thesis the brain samples from a previous study were included to also determine the accumulation of total tau protein in wild-type mice. The wild- type mice were administered with either the PREP inhibitor KYP-2047 or HUP-46 10 mg/kg (i.p.) immediately after each hit. After euthanasia, the Western blot assay and immunostaining were performed to study the amount of phosphorylated tau, neuroinflammation, activity of PP2A and autophagy. No differences were found between the sham group and TBI group on the locomotor activity and Barnes maze tests in PREP knockout mice. There was no consistency in total tau protein in wild-type mice treated with PREP inhibitors. In PREP knockout mice there was an upward trend in PP2A levels after mTBI. Repeated mTBI increased markers of phosphorylated tau and neuroinflammation significantly. No significant difference was observed in autophagic function. The results of this thesis are indicative. Due to the low number of animals, the results need to be confirmed in subsequent studies with greater amounts of animals. Based on the results, it seems that absence of the PREP enzyme protects from memory impairments after repeated mTBI. Increased tau protein phosphorylation and neuroinflammation were observed in the TBI group which indicate that PREP alone is not responsible for the development of pathological changes.
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(2022)Liposomes are biocompatible spherical nanosized vesicles consisting of hydrophobic phospholipid bilayer encasing an aqueous core. They can be utilized as drug carriers by either encapsulating molecules inside the core or embedding them in the bilayer accordingly to achieve numerous advantages such as prevention of rapid clearance and reduction of adverse effects as systemic exposure is reduced. Despite the marked efforts in designing the liposomes to improve therapeutic outcomes, only limited drug concentrations are achieved at the target sites such as in solid tumors. Stimuli-responsive liposomes could be applied as potential delivery systems to achieve spatiotemporally controlled drug delivery, i.e., the drug release could be pinpointed and restrained to the target site. In this thesis, the objective was to study the light-activated indocyanine green (ICG) liposomes as nanocarriers for peptide-based anti-tumor agents. The physicochemical characteristics, stability and functionality of the prepared liposomes were determined alongside optimizing the formulation as needed and utilizing different model peptides as encapsulated compounds. Additionally, the peptide stability during near-infrared (NIR) light illumination and the effects of the anti-angiogenic model peptides in vitro were investigated. The stability of the liposomes was assessed by monitoring the size of the liposomes, intactness of ICG, and passive leakage of the peptides over time, and by determining the phase transition temperatures of the different formulations. The liposomes remained adequately stable in different relevant conditions, and the observed phase transition temperatures did not indicate the lipid bilayer becoming permeable in physiological temperatures. However, the rate of passive leakage was rather high in all formulations, although with stiffer lipid bilayer in the “rigid” formulation, the unintended release was able to be decreased slightly in comparison to the other formulations. On the other hand, light-triggered release upon illuminating the liposomes remained considerably low in all formulations. The intactness of peptides seemed to not be impacted by the illumination. Also, no cytotoxic effects were observed after exposing human umbilical vein endothelial cells (HUVEC) to the peptides. The final “rigid” formulation showed the best functionality out of those included in the studies. It remains to be investigated whether the formulation could be improved further for optimal functionality and stability, and to what degree do the properties of the cargo molecule affect the performance of the liposomes.
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(2020)Liposomes are nano-sized vesicles, that are composed of a phospholipid bilayer structure. They can be utilized as drug carriers, in which case the drug is incorporated either to their hydrophilic internal cavity, or into their hydrophobic bilayer structure. For anticancer drugs, liposomal formulations have exhibited their capability in reducing adverse effects of anticancer drugs. This is achieved mainly by the enhanced permeability and retention (EPR) effect, in which liposomes accumulate into tumour tissue. However, the conventional liposomes release their drug content passively, and a proportion of drug is distributed to off-target tissues. Therefore, there is a demand to develop liposomes from which the content can be released in a controlled manner, by an external stimulus. The objectives of this master’s thesis project were to determine the potential of light-activated paclitaxel (PTX) liposomes for the treatment of lung cancer, and to optimize a dynamic cell culture system, QuasiVivo® (QV), to study the off-target effects of light-activated PTX liposomes. The hypothesis was that the induction of the light-activated PTX liposomes would increase the efficiency of paclitaxel treatment. For QV experiments, it was expected that the presence of flow would improve the viability of the cells. The encapsulation efficiency of PTX into the liposomes and the effect of the PTX incorporation into the phase transition temperature of the liposomes were determined. The stability of liposomes was determined by monitoring the liposomal size and light sensitizer absorbance during a storage period. The cells of lung cancer cell line A549 were cultured inside QV system, and their viability was monitored with two commercial cell viability assays. Incorporation of PTX decreased the phase transition temperature, but the liposomes remained stable in the studied conditions. The PTX liposome treatments with and without light activation resulted in the similar efficacy as free PTX treatment did. A549 cells failed to display superior viability inside the QV compared to static conditions. Cells cultured under lower flow rate portrayed modestly higher viability. The light-activated PTX liposomes did not improve the efficacy of PTX treatment. Neither of the flow rates were optimal for A549 cells, as the variation between experiments was high. The EPR effect is the main reason for the improved effects of liposomal anticancer drugs, therefore, it is likely that in vivo experiments would elicit the differences between the efficacy of the liposomal and free PTX. The non-existent effects of light activation on the viability are likely caused by the low total concentration of the light sensitizer in the treatment solution.
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(2014)The purpose of this study is to evaluate patients' quality of life and healthcare use before and after bariatric surgery and produce new, clinical data-based information on the cost-effectiveness of bariatric surgery. Healthcare resources are limited and expenditures have grown from year to year. Therefore it is important to make cost-effectiveness evaluations so that financial resources could be allocated properly. The research population consists of patients who have undergone gastric bypass or sleeve gastrectomy in the Hospital District of Helsinki and Uusimaa, during the years 2007-2009. The study population consists of 147 gastric bypass patients and 79 sleeve gastrectomy patients. In this study the decision analytic model, used in the Finohta study "Sairaalloisen lihavuuden leikkaushoito" was updated using actual, up-to-date information. The analysis was done using a decision tree and a Markov model with a time horizon of 10 years. The cost data in this study was based on actual data for the first two years after surgery. A forecast model was used to predict the costs for the years 3-10 after surgery. Patients' quality of life scores were based on real data for the years 1 (the year of operation) to 4. Quality of life scores for the other years were predicted. In the literature review section, international studies on the cost-effectiveness of bariatric surgery and its impacts on drug therapy were evaluated. The studies showed that the use of medicines, which were used to treat obesity-related diseases were lower in the surgery group. However, drugs used to treat vitamin deficiencies, depression and gastrointestinal diseases were higher in the surgery group. Most studies found that surgery is the most cost-effective way to treat morbid obesity. This study confirms the role of the bariatric surgery in the treatment of morbid obesity in Finland. Even though the healthcare costs were increased in the first two years after the operation, the conclusions of the Finohta study didn't change. The bariatric surgery is cheaper and more effective than ordinary treatment and the most cost-effective way to treat morbid obesity. The mean costs were 30 309 € for the gastric bypass, 31 838 € for the sleeve gastectomy and 36 482 € for ordinary treatment. The mean numbers of quality-adjusted life-years were 6.919 for the gastric bypass, 6.920 for the sleeve gastrectomy and 6.661 for ordinary treatment. However, there is demand for more information for the long-term effects, benefits and risks of the surgery. How much the surgery will actually save money, will be hopefully clarified in the long-term follow-up study, which should also include an actual control group.
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(2016)Pharmacologically induced neuronal plasticity holds unprecedented potential in treatment of several neurological disorders, such as depression. Several antidepressant drugs have been shown to induce neuronal plasticity by stimulating BDNF (brain-derived neurotrophic factor) receptor TrkB (tropomyosin receptor kinase B). Studies with rapid-acting antidepressant treatments suggest delta range slow wave EEG (electroencephalography) activity to function as a potential non-invasive biomarker for activation of TrkB-related neuroplastic signaling responses. A sedative GABAA-agonist THIP (gaboxadol) has been shown to induce slow wave EEG activity (SWA) and preliminary studies suggest it to activate TrkB signaling as well. The aim of the present study was to examine the potential connection between SWA, neuroplastic signaling responses and neuronal inhibition by utilizing EEG measurements and THIP administration in genetic and developmental mouse models. The pharmaco-EEG experiments showed acute THIP administration (6 mg/kg, i.p.) to increase SWA in wild-type but not in GABAA δ-subunit knockout mice. TrkB signaling responses from similar treatment groups showed a trend of increased TrkB-related protein phosphorylation in wild-type but not in GABAA δ-subunit knockout mice indicating a positive connection between SWA, neuronal inhibition and TrkB-related signaling response. Autophosphorylation response of TrkB and related proteins in mice of different age showed most TrkB phosphorylation in postnatal day 16 (P16) mouse pups, whereas phosphorylation response of CREB and p70S6k was the highest in postnatal day 8 (P8) mouse pups. Since SWA emerges during the second postnatal week in mice, the obtained result further supports the connection between SWA and TrkB signaling. Acute THIP administration caused no significant phosphorylation changes in P8 or P16 mouse pups. The results support the hypothesis of a positive connection between SWA, neuronal inhibition and TrkB-related signaling response. Further studies with different excitatory and inhibitory interventions are required to better understand the role of neuronal excitation and inhibition in TrkB signaling responses and corresponding EEG signatures.
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